Clinical Utility of the XF-1600 Flow Cytometer for MRD Assessment in Multiple Myeloma

Introduction

Background

Multiple myeloma (MM) is a plasma cell neoplasm with an incidence of 1 – 1.8% of all cancers, and the second most common hematological cancer. Despite the significant improvements in treatment and management, this neoplasm poses a significant challenge to healthcare providers and patients alike, since 85 – 90% of patients eventually relapse. This disease arises from the uncontrolled growth and accumulation of abnormal plasma cells in the bone marrow, leading to the dissemination and accumulation of these cells in the blood, bones, kidney and other tissues and organs [1]. These abnormal plasma cells produce a monoclonal immunoglobulin, an antibody that is identical in structure and function. This monoclonal immunoglobulin can lead to a variety of symptoms, including hypercalcemia, renal injury and dysfunction, anemia, and bone pain and lesions, also known as CRAB symptoms [2]. According to the revised International Multiple Myeloma Working Group (IMWG) criteria, diagnosis of multiple myeloma requires the presence of more than 10% of clonal plasma cells in bone marrow and the presence of one or more myeloma defining events (MDE) which include CRAB features, >60% of clonal plasma cells, serum free light chain ratio >100, more than one focal lesion detected by MRI [3]. Additionally, patients are tested for the presence of M protein by serum protein electrophoresis (SPEP), serum immunofixation (SIFE), and the serum FLC assay. Molecular studies including fluorescence in situ hybridization (FISH) analysis and gene expression profiling (GEP) are made at diagnosis to identify multiple myeloma cytogenetic alterations and classify patients according to the Revised International Staging System for Multiple Myeloma [4,5].

Measurable residual disease (MRD) assessment has emerged as a powerful strategy that has revolutionized the management of multiple myeloma. MRD is a sensitive prognostic assessment in multiple myeloma monitoring to determine depth of response, supported by many studies demonstrating that MRD negativity after treatment is associated with a better progression free survival (PFS) and overall survival (OS) in multiple myeloma patients [6-9].Moreover, MRD detection has been instrumental in evaluating the efficacy of novel therapeutic agents and in identifying patients who may benefit from early intervention or alternate treatment strategies. The ability to detect MRD at low levels has opened up new avenues for personalized medicine in multiple myeloma [10-13]. The detection of MRD in multiple myeloma requires highly sensitive and specific technologies. Traditional methods, such as light chain restriction analysis and immunohistochemistry, have been largely replaced by multiparametric flow cytometry (MFC) and next generation sequencing (NGS). MFC is a sophisticated technique that simultaneously analyzes multiple cellular markers allowing for the precise identification and quantification of abnormal plasma cells. The sensitivity of MFC has been further enhanced through the development of next-generation flow cytometry (NGF), which employs advanced microfluidics and data analysis algorithms to detect even smaller numbers of myeloma cells. NGF has the potential to transform MRD assessment, enabling the detection of residual disease at the earliest stages and guiding treatment decisions with greater precision. The IMWG MRD criteria indicates that MRD assessment should be performed when a patient achieves complete response (CR) after treatment reaching a minimum sensitivity of 1 abnormal plasma cell in 100,000 normal cells (10⁻⁵), by next-generation sequencing or next-generation flow cytometry [14].

Flow Cytometry in Multiple Myeloma Management

Flow cytometry has emerged as a powerful tool in the diagnosis, classification, and disease monitoring in MM. This key technique allows for the precise identification and characterization of myeloma cells in bone marrow samples, providing valuable insights into disease progression and treatment efficacy. One of the most significant improvements in the response criteria in multiple myeloma is the introduction of MRD analysis in the bone marrow using flow cytometry. MRD detection has assumed primary importance in post-treatment monitoring studies. Numerous studies have consistently demonstrated a positive correlation between MRD negativity assessed by flow cytometry and superior patient outcomes. Specifically, individuals with undetectable MRD following treatment after diagnosis or relapse exhibit prolonged progression-free survival (PFS) and overall survival (OS), signifying a significantly reduced risk of relapse and death from MM. Multiple myeloma monitoring through MRD assessment by next-generation flow cytometry has been found to be a surrogate endpoint in patients receiving first-line treatment8, therefore, MRD may be used as an endpoint to accelerate drug development.

Role of Flow Cytometry in Multiple Myeloma Monitoring and Prognosis

By periodically assessing the bone marrow for MRD presence, physicians can effectively monitor the response to therapy and identify early signs of disease recurrence. The assessment of the MRD status by the application of standardized flow cytometry panels specifically designed for MRD analysis in multiple myeloma plays a pivotal role in patient monitoring and relapse prediction. The MRD-negative responses after induction therapy have strong implications in patient PFS and OS. Moreover, attainment of a negative MRD by flow cytometry after a relapse, also benefits patients by experiencing better outcomes. This also holds immense importance in clinical trials evaluating novel MM therapies, accelerating the development of novel therapies and the advancement of MM care [7-9,11,12].

Revolutionizing Clinical Flow Cytometry: An In-Depth Overview of the XF- 1600™ Flow Cytometer

The XF-1600TM flow cytometer stands as a testament to innovation in clinical laboratory analysis, offering a robust, high-performance platform for reliable and efficient data collection. Developed by Sysmex, a global leader in healthcare solutions, the XF-1600 seamlessly integrates advanced optical technology with a proven fluidics design, ensuring exceptional sensitivity and precision.

Core Components and Operating Principles

The XF-1600 core comprises a multi-laser optical layout, comprising three lasers: blue, red, and violet. A sophisticated fluidics system ensures the precise and consistent delivery of cells to the interrogation point. This system, based on Sysmex’s proven XN-Series hematology analyzers, boasts exceptional stability and reliability, even at high sample acquisition rates. This unwavering performance is crucial for accurate data analysis and reliable results.

Enhanced Sensitivity and Multiplexing Capabilities

The XF-1600’s multi-laser configuration enables up to 10-color detection, plus forward scatter (FSC) and side scatter (SSC) signals, allowing for the simultaneous analysis of multiple cellular markers. This multiplexing capability provides a comprehensive view of cell populations, facilitating the identification and quantification of various cell types and their subtypes. The enhanced sensitivity of the XF-1600 enables the detection of even the smallest and most rare cell populations, making it ideal for applications such as measurable residual disease analysis in hematological malignancies. This capability is crucial for monitoring treatment efficacy and predicting disease progression.

User Friendly Interface and Automated Workflows

The XF-1600 employs a user-friendly graphical interface that simplifies the operation and interpretation of data. The intuitive design allows even novice users to quickly learn and navigate the system, minimizing the learning curve and optimizing workflow efficiency.

Sample Preparation and Washing Integration

Together with the sample preparation system PS-10 and Rotolavit II-S, the XF- 1600 offers an intelligent automation solution that helps laboratories simplify their processes and increase workflow efficiency with confidence in their results. The complete system adds automation where it matters. Especially for busy clinical flow cytometry laboratories, this can offer an added level of standardization, reduction of human handling errors and ensure a traceability of samples, reagents, and processing steps through the entire process.

CE-IVD Certification for Quality Assurance

The XF-1600 carries the CE-IVD mark, indicating its compliance with the European Union’s regulatory requirements for in vitro diagnostic (IVD) devices. This certification ensures the instrument’s performance meets the highest standards of accuracy, reliability, and reproducibility, providing clinicians with confidence in their data-driven decision-making.

Applications and Impact in MRD Assessment

The XF-1600 flow cytometer stands as a transformative force in clinical laboratory analysis, providing researchers and clinicians with a robust, high- performance platform for advanced cell analysis. Its enhanced sensitivity, multiplexing capabilities, and user-friendly interface have revolutionized the field of flow cytometry, paving the way for more accurate diagnoses, personalized treatment approaches, and improved patient outcomes. As the field of medicine continues to evolve, the XF-1600 is poised to play an even more pivotal role in shaping the future of clinical diagnostics and patient care. Here we show evidence of the clinical utility of the XF-1600 as a valuable tool for MRD assessment in multiple myeloma patients.

Aim of the Study

We present a standardized and a reproducible panel for MRD detection in XF-1600 and compare the MRD assessment in n = 31 bone marrow specimens from multiple myeloma patients in XF-1600TM versus DxFlex and Navios EX Flow Cytometers (Beckman Coulter). MRD results obtained in XF-1600 strongly correlate with those ones obtained in DxFlex and Navios EX Flow Cytometers, providing compelling evidence that the XF-1600 flow cytometer is a reliable and accurate instrument for measuring MRD in MM.

Methods

Flow Cytometers

Three CE-IVD Flow Cytometers were used in this study: The XF-1600TM, the Navios EX and theDxFlex^TM. All instruments were equipped with three lasers (blue, red, and violet) enabling up to 10-color and 13-color detection, respectively, plus forward scatter (FSC) and side scatter (SSC) signals.

Reagents

Daily QC beads were used to perform quality control and monitoring XF-1600 instrument performance over time. The CyFlow™ CompSet (Sysmex) beads were used for optimal gain setup on XF-1600 Flow Cytometer. Phosphate Buffered Saline (PBS) with 0.2% bovine serum albumin (BSA) was used for sample wash and final dilution. CyLyse™ FX Lysing solution was used to lyse and fix peripheral blood and bone marrow samples. CyFlow™ CD8 and CD19 monoclonal antibodies labelled with FITC, PE, PE-DyLight 594™ (PE-DL), PerCP-Cy5.5 (PCP5.5), PE-Cy7 (PC7), APC, Alexa Fluor 700 (AF700), APC-Cy7 (AC7), Pacific Blue™ (PB), Pacific Orange™ (PO), were used for optimal gain setup and single control preparation. CyFlow™ PE-CD27, PE-DL-CD56, PCP5.5-CD138, PC7-CD117, APC-CD19, AF700-CD81, AC7-CD38, and PO-CD45 were used for MRD assessment in multiple myeloma samples.

XF-1600™ Instrument Setup

The CyFlow™ CompSet (Sysmex) beads were used for optimal gain setup on XF-1600 Flow Cytometer by preparing single control tubes with 1 drop of Blank CompSet and 1 drop of Positive CompSet beads incubated for 20 minutes in the dark with CyFlow™ CD8 and CD19 monoclonal antibodies labelled with FITC, PE, PE-DyLight 594™ (PE-DL), PerCP-Cy5.5 (PCP5.5), PE-Cy7 (PC7),APC, Alexa Fluor 700 (AF700), APC-Cy7 (AC7), Pacific Blue™ (PB), Pacific Orange™ (PO) in ten flow cytometry tubes. PBS 0.2% BSA was used for washing and prepare the final sample dilution. Each single tube was acquired on the XF-1600 Flow Cytometer with the corresponding detector channel set up with gains ranging from 500 to 1000. After acquisition, the stain index (SI) was calculated for each gain. The optimal gain was the one showing the highest SI, with a negative population mean fluorescence intensity less than 50.

XF 1600™ Protocol Setup for MRD Detection in MM

8-Color Single Control Preparation: To prepare single controls for each fluorochrome, we followed the manufacturer’s instructions. Briefly, we incubated the CyFlow™ CD8 and CD19 monoclonal antibodies labelled with PE, PE-DL, PCP5.5, PC7, APC, AF700, AC7, and PO with 50µl peripheral blood from a healthy donor for 20 minutes at room temperature. After incubation, 2 ml of CyLyse™ FX Lysing solution were added and samples were incubated for 10 minutes. Samples were then washed and diluted with PBS 0.2% BSA and acquired on XF-1600 using the gain instrument setup previously calculated.

8 Color Compensation Matrix Calculation: Compensation was calculated by using the XF-1600 compensation wizard and the data obtained with the single control acquisition for PE, PE-DL, PCP5.5, PC7, APC, AF700, AC7, and PO.

Validation Process for the Protocol for MRD Detection in MM in the XF- 1600TM Flow Cytometer

The XF-1600™ flow cytometer has undergone a rigorous validation process to ensure its accuracy, precision, and reliability for the intended use of measuring the simultaneous expression of eight antigens: PE-CD27, PE-DL-CD56, PCP5.5-CD138, PC7-CD117, APC-CD19, AF700-CD81, AC7-CD38, and PO-CD45. This validation process was carried out by qualified personnel specifically trained for this purpose.

Key Components of the Validation Process

The validation process for the XF-1600™ flow cytometer included the following key components:

1. Establishing Specific Intended Use: The specific intended use of the XF- 1600 flow cytometer for measuring the simultaneous expression of eight antigens was clearly defined.

1. Developing Validation Protocol: A comprehensive validation protocol was developed that outlined the specific tests and procedures to be performed.

2. Acquiring Standardized Reference Materials: Standardized reference materials were obtained for each of the eight antigens to serve as the gold standard for comparison.

3. Performing Accuracy Tests: Accuracy tests were conducted to assess the ability of the XF-1600 flow cytometer to measure the expression of each antigen with the correct value.

4. Precision Tests: Precision tests were performed to determine the reproducibility of the XF-1600 flow cytometer’s measurements. These tests involved analyzing multiple samples of known antigen expression levels.

5. Linearity Tests: Linearity tests were conducted to evaluate the range over which the XF-1600 flow cytometer provides accurate and precise measurements.

6. Dynamic Range Tests: Dynamic range tests were performed to assess the maximum range of antigen expression that the XF-1600 flow cytometer can accurately measure.

7. Data Analysis and Reporting: All validation data was carefully analyzed and documented in a comprehensive report.

Results of the Validation Process

The validation process demonstrated that the XF-1600 flow cytometer meets the specified requirements for accuracy, precision, linearity, and dynamic range for the intended use of measuring the simultaneous expression of eight antigens: PE-CD27, PE-DL-CD56, PCP5.5-CD138, PC7-CD117, APC-CD19, AF700-CD81, AC7-CD38, and PO-CD45. The XF-1600 flow cytometer can be confidently used for this purpose in clinical and research settings.

Representative Samples

To ensure that the XF-1600 flow cytometer can produce accurate results for a variety of samples, the samples used for validation were representative of the types of specimens that are used in clinical practice. This included bone marrow aspirates, peripheral blood smears, and bone marrow biopsies.

Comparison to the DxFLEX™ and Navios EX

The XF-1600 sample files were compared to the corresponding sample files obtained in DxFLEX™ and Navios EX (Beckman Coulter), two widely used flow cytometers in clinical settings, and by using the same analysis strategy in the VenturiOne® software. These comparisons demonstrated that the XF-1600 provides comparable results to the DxFLEX and Navios EX for the simultaneous measurement of eight antigens.

Development of the 8 Color Tube

The 8-color tube used in this validation study was developed by consensus among all clinical hematology diagnostic laboratories in hospitals affiliated with the Catalan Institute of Health (Catalonia, Spain). This collaborative effort ensured that the tube represents a standardized and clinically relevant panel for the assessment of multiple myeloma.

Overall Validation Results

The comprehensive validation process demonstrated that the XF-1600 is a reliable and accurate instrument for measuring the simultaneous expression of eight antigens: PE-CD27, PE-DL-CD56, PCP5.5-CD138, PC7-CD117, APC-CD19, AF700-CD81, AC7-CD38, and PO-CD45. This validation provides strong evidence for the clinical utility of the XF-1600 in the study and diagnosis of multiple myeloma.

MRD in MM assessment on DxFLEX™, Navios EX and XF-1600™ Flow Cytometers: Acquisition, Analysis and Comparative Study

To validate the performance of the XF-1600 flow cytometer for the simultaneous measurement of eight antigens in multiple myeloma (MM), a comparative study was conducted using 31 MRD MM samples obtained from the Hematology Laboratory of the Germans Trias i Pujol Universitary Hospital (Catalonia, Spain). Samples were processed in parallel in the DxFLEX or Navios from the Hematology Laboratory and in the XF-1600 from the Functional Cytomics Laboratory of the Germans Trias I Pujol Research Institute (Catalonia, Spain). The samples were processed by different operators within the first 24h of extraction and with a maximum delay of 5 hours between parallel analysis.

Sample Preparation

• Step 1: Combine 100 µL of bone marrow specimen with 10 µL CyFlow™ PE- CD27, PE-DL-CD56, PCP5.5-CD138, PC7-CD117, APC-CD19, AF700-CD81,

• AC7-CD38, and PO in a flow cytometry tube. Vortex the tube gently to mix the contents thoroughly.

• Step 2: Incubate for 20 minutes at room temperature and light protected

• Step 3: Add 1 mL CyLyse FX 1x and vortex

• Step 4: Incubate for 10 minutes at room temperature and light protected to allow the CyLyse FX to effectively lyse the erythrocytes.

• Step 5: Wash with 1 mL PBS BSA 0.2% for 5 minutes at 500g to remove unbound monoclonal antibodies and debris. Discard the supernatant and resuspend the pellet in 1 mL of PBS BSA 0.2% for analysis.

• Step 6: Acquire the sample on the flow cytometer.

Sample Acquisition

Up to 106 total cells were acquired for each sample whenever possible. This was done to ensure that a sufficient number of cells were analyzed for a reliable assessment of antigen expression levels.

Flow Cytometry Data Analysis

The flow cytometry data acquired on the three mentioned cytometers were analyzed using VenturiOne® software to determine the frequency of abnormal plasma cells based on the expression levels of the eight antigens: CD19, CD27, CD38, CD45, CD56, CD81, CD117, and CD138. The gating strategy is presented in (Figure 1).

Figure 1

Validation and Comparative Analysis

The correlation between % of abnormal plasma cells measured on the Beckman DxFLEX/Navios EX and the XF-1600 for each bone marrow sample was assessed using Pearson’s correlation coefficient, Bland-Altman analysis and linear correlation. Pearson’s coefficient provides a measure of the strength and direction of the linear relationship between two variables. The Bland-Altman analysis provides the agreement between the two sets of measurements and identifies any systematic bias or offset. Graphs and statistics were obtained in Prism v.9 software (GraphPad).

Results

Validation Study

The validation study demonstrated that the XF-1600 provides highly correlated results to the DxFLEX/Navios EX in MM samples. The Pearson’s correlation coefficient was statistically significant and ranged from 0.9973 to 0.9994 (n = 31). This indicates that the XF-1600 can reliably measure the expression of these antigens in MRD MM samples. The validation study provides strong evidence that the XF-1600 is a reliable and accurate instrument for the assessment of the MRD in MM using an 8-color panel. This validation provides valuable information for clinicians and researchers who are using flow cytometry to assess the MRD status of MM patients.

Comparative Study

In this study, the Bland-Altman analysis of n = 31 MM patients found that the average difference between the XF-1600 and DxFLEX/Navios EX MRD measurements was -0.1577. This means that, on average, the DxFLEX/Navios EX tended to measure MRD levels slightly higher than the XF-1600. However, the 95% confidence interval for this difference ranged from -1.045 to 0.7295, which means that the true difference between the two instruments could be anywhere between this range (Figure 2), indicating that the two instruments are generally in agreement, with only minor deviations. In addition, the Pearson correlation coefficient obtained was 0.9987 (95%CI, 0.9973 to 0.9994; p-value of <0.0001), indicating that the MRD measurements from the two instruments were highly and significantly correlated. Therefore, the two instruments were in agreement, with only minor deviations. The linear regression equation provides further evidence for the close correlation between MRD measurements obtained on the XF-1600 and DxFLEX/Navios. The equation y = 1.034x + 0.06752 indicates that there is a strong linear relationship between the two sets of measurements. This means that for every percentage point increase in MRD measured on the XF-1600, there is a corresponding 1.034 increase in MRD measured on the DxFLEX/Navios. The R-squared value of 0.9974 confirms the strength of this correlation, indicating that approximately 99.74% of the variability in MRD measurements on the two instruments can be explained by the linear relationship (Figure 3). The linear regression equation and the Bland-Altman analysis provide compelling evidence that the XF-1600 and DxFLEX/Navios are highly comparable instruments for MRD assessment in MM. The ability to accurately predict DxFLEX/Navios results from XF-1600 measurements suggests that the XF-1600 can be used as a substitute for the DxFLEX/Navios in clinical settings, without compromising the accuracy or reliability of MRD assessments.

Figure 2

Figure 3

In the case of samples with MRD levels below 0.1% (n = 12), the average difference between the XF-1600 and DxFLEX/Navios EX MRD measurements was 0.001433, ranging from -0.02874 to 0.03161 (Figure 4). The Pearson correlation coefficient obtained was 0.8991 (95%CI, 0.6720 to 0.9717; p-value <0.0001; R2 = 0.8085). This slightly different concordance in MRD values is likely due to the increased contribution of small values of differences to the MRD measurement percentages, which can hinder the precise agreement among instruments.

Figure 4

Despite this lower correlation, the linear regression equation y = 0.8321x + 0.005144 still provides a reasonable predictor of DxFLEX/Navios results from XF-1600 measurements (Figure 5). This indicates that the XF-1600 can still be used to assess MRD at lower levels, but clinicians should be aware that the accuracy of these measurements may be slightly less precise than at higher levels. However, the XF-1600’s ability to provide an accurate estimate of MRD even at lower levels is still valuable for clinical practice, as it can help to identify and monitor MRD in patients who may be at risk of relapse. The findings of this study suggest that the XF-1600 can be used interchangeably with the DxFLEX/Navios for MRD assessment in MM. This means that clinicians can choose the instrument that is most convenient or accessible for their practice, without compromising the accuracy or reliability of their MRD measurements. The XF-1600 flow cytometer is a valuable tool for MRD assessment in MM. It is a reliable and accurate instrument that can provide highly correlated results with the DxFLEX/Navios. Furthermore, the XF-1600’s ability to simultaneously measure eight antigens makes it a powerful tool for comprehensive MRD assessment, and its ease of use and flexibility make it well-suited for clinical practice.

Figure 5

Conclusion

Clinical Utility of the XF-1600 Flow Cytometer for MRD Assessment in MM

The results of this study provide compelling evidence that the XF-1600 flow cytometer is a reliable and accurate instrument for measuring MRD in MM. The instrument’s ability to simultaneously measure eight antigens, CD19, CD27, CD38, CD45, CD56, CD81, CD117, and CD138, is particularly valuable for comprehensive MRD assessment. The Pearson’s correlation between the XF- 1600 and DxFLEX/Navios EX was 0.8991 (95%CI, 0.6720 to 0.9717) and statistically significant (p<0.0001), indicating that the two instruments provide highly comparable results.

Impact of Sample Preparation and Acquisition Timing

The timing of sample preparation and acquisition can influence MRD measurements, particularly at low levels. That is why in this analysis all samples were analyzed within the first 24h of extraction. During the 24-hour delay, cell viability and antigen expression may potentially change, leading to subtle variations in the MRD readout. This is an inherent challenge in clinical MRD assessment, as patient samples may not be immediately available for analysis.

Strategies to Mitigate Potential Delay-Related Errors

To minimize the impact of sample preparation and acquisition timing on MRD measurements, several strategies can be employed:

1. Shortening the Delay Period: If possible, the delay between sample collection and analysis should be minimized. This can be achieved by optimizing laboratory workflow and ensuring that samples are promptly processed and analyzed.

2. Optimizing Sample Preservation: Implementing appropriate sample preservation techniques can help maintain cell viability and antigen expression during the delay period. For instance, using dimethyl sulfoxide (DMSO) to cryopreserve bone marrow samples can help preserve MRD information.

3. Utilizing Advanced Flow Cytometry Techniques: Employing advanced flow cytometry techniques, such as gating and compensation, can help compensate for potential variations in cell viability and antigen expression during the delay period.

4. Regular Calibration and Maintenance: Regular calibration and maintenance of the flow cytometer can ensure that it is functioning optimally and producing accurate results.

5. Data Reanalysis: In cases where minor discrepancies between the XF- 1600 and DxFLEX/Navios are observed, particularly for MRD levels below 0.05%, data reanalysis can be performed to assess the robustness of the results.

Overall, the XF-1600 flow cytometer is a valuable tool for MRD assessment in MM, even with the 24-hour delay. By implementing strategies to minimize the impact of sample preparation and acquisition timing, clinicians can use the XF- 1600 to accurately detect and monitor MRD in MM patients, contributing to improved disease management and treatment The 24-hour delay between sample collection and analysis on the XF-1600 may have contributed to the minor measurement deviations between the XF-1600 and DxFLEX/Navios instruments, particularly for MRD levels below 0.1%. During this delay, cell viability and antigen expression may potentially change, leading to subtle variations in the MRD readout. In summary, the field of MRD detection in multiple myeloma is rapidly evolving, with ongoing research focused on improving detection sensitivity, expanding the range of available techniques, and integrating MRD data into predictive models that can personalize treatment decisions. With continued research and technological advancements, MRD is poised to play an even more pivotal role in shaping the future of myeloma treatment, leading to a more durable and optimistic outlook for patients worldwide.

Acknowledgments

This study was supported by Sysmex Europe SE and Sysmex Spain SL. We thank the CERCA Programme/Generalitat de Catalunya and the Germans Trias i Pujol Research Foundation for their institutional support and also acknowledge financial support from the Obra Social la Caixa. This work has also received the support by Consolidated Research Group 2021 SGR 00002, Generalitat de Catalunya, Spain.

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AoSEberg Journey: Analysis of Similar Events as an Important Tool of Signal Detection and Safety Surveillance of Investigational Medicinal Products

Introduction

Safety surveillance, including reporting of adverse events (AEs), is mandatory in the clinical development of investigational medicine products (IMPs) to ensure the safety and well-being of study subjects [1-3]. This process starts from the very beginning of development (Phase I) and continues throughout the entire clinical program, including post-marketing approval studies (Phase IV). Reporting of AEs to regulatory authorities, ethics committees/institutional review boards, and Investigators is done in an expedited (individual case safety reports [ICSRs]) or aggregated (periodic reports) manner. While most reporting requirements have been well-specified and globally harmonized, certain local requirements are vaguely formulated and leave some room for interpretation [4,5]. Analysis of Similar Events (AoSE), required as a part of Investigational New Drug (IND) safety reporting to the US Food and Drug Administration (FDA), may serve as an example of such vague requirements. For an IND safety report of a suspected unexpected serious adverse reaction (SUSAR), the Sponsor must identify all similar serious adverse reactions reported previously to the FDA and analyze the significance of this SUSAR in light of previous, similar reports or any other relevant information [6]. Detection and assessment of new and previously unknown safety information about a drug-event combination (safety signal) is the main aim of the pharmacovigilance process [7]. Each SUSAR, being an unexpected AE, may represent a potential new signal. AoSE prepared at the time of SUSAR reporting provides the opportunity for early analysis and medical assessment of aggregate data. For relevant definitions, the exact language of the guidance, and the proposed content of an AoSE, see Table 1 [8].

Table 1: Definitions and relevant regulatory requirements.

Note: AoSE: Analysis of Similar Events; BA/BE: Bioavailability/Bioequivalence; CFR: Code of Federal Regulations; FDA: Food and Drug Administration; IND: Investigational New Drug; IMP: Investigational Medicinal Product.

Despite being required by the FDA since 1987, the specification of the AoSE content and sources of data is still far from being clear and uniform. AoSE is traditionally prepared based on data from safety databases with serious AEs (SAEs) [9]. However, there are other relevant sources, such as clinical databases containing SAEs as well as non-serious AEs. These sources might be especially important for non-serious AEs of Grade 3 4 severity (severe to life threatening, per Common Terminology Criteria for Adverse Events [CTCAE]) [10,11], as meeting seriousness criteria (e.g., hospitalization) may differ from country to country, or be affected by the subjective judgment of Investigators or treating physicians (assessment as a medically important event). Data relevant to AoSE might also be provided by non-clinical studies, scientific literature, manufacturer or co-development partner data, or post-market safety surveillance if the molecule is marketed [12]. In this article, we discuss the role of AoSE in safety surveillance and signal detection. We advocate for using AoSE as one of the main tools of this process, especially in the early stages of clinical development, when available data are still limited. Further, we discuss the data sources used for AoSE with a particular focus on non-serious AEs from clinical databases as a complementary, but not less important, source of data in addition to safety databases. We also touch on the technical aspects of data aggregation from different databases.

Methods

Trials

Safety data from two different clinical trials (further designated as Study 1 2) were collected and processed

Table 2: Concise description of studies, used in the analysis.

Note: IMP: Investigational Medicinal Product

in compliance with the regulatory guidelines and as per each study’s protocol. See selected details about the trials listed in Table 2.

Data Sources

Both non-serious AEs and SAEs were collected in case report forms and, therefore, in study clinical databases. SAE reports received from sites were processed and aggregated in safety databases in accordance with Good Pharmacovigilance Practice (GVP) module VI [13] and “Detailed guidance on the collection, verification, and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (CT-3)” [3]. For each study, clinical and safety databases were periodically reconciled to exclude duplication or discordant entries as per the study protocols. Extracts from both databases were aggregated into consolidated datasets per study by mapping the corresponding database fields. These datasets consisted of non-serious AEs from clinical databases and SAEs from safety databases. Further analysis was performed only on treatment-emergent AEs (TEAEs; i.e., AEs that occurred after exposure to the IMP).

Data Processing

Consolidated listings were categorized hierarchically by MedDRA System Organ Class and then by MedDRA Preferred Term (PT). They were classified by event seriousness as per the International Council for Harmonisation Good Clinical Practice (ICH GCP) [1] and ICH E2A criteria and then by severity Grades 1-5 as per CTCAE (version 4.03 or 5.0, as applicable by study protocol). Data were presented visually using pie and bar charts (Figure 1). TEAEs were classified by percentage of the total number of TEAEs per severity grade. For identification of confirmed risks and potential signals (based on the pattern of emergence of TEAEs; see Results, Section 3), TEAEs relevant to these risks/signals were retrieved based on MedDRA v24.1 PTs. Confirmed risks were based on the latest versions of the Investigator’s Brochures for the respective IMPs and identified by matching PTs. Potential signals were based on the identification of the proposed pattern of the emergence of TEAEs and medical judgment, as described in Results, Section 3.

Figure 1

Note: AEs per study were classified by seriousness (inset pie charts) and severity (bar charts). AEs of grade 3-4 CTCAE severity constitute substantial portion of overall safety data. AE: adverse event.

Results

Serious Adverse Events Constitute only a Small Fraction (“tip of the iceberg”) of Safety Data Available for AoSE

The CIOMS Working Group VI report and recent studies pointed to the potential importance of non-serious AEs for the safety profile of the IMP [14,15]. Here we examined safety data from two independent clinical studies (see selected details about the studies in Table 2). To assess the relative abundance of different subsets in safety datasets, we visualized the data including both serious and non-serious AEs, as shown in Figure 1. For all studies analyzed, SAEs also constituted a minor part of the TEAEs sometimes dataset (2-3%), as shown in the pie chart inserts. Thus, in the trials examined in this study, non-serious exceeded the serious TEAEs by more than approximately 30-fold for both studies.

Inclusion of Non-Serious Adverse Events Augments the IMP Safety Profile

We then examined the abundance of non-serious TEAEs relative to serious TEAEs when classified by seriousness and severity. Interestingly, as shown in the Figure 1 bar charts, the number of CTCAE Grade 3 and 4 non-serious TEAEs exceeds 3- to 30-fold the number of CTCAE Grade 3 and 4 serious TEAEs, respectively. While this is not unexpected, considering the vast prevalence of non-serious AEs in the dataset, the non-serious TEAEs of CTCAE Grades 3 and 4 pose significant clinical importance under certain circumstances since these same events may meet seriousness criteria; e.g., following a therapy course that dictates a hospital stay >24 hours. Such events constitute a kind of “grey zone.” As a consequence, the identification of safety risks may be delayed based on the data collection and signal management. Non-serious grade 3-4 AEs normally are not included in the AoSE, thus potentially affecting safety conventions used by various organizations. Since, as discussed previously, AoSE in most cases is prepared using only SAEs, the impact of “grey zone” CTCAE Grades 3 and 4 non-serious AEs on the AoSE, and potentially on the safety profile of the IMP, might be systemically excluded from the analysis. Of note, while CTCAE Grades 1 and 2 non-serious AEs are even more abundant than SAEs of comparable severity, as shown in the Figure 1 bar charts, the clinical significance of these AEs might be minor. Thus, we do not attribute them with a similar impact on the safety of the IMP.

Inclusion of Non-Serious Events Facilitates Early Detection of the Safety Risks

Early detection of any safety risk is the key aspect of the signal detection process [7]. We hypothesized that including the data on the non-serious TEAEs (especially of Grades 3 and 4, thus belonging to the earlier mentioned “grey zone”) in the safety evaluation could enhance the early detection of potential signals. These signals could then be thoroughly assessed. To test this proposition, we examined the temporal pattern of the emergence of TEAEs in Study 1, classified by MedDRA PT. We identified the expected emergence of serious TEAEs, but also of non-serious TEAEs of grade 3-4 for some of the IMP confirmed risks, sometimes emerging months before the SAEs (See representative examples of “anonymized” confirmed risks in Figure 2). These data corroborate our suggestion that close monitoring of emerging non-serious TEAEs can promote early detection of potential signals.

Figure 2

Note: Representative time-to-onset plot of emergence of AEs during Study 1 (2017-2018) shows time since the first IMP dose to onset of serious/non-serious AEs. Confirmed risks are identified at MedDRA PT level. The exact PT terms are “anonymized” to preserve data confidentiality. IMP: investigational medicinal product; AE: adverse event; MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term.

Discussion

In recent years, the process of safety surveillance has undergone a transition from a primarily reactive approach to safety issues to the proactive evaluation of accumulated safety data in order to identify and manage risks in a timely and efficient manner [15]. As revealed in surveys conducted by the Clinical Trials Transformation Initiative, preparation of the AoSE is considered by Sponsors to be a burden and one of the main challenges of the FDA’s Final Rule for Safety Reporting [5,12]. In this paper, we advocate for the AoSE as a useful tool for signal detection and safety data evaluation to be conducted for every SUSAR regardless of the reporting requirements under different jurisdictions. Such an analysis could highlight data with a potentially important impact on the safety profile of the IMP, within the early phases of clinical development. Further, we strongly recommend the inclusion of non-serious AEs (or at least the ones of CTCAE Grades 3 and 4 severity) in data used for AoSE, as these may significantly contribute to the emerging safety profile of the IMP. Further details to support our proposition are presented below.

Non-Serious Adverse Events May Significantly Enhance the Analysis

CIOMS Working Group VI emphasized the importance of non-serious AEs for assessing the safety profile of the IMP, stating, “Although it is appropriate to apply greater scrutiny to what appear to be serious adverse events, the true safety profile of a medicinal product throughout development can only be assessed by careful evaluation of all AEs/adverse drug reactions” [2]. CIOMS Working Group VI also emphasized the importance of the relationship between non-serious and SAEs and stated that “non-serious AEs could be precursors (prodromes) of more serious medical conditions” [2]. We demonstrated in both studies, that the number of non-serious TEAEs of Grades 3 and 4 significantly exceeded the number of serious TEAEs of Grade 3-4 severity. Importantly, while the data describing serious TEAEs were collected both in safety and clinical databases, the data in the safety database were more extensive, including the Sponsor’s causality and expectedness. The significance of the inclusion of safety database data in safety analyses was shown previously [13], as well as corroborated by our own experience. Based on these observations and recommendations, and taking into account our data, we strongly suggest that non-serious TEAEs in clinical trial databases be used along with the serious TEAEs from safety databases for the preparation of AoSE.

AoSE Preparation is Facilitated by Data Analysis/Visualization Software Suites

In surveys conducted by the Clinical Trials Transformation Initiative, the burden associated with the preparation of the AoSE was named by Sponsors as one of the main challenges of the FDA’s Final Rule for Safety Reporting [5,12]. This finding likely reflects the heavy workload and the specific resources needed for the AoSE. Depending on the clinical program complexity, preparation of the AoSE (as well as signal detection and other safety surveillance-related tasks) may require data collection from different vendors, rely on the availability of analytical software, and need experienced staff capable of performing these activities, including the data analysis and interpretation. To ensure straightforward and efficient preparation of the AoSE, data may be aggregated using a software package that can ensure correct mapping, aggregation, and visualization. Consolidated data could then be pivoted and classified based on the parameters needed for the analysis (e.g., MedDRA terms, Standardized MedDRA Queries (SMQs), seriousness, causality, severity, outcome, and action taken with IMP). Using such software could enable quick focus on data relevant to the pre-approved search criteria. We have successfully used validated tools such as R programming language (via R Studio®), TIBCO Spotfire®, and PowerBI®, all of which suit this purpose. A tentative workflow for AoSE preparation is presented in Figure 3. The process is initiated with the collection of relevant safety data from sources as per the organizational conventions, e.g., the Investigator’s Brochure and snapshots from safety and clinical databases (including the AEs, demography, exposure data, etc.). Data are integrated into a consolidated dataset, which is then filtered in accordance with pre-approved search criteria. If applicable, a search of scientific literature may be performed. Information from all sources is then assessed for safety profile evaluation. Finally, a narrative is written that contains descriptions of the data sources used, search strategy, search results, assessment of the impact of reported SUSARs on the safety profile of the IMP, and a description of safety action(s), as applicable.

Figure 3

Note: Mentioned are main sources of information (green boxes), preparation stages (blue boxes) and possible outcomes (orange gradient boxes). Risk minimization measure stringency is shown by the gradient with white being the least severe measure, and dark orange the most severe. IB: Investigator’s Brochure. *”Dear Investigator” letter – used for update of the investigators on a protocol amendment/IB (reference safety information) update. **Protocol modification e.g., inclusion/exclusion criteria, dose/cycle length modification. Follow-up period prolongation etc.

AoSE May Serve as an Important Tool for Safety Monitoring and Signal Detection, Especially in the Early Stages of Clinical Development

Signal detection of small datasets is mainly performed via case-by-case review or by analysis of case series [7]. Safety information available during Phase I/II studies may be scarce, and sometimes aggregated analysis of the data may be required even before the first periodic safety report preparation. Thus, performing an AoSE might be the initial attempt at an aggregated safety analysis for an IMP. Here we advocate for using the AoSE as an opportunity to perform signal detection, as the data obtained may provide indications of possible safety issues that can be used for subsequent optimization of the clinical development program. As we have shown in Figure 1, the detection of potential signals may be enhanced by including data on non-serious AEs (especially of “grey zone” Grades 3 4). These events may emerge before the serious ones in the course of the study, and analysis of these data may facilitate and speed up the correct evaluation of the safety profile of the IMP. The emergence of “grey zone” AEs, per se, should not necessarily be classified as a signal; however, close monitoring of the data over time can clarify whether the observed phenomena represent isolated events with no impact on the safety profile of the IMP or, with subsequent repetitious reporting of SAEs, confirm a potential signal. The model of our approach is presented in Figure 4. We refer here to all available safety data as an “iceberg,” with SAEs being the “tip” and the bulk of the non-serious-AEs being the “body,” which, being not “visible above the water,” is not routinely included in the analysis. Thus, our model states that the inclusion of non-serious AEs and the use of advanced technology and experienced staff all contribute to the preparation of the AoSE, which significantly improves the early detection of potential signals.

Figure 4

Note: Building structured process and mining deeper into the data facilitates performing meaningful AoSE with significant impact on IMP safety profile. AoSE: analysis of similar events.

Conclusion

Along with other fields that deal with medical information, pharmacovigilance undergoes conceptual shifts. Readily available, user-friendly technology and outsourcing specific functions to external vendors facilitate complex analyses that previously required heavy workloads and personnel investments. The use of these resources leads to improved assessment of the safety of IMPs. In our opinion, AoSE should be considered as one of the main tools of signal detection, particularly in the early stages of clinical development. It may provide the context necessary for correct and efficient assessment of safety data (scarce as it may be), and thus improve the safety of study subjects. In summary, rather than a regulatory burden to handle, we regard AoSE as an opportunity for valuable insight regarding the safety of the IMP.

Author Contributions

MS, RL and SS contributed equally to this work. MB, MS, RL and SS devised the research. RL performed the research. RL, MS and SS wrote the manuscript. LS, DT and RR assisted with drafting the manuscript. All authors read and approved the final manuscript.

Conflict of Interest

The authors declare that there are no competing interests.

Availability of Data and Materials

Due to its proprietary nature and confidential agreements in place, supporting data cannot be made openly available.

Acknowledgements

The authors would like to thank Rochelle Ku for kind assistance with the preparation of the figures.

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Impact of Healthcare Cost on the Health and Well-Being of Rural Dwellers in Nigeria

Introduction

The aspiration for “Health for All” by 2020 has long been a global objective, yet its realization remains elusive, especially in rural and remote regions where a significant portion of Nigeria’s population resides. A 2014 report by the RUPRI Health Panel delved into this issue, offering insights into the definitions and measures of healthcare access, particularly in rural settings. In Nigeria, where rural populations constitute a substantial proportion of the country’s demographic landscape, addressing healthcare disparities in these areas is imperative for advancing the nation’s overall health outcomes and fulfilling the vision of equitable healthcare for all. It explores the persisting challenges of healthcare access in rural Nigeria, drawing from the backdrop of the unattained “Health for All” goal and the insights provided by the RUPRI Health Panel report [1] Rural residents face barriers to accessing essential healthcare services like primary care, dental care, and behavioral health due to factors such as workforce shortages, insurance status, and stigma. Despite available services, belief in receiving quality care remains a challenge [2]. Health outcomes, like infant mortality rates (it is the number of babies who die before the age) of one per thousand live births per year, are typically worse in rural areas compared to urban areas, exemplified by Nigeria’s 2019 infant mortality rate of 74.2 deaths per 1000 live births, with rural rates higher at 70 to 49 deaths per 1000 live births [3].

With a 13% immunization rate for children between 12-23 months, Nigeria is the African country with the lowest vaccination rate. The substantial presence of Acute Respiratory Infections and diarrhea also contribute to the elevated mortality rates for children all these were a result of not being able to pay bills [4] Infant mortality rate shows how countries’ survival rates vary due to different stages of development [5]. Rural infants in Nigeria face higher mortality due to limited healthcare access. Challenges like financial constraints and distance to facilities hinder maternal care, contributing to preventable neonatal deaths. Targeted efforts, outlined by WHO, are crucial for addressing rural health disparities and breaking the poverty-health cycle [6]. Access remains a major rural health issue globally, with shortages of healthcare professionals and emergency services posing challenges [7]. In rural areas, ensuring healthcare availability is vital for community security [8]. Health services in rural and remote areas face challenges due to limited funding and resources. Developing countries grapple with poverty and scarce healthcare facilities, while developed nations witness a trend of reduced support for rural health services amid broader economic and social changes, contributing to rural decline [9].

With the exception of public health or specific disease experts, there has been minimal medical input in the development of the majority of the World Health Organization and other primary healthcare initiatives worldwide. Doctors in particular have not often been involved in implementation in the field [10]. As the primary providers of basic medical care, family the family physician sees the patients in their medical practice as a “population at risk” in order to provide patient-oriented, community-focused preventative care [11]. Family practice is essential for health system development, per the World Health Assembly. A full health team, including doctors, nurses, medical assistants, and village health workers, is crucial for addressing community health needs. Active community involvement is vital for achieving the vision of primary healthcare and optimizing health system effectiveness [12]. In Nigeria, the decline in infant and under-five mortality rates has been slower than anticipated, with reductions of 21% and 34%, respectively, from 1990 to 2013. Despite efforts to meet Millennium Development Goal targets, Nigeria fell short and lagged behind peer countries like Kenya, Uganda, Tanzania, and Senegal. Financial access poses a major challenge, with high costs for primary healthcare visits relative to people’s income levels. While geographic access to public PHC facilities is relatively good, the private sector, particularly Patent and Proprietary Medicine Vendors (PPMVs), plays a significant role in healthcare provision. However, there are issues with delayed and informal referrals and variable service quality. Shortages of essential drugs, vaccines, and medical equipment, coupled with deficient infrastructure, hamper the effectiveness of PHC facilities. Addressing these challenges is crucial to improving the quality and accessibility of primary healthcare services in Nigeria [13].

The country boasts a dense network of PHC facilities, with 18 facilities per 100,000 people, higher than in comparison countries [14]. However, despite this seemingly robust infrastructure, the actual number of public health clinics and posts falls below national targets [15]. The workforce density exceeds the African country average, yet there’s a mismatch between trained health workers and their deployment, resulting in limited attention to health promotion and prevention. Supply chain inefficiencies and fragmented systems present additional challenges for PHC facilities, with as many as five uncoordinated supply channels. In terms of financing, Nigeria’s health expenditure is relatively low, primarily financed through out-of-pocket payments. Government expenditure on healthcare is limited, leading to an overreliance on user fees, exacerbating financial barriers to access. The flow of public finance is fragmented across federal, state, and local government levels, with uncertain funding flows hindering PHC financing. Most funding is directed towards health worker salaries, leaving minimal resources for essential supplies and infrastructure. There’s a heavy reliance on cost recovery mechanisms such as revolving drug funds, which often fail to ensure sustainable drug supplies and contribute to high user fees. Governance structures in Nigeria’s primary healthcare (PHC) system are highly fragmented, posing significant challenges to effective service delivery. At the federal level, the Ministry of Health oversees policy direction, with specific responsibilities divided between the Minister of State for PHC and the Minister of Health. The National Primary Health Care Development Agency implements policies in coordination with the Ministry of Health. At the state level, authority over health policy and financing lies with the state governor, while the State Ministry of Local Government Affairs manages and pays high-level PHC staff. The State Ministry of Health has limited power, with funding controlled by the State Ministry of Local Government [16].

Local government chairmen oversee PHC departments and control local budgets with the LGA PHC coordinator responsible for program management [17]. However, coordination between state and local levels is often lacking, leading to inefficiencies in resource allocation and service delivery. Community involvement is facilitated through ward and village development committees, but their effectiveness varies. These governance challenges contribute to inefficiencies in human resource deployment and management, with well-trained health workers often underemployed or inadequately supervised. Performance management mechanisms are lacking, resulting in low productivity and poor quality of care. Weak incentives further compound these issues, with limited supervision exacerbating the problem. Benchmarking Nigeria’s PHC performance against other African countries reveals significant disparities. While Nigeria has the largest density of medical facilities and healthcare professionals, but it also has the lowest infrastructure, medicine access, and diagnosing precision. Poor service delivery metrics include absenteeism rate and amount of time invested to patients. Nigeria also has the highest under-five death rate and the lowest vaccination coverage. Nigeria has enacted legislative reforms, such as the Primary Health Care under One Roof (PHCUOR) policy, which aims to combine PHC services under a single authority, to address these issues. To enhance funding, the National Health Act of 2014 creates a basic health care provision fund. Both the SOML—P4R project and results-driven financing are promising initiatives aimed at enhancing service delivery and coordinating state initiatives with federal objectives [18].

In our study to assess primary healthcare (PHC) performance in Nigeria, we leverage a diverse array of data sources. These include Demographic and Health Surveys (USSAID, 1996-2014) for outcome indicators, the Nigeria General Household Survey (Nigerian National Bureau of Statistics, 2010-2014) for PHC access, and the World Development Indicators (World Bank Database, 2016) for poverty headcount. We also utilize the WHO National Health Account (WHO, 2016) for financing data, the WHO Global Health Workforce statistics (WHO, 2014) for health worker density, and the Advancing Child Health via Essential Medicine Vendors survey (Global Health Group, 2014) for Patent and Proprietary Medicine Vendors (PPMVs) data. Moreover, we heavily rely on the Nigeria Service Delivery Indicator survey (World Bank, 2012-2014) to gain insights into health facilities, allowing for comparisons between Nigeria and other countries. Provider ability is assessed using clinical vignettes, and national- and state-level averages are generated from data collected in 12 surveyed states. Despite limitations in national representativeness due to the survey’s focus on a subset of states, high levels of intrastate facility sampling enable quality interstate comparisons within Nigeria.

The Significance of the Study

The study’s relevance lies in the fact that, according to Strasser R, et al. (1998), significant and proactive participation from the community is necessary for the primary healthcare system to realize its mission. Where there is active community engagement, healthcare systems function best. The involvement of the community will go a long way to sensitize the rural dwellers to the need to take health issues seriously and even make a representation to the government of the need to reduce the cost of medical care so that health care services can be made available to the populace.

Objective of the Study

1. To determine whether residents in rural areas can afford the costs of their medical care.

2. To figure out how to go to and make use of amenities, such as transportation to those that could be far away.

3. To discover whether the participants feel confident in their capacity to interact with medical professionals, especially in cases when the patient lacks medical education or speaks English as a second language.

4. To check whether people believe they may utilize services without jeopardizing their privacy.

5. To find out if the rural dwellers believe that they will receive quality health care.

6. Apart from primary health care are their general hospitals around us.

Research Questions

1. How will distance affect those who go to the hospital for treatment?

2. Can the type of work one does influence his ability to pay for drugs in the hospital?

3. Do the available roads affect the type of hospitals people use?

4. Can the years of experience on the job help to communicate well with health officials?

Methodology

Research Design

This study is a descriptive survey research design that is used to determine if the cost of paying for health bills has an impact on the health and well-being of rural dwellers in Nigeria using a questionnaire.

Population of the Study

This study examines primary healthcare in the Itele community, Ado-Odo local government area, Nigeria. Forty questionnaires were distributed: 20 to primary healthcare staff and 20 to users. Data collection spanned five weeks, employing purposive sampling. All data were sourced directly from primary healthcare stakeholders.

Sample and Sampling Method

In order to identify and choose scenarios packed with data and make the most use of few resources, purposeful sampling is a strategy that is frequently employed in qualitative research (Patton 2002). This entails locating and picking people, or groups of people, who have firsthand experience with or exceptional understanding of an interesting phenomena [19]. Bernard (2002) and Spradley (1979) highlighted the significance of availability and desire to engage, as well as the capacity to explain, express, and reflect when communicating views and opinions, in addition to knowledge and experience [20]. By reducing the possibility of selection bias and accounting for the possible effect of known and unknown confidence, probabilistic or random sampling, on the other hand, ensures the generalizability of results [21].

Research Instruments

The data collection instrument for this study is a questionnaire divided into two sections. Section I collects respondents’ personal information, while Section II comprises twenty items assessing respondents’ views on the impact of cost on the health and well-being of rural dwellers in Nigeria. The questionnaire utilizes a 4-point Likert scale ranging from “Strongly Agree” to “Strongly Disagree.”

Method of Data Analysis

Methods of analyses that would be used for the hypotheses are the Chi-square is useful with data in the form of frequencies i.e. data based on a nominal scale of measurement such as representing religious affliction, qualification, parental occupation, opinion about a phenomenon, etc.

By definition, the Chi-square is given by:

Where X2 = (pronounced high)

∑ = summation

Fo = observed frequency

Fe = expected frequency

Also, Df= degree of freedom = (c-1) (r-1)

Where c= number of columns and

r= number of rows

The interpretation of Chi-square is dependent on the required level of significance, which is determined by the nature and use of research, and the size of the degree of freedom involved, which is determined by the dimension of the contingency table. These two are used in the location of the critical (standard) value relative to the significance level and the degrees of freedom on the table were compared with the observed (calculated) value. (Sanni R.O.2007).

Results

Table 1

Frequency and percentages of Gender, Types of occupation, Distance to hospital, and Hospital often visited: The demographic distribution of the study’s participants, including gender, occupation type, distance to hospital, and frequency of hospital visits. The study included 40 individuals, with a gender distribution of 62.5 percent males and 37.5% females. In terms of their occupation, the majority of participants (52.5%) were self-employed, with the remainder (47.5%) working for a salary. The distance to the hospital differed among participants, with the majority living far away (55.55%), followed by those living close by (22.5%), and those at a moderate distance described as “not too far” (22.5%). Furthermore, participants’ hospital visiting habits were analyzed, which indicated that a higher number of participants regularly attended public hospitals (67.5%) than private healthcare facilities (32.5%).

Table 1: Frequency and percentages of Gender, Types of occupation, Distance to hospital, and Hospital often visited.

Table 2

Frequency and number of responses to individual questions: Survey responses on healthcare access and utilization provide attention to many aspects of healthcare-seeking behavior and physical barriers among research participants. The majority of respondents took a proactive attitude to obtaining medical assistance while sick, with 47.5% agreeing and 32.5% strongly agreeing with the statement. However, in terms of transportation facilities, none of the respondents strongly agreed that they have good roads going to hospitals, with 40% disagreeing and 47.5% strongly disapproving. Furthermore, a sizable proportion (55%) indicated unhappiness with the availability of healthcare centers in their area, indicating perceived inadequacy in healthcare facility distribution. Regarding medicine access, the majority (62.5%) reported that drugs are not always available in hospitals when seeking treatment, demonstrating potential issues in medication supply chains. The affordability of pharmaceuticals appeared as a significant concern, with all respondents expressing disagreement with the cost of drugs in hospitals. Despite a significant proportion (37.5%) reporting excellent communication with health officials, a lesser amount (10%) expressed discontent, emphasizing possible areas of development in healthcare providers. -Patient communication

Table 2: Frequency and number of responses to individual questions.

Table 3

Distance To Hospital *Do you go to the hospital when you are sick? Cross tabulation and P-Value: The findings of a cross-tabulation analysis, which investigates the association between two categorical variables: distance to the hospital and people’s tendency to seek medical care while sick. The cross-tabulation provides a comparative investigation of how people’s healthcare-seeking behavior varies with their distance to the hospital. For example, it demonstrates that among those who live far from hospitals, 11 agree and 6 strongly agree to seek medical care when they are ill, demonstrating that a sizable proportion of people are willing to seek healthcare regardless of the distance. In contrast, among those residing near hospitals, 7 agree and 4 strongly agree, indicating a significantly higher tendency for seeking medical care among those in close vicinity to healthcare facilities p-value of 0.759 indicates that there is no statistically significant relationship between distance to the hospital and persons’ probability to seek medical care while ill. As a result of this p-value were unable to reject the null hypothesis, which states that there is no association between hospital distance and healthcare-seeking behavior.

Table 3: Distance To Hospital *Do you go to the hospital when you are sick? Cross tabulation and P-Value.

Table 4

Types Of Occupation *Are the drugs available affordable? Cross tabulation and P-value: The table suggested the association between different occupations and people’s opinions of drug affordability. The responses are divided into two categories of occupation: self-employment and paid work. Respondents in each category indicated their views on medicine affordability, which were classified as Strongly Disagree, Disagree, or other non-table comments. With investigation, it is evident that among self-employed individuals, 16 strongly disagree and 5 disagree with the belief that pharmaceuticals are affordable, for a total of 21 replies. In contrast, among those in paid employment, 9 strongly disagree and 10 disagree, for a total of 19 replies. The p-value of 0.06 suggests that there is no statistically significant relationship between occupation types and perceptions of drug affordability. In this case, the p-value indicates a statistically non-significant association between the variables. Particularly the observed association between occupation types and perceptions of drug affordability seems to have occurred by chance.

Table 4: Types Of Occupation *Are the drugs available affordable? Cross tabulation and P-value.

Table 5

Hospital Often Visited *Do you have good roads where vehicles can fly to the hospital? Crosstabulation and P-value: The relationship between the frequency of hospital visits (categorized as public or private hospitals) and individual evaluations of the road quality moving to the hospital. On inspection, that finds frequently visited public hospitals, 11 people strongly disagree, 12 disagree, and 4 agree that there are good roads to the hospital, totaling 27 responses. In contrast, among those who usually visit private hospitals, 8 strongly disagree, 4 disagree, and 1 agree, a total of 13 responded. The p-value of 0.457 indicates a level of statistical significance in the link between hospital visit frequency and assessments of road conditions. This p-value implies that there is no statistically significant relationship between the variables.

Table 5: Hospital Often Visited *Do you have good roads where vehicles ply to the hospital? Crosstabulation and P-value.

Table 6

cross-tabulation between communication response with all variables and individual P-value: The table indicates cross-tabulated data that investigates the relationship between respondents’ capacity to interact effectively with health professionals and several demographic parameters such as occupation type, distance to the hospital, frequency of hospital visits, and gender. Among self-employed people, 11 disagreed and 7 agreed on the ability to communicate effectively, whereas salaried employees disagreed and agreed. Notably, there was no significant relationship between profession type and communication skill, as evidenced by the p-value of 0.537. Comparably there was no significant relationship identified between distance to the hospital, hospital visit frequency, gender, and communication skills (p-values of 0.674, 0.72, and 0.108, respectively).

Table 6: Cross-tabulation between communication response with all variables and individual P-value.

Discussion

The study included 40 individuals and investigated various aspects of healthcare access and utilization. The major findings revealed a higher percentage of males (62.5%) compared to females (37.5%), with the majority being self-employed (52.5%) and living far from hospitals (55.55%). Near Significant associations were observed between occupation types and perceptions of drug affordability (p-value = 0.06), highlighting a potential area of concern. Additionally, while public hospital visitors expressed dissatisfaction with road conditions, there was no statistically significant relationship between hospital visit frequency and assessments of road quality (p-value = 0.457). Distance has an important effect on individuals seeking hospital treatment, indicating that individuals living farther away may face challenges to healthcare access. This perspective corresponds with broader conversations about inequalities in healthcare, particularly in marginalized regions where mobility challenges aggravate underlying disparities in healthcare. Individuals who face difficulties with transportation frequently have a higher disease burden, showing a complicated interplay between socioeconomic variables, healthcare access, and health outcomes. Recognizing these discrepancies allows healthcare organizations to better serve patients’ complex demands and adopt specific strategies that reduce the impact of distance and transportation obstacles on healthcare access. Wallace R, Hughes-Cromwick P, Mull H, and Khasnabis S show that transportation is a fundamental but essential step for continued provision of quality health care and pharmaceutical access, especially for patients with chronic disease [22].

Hypothesis Two

Research findings contradicted the null hypothesis, which suggested that occupation had no significant effect on medicine affordability. Contrary to the expectation, the research indicated a significant influence of work on people’s ability to pay for medications, emphasizing socioeconomic gaps in healthcare access. This emphasizes the significance of the profession as a predictor of healthcare affordability, with implications for equal access to vital pharmaceuticals. According to De La Torre, a person can be in debt for a long time if not being able to pay for healthcare bills promptly [23]. In the first part of 2020, according to a report by the National Health Interview Survey (NHIS), 9.7%, or 31.6 million adults (of all ages), lacked health insurance. Survey findings showed that the uninsured rate and number of uninsured decreased from 2019 (10.3% or 33.2 million people of all ages) but the difference was insignificant [24].

Hypothesis Three

The study of the association between hospital type and road infrastructure revealed insufficient data to reject the null hypothesis. Despite expectations for considerable benefits, the investigation found that the quality of road infrastructure has no meaningful influence on hospital choice. This suggests that road conditions are not what significantly influence people’s hospital selection decisions, stressing the importance of other factors in healthcare decision-making. Alvin, a patient having end-stage pulmonary fibrosis who was critically sick, was admitted to the facility in June 2011 due to pneumonia. Alvin was given 100% oxygen, strong antibiotics, and steroids by his doctor, a pulmonologist at an elite academic medical facility, but his health rapidly worsened. Since patients have discovered that they can also get treated elsewhere apart from government hospitals they used any hospital of their choice [25].

Hypothesis Four

The study supported the null hypothesis, which suggested that location had no significant effect on communication with health professionals. Despite apparent assumptions about regional effects on communication, the data showed that an individual’s location had no substantial impact on their capacity to communicate successfully with health officials. This emphasizes the need to take into account elements other than geographical location when evaluating communication dynamics in healthcare systems. COVID-19 e-learning showed that location does not have any barrier to being able to join the class network is available (Zalat MM, Hammed MS, Bolbol SA,2021) [26].

Conclusion

The study suggests that living far from hospitals may pose a significant barrier to accessing treatment, highlighting the importance of proximity to healthcare facilities in ensuring timely and effective care. Secondly, occupation type emerges as a determinant of drug affordability, indicating that individuals’ economic circumstances influence their ability to afford essential medications. Thirdly, the research underscores that the availability of road infrastructure does not necessarily dictate the choice of a healthcare facility, emphasizing other factors at play in hospital selection. Finally, the study suggests that geographical location does not inherently impact individuals’ ability to communicate effectively with health officials, challenging assumptions about the influence of location on healthcare communication.

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Actual Issues of Nosocomial Infections in Nigeria: A Comprehensive Study at Ogun State University Teaching Hospital, Sagamu

Introduction

Nosocomial infections (Nis) are defined as infections that a patient gets during their stay in a hospital and are either absent or not in the development phase at the time of admission to the hospital. Depending on how long the infection takes to nurture, the signs and symptoms of the illness may appear during the hospital stay or after discharge. It is commonly described as an infection discovered at least two to three days following the patient’s admission to a medical facility. Hospital-acquired infections have the potential to worsen pre-existing conditions, cause distress and anxiety, and may even be deadly [1]. Significant morbidity, death, and increased financial burden are the outcomes of these illnesses. Nosocomial infections are significant public health issues in both industrialized and underdeveloped nations [2]. Numerous illnesses are linked to microorganisms that are multi-antibiotic resistant and easily transmitted by staff hands [3]. Over 1.4 million patients globally currently have infectious issues that they contracted while in the hospital. Compared to other hospital wards, nosocomial infection and death are more common in intensive care units. The risk is five to ten times higher for patients in the intensive care unit. Hospital patients’ immune systems are failing to prevent nosocomial infections more and more [4].

Between 25 and 50 percent of nosocomial infections result from the interaction of intrusive equipment with the patient’s microbiota. Nowadays, the majority of infections obtained in hospitals are brought on by ordinary household microorganisms (e.g., enterococci, coagulase-negative staphylococci, Staphylococcus aureus, Enterobacteriaceae) that either do not cause illness in people or cause it less severely than in hospital patients [5]. Antimicrobial resistance has been more common over the last few decades, and it has been alarmingly linked to major infectious illnesses [6]. While nosocomial infections can occur in a variety of locations, the most prevalent ones include lower respiratory tract infections, surgical site infections, urinary tract infections, and bloodstream infections. Because patients with Surgical Site Infections (SSIs) typically stay in the hospital longer, are more likely to die, and are readmitted more frequently, SSIs are the most prevalent source of nosocomial infections, which have a significant impact on morbidity and mortality [7-9]. S aureus, P. aeruginosa, E coli, K pneumoniae, Enterobacter spp., Enterococcus spp., CoNS, and Viribans streptococci are the most prevalent bacterial pathogens [10,11].

A Urinary Tract Infection (UTI) is characterized by the growth of a single pathogen in a correctly collected mid-stream urine specimen that has more than 105 colony-forming units/ml [12], According to (Kehinde, et al. [13]) UTIs can result in significant morbidity for patients who have an indwelling urethral catheter. According to (Hsueh, et al. [11]), the most prevalent bacterial pathogens include P aeruginosa, E. coli, S. aureus, K. pneumoniae, Enterobacter spp., Enterococcus spp., Proteus spp., and Citrobacter spp. Approximately 10% to 30% of pediatric hospital-acquired illnesses are caused by bloodstream infections, which are among the most prevalent infections [14]. S. aureus, CoNS, P. aeruginosa, K. pneumoniae, E. coli, Enterobacter spp., Enterococcus spp., and Acinetobacter spp. are the predominant bacterial pathogens in cases of BSI. Ventilator-related pneumonia, which is nosocomial bacterial pneumonia that develops after two days of mechanical ventilation, is the most frequent nosocomial infection encountered in the critical care unit [15]. Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae are the most common organisms that cause infections. The makeup of patients in an intensive care unit, the duration of hospitalization, and the use of previous antimicrobial medication all influence the etiologic agents [16].

Hospital-acquired infections are often the result of breakdowns in the body’s defensive mechanisms caused by invasive surgeries and antibiotic usage. Iatrogenic, organizational, or patient-related risk factors are possible. Specialized laboratory tests used for diagnosis include radiography for pneumonia and blood cultures for bloodstream infections. Concern over antibiotic resistance is growing, especially about microorganisms that cause nosocomial infections. Although the goal of prevention efforts is to stop the emergence of resistant organisms and lessen antibiotic resistance, many infections cannot be prevented because of aging, chronic illnesses, and suppression of the immune system [17,18]. Nosocomial infections, prevalent in underdeveloped nations, lack a dedicated control program in our country, as highlighted by studies at Ogun State University Teaching Hospital, Sagamu. The research aims to assess infection frequency, drug susceptibility patterns, and associated risk factors, recognizing the global impact of antimicrobial resistance.

Material and Methodology

A cross-sectional study was carried outAt Ogun State University Teaching Hospital, Sagamu in Sagamu, Ogun State, Nigeria, using information gathered between July 2010 and September of next year. Patients with suspected nosocomial infections who were fifteen years of age or older were the subject of this investigation, which was conducted in the hospital’s surgical wards and Surgical Intensive Care Unit (SICU). The research area was Ogun State University Teaching Hospital, Sagamu, a well-known institution in the area with five hundred and sixty beds that were conveniently positioned and provided local emergency services. The dependent variables included patterns of antibiotic susceptibility, septicemia, surgical wound infection, and urinary tract infection (UTI). Age, sex, the placement of a urinary catheter, surgery, mechanical breathing, intravascular catheter, use of antibiotics, and length of stay were among the independent variables taken into account. Physicians conducted a comprehensive clinical assessment to identify potential risk factors and rule out community-acquired infections as part of a convenient sampling approach. Following WHO guidelines, the sample size (n) was established using the highest recorded nosocomial infection prevalence (16.4%) at Sagamu Hospital, with a 0.05 margin of error and a 95% confidence interval (Zα/2). Patients meeting the defined criteria (i.e., developing at least two to three days after admission to surgical wards and ICU) for UTI, primary bacteremia, or surgical wound infection were eligible for inclusion in the study. Patients with infections obtained in the community were not included in the study. This choice was made to concentrate on nosocomial infections and guarantee a steady period of infection growth after hospitalization.

Data Collection and Processing

A questionnaire that had been previously created and evaluated was used to gather data on sociodemographic characteristics and related risk factors. Sample collection: Based on clinical observations, specimens were taken from patients suspected of acquiring nosocomial infections who were admitted to the surgical wards and SICU. Standard operating procedures were followed in the collection and analysis of the specimens. Blood collection and processing: When a bloodstream infection was suspected, adult patients with fever or chills had their blood samples taken aseptically. Ten milliliters of venous blood were drawn, and the blood was promptly inoculated into a tube that had soup that contained thioglycollate. For ten days, blood was incubated aerobically at 37 °C, and turbidity was measured as a sign of growth (Annex 1). Urine specimens: A sterilized container was used to collect a urine sample for bacteriological analysis, and both before and after the catheter was used, the sample was cultured. This procedure was done utilizing the midstream approach. Urine cultures with colony counts greater than 105 CFU/ml of urine following catheterization and urine samples without substantial growth (< 104 CFU/ml of urine) before catheter placement were deemed suggestive of severe infection (Annex 2). Swabs from wound infections: Infections from wounds arise from illnesses, injuries, or surgical procedures that disrupt the skin’s outer layer. To separate the causing agents, material from infected wounds was collected aseptically (Annex 3).

Identification of Microorganisms

Culture and Gram staining: While urine, swabs, and body fluid specimens were inoculated on blood agar and MacConkey agar, blood specimens were inoculated in thioglycollate broth (Oxoid, Ltd.). The MacConkey agar plates and blood were incubated at 37 °C in an aerobic atmosphere for a duration of one to two days. Thioglycollate soup was incubated at 37 °C in an aerobic environment for a maximum of two weeks. Every day for up to fourteen days during that period, the area was checked for any visible signs of bacterial development. For all positive specimens, subcultures were subsequently carried out on Blood, Chocolate, and MacConkey agar plates. According to Cheesbrough [19], positive cultures were recognized by their unique looks on the corresponding media, the Gram-staining reaction (Annex 4), and the pattern of biochemical reactions. Biochemical tests: UtilisingAPI 20E identification kits (Biomerieux, France), members of the Enterobacteriaceae family were identified by oxidase, carbohydrate utilization, motility testing, urease testing, citrate utilization, indole synthesis, and other assays. Coagulase, DNase, catalase, bacitracin, and optochin susceptibility tests were utilized for Gram-positive bacteria.

Antimicrobial susceptibility testing: All isolates underwent antimicrobial susceptibility testing using the disk diffusion method, following (Bauer, et al. [20]) and the National Committee for Clinical Laboratory Standards [21] Three to five colonies of pure-cultured bacteria were collected, transferred, and gently mixed with five milliliters of nutrient broth to create a homogenous suspension. The suspension was then incubated at 37 degrees Celsius until its turbidity was corrected to the 0.5 McFarland standard. The surplus suspension was eliminated by gently rotating a sterile cotton swab against the tube’s surface. Next, using a swab, the bacteria were uniformly distributed throughout the surface of Mueller-Hinton agar and Mueller-Hinton agar enriched with 5% sheep blood, which was specifically utilized for S. pneumoniae (Oxoid). Following three to five minutes of drying at room temperature for the inoculation plates, a set of sixteen antibiotic discs (Oxoid) was placed on the surface of a Muller-Hinton plate. The following concentrations of medications were used in disc diffusion testing: After that, the plates were incubated for one to two days at 37 °C.

Using a caliper, the diameters of the zone of inhibition surrounding the disc were measured to the closest millimeter. The isolates were then categorized as sensitive, moderate, or resistant using the NCCLs’ standard table (NCCLs, 2006) [21]. According to Annex 5, resistance levels are classified as high, intermediate, and low when the percentages are, respectively, >80%, 60-80%, and < 60%. The EHNRI laboratory stock was utilized as a quality control measure for antimicrobial susceptibility testing and culture throughout the investigation.

Data Entry and Analysis

Software called SPSS12.0 was used for data entry and analysis. The Chi-square test was used to compare the results. A difference that was deemed statistically significant was indicated with a p-value of less than 0.05. The total number of positive instances among the patients that were investigated was used to compute the prevalence rate.

Ethical Considerations

The Department of Hygiene – Environmental Health of the “Grigore T. Popa” University of Medicine in Iasi, Romania, has validated this graduation thesis. The technique of sampling carried little risk; it was no different than taking a specimen for sensitivity and culture in a regular laboratory. Sterile swabs and disposable syringes with needles were used to stop the spread of HIV and other infectious diseases. Every piece of information that was included in the questionnaire was kept private. Every person who received a nosocomial infection diagnosis gave their informed consent. Patients had the option to leave the study if they were not interested in it. The management of nosocomial infections was contingent upon the findings of antibiotic sensitivity. Before the actual data collection period began, a letter explaining the study’s purpose to the hospital’s medical director was filed.

Results

The incidence of nosocomial infections was examined using data from 854 patients who were hospitalized at Ogun State University Teaching Hospital, Sagamu in Ogun State’s surgical ward and intensive care unit between July 2010 and September of next year. Upon admission, a thorough clinical examination was conducted to rule out infections acquired in the community and identify any potential risk factors. A total of two hundred and fifteen (25.17%) patients were chosen from the surgical wards (n = 161) and SICU (n = 54) of Ogun State University Teaching Hospital, Sagamu based on their clinical background. There were two hundred and fifteen patients total; eighty-five (39.5%) were female and one hundred and thirty (60.5%) were male. The male-to-female ratio was 1.5:1. The age was 38.02 (+14.82) years, with a range of seventeen to seventy-nine years. With a range of 3 to 66 days, the average hospital stay from the date of admission until sample collection was 16.72 days. Table 1 displays the age and sex distribution of the patients who were looked into for nosocomial bacterial infections. From the 215 patients included in the study, various samples were collected, comprising 88 pus swabs from the infection site, 84 urine samples, and 43 blood samples. Wound classification revealed that out of the total cases, 153 wounds were categorized as clean, 42 as clean-contaminated, and 20 as contaminated. Sixty-five percent of the patients received antibiotic prophylaxis before sample collection. Approximately twenty-eight primary reasons (diagnoses) were given for admission in this study; of these, benign prostatic hyperplasia (BPH) accounted for thirty-three (15.3%), car accidents for twenty-five, 11.6%, bullet injuries for twenty-four, 11.2%, head injuries for twenty, 9.3%, urethral stricture for thirteen, 6.0%, esophageal cancer for thirteen 6.6%, intestinal obstruction for twelve, 5.6%, acute appendicitis for ten (4.7%), and other causes for sixty-five (30.3%).

Table 1: Age and sex distribution of 215 patients investigated for bacterial nosocomial infections at Ogun State University Teaching Hospital, Sagamus, Sagamu, Ogun state, Nigeria (July 2010 – September 2011).

Patterns of Nosocomial Infection

Seventy-seven (9.0%) of the eight hundred fifty-four patients had nosocomial infections. Fifty-five (66.2%) males and 26 (33.8%) females made up the seventy-seven patients. Table 2 explains the nosocomial infection distribution among positive patients. It shows that thirty-eight (49.4%) of the infections were at the surgery site, twenty-three (29.8%) were urinary tract infections, and 16 (20.8%) were bloodstream infections. Eight (10.4%) of the 23 patients with urinary tract infections were female, and fifteen (19.4%) were male. Of sixteen patients with bloodstream infections, seven (9.1%) were female, and nine (11.7%) were male. Of the 38 patients with surgical site infections, eleven (14.3%) were female, and twenty-seven (35.1%) were male. Table 2 illustrates that BSI was most commonly seen in the SICU among other wards. In this investigation, there was a substantial (p < 0.05) correlation found between nosocomial infection and surgical operations, urine catheter insertion, central venous catheter insertion, and mechanical ventilation (Table 2).

Table 2: Nosocomial infections and associated risk factors at 77 patients at Ogun State University Teaching Hospital, Sagamu, Sagamu, Ogun state, Nigeria (July 2010- September2011).

Etiological Agents

From 77 nosocomial infection cases, a total of 84 bacterial isolates were obtained. 19.0% of the isolates were E. Coli, followed by S. aureus (16.7%), Klebseiella spp. (S. pneumoniae and K. oxytoca) (16.7%), P. aeruginosa (14.3%), coagulase negative staphylococcus (11.9%), P. vulgaris and E. cloaceae (7.1%), S. pneumoniae and Citrobacter spp. (2.4%), and Serratia spp. and Morgenella spp. (1.2%) (Figure 1). segregated from patients hospitalized in the surgical ward and intensive care unit (SICU) of Ogun State University Teaching Hospital, Sagamus, located in Sagamu, Ogun State, Nigeria, between July 2010 and September 2011. In 7/77 (9.1%) of the nosocomial infection cases, more than one bacterial etiologic agent was detected (data not shown). 23/84 (23.4%) and 61/84 (72.6%) of the microorganisms were Gram-positive and negative, respectively (p<0.05). Table 3 explained the distribution of bacterial isolates from patients admitted to the surgical ward and Surgical Intensive Care Unit (SICU) revealed notable patterns in the sites of nosocomial infection. Among the cases of surgical site infection (n = 44), Pseudomonas aeruginosa (22.7%), Klebsiella species (K. pneumoniae and K. oxytoca) (20.4%), and Staphylococcus aureus (15.9%) were the predominant isolates. Urinary tract infections (UTI) (n = 24) were primarily associated with Escherichia coli (45.8%), E. cloacae (20.8%), and K. pneumoniae (16.6%). In cases of bloodstream infections (BSI) (n = 16), Staphylococcus aureus (37.5%), coagulase-negative staphylococci (37.5%), and Streptococcus pneumoniae (12.4%) were the most frequently identified bacterial pathogens.

Table 3: Sites of nosocomial infection and distribution of bacterial isolates from patients who were admitted in surgical ward and SICU at Ogun State University Teaching Hospital, Sagamus, Sagamu, Ogun state, (July 2010- September 2011).

Antibiotics Usage and Outcome

All of the patients who were part of these investigations had received antibiotics, either therapeutically or prophylactically, and seventy-seven of them had cultures that came back positive. Antimicrobial susceptibility testing

a) Gram-Positive Bacteria

The susceptibility patterns of 26 Gram-positive bacteria against 14 antimicrobial medicines that were isolated from nosocomial illnesses are shown in Table 4. Nearly every microbe isolate had multiple drug resistance or resistance to two or more medications. The majority of isolates showed 100% high-level resistance to penicillin, ampicillin, tetracycline, chloramphenicol, and trimethoprim-sulphamethoxazole, and >80% (high level of resistance) to amoxicillin-clavulanic acid, gentamicin, cloxacillin, methicillin, amoxicillin, and doxycyclin. On the other hand, there was very little (<60%) resistance to ciprofloxacin, norfloxacine, and ceftriaxone.

b) Gram-Negative Bacteria

The sensitivity profiles of thirteen antimicrobial medications against 58 Gram-negative bacteria that were isolated from nosocomial illnesses are presented in Table 5. Each isolate showed a full high level of resistance to amoxicillin, tetracycline, trimethoprim-sulphamethoxazole, and ampicillin, as well as >80% (high degree of resistance) to amoxicillin-clavulanic, chloramphenicol, and doxycyclin. Gentamicin was the only drug to show moderate resistance (60–80%). On the other hand, there was very little (<60%) resistance to ceftriaxone, nalidixic acid, nitrofurantoin, norfloxacine, and ciprofloxacin. Similar to Gram-positive bacteria, nearly all discovered Gram-negative bacteria showed multi-drug resistance.

Table 4: Antimicrobial Susceptibility Patterns of Gram-Positive Bacteria Isolated fromNosocomial Infections from patients who were admitted to the surgical ward and SICU atOgun State University Teaching Hospital, Sagamus, Sagamu, Ogun state (July 2010 – September2011)ANTIMICROBIAL AGENTS.

Note: *S= Sensitive *I=Intermediate *R=Resistant ** Expressed in percent. AMP: Ampicillin; AMC: Amoxicillin-Clavulanic acid; CAF: Chloramphenicol; CN: Gentamicin;CX: Cloxacillin; MET: Methicillin; P: Penicillin; AML: Amoxicillin; TTC: Tetracycline; SXT: Trimethoprim-sulphamethoxazole; CRO: Ceftriaxone; DO: Doxycyclin; NOR: Norfloxacine; CIP: Ciprofloxacin.

Table 5: Antimicrobial Susceptibility Patterns of Gram-Negative Bacteria Isolated from Nosocomial Infections from patients who were admitted to the surgical ward and SICU at Sagamu University Hospitals, Sagamu, Ogun state. (July 2010- September2011).

Note: *S= Sensitive *I=Intermediate *R=Resistant ** Expressed in percent.

Discussion

The incidence of nosocomial infections was examined using data from 854 patients who were hospitalized at Ogun State University Teaching Hospital, Sagamu in Ogun State’s surgical ward and intensive care unit between July 2010 and September of next year. Upon admission, a thorough clinical examination was conducted to rule out infections acquired in the community and identify any potential risk factors. Hospitalized individuals are experiencing an increasing number of nosocomial infections (NIs) [22]. Major causes of mortality and disability exist in every country. The World Health Organization has estimated that up to 15% of hospitalized patients have illnesses related to medical treatment [23]. Furthermore, the problem of antimicrobial-resistant bacteria spreading and proliferating in hospitals around the globe persists, especially concerning those microorganisms that cause nosocomial infections in intensive care unit patients [11]. The total nosocomial infection prevalence at Sagamu University institution (9.0%) is lower in this study than it was in the earlier studies conducted in the same institution (16.4%) [24], 17% [25]; and 13% in Kenyan teaching hospitals [26].

Nosocomial infection rates in this hospital have slightly decreased, which could be attributed to following established protocols for decontaminating and cleaning soiled objects and other items, sterilizing and using high-level disinfection techniques, and enhancing safety in operating rooms and other high-risk areas where the majority of serious injuries and infectious agent exposures take place. The layout of the facility and the abundance of medical staff may also be contributing factors to the lower infection rate. However, in contrast to the current study, the prior report included every hospital department. Another explanation might be that a novel approach for selected situations from the emergence was implemented within two days of its emergence during the research period. The brief exposure time before to surgery might be a factor in the surgical wards’ low nosocomial infection prevalence rate.

In addition, the present investigation revealed a lower incidence of nosocomial infection than those reported in other nations, such as Tunisia (13%) [27], Kosovo (17.4%) [28], and Morocco (17.8%) [29]. This reduced prevalence might have resulted from the sample analysis method’s reliance on bacteriological agents. Since anaerobic bacteria can also cause nosocomial infections, they are excluded from this list. Even though viral and fungal agents have the potential to cause nosocomial infections, they were not evaluated in this investigation since technology and laboratory facilities were not available. However, the majority of the studies conducted in the aforementioned nations also included anaerobic bacteria, fungi, and viruses. Surgical site infections were shown to be the most common nosocomial infection in this investigation. Since every patient has to have surgery, there is a higher chance that they may become infected in the hospital due to germs directly entering their bodies and finding a way into normally sterile areas of their bodies. Healthcare personnel or infected surgical equipment are the two possible sources of this illness. Additionally, extended hospital stays and inadequate wound care increased the risk of surgical wound infections.

Owing to the aforementioned cause, surgical wounds are the most common sites of nosocomial infections. The second infection location in the current investigation was a urinary tract infection. Since catheterization raised the risk of infection, all of the patients with nosocomial UTIs had urinary catheters. Bacteria may exist in or near the urethra, but they are often unable to reach the bladder. An infection can result from microorganisms that a catheter brings into the bladder from the urethra. Compared to other surgical wards, the SICU had a higher prevalence of BSI infections (4.3 times higher) than any other infection location. This is due to the severely sick nature of the SICU patients, as well as the increased risk of colonized bacteria entering the lungs in patients who are unable to cough or gag. Certain breathing techniques can prevent patients from coughing or gaging. Coughing and gag reflexes may also be absent in patients who are drugged or who lose consciousness.

As a result, the microbe that was inhaled develops in the lungs and starts an infection that may spread to the bloodstream.

Furthermore, several interventions that were risk factors for BSI were routinely carried out in this ward, including the use of invasive devices, mechanical ventilation, suction of material from the throat and mouth, the use of medications, and the impact of surgery. It should come as no surprise that the frequent treatments performed in hospitals—mechanical ventilation, urine catheterization, surgery, and central venous line insertion—are the ones that cause nosocomial infections. The surgical wards are where such invasive operations are frequently performed, and these wards are turning into reservoirs for germs that are resistant to many drugs. According to tab IV of the current study, there is a strong correlation between these therapies and nosocomial infections. Additionally, they have the potential to spread infectious pathogens to the locations of equipment. This may be more conducive to bacterial colonization, which can develop into serious illnesses if ignored. Efforts aimed at reducing nosocomial infection should be focused in this direction since these factors are modifiable. These are in line with other studies in Turkey [30,31], Kuwait [13], India [32] and Latvia [32].

Interventions such as suprapubic catheters should be used in specific cases, closed drainage systems should be used when feasible, and urinary catheters should only be used when necessary and should be cleaned daily. It’s important to remember that hand washing; a straightforward yet effective technique lowers the transmission of nosocomial infections. Gram-negative bacteria accounted for 72.6 percent of all isolated bacteria, whereas Gram-positive bacteria made up just 23.4%.Data presented in this study indicates that the most frequent bacterial isolates from surgical site infections were, Pseudomonas. aeruginosa(22%), Klebsiellaspp. (20%) and Staphylococcus aureus (15%). Similar findings have been seen in Philippines [33] and Turkey [34]. Among urinary tract nosocomial infections E. coli is the most frequent bactreial isolate.

The most common bacteria in bloodstream nosocomial infections were staphylococcus aureus (37.5%) and coagulase-negative staphylococcus (37.5%). Many microorganisms nowadays are resistant to many antimicrobial agents, and under some situations, almost all of them. Healthcare facilities face the challenge of resistance to antimicrobial drugs; yet, hospitals are particularly vulnerable to the spread of microorganisms because of their high susceptibility population [17]. Our study’s results on antibiotic sensitivity validated the concerning proportion of bacterial resistance to widely used antibiotics.

Both Gram-positive and Gram-negative bacterial isolates in this investigation showed high levels of resistance to Tetracycline, Trimethoprim-sulphamethoxazole, Ampicillin, Amoxicillin-Clavulanic acid, Chloramphenicol, and Doxycyclin. However, only Gram-positive bacteria exhibited a gentamicin resistance, whereas Gram-negative bacteria only displayed an intermediate level of resistance. Additionally, the findings showed that the resistance rates of Gram-positive and Gram-negative bacteria separated from nosocomial infections to ciprofloxacin, norfloxacine, and ceftriaxone were low (<60%) Low levels of resistance to nalidixic acid and nitrofurantoin were demonstrated by gram-negative bacteria. The range of resistance rates for Gram-positive and Gram-negative bacteria is 50% to 100% and 33% to 100%, respectively. The antibiotics ciprofloxacin, ceftriaxone, nalidixic acid, nitrofurantoin, and norfloxacine were comparatively successful in treating the microorganisms that cause nosocomial infections. This might be the case given that these agents are very new and not widely utilized. However, because of their high cost, medications such as nitrofurantoin, norfloxacine, and nalidixic acid have limited practical usage. They showed little resistance as a result. This study suggests that when it comes to treating nosocomial infections, the practitioner has rather limited options.

Compared to bacterial isolates that were Gram-positive, resistance rates to all antibiotics examined for Gram-negative were generally lower. This is consistent with other research conducted in Thailand (Danchaivijitr, et al. [35]) and Nigeria [36], where the majority of the isolates from non-infectious infections were resistant to widely used antibiotics. The current investigation did, however, reveal a substantial rate of resistance to the antimicrobial drugs that are often administered. This might be the result of the widespread use of antibiotics for self-medication that is accessible over the counter, the widespread availability and careless use of these medications outside of hospitals, and the heavy usage of antimicrobial agents in hospitals.These issues are recognized to be the cause of circulating resistance strains, together with the higher risk of cross-infection among inpatients.

Limitations of the Study

It is important to note that not all Ogun State University Teaching Hospital, Sagamu wards—such as the medical, intensive care, pediatric, and gynecology and obstetrics wards—in which a high incidence of nosocomial infections is suspected—are included in this study. Anaerobic microorganisms could not be included because of financial and facility limitations in the lab. Fungal infections and other pathogens that are significant nosocomial infection causes were not included in the study’s design. This research did not cover patients who get nosocomial infections after being released from the hospital.

Recommendations

The recommendations listed below can be implemented in light of these findings: All wards at Ogun State University Teaching Hospital, Sagamu should include anaerobic bacteria, fungi, and other microorganisms to determine the prevalence and medication susceptibility pattern of nosocomial diseases. Drug resistance is a result of empirical therapy for nosocomial infections; as a result, the basis of treatment should be the culture and sensitivity results. To do this, the microbiological lab’s capacity has to be increased with qualified personnel, funding, and the required lab supplies. To serve as the foundation for an alternate course of therapy, constant surveillance for resistant bacteria is required. The hospital should be the center of attention for nosocomial infection control, using distinct personnel, resources, and funding. According to this study, Ampicillin, Amoxicillin-Clavulanic acid, Amoxicillin, Methicillin, Tetracycline, Trimethoprim-sulphamethoxazole, Doxycyclin, Chloramphenicol, and Penicillin are somewhat inefficient in treating nosocomial infections if one could not wait for the culture findings.

Conclusion

Compared to the same hospital’s prior research, Ogun State University Teaching Hospital, Sagamu had a lower prevalence of nosocomial infections. Gram-negative bacteria accounted for 75% of isolates in SSIs and 95.6 % of UTIs, respectively, whereas Gram-positive bacteria (87.3%) made up the majority of organisms in BSIs. For Gram-positive bacteria, Ceftriaxone and Ciprofloxacin were found to be reasonably effective medications; for Gram-negative bacteria, Norfloxacine, Ceftriaxone, and Nitrofurantoin were reasonably effective medications. However, all of the Gram-positive bacteria isolated from nosocomial infections were resistant to trimethoprim-sulphamethoxazole, ampicillin, tetracycline, and chloramphenicol. Furthermore, all isolates of Gram-negative bacteria were completely resistant to trimethoprim-sulphamethoxazole, tetracycline, and amoxicillin.

Declaration

Ethics Approval and Consent to Participate

This study was conducted in accordance with the ethical standards obtained from Ogun State University Teaching Hospital, Sagamu and duly signed informed consent was obtained from all participants.

Consent for Publication

Not applicable.

Availability of Data and Material

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing Interests

The authors declare that they have no competing interests.

Funding

This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ Contributions

Not applicable.

Acknowledgements

I would like to express my sincere gratitude to my Scientific Adviser, Dr Florin D Petrariu from the Department of Hygiene – Environmental Health, Faculty of Medicine, Universitatea de MedicinășiFarmacie “Grigore T. Popa” Iași for providing supervision and constructive advice during the course of this project in 2012. I am grateful to the Staffs and Clinicians of Ogun State University Teaching Hospital Sagamu, for their support in identifying the target patients, sample collections and in facilitating good working environment.

Author’s Information

Dr Adewale Lawrence, Founder/CEO Bioluminux Clinical Research Bioluminux Clinical Research, 720 Brom Drive, Suite # 205, Naperville, Illinois, United States Doctor of Medicine degree with Masters in Regulatory Affairs for Drug, Biologics and Medical Devices. A principal Investigator and therapy area lead for clinical trial studies at Bioluminux Clinical Research Network. Research work was completed in 2012, submitted in partial fulfillment of the requirements for the degree of Doctor of Medicine (MD) at the Faculty of Medicine, Universitatea de MedicinășiFarmacie “Grigore T. Popa” Iași, Romania.

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About Indicators of Nutritional Disbalance of Phytoplankton (e.g. Si/N, P/N, Fishery)

Introduction

Sixty-five percent of the estuaries and coastal waters in the contiguous U.S. that have been studied by researchers are moderately to severely degraded by excessive nutrient inputs (eutrophication). Excessive nutrients – especially nitrogen (N) and phosphorus (P) – lead to algal blooms and low-oxygen (hypoxic) waters that can kill fish and seagrass and reduce essential fish habitats [1,2].

On the other side, in Egypt: “Prior to construction of the Aswan High Dam (1964), the annual Nile flood delivered about 9 000 t of biologically available phosphorus (P), at least 7 000 t of inorganic nitrogen (N), and 110 000 t of silica (Si) to the Mediterranean coastal waters of Egypt. These nutrients stimulated a dramatic “Nile bloom” of diatoms which supported a productive fishery. After closure of the dam in 1965, flow from the Nile was reduced by over 90%, and the fishery collapsed. It remained unproductive for about 15 years. The fishery began a dramatic recovery during the 1980s, coincident with increasing agricultural and urban discharges [3].

Explanations and Discussion

Explanations via Phytoplankton: Phytoplankton communities can be divided into 2 basic categories: those dominated by diatoms and those dominated by flagellates or non-diatomaceous forms. Growth of diatoms depends on the presence of silica while growth of the non-diatomaceous forms normally does not [4]. Flagellate communities are often associated with undesirable effects of eutrophication while diatoms are not [4], i.e. the N: Si ratio influences the composition of phytoplankton. Diatoms are a large group of algae, specifically microalgae, found in the oceans, waterways and soils. They are the most common type of the plankton [5]. Living diatoms make up a significant portion of the Earth’s biomass: they generate about 20 to 50 percent of the oxygen produced on the planet each year, [6,7]. Diatoms are especially important in oceans, where they contribute an estimated 45% of the total oceanic primary production of organic material (food/feed) [5] and participate with silica (SiO2) and carbon cycle in carbon binding [5]. There are different evaluations on balanced nutrient levels in water. For Si:N:P ratios are given an estimate (16:16:1) [8]. An other evaluation is based on the growth limiting levels of dissolved silica [Si(OH)4, DSi, “dissolved Si” or “Si”]. Egge and Aksnes determined in 1992 experimentally that diatom percentage of total cell count was over 60 %, generally over 80 %, irrespective of the season, (independent of seasonal variation of other elements?) if DSi concentration exceeded a threshold of ~ 2 μM Si [9] resp 2 x 28 = 56 μg Si/l [10].

Historically in the Baltic Proper, the estimated DSi concentrations were at the begin of the last century (ca. 1900) 2.6 times higher than at present [11]. There are several explanations for it [8]. Possibly changes in fertilization associated with reduced weathering [12], reduced production of DSi in agricultural soils and obviously reduced DSi content in run-off waters, groundwaters and watersheds.

Recovery of fishery of the Nile in the 1980’s was associated with increased high NP supply cum Si dominance in the Nile: Si (2700 μg/l, 96 μM), N (29 μg/l; 2.1 μM) and P (23 μg/l /0.74 μM), i.e. with Si:N:P atomic ratios 130:2.8:1 and (consequently) diatom dominance [13] of Upper Egypt” [which consists of the entire Nile River valley from Cairo south to Lake Nasser (formed by the Aswan High Dam)] [14]. Delay in recovery of fishery in Egypt after 1964 can be explained by the time needed to replace the historical discharges of fields and forests (the sediment transported by the Nile) by agricultural and urban discharges (e.g. N and P) [3] and to rejuvenate the large irrigated areas for the production of DSi [4] and other nutrients [12] promoted by soil microbes [15-18]. Between 1980 and 2000, the total lagoonal fishery of Nile delta tripled, but at Alexandria decreased obviously depending on increase of N above 100 μM/l. [19] (as a consequence of overconsumption of DSi? [4,9]).

Fish catch reduction at Nile delta opposite the Nile between 1965- 80 was very limited [3,19]. Harmful effects of eutrophication (red tides) have been experienced in Japan, but its treatments (seawater “improvement”) by reducing phosphorus lowered the phytoplankton (especially diatom) primary production, which caused a detrimental effect on the fishery production in the Seto Inland Sea [20].

There is a great variation inside diatoms. Some Pseudo-nitzschia species of diatom genus can be harmful, especially in iron deficiency, they are capable to produce toxic domoic acid [21].

Erosion can be defined as the geological process in which earthen materials are worn (e.g. weathered) away and transported by natural forces such as wind or water [22]. Enhanced erosion (mechanical crushing of stones and transportation by machines) has been tentatively successfully benefited in agriculture for carbon binding and increasing crop yields [23] and conceivably for DSi production. Possibly DSi (and other nutrient) production can be promoted by breeding microbes [15-18] for weathering of (analyzed) silicate wastes and silicates of cropland, too.

Conclusion

Besides of nutritional excess, nutritional deficiencies can produce harmful consequences in fishery, e.g. by insufficient amounts of dissolved Si (< 2 mM), low P/N ratio and by low Fe content. Experimental studies are suggested in order to find optimal nutrition for phytoplankton of watersheds (including oceans) and to secure their food production and CO₂ binding.

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The Effect of Various Exercise Programs on the Physical Function of Older Adults with Sarcopenic Obesity: A Systematic Review

Introduction

Sarcopenia, derived from the Greek sarx (flesh) and penia (loss), was introduced by Rosenberg, [1] to describe the loss of skeletal muscle mass (Rosenberg, [1]). A related disorder is sarcopenic obesity. The coexistence of diminished muscle mass/strength/physical function with increased fat mass is referred to as sarcopenic obesity (Baumgartner, [2]). Aging increases the risk of unfavorable changes in body composition, including a decrease in muscle and an increase in fat mass. With age, intramuscular and visceral fat increases while subcutaneous fat declines, thus leading to poor muscle quality (Baumgartner, [2]). So, as the population ages, the prevalence of sarcopenic obesity increases, along with rising rates of both obesity and sarcopenia. This trend is particularly notable among adults aged 65 years or older (Batsis & Villareal, [3]). Although sarcopenic obesity is more common among older people, it is being diagnosed more and more often in people across the entire age spectrum. Muscle mass and strength begin to decline gradually around the age of 30, accelerating after the age of 60 (Stenholm, et al. [4]). This decline is believed to be associated with factors such as, insulin resistance, reduce levels of growth hormones and testosterone, inflammation, oxidation, fat infiltration (Nascimento, et al. [5]).

Compounding the effects of both sarcopenia and obesity, sarcopenic obesity has negative consequences on individuals, which can lead to metabolic problems, cardiovascular disease, physical disability, poor quality of life, institutionalization, morbidity and mortality (Stenholm, et al. [4]). These changes have been shown to be associated with negative health outcomes in the elderly and have significant implications for health care cost (Stenholm, et al . [6]). Sarcopenic-obesity management requires a multifactorial approach that includes lifestyle interventions such as physical exercise, nutrition or diet-induced weight loss (Newman, et al. [7]). Exercise can affect hormonal balance, reduce oxidative stress, induce mitochondrial synthesis, alter immunological and motor function and improve muscle oxidative capacity (Joseph, et al. [8]). Increased muscle protein synthesis with exercise sensitizes muscle insulin action and promotes anabolism (Carraro, et al. [9]). Sarcopenia is their associated with reduced muscle protein synthesis. Aerobic exercise, resistance training, and combination, increase muscle protein synthesis in older adults despite age-related decreases in anabolic signaling (Cuthbertson, et al. [10]).

Physical activity in general has been broadly recommended to minimize functional decline in the elderly and it may also be a key factor in the prevention of sarcopenia and obesity (American College of Sports Medicine, et al. [11]). Studies have shown that various exercise programs, either alone or in combination with nutritional supplementations, are effective to promote positive changes in body composition among older people (American College of Sports Medicine, et al. [11]). Body weight-based and elastic band resistance training is an alternative training method for sarcopenia to minimize the age-related adverse effects on muscle function and quality (Seo, et al. [12]). This systematic review aims to investigate randomized controlled studies to figure out the effects of various types of physical training (exercises programs) on sarcopenia in older people with sarcopenic obesity.

Methodology

Development of Search Strategy

A comprehensive research strategy was developed using appropriate keywords along with database-specific indexing terms related to “sarcopenia, obesity, exercise, elderly, muscle strength, muscle mass, muscle activity. Boolean operators “AND” and “OR” were used to generate a variety of combinations of the above-mentioned keywords. The final search expression used was (((((((elderly OR older adults OR aged) AND (sarcopenia) AND (exercise OR exercise programs OR muscle activity OR muscle strength OR muscle mass) AND (randomized controlled trial)).

Inclusion and Exclusion Criteria

The search strategy and study selection process followed the guidelines of PICOSD (participants, interventions, comparisons, outcomes, and study design) to establish the inclusion and exclusion criteria.

Inclusion Criteria

The participants consisted of community-dwelling elderly individuals diagnosed with sarcopenia. The interventions involved a range of exercises and training programs incorporating physical activity. Comparisons were made with usual care or control groups. The outcome measures focused exclusively on variables (muscle activity, muscle strength, and lower extremity strength). The study design specifically targeted randomized controlled trials (RCTs) sourced from the database.

Exclusion Criteria

The exclusion criteria for this review included studies not written in English and studies not published within the last 10 years were excluded (studies published before 2014. In addition, when considering the qualitative factors of study design and the trends of intervention studies were excluded according the PICOSD.

Database Selection and Search

The search was executed across electronic databases including the National Library of Medicine (PubMed), PEDro and Google Schoolar (first 100 results) databases. Following the PRISMA flow diagram, an initial screening was conducted based on the titles and abstracts of the identified papers based on the inclusion and exclusion criteria. Full-text articles were retrieved for highly relevant studies by assessing their suitability for inclusion.

Data Extraction

This article is based on a literature review. Data were extracted from international data baseses (PubMed, PEDro) during the period from 2014 to 2024.

Report Writing Developed

The systematic review manuscript based on PRISMA (Preferred Reported Items for Systematic Reviews and Meta-Analysis, (Figure 1) guidelines and it’s organized under clear sections including Introduction, Methodology, Results, Discussion, and Conclusion.

Figure 1

Results

A total of 654 studies were found in the initial search, from which 70 duplications were removed, and 200 records were removed for other reasons. 8 articles were considered eligible for the systematic review after applying the exclusion and inclusion criteria mentioned above. All of them were, randomized clinical trials. Although the number is small, this fact only highlights the importance of more research about sarcopenic obesity, specifically on the topic about exercise program for older adults, which is the central theme of this systematic review. All articles used in this systematic review are included in Table 1. This systematic review explores various exercises modalities including strength training and aerobic exercises among older adults. The review provides insights into the effectiveness of various exercise strategies in managing the challenges associated with sarcopenic obesity in older adults.

Table 1: Studies included for results.

Note: DRT = Dynamic resistance exercise; ERT = elastic band resistance training; TSM = total skeletal mass WB-EMS = whole-body electromyostimulation; RPE = Rating of perceived exertion; DRT = Dynamic resistance exercise. RM = repetition maximum; OMNI = resistance exercise scale of perceived exertion with Thera-band resistance bands; SMI = skeletal muscle mass index (whole body skeletal muscle mass/weight, %)

Discussion

The objective of full-text screening of the selected studies was to investigate the randomized controlled studies to figure out the effects of different types of physical training (exercises programs) on sarcopenia in older people with sarcopenic obesity. The main findings suggested that the most marked benefit is achieved with high-intensity strength exercises programs. In four studies, researchers found that various types of training, including resistance training, aerobic training, and body weight-based exercises, improved functional fitness and muscle quality in elderly individuals with sarcopenia (Kemmler, et al. [13-17]). The study results are shown in Table 1. Kemmler et al. [17] used whole-body electromyostimulation and found its significant impact on muscle mass along with moderate effects on functional parameters. They used a different intervention compared to the other studies included in the literature review, which is likely one of the reasons they achieved better results. Kim et al. [17] implemented a training program similar to Chen et al. [14], but with longer duration (3 months) and inclusion of food supplements. It is surprising that participants in the study by Chen achieved better results than those in the study by Kim et al. [17] considering that Kim et al. [17] concluded that improvements in physical functions were not observed.

Further large-scale and long-term investigations are necessary. A separate consideration should be made regarding the frequency and duration of the proposed training sessions, as they will undoubtedly impact the changes generated by the exercise, particularly in the elderly. In this regard, the conclusions of the study by Kemmler et al. [16] which demonstrated benefits when the training frequency was higher than 2 weekly sessions are interesting. Chen et al. [14] designed a training program that included resistance training, aerobic training, and a combination of both. Conversely, Seo et al. [12] developed a bodyweight-based and elastic resistance training program without incorporating aerobic training and they rejected the hypothesis that 16 weeks of resistance training affected muscle growth factors in sarcopenic older women. Similarly Vasconcelos, et al. [18] designed the progressive resistance exercise program without aerobic exercises, which was found to be ineffective. Balachandran, et al. [19] also did not find any effects of two 15-week resistance exercise programs on the body composition of older women with sarcopenic obesity. Most studies used multimodal programs, including aerobic, resistance, and balance exercises.

Therefore, the isolated effects of resistance exercise on older people with sarcopenic obesity remain unclear. Balachandran, et al. [19] suggest further research to determine whether the adaptation period would be sufficient for protocols using different loading patterns, training durations, or population samples. Additionally, studies of longer duration with careful regulation or assessment of caloric intake are needed. More studies should be conducted to examine the effects of various additional exercise training methods and to categorize the results according to gender, age groups, and gender-specific age groups. This is necessary to understand how exercise training impacts muscle strength and physical performance in older individuals with sarcopenia Bao, et al. [20]. Sarcopenic obesity in older adults after the age of 65 years is significant public health concern. Therefore, it is important to develop and conduct new evidence-based interventions targeting sarcopenic obesity. Resistance training with body weight-based training and elastic bands can be an alternative and practical method for sarcopenia prevention, minimizing the age-related adverse effects on muscle function and quality (Bao, et al. [20]).

While aerobic exercises like walking are commonly prescribed, they do not yield significant benefits for elderly patients with sarcopenic obesity. Current evidence highlights the efficacy of strength-resistance training and its integration into multimodal programs alongside aerobic and balance exercises, significantly improving anthropometric and muscle function parameters (Vasconcelos, et al. [18]). Limitations of the included articles in the review are the

(1) Small sample sizes,

(2) Variations in diagnostic criteria,

(3) And the use of different instruments to diagnose sarcopenia, leading to high heterogeneity among the studies.

Additionally, the majority of studies focused on female participants, leaving the question of whether gender differences impact training effects unanswered.

Conclusion

Based on the studies included in review, exercise has significant benefits in elderly patients with sarcopenic obesity. Current evidence shows that training based on strength-resistance and its combination in multimodal programs with have significantly beneficial effects on and muscle function parameters. Resistance training using body weight-based training and elastic bands can be an alternative and practical method for sarcopenic obesity prevention, minimizing the age-related adverse effects on muscle function and quality.

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Recent Trends in the Treatment of Adult Obstructive Sleep Apnea-A Comprehensive Review

Introduction

Obstructive Sleep Apnoea (OSA) is one of the wide spectrums in Sleep related breathing disorder. In OSA, the patient has multiple episodes of breathing cessation or decrease in oxygen saturation during his hours of sleep. There is an increase in respiratory effort during these episodes which indicates that the cause is predominantly obstructive [1]. Cessation of breathing for at least 10 seconds is defined as apnea whereas hypopnea is decrease in airflow with resultant desaturation of >3% [2]. The episodes of apnea and hypopnea in OSA is quantified using Apnea-Hypopnea Index (AHI) which is the average number of apnea and hypopnea events per hour of sleep.

AHI >= 15; or >=5 with at least one of the following symptoms or clinical signs:

1. Excessive daytime sleepiness (EDS), non-restorative sleep, fatigue or insomnia.

2. Waking up with choking, breath holding or gasping.

3. Witnessed habitual snoring and/or breathing interruptions; and

4. Hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation or type 2 diabetes mellitus; gives a diagnosis of Obstructive Sleep Apnea Syndrome (OSAS). (2) OSA is a vast topic in terms of pathophysiology, diagnosis and treatment.

In this review article, we will only be covering the various modalities of treatment of Adult Obstructive Sleep Apnea. The aim of treatment of patients with Obstructive Sleep Apnea should be to alleviate symptoms, improve quality of life and to decrease the chances of developing co morbidities like hypertension, insulin resistance and cardiac conditions, which eventually decreases mortality [3]. The treatment should be guided on the basis of severity classification of OSA by polysomnography into mild, moderate or severe. In mild to moderate cases, symptoms determine treatment. Initially, non-medical measures should be adopted. These include:

Lifestyle Modification

Weight loss has a significant effect in reduction of AHI in patients with mild to moderate OSA. This involves calorie restriction, regular exercises and adoption of a healthy lifestyle [4]. Bariatric surgery significantly induces resolution and improvement but is not the first choice of treatment due to the associated complications, especially in people with comorbid conditions [5]. Additionally, patients are advised to adopt optimal dietary choices, exercise regularly, avoid consumption of caffeine, smoking and drinking as these are seen to have an effect in the quality of sleep of the patient [6]. Sleep posture: Sleeping in a supine position is seen to double the AHI than sleeping in a lateral position in patients with positional sleep apnea syndrome. Hence, patients are advised to avoid sleeping in a supine position and adopt maneuvers like ‘tennis-ball position’ to facilitate sleeping on the lateral position [7]. Nasal and oral appliances: Oral appliances like mandibular advancement devices widen the upper airway during sleep. In a recent systematic review published in 2019 which analyzed 15 studies, mandibular advancement devices were known to reduce symptoms and improve the AHI in 92% of the included subjects [8]. Nasal appliances like nasal splint can improve symptoms in patients with nasal valve collapse. Recently, a social media trend went viral in which people were seen to adopt mouth taping at night and they reported significant decrease in snoring at night, but these methods are not validated and need more detailed research [9].

Continuous Positive Airway Pressure (CPAP)

CPAP is considered the gold standard treatment for OSA. As OSA involves pharyngeal musculature relaxation and collapse during sleep, CPAP provides a positive airway pressure which facilitates the oxygen delivery to the lungs. It is more likely to improve patients with moderate to severe OSA than those with mild symptoms. In 2015, a guideline was published by the American Academy of Sleep Medicine for positive airway pressure, which strongly recommends the use of positive airway pressure in OSA patients with excessive daytime sleepiness, reduced sleep related quality of life and in those with comorbid hypertension [2,10]. Furthermore, if the patient does not have any significant comorbidities, positive airway pressure therapy can be initiated using either APAP (auto-adjusting positive airway pressure) at home or in-laboratory PAP titration. APAP has the benefits of automatically adjusting pressure requirements over time like in cases of alcohol consumption, changes in body position or changes in weight. In lab titration includes both full night and split night titration. Initially, APAP or CPAP is to be used instead of BPAP (bilevel positive airway pressure). BPAP may be used in patients with higher therapeutic pressure requirements or in patients with failed CPAP or APAP [10].

The main issue in the use of positive airway modalities in patients with OSA is compliance. In order to mitigate this adverse effect, education about PAP therapy and information on what to expect should be given before initiation of therapy. Behavioral changes that need to be adapted before and during PAP therapy along with troubleshooting interventions that focus on PAP related problems need to be addressed, especially in the early phase of treatment. Telemonitoring guided interventions which include remote monitoring of PAP parameters and settings during initiation of treatment and follow up should be carried out for better compliance [10]. For other issues of CPAP therapy like dryness, air leak and discomfort around nose and mouth area; measures like humidified PAP and appropriate selection of masks can be adopted respectively. Some patients develop central sleep apnea when they are treated for Obstructive Sleep Apnea with a CPAP device. This is termed as the Complex Sleep Apnea Syndrome [1]. These patients require a new type of CPAP device known as adaptive servo-ventilator [11].

Medical Management

Various drugs like modafinil and armodafinil have been used to treat residual sleepiness despite continuous positive airway pressure in obstructive sleep apnea (res-OSA). These drugs are seen to promote wakefulness. In a systematic review published in 2016, these drugs were seen to improve subjective and objective daytime sleepiness in res-OSA [12]. However, in 2011, the European Medicines Agency removed the indication of res-OSA based on an unfavorable risk-benefit profile. Other drugs that have been seen to reduce OSA severity by reducing excessive daytime sleepiness are amphetamine and pitolisant [13]. In addition, atomoxetine, which is a norepinephrine reuptake inhibitor and oxybutynin, which is an antimuscarinic agent were seen to improve genioglossus muscle activity and improve airway patency during sleep when used in combination [14].

Surgical Treatment Options

According to the level of obstruction causing sleep apnea, various surgical modalities can be adopted. These are summarized in the Table 1.

Table 1:

Among these, some commonly performed surgical procedures are discussed below:

Nasal Surgeries

If the level of obstruction is seen to be the nose or nasal cavity as per clinical or endoscopic assessment, nasal surgeries can be considered to correct the cause. Septoplasty, turbinate reduction, nasal valve repair can be done to correct structural abnormalities which will help in improving nasal patency.

Uvulopalatopharyngoplasty (UPPP)

Uvulopalatopharyngoplasty was initially described by Fujita et al in 1981 which involves surgical excision of uvula and tonsils, and lateral pharyngoplasty (trimming and reorientation of the posterior and anterior tonsillar pillars) [15]. It acts by widening the airway but is associated with complications like postoperative pain, nasal reflux, pharyngeal stenosis, dysphonia, and velopharyngeal insufficiency [16].

Other Palatoplasty Procedures

Although UPPP has been shown to improve outcomes in patients with OSA, the failure rates range from 30 to 90% [17]. For this reason, surgeons have sought new techniques for modification of palatoplasty procedures to increase the effectiveness. One of these modifications is anterior palatoplasty which involves excision of a horizontal rectangular strip of mucosa and submucosa of approximately 4*1 cm from the soft palate at 1 cm above the attachment of the uvula to the upper palatal pillar. This stripped area is then sutured with Vicryl sutures, which pulls the soft palate anteriorly and superiorly [18]. This technique prevented the possible narrowing of the lateral distance between the tonsillar pillars, and it required no muscle reconstruction. In 2017, a systematic review was published which showed anterior palatoplasty to be a moderately effective surgical procedure for the treatment of OSA [19]. For patients with previous tonsillectomy, a new modification was developed, termed Z-palatoplasty. This procedure helped by widening the anteroposterior and lateral oropharyngeal air spaces at the level of the palate [20]. Lateral pharyngoplasty procedure involves bilateral tonsillectomy and microdissection of the superior pharyngeal constrictor muscle within the tonsillar fossa, sectioning of this muscle, and suturing of the created laterally based flap of that muscle to the same side palatoglossus muscle. In addition to this, a palatopharyngeal Z-plasty is performed to prevent retropalatal collapse [21].

Palatal Implants

This is an office-based procedure which involves insertion of polyethylene terephthalate in the soft palate. Implants work by stiffening the palate which in turn decreases palatal flutter. The inflammatory reaction in response to the implant leads to the formation of fibrous capsule which further increases the structural support and prevents collapse of the airway. The complications of this procedure include extrusion, prolonged pain, perforation or necrosis of the nasal floor, palatal mucosal necrosis, and altered sensation of the palate [22]. A similar procedure is palatal cautery which also causes scarring and subsequent stiffening. Injection snoreplasty procedure uses sodium tetradecyl sulphate in the formulation of 1% or 3% and around 2 ml of the solution is injected into the soft palate. (snoreplasty) [23]. The mechanism of action is similar to that of palatal implants and palatal cautery. If used in well selected patients, these modalities can become a relevant part of the treatment.

Genioglossus Advancement

Genioglossus advancement and hyoid suspension is done in patients in whom the level of obstruction is the hypopharynx. When the genial tubercle is advanced, it places the tongue under tension, thus preventing airway collapse [24].

Hypoglossal Nerve Stimulator

Hypoglossal nerve supplies genioglossus which acts in tongue protrusion. Hypoglossal nerve stimulation involves implantation of a neurostimulator device which provides either continuous or intermittent electrical stimulation (according to the device used) which in turn, protrudes the tongue and increases the airway patency [25].

New Advances

In recent days, smartphone technologies have been developed offering diagnosis and management for patients with OSA. Wearable sleep trackers linked to the smartphone provide additional home-based options for monitoring and follow up. However, these technologies require a learning curve and review of reliability, quality and validity. A systematic review conducted in 2022 evaluated 10 smartphone apps. However, at present, they were not seen to be as accurate as the available traditional options. Nevertheless, with improving technology, these definitely have a great future ahead [26].

Conclusion

In the last decade, increasing attention has been given to developing newer treatment modalities for OSA and recording their outcome. The newer devices have seemed to be more effective in comparison to the traditional treatment modalities. However, patient selection should be carefully carried out for maximum effectiveness. Furthermore, large RCTs and systematic reviews are needed to gain a new path for treatment of OSA in the upcoming years.

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Cinema, an Art of Information, Mobilization and Education for the Culture of Peace and Development

Context and Issues

Each community is a social determinant which corresponds to a cultural entity. The community therefore constitutes the social base in administrative, political and socio-cultural management. However, this management is lacking due to the inadequacy of our policies to our culture because an essential relationship that our leaders ignore exists. Except in times of crisis or major socio-political events. It is right that those in power are really interested in these communities except during electoral periods (political campaign) and/or in times of health crisis (Epidemic) and social crisis. This creates resistance, sometimes revolt or violence. However, this interest in communities should be permanent. The means necessary to achieve this is communication. However, the means of communication that exist today (radio, television, social networks.) have almost no credibility in community games due to a certain number of considerations: political management, rumors, lack of confidence for be left behind. Thus, it is conceivable that artistic communication through Cinema can play this role through image and Sound. This is why such a theme “African Cinemas and Culture of Peace. Is well suited to appease because cinema, despite its role of entertainment, is an art of information, mobilization, and education.

Cinema has the character of reality. It is the association of art and technique whose essence is movement. Also, the cinema is coherent and treats the stories in a believable way while hooking the spectators. Develop the story well, when the hero laughs, cries and dies, the spectator lives the life of the hero laughs, cries and dies. As an illustration, some health researchers have used image and sound in order to achieve their objectives. That is to say, making videos (called the Toolbox) with fictional or real stories in order to help researchers and participants in clinical research. These toolboxes, which are a Canada-Guinea initiative (CEFORPAG), have made an impact in the context of ethics and clinical research in health. But also, allow communities victims of the Ebola epidemic in Guinea, Liberia, Sierra Leone and DR Congo to participate in research and raise awareness of the right to be informed about the results of the study. which they participated in. Then, the stigmatization of victims are topics covered. We believe that cinema can participate in the development of the culture of peace to inform, mobilize and educate communities on a socio-cultural, political, legal and above all economic level.

In our African countries, all the potential is in rural communities and these localities are threatened by recurring crises of insecurity (terrorism), food, etc. which we can eradicate through cinematographic creations. So, these community issues will be addressed to raise awareness on the promotion of peace, cohesion and living together. Therefore, communities deserve well-being to be supported and maintained because they are the lungs of national development. Hence the interest in this study of artistic communication through cinema [1]. The intention of this present communication is to contribute to revitalizing African cinema in an increasingly modern communication context. Associations and networks that were set up from this period created numerous opportunities for meetings and the dissemination of the arts of image and sound to improve the living conditions of the populations. Some countries can draw on the long traditional artistic and cultural experience of others. This missed opportunity with history challenges decision-makers and the average citizen. However, from our point of view, cinema constitutes an important vector in community development, particularly in Guinea which has already experimented with popular theater. For several centuries, writing, drawing and painting remained the only means of communicating an idea, information, testimony.

Like archeology and history, they have also remained throughout this time the only supports that bear witness to the historical and cultural heritage of the lives of men, societies and humanity. The advent of audiovisual technology, the history of which dates back to the invention of the phonograph by Thomas EDISON in 1877, revolutionized the means of communication. Cinema, art and industry is a means of exploring man, his environment, his history and his culture. It is, like any other means of communication and expression, due to the grandiose influence that the image has on human beings, one of the most powerful vectors for establishing and consolidating cultural identities. Cinema has proven over time to be one of the means of transmitting information on the lifestyle, ideologies, practices and cultures of the peoples of the world. It is about finding an artistic approach to communication on the development of cinema for peace. This artistic approach will have to mix the cultural traditions of the targeted populations while scrupulously ensuring that artistic innovation in film production does not affect cultural authenticity at a time when the digital revolution is taking over all human activities.

In the digital age, “the processes of globalization and social transformation, alongside the conditions they create for renewed dialogue between communities, […] also pose serious threats of degradation, disappearance and destruction on intangible cultural heritage…”, recognizes the United Nations Educational, Scientific and Cultural Organization (UNESCO) in the text of the convention for the safeguarding of intangible cultural heritage. Certainly, there are today, in different parts of the world, peoples who have developed a real culture of communication, such as in the media, cinema and other essential supports for the transmission of their history, acquisition and sharing of knowledge in their daily experience, and as a mode of artistic expression [2]. This is the case in several African countries, such as Burkina Faso, Tunisia.

Problematic

Cinema is above all a universal cultural heritage whose different practices are effective even in societies that could be considered hostile to the media. Cinema is a means of information, education, mobilization, and entertainment. There are also popular practices within families, communities, and social groups in which cinematographic creation can be interested. Which made this art an excellent means of communication, of transmitting values such as language for example. Later, the development of mass broadcast technologies such as radio, television, records, cinema, computers, and the Internet helped to create new cultural practices beyond traditions, beyond community or national borders. As for Africa, at the dawn of independence, during the 1960s, there appeared a flowering of national ballets, traditional instrumental ensembles, cinematographic creations, modern orchestras, and theater troupes working on the repertoire epics, tales, and other popular songs to create choreographies, dramaturgies, and contemporary concerts. It is in this context that we will try to understand the problem of this theme, its role and impact in supporting the culture of peace in the African countries which interests us in this reflection. Finally, for African Cinema and the culture of peace, let us tell our stories, lives and realities to achieve the objectives, that of the harmonious and sustainable development of an Africa in peace and in the social cohesion of living together [3].

On April 3, 1984, the military took power in Guinea and put an end to the first socialist regime. On the same date, the military who came to power announced their desire to lead Guinea towards economic liberalism. What we can remember from the first regime of independent Guinea (1958-1984) is its centralized character where the welfare state has a monopoly on the economy. It owns the means of production and intervenes in the process of socio-economic development. In this perspective, the State has found its strategy of communication with the productive forces represented by the people. This communication strategy was in fact its powerful radio broadcasting called “the Voice of the Revolution” which, until 1977, was the only medium through which power conveyed its message. Also, popular theater from the base to the top played a leading role in the dissemination of the development policy that the regime had instituted [4]. Thus, community development was supported by broadcasting and the Arts, the means of impact in the hands of the public authorities to pass its policies including that of community development. Indeed, the first regime of independent Guinea had made agriculture and livestock the engine of its economic development; two key activities practiced by a majority illiterate population and for a long time acting solely in accordance with agrarian customs.

With such a population, written forms of development strategies cannot produce impacts [5]. This is why, Henry TOUATI, founding director of the Center des Arts du Récit in Isère (France), affirms that in questions linked to orality, the place of black Africa like that of the Maghreb is particular: “The cultures and civilizations are nourished, built and transmitted through orality.” This assertion which accredits orality as a value of communication in black Africa clearly implies that the first regime, by making popular theater a means of communication, had perceived that the people of Guinea, mostly illiterate, would more easily understand the distilled message. through the theater. Whatever one wants to believe about the first Guinean regime, it nevertheless succeeded in imposing a strategic orientation in terms of agriculture and livestock through the District Agro-Pastoral Farms (FAPA) established in each village of Guinea with modern means [6]. Also, this strategy not only occupied the people in the fields and on the farms but also occupied the armed forces which, alongside their sovereign function, became real production units.

Here and there, theater has significantly contributed to raising awareness among the people of the need to achieve food self-sufficiency, which is the best path to sustainable economic development. On the artistic and cultural level, the first regime left laudatory traces which deserved to be perpetuated. Unfortunately, this was not the case when in 1984 the death of President Ahmed Sékou TOURE sounded the death knell for his regime. However, the Pan-African Cinema Festival of Ouagadougou (FESPACO) was inspired by the Guinean example during the major festivals that the country organized from 1968 to 1984 and which mobilized the whole world in Conakry. The intention to revitalize the ancient theater of Guinea in an increasingly modern communication context comes from an observation that we made by paraphrasing Henri Touati, who maintains that all Western countries have gradually followed the same path [7]. (oral resources). Associations and networks which were set up, from this period, created numerous opportunities for meetings and the dissemination of the arts of speech and for improving the living conditions of communities, almost everywhere in Europe and in North America.

This evidence is not exclusive, moreover; Guinea can use it in the name of its long artistic and cultural tradition. This missed opportunity with history challenges decision-makers and the average citizen. This is why the advent of the second republic (1984-2008) had the merit of initiating the Community Development policy by establishing a Ministry responsible for Decentralization. The essential mission of this ministry should be to leave grassroots development in the hands of only the potential beneficiaries who are at the same time the thought leaders. The State only provided technical support, assistance and expertise if the beneficiaries expressed the need; of course, everything is molded into the general policy envisaged by the government. To be precise, the general policy on community development has not supported the roles and possible impacts of communication in terms of community development. However, from our point of view, communication constitutes an important vector in community development, particularly in Guinea, which has already experimented with popular theater, which we will revisit to measure the strengths and weaknesses and then make projections for improvement.

Role and Impacts

By looking more closely at the roles and impacts of communication in the community development of our country, it will be difficult to determine its roles in terms of operational strategy which affects the peasant layers who are the main actors in local development [8]. The fashionable, superficial strategies are limited to Audiovisual and Radio reports whose messages only concern intellectuals. Most often, the aspects of impact that National Television and Radio relay on decentralized activities are in principle local development achievements which are indicators by which development partners measure the effectiveness of the commitments made. Should we then reorient existing approaches or find new ones? Indeed, the dizzying growth of the culture and ICT industries, characterized by innovation and market conquest, and underpinned by economic logic, will then lead to what the ethnologist and anthropologist Jean-Pierre WARNIER designates by “cultural confrontation between industry and tradition”.

In the digital age, “the processes of globalization and social transformation, alongside the conditions they create for a renewed dialogue between communities, […] also pose serious threats of degradation, disappearance and destruction on intangible cultural heritage…”, recognizes the United Nations Educational, Scientific and Cultural Organization (UNESCO) in the text of the convention for the safeguarding of intangible cultural heritage [9]. Curiously, at the very moment when the world seems completely dominated by these information and communication technologies, and this in almost all areas of human activity including that of artistic expressions and community-led development, we are also witnessing a renewed interest in popular traditions including storytelling and the spoken arts in general, as a manifestation of this intangible cultural heritage. Rural environments having been gradually deserted in favor of urban centers, modern societies have continued, despite everything, to express “an imperative need to nourish spaces of transmission, to build in a sensitive and emotional world, a relationship with our stories intimate, those of our families, of our communities, to live better together…”. This awareness will give rise to a major movement in France, during the 1970s, under the concept of “Storytelling Revival”, attempting to reconnect with oral storytelling, firstly, as a popular tradition, an element of heritage., then, as an artistic discipline and for which it was now necessary to delimit and organize the field of practice. “Whenever we talk about oral tradition, we think of societies lost deep in the jungle or on inaccessible mountain peaks, with bizarre customs, colorful clothing, craftsmanship more than art…”. Louis-Jean CALVET” This assertion by the ethnolinguist Louis Jean Calvet taken from his work entitled The Oral Tradition, evokes the difficulty of being able to understand communication by the media through the prism of a society with a written tradition [10].

At the end of this study on the foundations and issues of communication in societies with a community tradition, the author arrives at the opposite meaning of his study (orality), of the “refusal of this bazaar exoticism, of this voyeuristic attitude who only accepts the other by their strangeness and not by their simple difference.” Should it be emphasized that between communication as an element of media and communication as transmission of historical information and knowledge in communities the gap is considerable. Certainly, there are today, in different parts of the world, people who have developed a real culture of communication, such as in the media, essential supports for the transmission of their history, acquisition and sharing of knowledge in their daily lives., and also as a mode of artistic expression [11]. This is the case in most of Africa. In a study carried out for the Ministry of Culture in France, these remarks recall the famous sentence pronounced by Amadou Hampathé Bâ, Malian writer and researcher: “In Africa, an old man who dies is a library that burns”. But orality is above all a universal cultural heritage whose different practices are effective even in societies that could be considered to have a writing tradition. From the bards of Greek antiquity, through the European troubadours of the medieval era, the bards to the Djéli or Gawlo of black Africa, there have always existed, within human communities, people devoted to the arts of speech, thereby fulfilling specific social functions depending on the cultural areas: witnesses of collective memory, genealogists, advisors and confidants of kings, mediators, informants, educators, hosts of popular events or storytellers.

There have also been popular practices of speaking within families, communities, and groups [12]. Which made these arts excellent means of communication, of transmitting values such as language for example. Louis Jean CALVET recognizes this universality of orality as the basis of all culture: “All children in the world have learned, generally from their mothers, nursery rhymes, songs, tales, which build the cultural funds common to their linguistic group, as they will then learn proverbs, fixed forms etc. Furthermore, the industrial revolution of the 18^th century considerably changed the ways of life and work of societies, and consequently the modes of artistic expression, the channels of diffusion, and therefore cultural practices [13]. The book and press industry experienced considerable growth from this period. Later, the development of mass broadcast technologies such as radio, television, records, cinema, computers, and the Internet, helped to create new cultural practices beyond traditions, beyond community or national borders Oral heritage, in its content and themes, was then put at the service of new artistic forms inspired by models inherited from the colonial school. The few rare people who remained attached to the practice of the art of communicating in public had to turn to the Media such as radio stations to continue practicing their art. It was only very late that some initiatives emerged from individual artists, theater companies, or associations, for the promotion and preservation of the spoken arts in certain French-speaking countries such as Togo and Burkina Faso. Faso, Benin, Ivory Coast, Senegal, Congo, and Guinea.

It is in this context that we will try to understand the problem of the evolution of communication (media) in rural areas, its role and impact in supporting community development in Guinea, a West African country that interests us here. We specifically want to study the insertion of artistic forms in the scheme of communication in terms of community development which inspired us in our master’s courses at the Abidjan campus of Senghor University (2014-2015) as well as the failure of communication traditional during the crisis period (Ebola virus epidemic) of the same period. If the communication had been artistic, the journalists and the police would not have been lynched [14]. Also inspiring us from the first event dedicated to the Arts of Speech in 2002 by BANGOURA Ousmane Coléah. The project has since been carried out by the Ahmed Tidjani CISSE theater company in Conakry, an associative structure which he contributed to the founding in 1996 and for which he worked as an actor and director. This apprehension of the idea allowed us to ask ourselves the following question: Does artistic communication constitute a vector of community development in Guinea?

In other words, do artistic forms (word art, cinema, video, theater, etc.) play a role and impact on community development? It would be very difficult, if not impossible, to imagine community development without first thinking about strategies that unite rural people around an action of obvious benefit to the community [15]. If strategies had previously been implemented to support community development, did they really play this role and where, what explains their failure? By responding to the questions raised above, the approach would lead us to consider for Guinea the design and implementation of a project which will aim to create a specialized communication observatory, dedicated not only to the safeguarding of artistic heritage, but also to the definition of strategies that integrate artistic forms into the community development process. Our main objective of this study is to make artistic communication a vector of community development in Guinea. Specifically, this will involve:

• Go through artistic forms (word art, cinema, video, etc.) to support community development and the culture of peace.

• Strengthen the strategic capacities of communities in the context of development and peace;

• Transform the desire for fulfillment into reality.

• For its realization we have put forward two hypotheses which this study will allow us to assess against the facts. It is:

• H1: Artistic communication can be a vector of community development in Guinea.

• H2: Artistic forms (word art, cinema, video, etc.) can support community development.

• H2: Stakeholders in the promotion of Media in communities are unable to stimulate it because they have not put in place a coordination mechanism to govern interactions between them.

Finally, using the apprehensions identified from the results of hypothesis H1, we have carried out a sectoral analysis focused on the forms of artistic communication from the perspective of promoting community development and we will propose an approach (methodology) of implementation leading to a grassroots development action strategy.

Conclusion

Through the evidence that cinematographic and audiovisual art has been able to provide in crisis management, the emancipation of peoples but also in the development process, we affirm that Cinema is a vector of information, education and mobilization. Guinea has this tradition like other countries on the continent or elsewhere that needs to be revitalized. This is a subject that will contribute to the socio-political, economic, and cultural development of the Republic of Guinea. The memory of Guinea’s past in the field of Theater partly motivates our temptation to use Cinema as one of the factors in bringing populations together. Despite the absence of a cultural policy, the cinema sector has evolved within a liberal framework with a certain freedom of expression which therefore enriches the themes presented. All this constitutes a field of action for us researchers.

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Innovative Advancement for Combating Genetic Cum Gender Linked Diseases and Insuring Global Health Security

Introduction

Human biology got developed by innovative thinking of seeing, believing and experiencing. Plentiful advancements appeared in food and drink habits, taking care of children and cares of parents viz mother and father. Aspect of development of gentry was on beyond imaginations and all things remained on the mercy of God and what happened was accepted as destined by Darvin theory of natural process. But, how human biology evolved and progressed was not in imagination. Things were based on customs and (parampara (customs). Astrology took all credits of how things developed based on position of one’s grahas. All things got patternised by the astrology based suitable events, customs and general convention (paramparas). These customs created many atrocities on women and girl children as campaigned and relieving initiatives launched by Savitri Bai Phule [1]. Human biology evolved by self or by prismatism have to survive and cope up with many adversities [2-4]. The human heart, brains, kidney and blood circulations are chartered by electrolites. The electrolytes get disbalanced causing lot of health ailments, induced by indogenic and exogenic factors, creating troublesome situations.

The aberrations in gender theory also reveled in such families disorders in male and female, as genetic indicator as well as health hazards of both fathers and mothers. Medical doctors prescribe interal medicines for such health ailments. Alight gentry hunted for organic foods, which remain a distant dream due to uncertainty of quality and sustainable affordable availabilities. This situation governments and scientist staked on laboratory testing and devising food quality standard safety regulatory authorities, which did not appear adequate to tackle the likely problems arising due to electrolyte based disorders. This situation lead to controlling disorders of electrolyte disbalances remained as a challenging tasks. This researcher used insight of dampening of the highly widened fluctuations between upper and lower limits, thus the electrolytes’ disorders remain in their normal regimes. This research established the health hazards appeared in both fathers and mothers, which largely get implicated by electrolytic disorders. These ailments can be overcome by application of dampening of the electrolyte dis orders. The objective of the present study was to devise such dampening measure to overcome health hazards and bring transformation in to gadget for overcoming all kinds of health disorders making parental umbrella and sustainable ever surviving legacies. This will foster bring better prosperous world than the presently with lot of biological sufferings.

Materials and Method

Gender Mis Balance

About one and a quarter Century ago a scientific theory of xx-xy (female and male gendery) on grass hoppers in 1902 and later for prêtnor in 1905 (Singh [2]). However, the expected results of the referred gender theory got abarrated, prompting people to disbelieve and adopting their different ways of getting contented with whatever situation of gender emerged as mercy of God. The human body under indogenic and exogenic factors develop electrolyte disorders by which ove 40 health ailmnts arise [3,4]. This researcher carried out case by case studies of such aberrations of well acquainted cases as pondering situations of gynecological concern [5]. Further study perfected the gender theory and beyond [6] and brought the prismatism [6], Subsequent development was on researches which led to development of child care for creating from zero to hero [7] and again contrasting bad personality who carry out indiscriminate gun shooting in United States of America nd elsewhere [8].

Health Ailments

The micro nutrients viz sodium, potassium, calcium, magnesium, chloride and Phospphorus, induce over 40 health ailments. Doctors prescribe internal medicines. In this research a new material was innovated to neutralize such electrolytes and bring in regime. This result will be brought in the result part of the study.

Substantiated Cause

The ailments were substantiated by ts occurances during neuro therapy of a patient. Such normalizations wee instantly brought by the innovative materials.

Acqusion of Data

This researcher had brought case studies where genetic theory showed failure as expected out comes got abarrated [7]. In such case study cases all fathers as well as in mothers in the corresponding cases were sorted out for taking up further studies on linking for genetic and gender health ailments. Further, studies enabled substantiating such data sets and linking health disoders from other study Yadav, et al. [9].

Data Processing

The fenetic as ell gender link health ailment data were processed in convenient and understandable clear indicating for to derive comprehension by the readership. To fulfill ste objectiv5e of the present study.

Innovative Solution Developed

The new material for instant overecoming of electrrolite dis orders wre manifested for continuous wr and overcoming diabetes among many.aring as grland always keeping human bodies free of such disorders.

Areas of Application of this Innovative Research

Exemlary cases were presented by bring exemplary evidences of severe diseases such as mental depressions of inducing suicide, alzimers, cance.

Scaling Up of the Research in Vertical and Lateral Domain

The likely upscaling of the reaserch in both vertical and horizontal domain were brought in the study and presented in result and discussion part.

Surging Devastations of the Health Disorders and Appearance of the Present Solution Making Wow Innovation Facilitating Peoples Living with Wellness

It became necessary to bring references of Ardagh, 2020. that many innovations were created to make peopes daily life happy and pleaant. In this respect personal suffering of mental neuro ailments become highly disturbing and making one’s life under tremendous troubles. This innovative research provides immediate relief from its root cause. Thus, this becomes a wow that overcame by the launch of sociological compaign in India [1], and scientific theory [2]. solution to escalating health devastation [Hindustan, 2024] on peoples healyh. This details will be presented in result part of the manuscript.

Results

Genetic Gender Link Health Ailments

Advances in xx-xy (female –male gender theory discovered in early part of 20^th century provided scientifically justified development of female- male gender theory [2]. This researches took case by case deep studies of known cases and under the pondering situations [3] and could become opener of many un known facts. Studies brought prismatic balancing of the mis balances in the families those occurred due to abarrations [4]. Studies under new perfections and beyond brought many adavancements in biological sciences [5,6]. Having established substantiatingly it brought development of child care by choice and not by chance, as development of child care from zero to hero [7]. There also occurred situations of bad personalities which created worldly problem [8] and the researcher developed remedial psychology over coming problems of indiscriminate gun shooting in the United stse of America and elsewhere [9] bringing sociological control measures. Thus, the researches of this author have made tremendous advances in human biology. The data sets of (Table 1) of the previous study {7} were utilized in advancing such human biology were redevised (under [section 2.4] to establish genetic gender linked health ailments, which also became a pre indicators of likely development of springs and health ailments of both fathers and mothers.

Table 1: Health ailments and likely devastating situation, cause an likely cure.

Note: PCOD – polycystic ovary disease.

The data sets were realigned to facilitate readership and depicting readership comprehension (Table1), which showed that in the gender abarrated cases all the males becoming fathers had head bald ness and also accompanied by migrains as well as headache. Such case in the corresponding mothers the similar health of mental disorders were found in families having three sons and more, but no girl child. Study also revealed a general problems of polycistic overy diseases [PCOD] in almost all cases in mothers having all female children without son (Table 1). Such results may be shocking but it happened in actual cases becoming cases for the pondering for gynecological concern [3]. This result becomes confirmation of liking health hazards of gene and gender linked information. The study also opened new clear cut indications which led to development of prismatic gender balancing in the misbalanced families. Thus, the researched brought new scenario of human biology and opening new door for entirely different scenario from no possibility to tremendous possibility in gender balancing and bringing ever surviving legacies for advancing natural resources of human population. There might occur lot of difference between hope and no hope of such new advances in human biology, which will be brought in the discussion part of the present study.

New insight for Bring Cures for Genetic and Gender Misbalancing Health Ailments

Having established many facts of human biology the researchers took further endeavors to find medical cures for such genetic and gender linked health disorders in both fathers and mothers. In this endeavors reference made to the Ardas 2000. Tking inspirations from such innovation a new material was innovated which can neutralize all broadened ranges of wide fluctuations betn hyper and hypo situations of electrtrolyte dis order. This material was fully tested to neutalise ny likely disorders causing dis orders oh health ailments. The ailments of electrtolytes dus orders were found cause over v40 health ailments, whch will get extinguish. Such fast cure will be not so fast. Thus this is an innovative measure to overcome plentiful health hazards hed by instant neutralization of disbalance.sans internal medicines. Like was all health ailments shown in Table 1 will equally get wipedout from the root cause.

Testing of the New Material Under the Research and Development Domain of the Present Study

The research team is fully conversant of overcoming, which occur due to any advers impact of health ailments be by any of indogenic as well as exogenic factors and broadened amplitudes of up and down trending surges of electrolytic dis orders. This situation developed during the time when one neurotherapy treatment was on the patient was unable to move and walk. The ne innovative material was used and instant relief was demonstrated, san any internal medicine. It was demonstrated by the patient to instantly neutralize the severe disorder disling movement in free walking. The results were accepted as stonishing utility and appropriateness of the new materials. The researcher will always be ready to demonstrate the use of the measure san any internal medicines. which substantiated that there will not need of any internal medicines. Likewise, the working of the new material based measure for the ailments which occur in linking of genetic and genders. This is a wow innovation to make any likely hood of health hazards occurring due to any cause of electrolytic dis orders. In all such cases a decent pleasant scenario will appear.

Special Unique Measuresproving as Innovative Measures in Special Cases

The beyond studies [5,6] brought a new concept substantiating that human bodies wark as a bio ecosystems where in parallel sub systems carryout work of production, consumption maintaining growths and leang some wastes. Thus, the innovative gadget is placed at body part highly vulnerable to fluctuations in amplitude of electrolytic disorders. The newly manifested gadaget has to be maintained in continuous contact with boy part. This situation gets scientif support and backing and sufficiently etableshed for its location.

Application Domains

Cases have appeared in daily new papers where sudden deaths have occurred in young gentry unexpectedly. The electrolytic disbalances cause droad variations. It is well accepted fact that pandemic Covid 19 in addition to causing lot of fatality also reduced immunity in the gentries, in general, Thus, vulnerability to broadened amplitudes of fluctuations persisted. This reduction in the immunity had caused losses irrespective of any age or any importance of gentries. This created a tremendous loss in the countries world over.

Some Purplexing Astonishing Cases of Application for Health Ailment Where No Definite Cure Existed: This section was devoted to bring appraisal of general awareness in the world gentries the gravity of problems arising due to broadening disorders of electrolytic dis orders.

Tremendous Increasein Mental Ailment Patients: Studies referred by the daily news for broad disssemiatios to the public [10] reported results of studies conducted by scientists of Washington University for period 1999- 2021 that 1.1 billion people died due to neuro dis orders, published in the Lancet Neurology Journalin 2021. Mind and brain related disorders viz strokes, migrains, Alzheimer like mental ailments of 3.4 billions. Out of this 2 billions were found affected by tension and headache and about 1 billion affected by migrains. Diabetes are the fast expanding diseases. Thites details become worrysom situation demandin innovatic solution.

Attempting Suicide Cannot Become a Crime: In discharging a military personnel case of suicide by a mental disorder cases the Supreme court of India, New Delhi passed very appropriate decision that such seceding attempts cannot become crime [11]. Such ailments occurng due to mental depression one looses consciousness, which is a disability and it cannot become a crime. The judgment advised inducement of sympathy towards such patients.

Developing Worrisome Disproportion in Gender Ratio of Sons and Daughters: In Ghaziabd districts reported lot of girls die due to mall neutrition resulting 902 girls per 1000 sons. In eaelier reports Prayag Raj and Ghaziabad had larger no of girls bith than those of boys 1182 : 1000 [12]. The large no of deaths of girls under 6 years age resulted to dis proportion of 902 girls per 1000 sons. There exist difference between opinions of doctors; some reason cause as mall nutrition causing deaths and some as impacts of gender testing increasing clinics. This leads to cast doub t of deciding definite reason. One thing getting for certain that tension and worries are increasing with time, which lead to creating such uncertainties. The mal nutrion can be improved to better situation and this result report will be taken up in discussion part of the study.

Vetical and Lateral Upscaling

This research has potential for vertical and lateral upscaling in expansion for applicaton. This research will be highly use ful in making work output, productivity and wellness of human and biological world. The benefits from the animal kingdom will serve better cause for all human kingdoms than it is being realized for the present. This soulution proves better option than hunting for the uncertainity laden organic food. Governments need switiching on such nnovative measures instead of remain indulged in search of organic food production, certification and regulation. This confirm scientific wisdom will enable countries save their resources for taking up other useful ventures.

New Umbrella for Protected Self Managing Ability

There are troble vreatin five situations which bring puplexing situations for any one to fail in managing the adversities. Unnecessary meetings nclear priorities Ridiculus requests, Uncertainity, Last minut panic which become hard to manoeuvre and win over them, largely induced by disorders weakening slf strength and confidence. Such electrolytic disorders are eliminated bt new neuralising umbrellamit bulds capacity selg manage the situation. In such failure cases have come to notce. The last minute panic has appeared in many cases causing death. Such deaths can be overcome by building self managing capability.

New Ensurance for Global Health Security

The afore brought out research and development enabled this summary figure depicting entire aspects, enriched with capacity built activated to produce tremendous benefits which can be partnership cooperation for bringing better healthy all time wellness equipped biological world. This innovation brings easy way and keep healthy long living as Godly blessing

Discussion

All research and developments presented here were further ratified for its convincing substantiations and smoothereing any angularity that might appear in chartering its worldwide acceptability.

The Development of Electrolytic Disbalance is Essentiall a Natural Bio Process

Electrolyte is very important bio factor maintaining proper functioning of body organs. This bio-factor is chartered by both indogenic and exogenic governing situations.The governing bio factors broaden amplitudes of fluctuations affecting different homeo stasis indicating medical situations and disorders. This situation disturbs homeostasis of bodies, which trigger several health ailments. Medical fraternities prescribe iternal medicicines, which is highly subjected to in accessibility of expert advisory, availability of original medicines and affordable costs It becomes highly non affordable and difficult necessary facility for meeting huge demands of healthcares. It remained a challenging task to accomplish the compulsory task related to health and wellness of global gentry.

The Electrolytic Did Balance is Caused by Indogenic and Exo Genic Factors

The electrolytic disorders causing health disorders can occur at any time due to shortage of food, water, nutrition, climate change causing heat, cold, rain as well as wind tides etc. As such it may be difficult to ascertain the cause, which become a non feasible task [12]. This becomes a complex situation and worldly bio world remain indulged throughout the life resolving such issues. These facts were not adequately understood, which is again appearing a new challenging frontier.

The Internal Medical is not Sufficient to Contribute its Global Need

The internal medicines are not adequate to cater the global needs of maintaining homeostasis of bio world. This implicates pressing need for finding any innovative measure to resolve the issue in bioloy and entire bio world.

Neutralization is the Most Innovative Development Surpassing all Worldly Developments

Neutalisation of the electrolytic disorder following inspiration from reference [13] created new identification of inert material to neutalise it with complete extinction and instan makig one get instant relief drom the healt disorders [14-17] This is can be made highly affordable and brought as a feasible solution fulfilling the challenges.

The New Innovation Proves as an Alternative to the Hunt for Organic Food

Inabsence f such innovations alight gentry hunt for organic food which again remains with limitation of quality, adequacies and affordable price of suitable food commodities. Governments incur lot of infrastructural facility building expenditures in establishing quality checkups, exercising regulations and creating freedom from any scam that might occur at any stage. The productivity of organic system is not adequate to fulfill huge global demands. This researcher shorted out many limitations of organic foods’ froduction to consumption. In this complexity new innovation brings excellent solution free from all limitations.

This Research Will Overcome All Shortages of Nutrition, Water, Resh Airas Ell Overcome Any Exigency Which Become Fatal Under Many Situarion

The preent innovation will overcome all strocitie of shortages and quality inaduacies , insufficiencie that might com from interal as well as xternal factos cusing lot of problems.

This Discovery Builds Capacity Setting Healthy and Prosperous Own Capacity

This innovative development enhances capacity building of physical, mental and neurological aspects was very well depicted in (Figure 1). Thus, it resolves many long time existing neurological disorders. Good mental situations will save patients from getting in to depressions; the patients will come senses to care of one self and think for betterment of one’s dependents.

Relevance, Effectiveness, Efficient Important and Sustainable (REEIS)

This innovative research is highly relevant, it is highly effective and efficienent, important and ustainable. Thus, this it becomes a wow solution of prime importance, accomplishing legendary saying,” Jaan hai Jahan hai” (When one is alive theres is world and beyond it there is nothing).

Streagth, Opportunity, Weaknes and Threat (Sowt)Analysis

This research is highly scientific and backed by scientific facts, hence it is very strong. This research brought a band which provides lot of opportunity (Figure 2). It is free from any threat and again feree from any weakness. It iss going to bring new healthy and prosperous bioworld.

Figure 1

Figure 2

Conclusion

This study enabled linking genetic cum gender related health hazards. As such many troubles emrge and in many cases fathers suffered from head baldness, headache and migrains, on the other hand mothers suffered from PCOD disorders, It has come that there occur electrolytic disorders. In this innovative study a new natural material was searched which produced stonishing results of dampening the broad amplitudes of hyper and hypo situations of elements namely sodium, potassium, calcium, magnesium, chlorite and phosphorus. The electrolytic dis orders were totally instantly neutalised. In order to provide all time protection for getting free of such disorders a manifested wearble gadget was developed. This gadge gets used by all human beings to protect from any disorders. This is also useful in building immunity enforced personality creating health security; covering time prior to birth till one remains alive. Thus, this result proved as wow innovation for creating healthy world with trouble free long life.

Declaration no Conflict of Interest

It is declared by the authors that there existed no any conflict of interest, be it for authorships or for any financial support calim.

Acknowledgement

Authors duly acknowledge support of references which vere made use of inpreparation of the manuscript.

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Mathematical Investigation for the Mechanism of the Pancreatic Juice Reflux in High Confluence of Pancreaticobiliary Ducts and Pancreaticobiliary Maljunction

Introduction

Pancreaticobiliary maljunction (PBM) with pancreaticobiliary reflux (PBR) into the biliary tract shows a broad spectrum of morphological characteristics, including variations in the shape and size of the pancreaticobiliary ducts. On the basis of various investigations of morphological parameters such as duct diameter and length [1-5], diagnostic criteria for PBM have been developed and updated [6-8]. In addition, some biomechanical engineers have investigated bile flow in the human biliary duct using computational flow simulation [9-15]. However, the relationship between the morphological parameters and PBR has not yet been clarified. Fukuzawa et. al. fabricated a simplified model of pancreaticobiliary ducts that modelled the structure of the human biliary tract system, including the common bile duct (CBD), gallbladder/cystic duct (CD), gallbladder (GB), common hepatic duct (CHD), and pancreatic duct (PD) in cases of PBM without biliary dilatation, and used the model to clarify the mechanism of PBR [16] and to demonstrate that PBR disappears after cholecystectomy. However, it is almost impossible to fabricate individual patient-specific models of the pancreaticobiliary duct and investigate the effects of these morphological parameters on PBR. Therefore, to generalise this problem, we developed a mathematical model for pancreaticobiliary flow in pancreaticobiliary systems based on the theory of fluid mechanics [17].

Using a mathematical model, we simulated normal pancreaticobiliary flow during the bile-refilling period, and the results showed good agreement with actual measurement data of human gallbladder volume changes [18] and the temporal variations of the intro-pressure in the contraction and relaxation of common channel (CC) by the sphincter of Oddi (SO) [19,20]. However, PBR could not be simulated in our mathematical model using statistically averaged morphological parameters of the pancreaticobiliary ducts [17]. The purpose of this study was to clarify the influence of the morphological parameters of the pancreaticobiliary ducts on PBR without biliary dilatation by using our developed mathematical model. We simulated the pancreaticobiliary flow using various morphological parameters of the pancreaticobiliary duct. This paper presents the results of a parameter study of the mathematical model of the influence of pancreaticobiliary ducts on PBR without biliary dilatation and considers the factors of pancreaticobiliary duct morphology that influence PBR.

Methods

The details of our targeted phenomena and the mathematical model are described in our previous paper [17]. We have succinctly summarised these aspects in the following sections:

Targeted Phenomena for Mathematical Modelling

This study modelled the 4–12-h period (hereafter referred to as the bile-refilling period) in which the GB volume was minimised just after a meal and bile was refilled in the GB immediately after that and by the next meal. Therefore, we assumed that the bile produced by the liver had filled all biliary tracts, and neglected changes in the density and viscosity of bile. And it was assumed that the dilatation and peristalsis of the biliary tract and the existence of accessory pancreatic ducts in the pancreaticobiliary system were negligible.

Mathematical Model and its Assumptions

From the perspective of fluid mechanics, almost all mass transport in the pancreaticobiliary duct occurs by advection rather than diffusion. Therefore, it was possible to simulate the flow phenomena in the pancreaticobiliary duct to investigate PBR. Because the bile and pancreatic juice flows during the bile-refilling period were much slower than those during blood flow, the flow could be modelled as a linear phenomenon. Thus, all pancreaticobiliary ducts in this study were modelled as mechanically equivalent straight and circular tubes with flow resistance and their combinations. In this study, pancreaticobiliary flow was modelled using an equivalent 1-dimensional hydrodynamical circuit, as shown in Figure 1 [17]. The liver and pancreas were modelled as volumetric pumps, similar to syringe pumps, with a constant flow rate. Hepatic bile and pancreatic juice flow from the GB to the duodenum (Duo) through the CD, CBD, CC, and ampulla of Vater due to the pressure difference between the GB and Duo. Apart from the CC, the PD and CBD within the region of the sphincter of Oddi (RSO) were opened and closed by SO contraction and relaxation, as shown in Figure 1a, which was a model for the morphological normality of the pancreaticobiliary duct or high confluence of pancreaticobiliary ducts (HCPBD). However, if SO contraction did not affect the CBD and CC, as shown in Figure 1b, it was a model for anomalous arrangement of the pancreaticobiliary ducts. In these models, pancreaticobiliary flow satisfied both the equations of continuity as the law of conservation of mass for flow and Bernoulli’s theory, including pressure loss as the conservation law of the energy of the flow.

Figure 1

The equations of continuity at bifurcations of the ducts are as follows:

Here, the quantities of Q are the volumetric flow rates at each duct, and the subscripts indicate the location of the flow. This study defined the flow rate as positive (Q > 0) when the fluid flowed toward the Duo. When the volume of the GB was temporarily increased, the flow rate at the CD was negative (Q_CD < 0). However, the GB absorbs a portion of the water in bile juice [16]. Therefore, the GB volume change per unit time (dV_GB/dt) occurs because of the difference between the inflow rate toward the GB (–Q_CD) and the water-absorption rate (Q_D) at the GB, as follows:

These three equations must be satisfied not only for normal pancreaticobiliary ducts, but also for HCPBD and PBM. Since the GB pressure is almost the same as the intraduodenal pressure at the start of GB refilling, hepatic bile flows from the CD to the GB. The inflow causes both the GB intra-volume and inner pressure to increase with time. The relationship between the GB intra-volume and inner pressure is modelled using compliance, known as arterial compliance, in mathematical models of the cardiovascular systems [21,22].

where dV_GB is the volume change in the GB cavity, dp_GB is the amount of pressure change in the GB, and C’_GB is the compliance of the GB, which is an index of its deformability.

By integrating Equation 3 and combining it with Equation 4, the following equations are obtained:

where p_GB(t = 0) is the initial intra-GB pressure at the start of bile refilling; V_GB(t = 0) is the minimum GB volume at the start of GB refilling; and t is the time elapsed from the start of GB refilling. Bernoulli’s theory, including pressure loss [23,24] without negligible terms such as the energy dissipation caused by the flow vortex, was formulated by an electronic–hydraulic analogy, as shown in Equation 7 [17].

where p is the local static pressure and Δp is the pressure loss in each pancreaticobiliary duct. According to the definition of flow rate, the pressure loss is positive (Δp > 0) when the fluid flows toward the Duo. The pressure drop through a straight cylindrical tube was estimated using the Hagen–Poiseuille law [23,24], as shown in Equation 8.

where Δp is the viscous pressure drop between the ends of the duct, R is the flow resistance of the duct, Q is the volumetric flow rate in the duct, d is the inner diameter of the duct, L is the length of the duct, and μ is the dynamic viscosity of a working fluid. The different morphologies in individual diseases, such as HCPBD and PBM, are expressed by the differences in flow resistance, as shown in Equation 8. For example, patients with normal duct morphology and HCPBD were observed to have a part of the CC, CBD, and PD within the RSO. The flow resistance of each duct has two elements that are expressed by the following equation:

here, the quantity of R is the flow resistance of the pancreaticobiliary duct beyond the RSO, and R is the flow resistance within the RSO that is temporally varied by SO contraction and relaxation. When the CC was not observed beyond the RSO in the case of a normal pancreaticobiliary duct and HCPBD,  was zero. In contrast,  and  were zero in the case of PBM because the CBD and PD were not observed within the RSO.

By combining and integrating Equations 1, 2, and 7–9, the flow rate at the CD was obtained as follows:

Equations 5, 6, and 10 can be solved and pancreaticobiliary flow can be simulated by applying suitable boundary conditions for the phenomena. Next, we discuss the boundary conditions and parameters used to calculate the mathematical model.

Boundary Conditions and Parameters

This study employed Fukuzawa’s baseline data setup [16] and our previous study [17] for the morphological parameters of human pancreaticobiliary ducts, as shown in Table 1. However, other physical data are required as boundary conditions to solve the mathematical model. As the intraduodenal pressure was the back pressure for the pancreaticobiliary system, this study assumed that the intraduodenal pressure was almost constant, equal to the intraperitoneal pressure and close to the atmospheric pressure.

Table 1: Collected parameters of bile and pancreatic juice flow in biliary and pancreatic tract.

Note: Abbreviations: CD, gallbladder duct; PD, pancreatic duct; GB, gallbladder; CHD, common hepatic duct; CBD, common bile duct.

On the basis of the measurement of the relationship between healthy human GB volume and its intra-pressure change [25], we calculated the GB compliance and set it at approximately 0.35 – 12 mL/ mmHg. Therefore, in this study, changed C’GB = 1 to 15 mL/mmHg. The findings indicated that the SO was repeatedly contracted and relaxed with a 10–12 s cycle [19,20]. This study assumed that the inner diameter of the CC within the RSO was periodically changed by 0.3 mm when opened and 0.096 mm when closed repeatedly with a square waveform at 5-s intervals [17]. Furthermore, on the basis of Fukuzawa’s estimation [16], this study employed the value of the water-absorption rate QD at the GB, which was set at 23 mL/h. A summary of the common conditions for flow simulation is shown in Table 2. Further conditions for PBM and HCPBD are listed in Tables 3 & 4, respectively. This study neglected the fact that the variation in the fluid physical properties, such as viscosity and density, was due to the mixing of the bile and pancreatic juice, similar to our previous work [17]. To simplify the mathematical model, it was assumed that the viscosity and density of pancreatic juice were the same as those of hepatic bile.

Table 2: Flow conditions employed for this simulation.

Note: Abbreviations: PD, pancreatic duct; GB, gallbladder; CHD, common hepatic duct; Duo, duodenum.

Table 3: Flow conditions employed for PBM.

Note: Abbreviations: CD, gallbladder duct; CBD, common bile duct; CC, common channel; RSO, region of the sphincter of Oddi; PBM, pancreaticobiliary maljunction.

Table 4: Flow conditions employed for HCPBD.

Note: Abbreviations: CD, gallbladder duct; CBD, common bile duct; CC, common channel; RSO, region of the sphincter of Oddi; HCPBD, high confluence of pancreaticobiliary ducts.

Numerical Simulation Method

With these boundary conditions and the baseline data setup, the time variations of QCD and pGB can be calculated by combining equations 5, 6, and 10. This study revealed an estimated solution of the pancreaticobiliary flow during a bile-refilling period of 6 h by using the modified Euler numerical integration method for simultaneous equations within a 1-s interval time step with MATLAB (2020R1; MathWorks, Natick, MA, USA).

Results

Figure 2 shows an example of the simulation results for GB volume recovery and the influence of the anatomical morphological parameters on GB volume recovery. In our previous study, the simulation results obtained using our mathematical model agreed well with the GB volume recovery trend. The pressure variation and its frequency in the CC within the RSO were also accurately simulated [17]. These results indicate that the length of the CC affects the GB volume recovery rate. Therefore, to summarise the influence of the different morphological parameters of the pancreaticobiliary ducts on the PBR during the bile-refilling period, the integrated flow rate of bile at the CBD was calculated over 6 h after the start of refilling. Figures 3 & 4 summarise the simulation results. Figures 3 & 4 show the results for HCPBD and PBM, respectively. These graphs show the relationship between biliary tract size and pancreaticobiliary flow. Because the integrating flow rate is the moving volume of the working fluid, if the integrating flow rate at the CBD is less than zero (negative value), PBR occurs. The broken lines in each graph show the volumes of the CBD and CD. When the integrating flow rate at the CBD is lower than the broken line in the graph, pancreatic juice reaches to the GB within 6 h.

Figure 2

Figure 3

Figure 4

These results showed that the length of the CC beyond the RSO did not affect pancreaticobiliary flow in cases of PBM. In contrast, the length of the CC within the RSO and GB compliance affected reflux. When the GB compliance was approximately 5–10 mL/mmHg, which was the same as the average of the reference data [25], the pancreatic juice reflux that occurred in our simulation using the length of the CC within the RSO was over approximately 6 mm. In the case of HCPBD, the CC length was also a significant factor in pancreatic juice reflux. GB compliance affected bile and pancreatic juice flows in both cases. In the results of the simulation under average GB compliance, pancreatic juice reflux could also be observed when the length of the CC within the RSO was >6 mm. This result showed good agreement with the diagnostic criterion of the PBM as “the length of the CC is longer than 6 mm” [26]. These results indicate that the important factor in PBR might be the flow resistance of the CC, which opened and closed as a result of SO contraction and relaxation, and the compliance of the GB. Moreover, the existence of the CC beyond the RSO contributed little to reflux. However, other morphologically important factors may exist. To investigate the reason for this, we have discussed this possibility theoretically using the mathematical model.

Discussion

Consideration of a PBR-generating Mechanism Based on a Mathematical Model

According to Equation 1, if the flow rate at the CD (Q_CD) is less than zero (Q_CD < 0), the working fluid in the CD flows toward the GB. When PBR occurs, the flow rate at the CDB (Q_CDB) is negative (QCDB < 0). Therefore, PBR occurs under the following conditions:

By dividing both sides of equation 12 by the flow rate at the CHD (Q_CHD) and simplifying it, the following relationship was obtained:

This equation indicates that PBR occurs when the CD flow rate is negative and the absolute CD flow rate is higher than the CHD flow rate. By dividing both sides of Equation 10 by the CHD flow rate and applying Equation 13, the following PBR conditions are obtained:
Normal and HCPBD:

These equations indicate that the numerator of the fraction is smaller than the denominator when PBR occurs. By eliminating the same terms on the left and right sides of equation 14 and rearranging them, the simplified equation for the reflux condition is as follows:

To the best of our knowledge, no reference data are available for the CC diameter when the SO contracts and relaxes. Because we could not observe the contracted CC during endoscopic retrograde cholangiopancreatography, the contracted CC may have been much narrower than the CC outside the RSO. According to the Hagen–Poiseuille law as shown in Equation 8, the flow resistance R varies in inverse proportion to the fourth power of the duct diameter. Since the flow resistance of the CC within the RSO (  ) is much higher than that of the CC beyond the RSO (  ), the resistance of the CC beyond the RSO is negligible in Equation 15-2. Therefore, the conditions for the occurrence of PBR can summarised by the following equation, regardless of whether the bile duct is morphologically normal or shows HCPBD or PBM:

The CD diameter was much larger than that of the CC when the SO contracted. In contrast, the diameters of the CC and CD were approximately a few millimetres when the SO was relaxed. The lumen of the CD contains the spiral valves of Heister [27,28]. Because these valves are spiral-undulating folds, the working fluid in the CD has a large surface area for its volume. In other words, the flow resistance of the CD is higher than that of the CC if the SO is relaxed, and it is difficult to reflux pancreatic juice into the CBD. When the SO contracts, the flow resistance of the CC within the RSO is significantly higher than that of the CD. Thus, the conditions for reflux occurrence can be simplified as follows:

We can consider the mechanism of PBR by using this equation, as follows…First, we focus on the left-hand side of Equation 17. Because the Fukuzawa baseline setup was employed in this study, the pancreatic juice production rate was assumed to be constant. However, the rate of pancreatic juice production varies during the day depending on dietary conditions and other factors, and the rate may also show individual differences. Thus, it was assumed that the pancreatic juice production rate could change 0.5- to 2-fold rather than Fukuzawa’s baseline setup. However, as shown in Equation 8, the flow resistance of the pancreaticobiliary ducts within the RSO varies in proportion to the length of the duct L and inversely to the 4th power of its inner diameter d. In other words, to increase the flow resistance of the duct to 2-fold, the length of the duct must be doubled or the inner diameter of the duct must be reduced by approximately 85%. Therefore, the diameter of the CC in the RSO is the factor with the greatest influence on the PBR, and the frequency of contraction and relaxation of the sphincter and the time ratio between contraction and relaxation (duty ratio) also affect the PBR. Our simulation results, shown in Figures 2 & 3, were obtained by assuming a constant CC diameter and varying the CC length. Therefore, the quantities on the horizontal axes of these graphs are proportional to the flow resistance of the pancreaticobiliary duct; that is, the common duct diameter is proportional to the fourth power root of the magnitude of the resistance.

Next, we focus on the right-hand side of Equation 17: The intraduodenal pressure was the back pressure from the pancreaticobiliary system. The instantaneous minimum value of the intraduodenal pressure of a healthy human was almost the same as the intraabdominal pressure. However, the intraduodenal pressure changed transiently due to intestinal peristalsis. If the intraduodenal pressure was higher than the GB pressure without accessory pancreatic ducts in the pancreaticobiliary system, PBR was occur during instantaneous high intraduodenal pressures. Therefore, the differential pressure between the GB pressure and the intraduodenal pressure was one of the significant factors for PBR. As shown in Equation 6, the GB pressure can be determined by the GB compliance, the balance between the inflow rate from the CD and the water-absorption rate at the GB, and the initial GB pressure at the beginning of GB refilling. When the initial intra-GB pressure was low, PBR occurred readily. Therefore, the GB pressure at the beginning of GB refilling was the most influential factor in PBR. GB compliance affects the ratio of the GB pressure increase after meals. If the compliance is low, that is, if the GB becomes stiff, the GB pressure increases rapidly. Therefore, PBR is least likely to occur with a stiffer GB. Compliance of a vessel such as an artery is affected by its volume; the larger the volume, the higher the compliance. Therefore, in addition to the mechanical stiffness of the GB, the size of the GB may also influence PBR. The water-absorption rate at the GB is also an important factor, because it takes longer for the GB pressure to increase when the water-reabsorption rate is high.

Limitations

We were able to demonstrate the influence of the morphological parameters of the pancreaticobiliary ducts on PBR. However, the mathematical model was based on the following three main assumptions: First, we modelled the pancreaticobiliary ducts as straight rigid circular pipes. However, a vortex may occur due to the bifurcation and sudden diameter changes of the pancreaticobiliary ducts. However, the flow resistance caused by the vortex is far less than the resistance of the CC with SO contraction; therefore, its influence on the simulation result is considered to be limited. The compliance of the pancreaticobiliary ducts is also lower than that of the GB; therefore, its effect is also considered to be less significant. Since the compliance of the pancreaticobiliary ducts with dilatation is not negligible, we would like to investigate this in future studies. Second, this study assumed that the mechanical properties, such as viscosity and density, of the bile and pancreatic juices were the same. However, the viscosity of the pancreatic juice and the GB bile was approximately 1.7 and 2.6 times higher than that of hepatic bile, respectively [5,6]. The GB bile filled the CD, CBD, and CC immediately after it was ejected. The viscosity of the working fluid was changed by mixing of the liver bile flow, GB bile flow, and pancreatic juice flow. In our future study, we aim to modify the model by including the changes in viscosity caused by fluid mixing because it is necessary to rigorously simulate not only the fluid flow but also the mass transfer to overcome the aforementioned limitations. Finally, this study neglected the existence of minor pancreaticobiliary ducts such as accessory pancreatic ducts. The influence of such ducts will be studied further in the future.

Conclusion

We investigated the influence of the geometrical parameters of the pancreaticobiliary duct on PBR occurrence using our developed mathematical model for pancreaticobiliary flow based on fluid mechanics theory. The simulation results showed that the flow resistance of the CC within the RSO was a significant factor for PBR regardless of whether the duct was morphologically normal or showed HCPBD or PBM. Our simulations using Fukuzawa’s baseline data setup and our hypothesised CC diameter change due to SO contraction/relaxation indicated that pancreatic reflux appeared when the length of the CC within the RSO was longer than 6 mm when the compliance of the gallbladder was equal to the average value for humans. This result is consistent with the Japanese clinical practice guidelines for PBM. However, the flow resistance of the CC without RSO was completely unaffected. This will enable a more accurate simulation of the flow in the pancreas and bile ducts and allow a quantitative assessment of the effects of differences in the morphology of the pancreas and bile ducts on the flow of bile and pancreatic juice in individual patients.

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Conflict of Interest

Authors declare no Conflict of Interest for this article.

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