The Neuroprotection Effect of GLP-1 Receptor in Murine Stroke Model

Introduction

Brain ischaemic, which is also called cerebral ischaemia or ischaemic stroke, occurs when the blood flow to the brain is insufficient [1-3], causing deprivation of both oxygen and glucose to the brain and upsetting the balance of metabolism in the nervous system [4,5]. These may include abrupt numbness or weakness in one side of the body, particularly in the arms or legs, as well as facial drooping and difficulty speaking or understanding speech. Other signs of a stroke can include confusion, trouble with coordination and balance, and loss of vision [6]. Based on the infarct region, ischaemia can be either focal or global, if an area of the brain is affected, it results in focal ischaemia, and if the whole brain’s blood supply is blocked, it results in a global ischaemia. An ischaemic stroke may be transient or permanent depending on reperfusion. Global cerebral ischaemia (GCI) commonly occurrs after cardiac arrest, which causes a decrease in the whole brain blood circulation. If the blood supply is restored within a short time, the ischaemia may be transient, but, if a long period passes before reperfusion, the damage to the brain tissue can be permanent [7,8]. Although restoration of the blood supply is significant to the brain tissue, it sometimes induces reperfusion complications that can also cause damage to the brain [9,10].

During the acute period of ischaemia, axons are lost quickly [11]. In the early stage,axon loss is triggered by pathophysiological issues and both intra-cortical and connected downward axons are involved from the cortex with deprivation of the oxygen, nutrients, and metabolic supply necessary to maintain a normal environment [12,13]. Exendin-4 (Ex-4), also called exenatide, is a glucagon-like peptide-1 (GLP-1) agonist drug that can decrease blood glucose levels. Its half of the amino-acid sequence is the same as that of the GLP-1 receptor, which allows Ex-4 to perform in a similar manner to GLP-1, and gives it a longer half-life, approximately 2 hours. After administration of Ex-4, the insulin level in plasma remains higher and is maintained for a longer time than GLP-1 [14,15]. Ex-4 was approved by the FDA in 2005 for the clinical treatment of type II diabetes mellitus and is regarded as a forward therapeutic approach for controlling blood glucose levels [16,17]. In addition to the treatment of type II diabetes, Ex-4 has shown neuroprotective functions after brain insult and can also enhance neurogenesis in patients with Parkinson’s disease [18,19]. In this study, we aim to mimic brain tissue infarct condition after cardiac arrest by using mice global cerebral ischemia (GCI) model, and investigate the neuroprotection effect of GLP-1 receptor [20].

Methods and Materials

Animal preparation and Global Cerebral Ischemia (GCI) Model

The protocols we use for animal were approved by the Animal Ethics Committee of Shenzhen Second People’s Hospital. Forty eight-week-old C57BL/6 mice with body weights between 20 and 25g were used. All the animals were received standard welfare of 12h light/12 h dark housing with free access to food and water. The mice were anaesthetised with an intraperitoneal injection of ketamine100mg/kg and xylazine 10mg/kg body weight. A sterile cervical incision was made at the midline of the ventral surface of the neck. Both common carotid arteries were exposed. The tissue was carefully separated with fine forceps while ensuring that the vagus nerve was not damaged. A 5-0 silk suture was looped around the common carotid artery, a micro-clip was used to clip it by lifting the suture, and the blood flow was blocked for 20min. The animals were placed in a warming box (33~35°C). After 20 min, the clipswere removed, and the wound was closed with silk suture. Buprenorphine was administered by subcutaneous injection for 3 d at 0.02mg/kg body weight. The mice were returned to the warming box to maintain their body temperature to prevent hypothermia as a result of global ischaemia [21].

Electroencephalography (EEG)

Because cortical potential activity can be depressed during brain ischaemia infarct, electroencephalography can be used as a measurement method to evaluate ischaemic stroke [22]. Two recording probes were placed subdermally each side of the cranium,a reference electrode was placed subdermal on the nasal bone, and a ground electrode was connected to the tail.

Ex-4 Injection

After 1h of reperfusion, the anaesthetized mice were placed in a prone position. The tails were immersed in 40°C water for 3 to 5 min to enlarge the tail vein. A 1-ml syringe and 31-G needle were used to inject 330μg/kg body weight Ex-4 through the tail vein, followed by a 3-μg/kg low-dose supplement for 5 d.

Immunohistochemistry

The mice were given an overdose of phenobarbital and placed in a supine position. Saline solution (0.9%) was pumped                into the body       to replace the blood,Paraformaldehyde (4%) was pumped after the saline solution. After perfusion, the brain was dissected out and immersed in 4% paraformaldehyde and dehydrated by 15%, 20% and 30% sucrose subsequently. Six micrometer paraffin processed tissue sections were collected through the forebrain and stained with Neuron Nuclear (NeuN; 1:200; Abcam)antibody. Neuron cell lose was then observed by using Spot Imaging System.

Western-Blot Analysis

Western blot analysis was performed at day 5 after GCI. Brain cortex tissue and sufficient cold RIPA lysis buffer containing protease inhibitor cocktail were together mixed well. After the extraction, protein concentration was measured with a BCA kit. 10µg-20µg proteins were loaded into 8 to 10% SDS-polyacrylamide gel. Proteins were then transferred to nitroate cellulose membrane, following 5% non-fat milk blocking, incubated at 4°C overnight with first antibody. Washed membrane for three times with TBST for 10 min, and then incubated with secondary antibodies for another 2 h at room temperature, detected signals by using enhanced chemiluminescent (Thermo Fisher Scientific).

Real-Time PCR

After brain cortex RNA extraction by TRIzol (Ambion), 1µg of total RNAs were used in reverse transcription by using High-Capacity cDNA Reverse Transcription Kits (Applied Biosystems). 100ng of total RNAs were then transcribed by using M-MuLV reverse Transcriptase (New England Biolabs) and a RT primer adding an anchored poly (T) tag to genes sequence (Alvarez and Nourbakhsh, 2014) for target genes detection. The following PCR procedure conducted with a universal primer and target genes specific primer. The products of PCR were detected with SYBR green dye, and SYBR assays were applied on an Applied Biosystems 7500 Real-Time PCR system. Related expression was calculated by delta threshold cycles (Ct), using normalization to GAPDH.

Behaviour- Catwalk Test

The Catwalk system consists of a glass walking plate, a green light source, and two rectangular brace plates placed vertically along the glass plate; above the plate is a cover with red light source. A recording camera is placed below the glass plate and connected to a computer [23,24]. The Catwalk software is then used to analyse gait functions. Before the global ischaemia surgery, mice were trained for 3 days to get familiar with the system. On day 5 after ischaemia, catwalk gait analysis data were collected, and the mice were then sacrificed [25].

Statistical Analysis

GraphPad Prism 8.3.0 software was used for statistical analysis and graphics production. A one-way ANOVA with Tukey’s multiple comparison test was performed to assess the results of the behavioral tests and immunohistochemistry analysis. A p value of < 0.05 was considered significant to reject the null hypothesis. Normal distribution was checked by Kolmogorov-Smirnov test, a p value of > 0.1was considered pass the normality test.

Results

Mice Global Ischaemia Model Established

During the occlusion, mice EEG detection was set to investigate whether the blood flow to both left and right forebrain was decreased to a certain level. Figures 1 & 2 show the mice EEG wave change under normal, ischaemia and reperfusion situation, the upper line represents left brain EEG, while the lower line stands for right brain. Picture A in Figure 1 shows the initial mice EEG typical waveform. B, C, D, E show EEG changeat 1, 5, 10, 15 minutes after occluded both bilateral common carotid arteries, EEG change from wave shape to plate style. Picture A in Figure 2 illustrates the time removing the clips at 20 minutes after occlusion. B, C, D, E, F display EEG form gradually become normal from 1 to 30 min after removal of clips.

Figure 1

Figure 2

Immuno-Staining, Real-time PCR and Western-Blot analysis

Picture A, B, C, D of Figure 3 show real-time PCR results of anterior cortex tissue, synapse (syn2), axon (Nefh) and neuron nuclear markers (NeuN) were down-regulated in ischaemia group, while in the Ex-4 treated group, remain the same level with normal control group. In the Western-Blot (Figure 3E), the expression of neuron markers we selectedwas also reduced in the ischaemic mice, and enhanced in Ex-4 treated group. F, G and H illustrate the immunostaining results of Neuron Nuclear (NeuN) marker on the section of anterior motor cortex. In the ischemia mice, a neuron cell body loss was observed, while after Ex-4 treated, such phenomenon was not found and remain the similar cell density compare with the normal mice.

GLP-1 Receptor Agonist Improves Loco-Motor Function on Ischaemic Mice Model

Ex-4 enhances ischaemic mice loco-motor function which was determined by Catwalk test. For behaviour test, we select single stance, stand, swing and swing speed as parameters. Figure 4 shows the Catwalk results and picture A, B, C represent parameters of single stance, stand and swing, both these three parameters of the ischaemia group are significantly shorter than the control group (p<0.05, t-test), while in the Ex-4 group stay the same level with the normal group. In picture D, the swing speed of ischaemic mice was faster than normal mice as well as ischaemic mice treated with Ex-4 (p<0.05, t-test).

Figure 3

Figure 4

Discussions

In this research, we investigated the effect of Ex-4, a GLP-1 receptor agonist, on axon outgrowth in animal model. For the cell culture part, we chose primary mice embryo cortex neuron culture as cell model. We selected C57 mice as research subjects which bilateral common carotid artery occlusion was established on it. In our study, we observed the phenomenon of EEG reduction in the global ischaemic model. Due to the usage of the EEG detection, we could know whether the model was established or not in a directly way and it is the first time EEG is administrated in global ischemia model. In previous research [26] observed there was a reduction in cortical spontaneous EEG after middle cerebral artery occlusion. Other research teams [27,28] also detected a reduction in EEG on unilateral common carotid artery occlusion. The neuroprotective effect of GLP-1 receptor was further proved by immunostaining, Real-time PCR and Western-Blot analysis. The immunostaining results showed a neuron cell body loss in the ischemia mice, after given Ex-4, remain the same cell intensity with normal mice. In the Real-time PCR detection, synapse (Syn2), neuron-specific nuclear protein (NeuN), neurofilament heavy chain (Nefh) and Glp1 receptor (Glp1r) markers were found down-regulated in global ischaemia mice, however, in Ex-4 treated mice, these markers’ mRNA expression level were almost stay at the same level except Glp1R, which was up-regulated, cause the injection of the Glp1 Ragonist [29].

Moreover, in the Western-Blot analysis, another two markers were further detected, beta III Tubulin (Tubb3) and central nervous system specifically expressed PKC gamma, which was class III beta tubulin and Protein kinase C gamma protein markers respectively, which still showed an equal result in PCR detection. As a recommendation of future study [30], some cell proliferation and neurogenesis markers like Ki-67 [31], Mash-1 [32] and GFAP, an astrocytes and microglia cell markers [33] can be further detected to help making sure more effects of Ex-4 on rodent stroke model. Therefore, based on the results of animal model study, we draw the conclusion that, Ex-4 a Glucagon-like peptide 1 receptor agonist prevent neuron from death in the ischaemicmice model.

Contribution

Hao Lyu and Meng Zhang conceived and designed the study. Rui Chen and Zetao Wu contributed to the animal experiments, behavioral tests, histology, and statistical analysis. Xiaojia Liu, Yi He Raxida Umar contributed to the animal observation and care. Hao Lyu, Meng Zhang and Jianming Wu supervised the study. Rui Chen drafted the manuscript. Hao Lyu and Meng Zhang revised the manuscript.

Declarations of Interest

NO.

Ethics Declarations

The procedures involving animals and their care were conducted under the approval of the Animal Ethics Committee of the Second People’s Hospital of Shenzhen.

Funding

Shenzhen Fundamental Research Program (JCYJ20200109110420626).

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Clinical Pharmacology of Clarithromycin

Introduction

Antimicrobial Activity of Clarithromycin

Clarithromycin is a macrolide antibiotic and has good activity against Moraxella catarrhalis, Chlamydia species, Mycoplasma pneumoniae, Helicopter pylori, Borrelia burgdorferi, Legionella pneumonia, and Mycobacterium leprae. Clarithromycin has enhanced activity against some non-tuberculous mycobacteria, as well as against some protozoa (e.g., Toxoplasma gondii, Cryptosporidium, and Plasmodium species) [1].

Absorption, Distribution, Metabolism and Elimination of Clarithromycin

Clarithromycin is absorbed rapidly from the gastrointestinal-tract after oral administration, but hepatic first-pass metabolism reduces its bioavailability to 50% to 55%. Peak concentration occurs about 2 hours after drug administration. Clarithromycin may be given with or without food, but the extended-release form should be administered with food to improve the bioavailability. Clarithromycin and its active metabolite, 14-hydroxy-(R)-clarithromycin, achieve high intracellular concentrations throughout the body, including the middle ear. Clarithromycin is metabolized in the liver to several metabolites and the active 14-ydroxy metabolite is the most significant. The elimination half-life is 3 to 7 hours for clarithromycin and 5 to 9 hours for 14-hydroxy-clarithromycin. Metabolism is saturable, resulting in nonlinear pharmacokinetics and longer half-lives with higher dosages. The amount of clarithromycin excreted unchanged in the urine ranges from 20% to 40% depending on the dose administered and the formulation (tablet versus oral suspension). An additional 10% to 15% of a dose is excreted in the urine as 14-hydroxy-claritrhinycin. Dose adjustment is not recommended unless the creatinine clearance is less than 30 ml/min [1] (Figure 1).

Figure 1

Literature Search

The literature search was performed electronically using PubMed database as search engine and the following key words were used: “clarithromycin efficacy, safely”, “clarithromycin prophylaxis”, “clarithromycin treatment”, “clarithromycin trials”, “clarithromycin metabolism”, “clarithromycin pharmacokinetics”, clarithromycin tissue concentration”, “clarithromycin drug interactions”, and “clarithromycin toxicity”. In addition, the book: Goodman@Gilman’s. The Pharmacological basis of Therapeutics [1] has been consulted.

Results

Efficacy and Safely of Clarithromycin

Forty-six patients with chest infected by Legionella pneumonia received clarithromycin orally at the dose of 500 to 1,000 mg twice-daily and the response-rates were as follows: clinical cure-rate 98%, clinical success (cure or improved) 100%, radiographic success (cure and improved) 93%, and bacteriological cure 100%. Ten patients reported 13 adverse-effects (7 mild, 4 moderate, and 2 severe). Clarithromycin is an effective and safe treatment of patients with severe chest infections due to Legionella pneumophila [2]. Six patients with pan-bronchiolitis were treated with clarithromycin orally at the daily dose of 200 mg for 4 years and the pulmonary function improved in most of patients within 6 months of treatment. The forced expiratory volume in 1 second showed a maximal increase from 1.74±0.12 at baseline to 2.31±0.22 at 6 months (P-value < 0.01) and the volume of forced vital capacity also showed a maximal increase within 6 months of treatment. The partial pressure of arterial oxygen significantly increased within 3 to 6 months of treatment. The comprehensive improvement scores also reached maximum within 6 months of treatment. Patients maintained a stable condition with continued therapy and no adverse-effects due to clarithromycin were observed. These results indicate that 6-month treatment with clarithromycin is sufficient to improve the clinical conditions of patients with pan-bronchiolitis and the drug was safely used for a long-term treatment [3].

A total of 2,351 patients with acute, mild, or moderate respiratory- tract infection received clarithromycin orally at the dose of 250 mg twice-daily for 7 days. The clinical-rate was 93.2% and 110 adverse-effects (4.7%) were reported. Of these, 71 adverse-effects (64.5%) were related to the gastrointestinal-tract. This treatment was well-tolerated and was an effective therapy for the management of acute, mild, or moderate respiratory-tract infection [4]. Thirty-nine patients with multidrug-resistant tuberculosis, aged 41 years (range, 29 to 49), received clarithromycin orally at the daily dose of 1,000 mg. The minimum inhibitory concentration (MIC) for clarithromycin ranged from < 2 to 8 μg/ml and the serum concentration of clarithromycin was one order of magnitude higher than the MIC for clarithromycin. Clarithromycin was efficacy and well-tolerated in patients with multidrug-resistant tuberculosis [5]. Children, aged ≤ 12 years, with upper respiratory-tract infection received clarithromycin and the treatment was safe and effectively treated children with upper respiratory-tract infection. Clarithromycin was superior to other antibiotics for the treatment of children with upper respiratory-tract infection [6].

Prevention of Bacterial Infections with clarithromycin

Two-hundred-forty pregnant women undergoing non-elective Caesarean delivery were enrolled and 133 women (62.1%) received clarithromycin and 81 women (37.8%) received placebo. Women who received clarithromycin had significantly lower-rate of postpartum endometritis (P-value = 0.025) and significantly lower risk of developing endometritis (P-value = 0.040) than women who received placebo. The surgical prophylaxis with clarithromycin in women undergoing non-elective Caesarean delivery lowers postpartum endometritis and reduces the risk of developing endometritis compared the women who received placebo [7]. It was evaluated the effect of prophylactic clarithromycin in prevention of disseminated Mycobacterium- avium-complex infection in patients with advanced HIV disease. One-hundred-ninety-two HIV-infected patients were enrolled, 84 patients (43.7%) received clarithromycin orally at the dose of 500 mg once-daily, 47 patients (24.5%) received rifabutin orally at the dose of 300 mg once-daily, and 61 patients (31.8%) did not received the prophylaxis. The prophylaxis with clarithromycin was associated with a reduction in the incidence of disseminated Mycobacterium- avium-complex infection, appeared to be superior to rifabutin, and was associated with prolonged survival in patients with advanced HIV disease [8]. It was assessed the effect of prophylactic clarithromycin on Mycobacterium-avium-intracellulare infection in patients with acquired immunodeficiency syndrome. Six-hundred-eight-four patients with Mycobacterium-avium-intracellulare infection were enrolled. The Mycobacterium-avium-intracellulare infection occurred in 31 patients (4.5%) treated with clarithromycin and in 87 patients (12.6%) who received placebo (P-value < 0.001). Clarithromycin prevented the Mycobacterium-avium-intracellulare infection, prolonged survival, and was well-tolerated. [9].

Treatment of Bacterial Infections with Clarithromycin

A 74-year-old woman and a 77-year-old man with rheumatoid arthritis underwent bronchoalveolar lavage which was infected by Mycobacterium-avium. The patients received clarithromycin orally at the daily dose of 1,000 mg for 10 days and both patients were cured [10]. Forty-one patients with erythema migrans received clarithromycin orally at the dose of 500 mg twice-daily for 21 days for treatment of early Lyme disease. Symptoms resolved in 37 patients (90.2%) immediately after the start of treatment and symptoms disappeared in all patients at the end of treatment. Clarithromycin is an effective agent for treatment of early Lyme disease [11]. Clarithromycin was administered orally at the dose of 250 mg twice-daily for 5 to 14 days to 299 patients suffering from dermatologic bacterial infections and clarithromycin effectively treated skin and skin-structure infections [12]. Forty-three patients, aged 32 years (range, 21 to 56), had chronic rhinosinusitis and were treated with clarithromycin orally at the dose of 500 mg twice-daily for 7 days (high-dose) followed by 250 mg twice-daily for 7 days (low-dose). The high-dose of clarithromycin treated chronic rhinosinusitis significantly better (P-value = 0.025) in terms of clinical efficacy than the low-dose. The high-dose of clarithromycin was more effective than the low-dose for treatment of chronic rhinosinusitis [13]. Three-hundred-seventy-six patients with acute exacerbations of chronic bronchitis received either ciprofloxacin or clarithromycin orally at the dose of 500 mg twice-daily for 14 days. The clinical resolution was observed in 89.9% of patients who received ciprofloxacin and in 82.4% of patients who received clarithromycin (P-value > 0.05). The median infection-free interval was 142 days for ciprofloxacin recipients and 51 days for clarithromycin recipients (P-value = 0.015). Bacteriological eradication-rate was 93.6% for ciprofloxacin recipients and 77.0% for clarithromycin recipients (P-value = 0.01). Ciprofloxacin was associated with longer infection-free interval and a higher bacteriological eradication-rate [14].

Trials Conducted with Clarithromycin

A prospective, self-controlled trial was conducted in 18 patients with refractory chronic rhinosinusitis who received clarithromycin orally at the dose of 250 mg once-daily for 12 weeks. Significant improvement was observed in nasal congestion, rhinorrhoea, and postnasal drip (P-value < 0.05) within 4 weeks of treatment. Analysis of middle nasal meatus flora revealed a significant decrease of Streptococcus pneumoniae after 12 weeks of treatment (P-value < 0.05). Low-dose and long-term clarithromycin treatment improved the clinical symptoms in patients with refractory chronic rhinosinusitis and facilitates the nasal mucosal epithelialization [15]. A randomized, placebo-controlled, double-blind trial was conducted with clarithromycin in patients with AIDS. Mycobacterium-avium-complex infection developed in 19 of the 333 patients (5.7%) assigned to clarithromycin and in 53 of the 334 (15.9%) assigned to placebo (P-value < 0.001). During the follow-up period of 10 months, 32.0% of the patients who received clarithromycin died and 41.1% of those who received placebo group died (P-value = 0.026). In patients with AIDS, the prophylactic administration of clarithromycin was well-tolerated, prevented Mycobacterium-avium-complex infection, and reduced the mortality [16]. A randomized, blinded, multicentre trial compared the efficacy and safely of oral clarithromycin and amoxicillin/clavulanate in treatment of acute otitis media in 338 children aged 6 months to 12 years. Children received either clarithromycin 7.5 mg/kg twice-daily (N = 161, 47.6%) for 10 days or amoxicillin/clavulanate 13.3 mg/kg thrice-daily (N = 177, 52.4%) for 10 days. The efficacy was assessed by clinical examination performed within 48 hours of finishing the medication. A successful clinical response was seen in 121 of 135 children (89.6%) who received clarithromycin children and in 133 of 145 children (91.7%) who received amoxicillin/clavulanate (P-value = 0.681). The clinical failure or relapses occurred in 14 of 135 children (10.4%) who received clarithromycin and in 12 of 145 children (8.3%) treated with amoxicillin/clavulanate-treated (P-value > 0.05). Diarrhoea was the most frequent adverse-effect which occurred in 19 of 161 children (11.8%) treated with clarithromycin and in 57 of 177 children (32.2%) who received amoxicillin/clavulanate (P-value < 0.001). These results indicate that the efficacy of clarithromycin was comparable to that of amoxicillin/clavulanate in treatment of children with acute otitis media and clarithromycin induces less diarrhoea than amoxicillin/clavulanate [17]. A multicentre, single-blind, comparative trial was conducted in 379 children, aged 6 months to 12 years, with acute otitis media. Children were randomized to receive either clarithromycin orally at the dose of 7.5 mg/kg once-daily for 10 days (N = 229, 60.4%) or cefaclor orally at the dose of 20 mg/kg twice-daily (N = 150, 39.6%) for 10 days. The clinical success (cure or improvement) was achieved in 86.1% of children who received clarithromycin and in 90.2% of children who received cefaclor (P-value > 0.05) and both drugs were well-tolerated. Clarithromycin and cefaclor were similarly effective for treatment of children with acute otitis media [18]. A prospective, randomized, single-blind, parallel-group trial was conducted to compare the clinical efficacy of clarithromycin versus that of erythromycin in 153 children with pertussis aged 1 month to 16 years. Children received either clarithromycin orally at the dose of 7.5 mg/kg twice-daily for 7 days (N = 76, 49.7%) or erythromycin orally at the dose of 13.3 mg/kg thrice-daily day for 14 days (N = 77, 50.3%). Microbiologic eradication and clinical cure-rates were 100% for clarithromycin and 96.2% for erythromycin (P-value > 0.05). The adverse-effects occurred in 34 of 76 children (44.7%) treated with clarithromycin and in 48 of 77 children (62.3%) treated with erythromycin (P-value = 0.035). A 7-day regimen of clarithromycin and a 14-day course of erythromycin were equally effective for treatment of children with pertussis and clarithromycin was better tolerated than erythromycin [19]. A multicentre, double-blind, randomized trial was conducted to assess the efficacy and safely of clarithromycin versus those of erythromycin stearate in treatment of community-acquired pneumonia. Two-hundred-eight patients were enrolled and 96 patients (46.1%) received clarithromycin orally at the dose of 250 mg twice-daily and 112 patients (53.8%) received erythromycin stearate orally at the dose of 500 mg 4 times-daily. The clinical cure, the clinical success, and the radiological response were similar in patients treated with clarithromycin and in those treated with erythromycin. The clinical cure-rate after two weeks of treatment occurred in 43 patients (47.9%) who received clarithromycin and in 17 patients (15.1%) who received erythromycin stearate (P-value = 0.003), whilst improvement in cough was observed in 93 patients (96.9%) who received clarithromycin and in 89 patients (80.0%) who received erythromycin stearate (P-value = 0.07). The adverse-effects, mainly gastrointestinal, causing the discontinuation of treatment occurred in 4 of 96 patients (4.1%) treated with clarithromycin and in 21 of 12 patients (18.7%) treated with erythromycin (P-value < 0.01). These results indicate that clarithromycin twice-daily was as effective as erythromycin stearate 4 times-daily for treatment of community-acquired- pneumonia and clarithromycin was better tolerated [20].

Metabolism of Clarithromycin

The metabolic fate of clarithromycin was studied following the administration of a single oral dose of 250 mg or 1,200 mg of 14C-clarithromycin to 6 healthy adult males. The peak plasma concentration of clarithromycin averaged to 0.6 μg/ml after the low-dose and to 2.7 μg/ml after the high-dose. The major metabolite found in plasma and in urine was the microbiologically active 14-hydroxy-(R)-clarithromycin. The low-dose and the high-dose of 14C-clarithromycin were administered for 5 days to 6 healthy adult males. Following the low-dose a mean of 38.1% of radioactivity (18.0% as clarithromycin) was recovered in the urine and following the high-dose a mean of 46.2% of radioactivity (29.1% as clarithromycin) was recovered in the urine, with approximately one-third eliminated during the first 24 hours. The urinary and faecal metabolites revealed the involvement of three metabolic pathways, hydroxylation which gives rise to 14-hydroxy-(R)-clarithromycin and 14-hydroxy-(S)-clarithromycin, N-demethylation, and hydrolysis of the cladinose sugar. The overall recovery of metabolites decreased up to 42.0% after the high-dose suggesting that the metabolism of clarithromycin is saturated [21]. The main metabolites of clarithromycin are 14-hydroxy-(R)-clarithromycin a microbiologically active metabolite and 14-hydroxy-(S)-clarithromycin an inactive metabolite and these metabolites are formed by CYP3A4 [22]. Clarithromycin is rapid absorbed following oral administration and the peak concentration is reached within 2 hours after dosing. The bioavailability of clarithromycin is about 50% after the oral administration and clarithromycin is converted into 14-hydroxy- clarithromycin in the liver before entering the systemic circulation. The antimicrobial activity of 14-hydroxy-(R)-clarithromycin is superior to that of the parent compound. Following the oral administration of 250 mg of film-coated clarithromycin, the peak serum concentration of clarithromycin and that of 14-hydroxy-(R)-clarithromycin is 1.5 and 0.8 μg/ml, respectively. There is a progressive increase in serum concentrations of clarithromycin and 14-hydroxy-(R)-clarithromycin with renal impairment so that the clarithromycin dose should be reduced in severe renal impairment (glomerular filtration- rate < 30 ml/min) [23].

Pharmacokinetics of Clarithromycin and Penetration of Clarithromycin into Human Tissues

Traumuller, et al. [24] studied the pharmacokinetics of clarithromycin in plasma, in interstitial-space fluid of subcutaneous adipose tissue (subcutis), and in skeletal muscle of 6 healthy male volunteers, aged from 25 to 37 years, following a single oral dose of 250 mg of clarithromycin. A plastic cannula was inserted into an antecubital vein to monitor the blood concentrations of clarithromycin at defined time points. Concentrations of clarithromycin in subcutis and in skeletal muscle were determined by micro-dialysis. A micro-dialysis probe with a molecular weight cut-off of 20,000 was inserted into one thigh muscle and into the subcutis and the probe was constantly perfused with ringer’s solution at a flow rate of 1.5 μl/min by means of a precision pump. After a 60 min equilibration period, 250 mg of clarithromycin was administered orally to the fasting volunteers. At 12 hours after the initial single dose of 250 mg, each volunteer continued to receive oral clarithromycin at the dosage of 500 mg twice-daily for 3 to 5 days. Table 1 summarizes the pharmacokinetic parameters of clarithromycin following a single oral dose of 250 mg of clarithromycin and Table 2 summarizes the pharmacokinetic parameters of clarithromycin following an oral dose of 500 mg twice-daily.

Table 1: Pharmacokinetic parameters of clarithromycin which have been obtained following the administration of a single oral dose of 250 mg of clarithromycin to 6 healthy male volunteers. Values are the mean±SD by (Traunmüller et al. [24]).

Note: AUC = area under the concentration-time curve. Tmax = time to reach the peak concentration. *Elimination half-life. DV = distribution volume. TBC = total body clearance. ^bCalculated for single dose of 250 mg. ^cThe area under the concentration-time curve and the peak concentration of clarithromycin in subcutis and muscle are lower (P-value < 0.03) that those in plasma.

Table 2: Pharmacokinetic parameters of clarithromycin which have been obtained following the oral administration of 500 mg of clarithromycin twice-daily to 6 healthy male volunteers. Values are the mean±SD by (Traunmüller et al. [24]).

Note: AUC = area under the concentration-time curve. Tmax = time to reach the peak concentration. *Elimination half-life. DV = distribution volume. TBC = total body clearance. ^bValues calculated on the basis of dosing twice-daily. ^cThe area under the concentration-time curve and the peak concentration of clarithromycin in subcutis and muscle are lower (P-value < 0.03) those that in plasma.

The area under the concentration-time curve and the peak concentration of clarithromycin are higher in plasma than in subcutis and in muscle. The mean elimination half-life of clarithromycin in plasma is 1.9 hours and is 2.4 and 3.1 hours in subcutis and in muscle, respectively. The concentration of free clarithromycin is lower than the total concentration of clarithromycin. Clarithromycin rapidly penetration into the subcutis and into the muscle as the time to reach the peak concertation is about 3 hours. The distribution volume of clarithromycin is similar to the water volume. This table shows that the area under the concentration-time curve and the peak concentration of clarithromycin in plasma, in subcutis, and in muscle are higher than those obtained following the single oral dose of 250 mg of clarithromycin. The area under the concentration-time curve and the peak concentration of clarithromycin are higher in plasma than in subcutis and in muscle. Clarithromycin rapidly penetrates into the subcutis and muscle as the time to reach the peak concentration is about 4 hours. Clarithromycin is rapidly eliminated as the elimination half-life is about 3.7 hours in plasma, in subcutis, and in muscle and the elimination half-live of clarithromycin in plasma, in subcutis, and in muscle are longer than those obtained following a single oral dose of 250 mg. The metabolism of clarithromycin is saturated thus longer half-life is obtained with higher doses of clarithromycin. The distribution volume of clarithromycin is larger than the water volume and is larger than that obtained following the single oral dose of 250 mg.

Concentrations of Clarithromycin and 14-Hydroxy-( R)-Clarithromycin in Serum and in Sputum

Tsang et al. [25] measured the concentration of clarithromycin and 14-hydroxy-(R)-clarithromycin in serum and in sputum 4, 8, and 24 hours after the administration of a single oral dose of 250 or 500 mg of clarithromycin to 8 patients with idiopathic bronchiectasis having a mean age of 53.3 years. Table 3 summarizes the concentrations of clarithromycin and 14-hydroxy-(R)-clarithromycin in serum and in sputum of 8 patients with idiopathic bronchiectasis. (Raghunatha [26]) administered clarithromycin orally at the dose of 500 mg once daily for 3 days to 20 patients aged 25 to 45 years. Six hours after the last dose, the mean concentrations of clarithromycin in serum and in periodontal tissue were 0.465 μg/ml and 2.61 μg/gram, respectively, indicating that clarithromycin accumulates into the periodontal tissue. (Burrell [27]) administered clarithromycin orally at the dose of 500 mg once-daily for 6 consecutive days to 8 healthy volunteers and experimental gingivitis was induced in these subjects. The mean clarithromycin concentrations in gingiva of healthy control subjects and in inflamed gingiva were 2.4 and 3.0 μg/gram, respectively, and were significantly higher than that found in serum which was 0.5 μg/ ml; P-value < 0.05. Clarithromycin concentrations in gingiva of control subjects and in gingivitis were higher than in serum by 5.7-fold and 7.0-fold, respectively; P-value = 0.02. Clarithromycin attained higher concentration in gingiva than in serum and reached higher concentration in inflamed gingiva than in healthy gingiva.

Table 3: Concentrations of clarithromycin and 14-hydroxy-(R)-clarithromycin which have been obtained in serum and in sputum of 8 patients with idiopathic bronchiectasis. Values are the mean±SD, by Tsang, et al. [25].

Note: CLA = clarithromycin. HCL = 14-hydroxy-(R)-clarithromycin. This table shows that the concentrations of clarithromycin and 14-hydroxy-(R)-clarithromycin are similar in serum and sputum.

Wust and Hardegger [28] administered a single oral dose of 500 mg of clarithromycin to 10 healthy volunteers. Two hours after administration, clarithromycin concentration was 4.04±1.14 μg/ml in serum and 2.72±0.87 μg/ml in saliva. Seven hours after administration, these concentrations were 1.98±0.65 and 1.21±0.34 μg/ml, respectively, and at the end of the dosing interval of 12 hours these concentrations were 0.95±0.38 and 0.73±0.35 μg/ml, respectively. These results indicate that the concentration of clarithromycin is lower (P-value < 0.05) in saliva than in serum. (Gotfried, et al. [29]) administered clarithromycin orally at the dose of 1,000 mg once-daily for 5 consecutive days to 42 non-smoking, healthy volunteers, aged 18 to 54 years. The concentrations of clarithromycin were measured in plasma, epithelial lining fluid, and in the alveolar macrophages and the concentrations of 14-hydroxy-clarithromycin were measured in plasma and in alveolar macrophages. Table 4 shows the steady-state concentrations of clarithromycin in plasma, epithelial lining fluid, and in alveolar macrophages and the concentrations of 14-hydroxy-clarithromycin in plasma and in alveolar macrophages obtained at 6 times after the oral administration of 1,000 mg of clarithromycin to 42 non-smoking healthy volunteers.

Table 4: Steady-state concentrations of clarithromycin which have been obtained in plasma, epithelial lining fluid, and alveolar macrophages and concentrations of 14-hydroxy-clarithromycin which have been obtained in plasma and in alveolar macrophages following the oral administration of 1,000 mg once-daily of clarithromycin to 42 non-smoking, healthy volunteers. Values are the mean±SD, by (Gotfried et al. [29]).

Note: ELF = epithelial lining fluid. AM = alveolar macrophages. ASubjects who had clarithromycin concentration equal or below the quantitative limit of detection. This table shows that the concentrations of clarithromycin in the epithelial lining fluid (P-value < 0.05) and in the alveolar macrophages (P-value < 0.001) are significantly higher than that in plasma and the concentration of clarithromycin in alveolar macrophages is significantly higher (P-value < 0.001) than that in the epithelial lining fluid. The concentration of 14-hydroxy-clarithromycin is significantly higher (P-value < 0.01) in the alveolar macrophages than in plasma.

Interaction of Clarithromycin with Drugs

It was assessed the interaction between clarithromycin and the calcium-channel-blocker amlodipine. Clarithromycin is an inhibitor of CYP3A4 which metabolizes amlodipine thus clarithromycin inhibits the metabolism of amlodipine causing an increase in amlodipine serum concentration [30]. The area under the concentration-time curve of esomeprazole approximately doubled when esomeprazole was co-administered with clarithromycin. Clarithromycin decreased the metabolic-rate of esomeprazole being an inhibitory of CYP2C19 leading to an increase in the serum concentration of esomeprazole [31]. It was assessed the interaction of clarithromycin with rifampicin. Rifampicin induces CYP3A4 which metabolizes clarithromycin thus the co-administration of rifampicin with clarithromycin caused a reduction of the serum concentration of clarithromycin [32]. It was assessed the interaction of clarithromycin with rifampicin. It was measured the plasma concentration of clarithromycin and 14-hydroxy-( R)-clarithromycin in 9 patients before and after the addition of rifampicin. After the addition of rifampicin, the mean plasma concentration of clarithromycin significantly decreased while that of 14-hydroxy-(R)-clarithromycin did not [33]. It was evaluated the pharmacokinetic interaction between clarithromycin and rifabutin. Rifabutin caused a mean reduction of 44% (P-value = 0.003) of the area under the plasma concentration-time curve (AUC) of clarithromycin while caused a mean increase of 57% (P-value = 0.004) in the AUC of 14-hydroxy-clarithromycin.Clarithromycin caused a mean reduction of 99% (P-value = 0.001) of rifabutin AUC and a mean increase of 375% (P-value < 0.001) of the AUC of rifabutin metabolite 25-O-desacetyl-rifabutin. The co-administration of clarithromycin with rifabutin resulted in significant bidirectional pharmacokinetic interactions [34].

Toxicity Induced by Clarithromycin Co-Administered with Drugs

It was assessed the effect of the co-administration of clarithromycin with colchicine in 116 patients. Nine of 88 patients (10.2%) who received clarithromycin and colchicine concomitantly died and only 1 of 28 patients (3.6%) who received the drugs sequentially died. Multivariate analysis of 88 patients who received concomitant therapy showed the presence of renal impairment (relative risk: 9.1; 95% confidence interval: 1.75 to 47.06; P-value < 0.001). Clarithromycin increased the risk of fatal colchicine toxicity especially in patients with renal insufficiency [35]. Carbamazepine is metabolized into carbamazepine- 10,11-epoxide by CYP3A4 and clarithromycin is an inhibitor of CYP3A4 and the serum levels of carbamazepine increased in patients while taking clarithromycin and 3 patients developed toxic serum levels of carbamazepine. There was a serious drug interaction between carbamazepine and clarithromycin thus the dosage of carbamazepine should be reduced by 30% to 50% when carbamazepine is co-administered with clarithromycin and the serum concentration of carbamazepine should be monitored [36]. An epileptic woman 64-year-old was maintained on carbamazepine and received clarithromycin to treat chest infection. Three days after the administration of clarithromycin the serum concentration of carbamazepine became 17.6 μg/ml and this toxic serum concentration of carbamazepine caused symptoms like ataxia, nystagmus, drowsiness, agitation, dilated pupil, respiratory depression, coma and electrolyte disturbances like hyponatraemia and hypokalaemia [37]. A 56-year-old woman with history of severe rheumatic mitral stenosis and atrial fibrillation was treated with digoxin orally at the daily dose of 0.25 mg and she also received clarithromycin orally at the dose of 500 mg twice-daily to treat community-acquired-pneumonia. Two days after clarithromycin administration, she developed profound weakness, associated with nausea, vomiting, dizziness and dyspnea. Clarithromycin inhibits CYP3A4 which metabolizes digoxin thus the serum concentration of digoxin became high and caused toxicity when digoxin is co-administered with clarithromycin [38]. A 78-year-old woman was maintained on digoxin orally at the daily dose of 0.25 mg to treat congestive heart failure and she also received clarithromycin orally at the dose of 500 mg twice-daily. Three days after clarithromycin treatment she developed nausea, vomiting, and diarrhea. The treatment with clarithromycin was discontinued and the toxic symptoms ceased [39].

Discussion

Clarithromycin is a macrolide antibiotic and has good activity against Moraxella catarrhalis, Chlamydia species, Mycoplasma pneumoniae, Helicopter pylori, Borrelia burgdorferi, Legionella pneumonia, and Mycobacterium leprae. Clarithromycin has enhanced activity against some non-tuberculous mycobacteria, as well as against some protozoa (e.g. Toxoplasma gondii, Cryptosporidium, and Plasmodium species). Clarithromycin is rapidly absorbed from the gastrointestinal- tract but is metabolized presystemically and the bioavailability of clarithromycin is about 50%. The metabolism of clarithromycin is saturable resulting in nonlinear pharmacokinetics and longer half-life occurs following the administration of higher doses of clarithromycin [1]. The efficacy and safely of clarithromycin have been reviewed. Following the oral dose of 500 to 1,000 mg twice-daily of clarithromycin to 46 patients with severe chest infection this drug has been found efficacy and safely and causes adverse-effects in only 10 patients (21.7%) [2]. Patients with pan-bronchiolitis were treated with clarithromycin orally at the daily dose of 200 mg for 4 years and the pulmonary function improved in most patients within 6 months of treatment. Patients maintained stable condition with continued therapy, not adverse-effects were observed, thus 6 month treatment with clarithromycin is sufficient to improve the clinical conditions, and clarithromycin has been found safe for a long-term treatment [3]. Patients with acute, mild, or moderate respiratory-tract infection received clarithromycin orally at the dose of 250 mg twice-daily for 7 days. The clinical-rate was 93.2% and the adverse-effects were reported in only 4.7% of patients. This treatment is well-tolerated and is an effective therapy for the management of respiratory-tract infections [4]. Patients with multidrug-resistant tuberculosis received clarithromycin orally at the daily dose of 1,000 mg and this treatment is found efficacy and well-tolerated [5]. Children with upper respiratory-tract infection received clarithromycin which effectively treats the children and is superior to other antibiotics for the treatment of children with upper respiratory-tract infection [6]. These results indicate that clarithromycin is efficacy and safe in treatment of chest infection caused by Legionella pneumonia, pan-bronchiolitis, and respiratory-tract infection in adults and in children. The prevention of bacterial infections with clarithromycin has been reviewed. Pregnant women undergoing non-elective Caesarean delivery received clarithromycin or placebo. Women who received clarithromycin had lower-rate of postpartum endometritis (P-value = 0.025) and lower risk of developing endometritis (P-value = 0.040) than women who received placebo [7]. Patients with disseminated Mycobacterium-avium-complex and with advanced HIV disease received prophylactic clarithromycin administered orally at the dose of 500 mg once-daily (43.7% patients), or prophylactic rifabutin administered orally at the dose of 300 mg (24.7% patients), or did not received prophylaxis (31.8% patients). Clarithromycin is associated with a reduction in the incidence of disseminated Mycobacterium-avium-complex, is superior to rifabutin, and prolongs survival in these patients [8]. Patients with Mycobacterium-avium-intracellular infection and with acquired-immunodeficiency-syndrome received prophylactic clarithromycin or received placebo. The Mycobacterium- avium-intracellulare infection occurs in 4.5% of patients treated with clarithromycin and in 12.6% of patients who received placebo (P-value < 0.001). Clarithromycin prevents the Mycobacterium- avium-intracellular infection, prolongs survival in these patients, and is well-tolerated [9]. These results indicate that the prophylaxis with clarithromycin reduces the postpartum endometritis and lowers the risk of developing endometritis in women undergoing non-elective Caesarean delivery, prevents disseminated Mycobacterium-avium- intracellular infection in patients with HIV disease, and prolongs survival in patients with Mycobacterium-avium-intracellular infection. The treatment of bacterial infections with clarithromycin has been reviewed. An old woman and an old man had the bronchoalveolar lavage infected by Mycobacterium-avium, received clarithromycin orally at the daily dose of 1,000 mg for 10 days and the bronchoalveolar lavage became sterile [10]. Patients with erythema migrans received clarithromycin orally at the dose of 500 mg twice-daily for 21 days to treat early Lyme disease. This treatment cured 90.2% of patients immediately after the start of treatment and symptoms disappeared in all patients at the end of treatment [11]. Clarithromycin was administered orally at the dose of 250 mg twice-daily for 5 to 14 days to patients suffering from dermatological infections and this treatment effectively treats skin and skin-structure infections [12]. Patients with chronic rhinosinusitis received clarithromycin orally at the dose of 500 mg twice-daily for 7 days (high-dose) followed by 250 mg twice-daily for 7 days (low-dose). The high-dose is more effective (P-value = 0.025) than the low-dose for treatment of chronic rhinosinusitis [13]. Patients with acute exacerbations of chronic bronchitis received either ciprofloxacin or clarithromycin orally at the dose of 500 mg twice-daily for 14 days. The clinical resolution of symptoms was similar in patients who received ciprofloxacin and in those who received clarithromycin but the median infection-free interval was 142 days for ciprofloxacin recipients and 51 days for clarithromycin recipients (P-value = 0.015) and the eradication-rate was 93.6% for ciprofloxacin recipients and 77.0% for clarithromycin recipients (P-value = 0.01). Ciprofloxacin is associated with longer infection-free interval and with higher bacteriological eradication-rate [14]. These results indicate that clarithromycin sterilizes the bronchoalveolar lavage infected by Mycobacterium-avium, treats patients with Lyme disease, patients with skin and skin-structure infections, with chronic rhinosinusitis and treats the chronic bronchitis as ciprofloxacin. The trials conducted with clarithromycin have been reviewed. A prospective, self-controlled trial was conducted in patients with chronic rhinosinusitis who received clarithromycin orally at the dose of 250 mg once-daily for 12 weeks. Nasal congestion, rhinorrhoea, and postnatal drip improved (P-value < 0.05) within 4 weeks of treatment and the decrease of Streptococcus pneumoniae density in middle nasal meatus was observed after 12 weeks of treatment (P-value < 0.05). Lowdose and long-term clarithromycin treatment improves refractory chronic rhinosinusitis and facilities the nasal epithelization [15]. A randomized, placebo-controlled, double-blind trial was conducted with clarithromycin in patients with AIDS. Mycobacterium-avium- complex infection developed in 5.7% of patients who received clarithromycin and in 15.9% of patients who received placebo (P-value < 0.001). During 10 months of follow-up, 32.0% of patients who received clarithromycin and 41.1% of patients who received placebo (P-value = 0.026) died. Clarithromycin is well-tolerated, prevents Mycobacterium- avium-complex, and reduces the mortality [16]. A randomized, blinded, multicentre trial compared the safely and efficacy of clarithromycin administered orally at the dose of 7.5 mg/kg for 10 days versus those of amoxicillin/clavulanate administered orally at the dose of 13.3 mg/kg thrice-daily for 10 days in children with acute otitis media. The successful clinical response and the clinical failure or relapses were similar in both treatments. Diarrhoea was the most frequent adverse-effect and occurred in 11.8% of children who received clarithromycin and in 32.2% of children who received amoxicillin/ clavulanate (P-value < 0.001). Clarithromycin is effective as amoxicillin/clavulanate in treatment of acute otitis media and induces less diarrhoea [17]. A multicentre, single-blind, comparative trial was conducted in children with acute otitis media who received either clarithromycin orally at the dose of 7.5 mg/kg once-daily for 10 days or ceflacor orally at the dose of 20 mg/kg twice-daily for 10 days. Clarithromycin and ceflacor are similar effective in treatment of acute otitis media and both drugs are well-tolerated [18]. A prospective, randomized, single-blind, parallel-group trial was conducted in children with pertussis who received clarithromycin orally at the dose of 7.5 mg/kg for 7 days or erythromycin orally at the dose of 13.3 mg/kg thrice-daily for 14 days. The clinical cure was excellent in both treatments and the adverse-effects occurred in 44.7% and in 62.3% of children (P-value = 0.035) who received clarithromycin and erythromycin, respectively. A 7-day regimen of clarithromycin and a 14-day course of erythromycin are equally effective for treatment of children with pertussis and clarithromycin is better tolerated than erythromycin [19]. A multicentre, double-blind, randomized trial was conducted in patients with community-acquired-pneumonia who received either clarithromycin orally at the dose of 250 mg twice-daily or erythromycin stearate orally at the dose of 500 mg 4 times-daily. The clinical cure, the clinical success, and the radiological response were similar in patients treated with clarithromycin and in those treated with erythromycin but the clinical cure-rate after two weeks of treatment occurred in 47.9% and in 15.1% of patients who received clarithromycin and erythromycin stearate (P-value = 0.003), respectively, whilst improvement in cough was similar in both treatments. Adverse- effects, mainly gastrointestinal, occurred less frequently in patients treated with clarithromycin than in those who received erythromycin stearate (P-value < 0.01). Twice-daily clarithromycin is affective as 4 times-daily erythromycin stearate in treatment of community-acquired-pneumonia and clarithromycin is better tolerated [20]. The metabolism of clarithromycin has been reviewed. Following the administration of a single oral dose of 250 mg or 1,200 mg of 14C-clarithromycin to healthy men volunteers the plasma concentration of clarithromycin averaged to 0.6 and 2.7 μg/ml after the lowdose and the high-dose, respectively. The major metabolite found in plasma and in urine is the microbiologically active 14-hydroxy-( R)-clarithromycin and clarithromycin is also N-demethylated. The overall recovery of clarithromycin decreased up to 42.0% after the high-dose suggesting that the metabolism of clarithromycin is saturated [21]. The mean metabolites of clarithromycin are 14-hydroxy-( R)-clarithromycin a microbiologically active metabolite and 14-hydroxy-(S)-clarithromycin an inactive metabolite and both metabolites are formed by CYP3A4 [22]. Clarithromycin is rapidly absorbed following oral administration and the peak concentration is reached within 2 hours after dosing. Clarithromycin is metabolized presystemically in the liver and the bioavailability of clarithromycin is about 50% after oral administration. Following the oral administration of 250 mg of film-coated clarithromycin, the peak concentration of clarithromycin and that of 14-hydroxy-(R)-clarithromycin is 1.5 and 0.8 μg/ml, respectively. There is a progressive increase in serum concentrations of clarithromycin and 14-hydroxy-(R)-clarithromycin with renal impairment so that the clarithromycin dose should be reduced in severe renal impairment [23]. Traunmuller, et al. [24] studied the pharmacokinetics of clarithromycin in plasma and the penetration of clarithromycin into human interstitial-space fluid of subcutaneous adipose tissue (subcutis), and into the skeletal muscle. Following the administration of a single oral dose of 250 mg of clarithromycin to 6 healthy male volunteers, the elimination half-life of clarithromycin in plasma is 1.9±0.6 hours and following the oral administration of 500 mg of clarithromycin twice-daily the elimination half-life of clarithromycin in plasma is 3.7±0.6 hours. The metabolism of clarithromycin is saturable, resulting in longer half-life with higher doses. Following a single oral dose of 250 mg of clarithromycin to 6 healthy male volunteers, the peak concentration of clarithromycin is 1.09±0.35, 0.07±0.03, and 0.08±0.03 μg/ml in plasma, in subcutis, and in skeletal muscle, respectively, thus the peak concentration of clarithromycin is higher in plasma (P-value < 0.03) than in subcutis and in skeletal muscle. These results indicate that clarithromycin poorly penetrated into the subcutis and skeletal muscle. The elimination half-life of clarithromycin is 1.9±0.6, 2.4±1.2, and 3.1±0.9 hours in plasma, in subcutis, and in skeletal muscle, respectively, indicating that clarithromycin is eliminated faster in plasma than in subcutis and in skeletal muscle. Following the oral administration of 500 mg twice-daily to 6 healthy male volunteers the peak concentration of clarithromycin is 2.21±0.33, 0.23±0.10, and 0.23±0.09 μg/ml in plasma, in subcutis and in skeletal muscle, respectively, indicating that clarithromycin poorly penetrates into the subcutis and skeletal muscle. The elimination half-life of clarithromycin is 3.7±0.6, 3.4±1.2, and 3.8±1.1 hours in plasma and in subcutis and in skeletal muscle, respectively. These half-lives are longer than those obtained following a single oral dose of 250 mg of clarithromycin. The metabolism of clarithromycin is saturable, resulting in longer half-live with higher doses. (Tsang et al. [25]) measured the concentration of clarithromycin and 14-hydroxy-(R)-clarithromycin in serum and in sputum of 8 patients with idiopathic bronchiectasis following a single oral dose of 250 or 500 mg of clarithromycin and found that the concentrations of clarithromycin and 14-hydroxy-(R)-clarithromycin are similar in serum and in sputum. Raghunatha and George [26] administered clarithromycin orally at the dose of 500 mg once-daily to 20 patients and found that the mean concentration of clarithromycin is 0.465 and 2.61 μg/ml in serum and periodontal tissue, respectively, indicating that clarithromycin accumulates in the periodontal tissue. Burrell and Walters [27] administered clarithromycin orally at the dose of 500 mg once-daily for 6 days to 8 healthy volunteers and experimental gingivitis was induced in these subjects. The mean clarithromycin concentrations in healthy control subjects and in inflamed gingiva were 2.4 and 3.0 μg/gram, respectively, and were higher (P-value < 0.05) than that in serum which was 0.5 μg/ml. These results indicate that clarithromycin accumulates in gingiva. Wüst and Hardegger [28] administered a single oral dose of 500 mg of clarithromycin to 10 healthy volunteers. Two hours after dosing, the concentration of clarithromycin was 4.04±1.14 and 2.72±0.87 μg/ml in serum and in saliva, respectively, after 7 hours, these concentrations were 1.98±0.65 and 1.21±0.34 μg/ml, respectively, and after 12 hours these concentrations were 0.95±0.38 and 0.73±0.35 μg/ml, respectively. These results indicate that the concentration of clarithromycin is lower in saliva than in serum. Gotfried et al. [29] administered clarithromycin orally at the dose of 1,000 mg once-daily for 5 consecutive days to 42 non-smoking healthy volunteers and measured the concentration of clarithromycin in plasma, in epithelial lining fluid, and in the alveolar macrophages for 6 times, ranging from 3 to 48 hours, after the dose. The concentration of clarithromycin is higher in the epithelial lining fluid (P-value < 0.05) and in the alveolar macrophages (P-value < 0.001) than in plasma. These authors also measured the concentration of 14-hydroxy-(R)-clarithromycin in plasma and in alveolar macrophages and the concentration of 14-hydroxy-(R)-clarithromycin was higher (P-value < 0.01) in alveolar macrophages than in plasma. These results indicate that clarithromycin accumulates in the epithelial lining fluid and in the alveolar macrophages and 14-hydroxy-( R)-clarithromycin accumulates in the alveolar macrophages. The interaction of clarithromycin with drugs has been reviewed. Clarithromycin is an inhibitor of CYP3A4 which metabolizes amlodipine thus clarithromycin inhibits the metabolism of amlodipine causing an increase in amlodipine serum concentration [30], clarithromycin is an inhibitory of CYP2C9 which metabolizes esomeprazole thus clarithromycin decreases the metabolic-rate of esomeprazole increasing the serum concentration of esomeprazole [31], rifampicin induces CYP3A4 which metabolizes clarithromycin thus rifampicin reduces the plasma concentration of clarithromycin [32], rifampicin reduces the plasma concentration of clarithromycin while does not alter that of 14-hydroxy-(R)-clarithromycin [33], rifabutin reduces the area under the concentration-time curve (AUC) of clarithromycin, increases the AUC of 14-hydroxy-clarithromycin and clarithromycin reduces the AUC of rifabutin and increases the AUC of 25-O-desacetyl-rifabutin, a metabolite of rifabutin [34].

The toxicity induced by clarithromycin co-administered with drugs has been reviewed. The co-administration of clarithromycin with colchicine causes death in 10.2% of patients who received both drugs concomitantly and causes death in 3.6% of patients who received both drugs sequentially [35], carbamazepine is metabolized into carbamazepine-10,11-epoxide by CYP3A4 and clarithromycin is an inhibitor of CYP3A4 and the co-administration of clarithromycin with carbamazepine causes high concentration of carbamazepine which induces toxicity [36], an epileptic woman was maintained on carbamazepine and received clarithromycin to treat chest infection and the serum concentration of carbamazepine became 17.6 μg/ml and this toxic concentration of carbamazepine induced symptoms like ataxia, nystagmus, drowsiness, agitation, dilated pupil, respiratory depression, coma, and electrolytic disturbances like hyponatraemia and hypokalaemia [37], a woman received digoxin orally at the daily dose of 0.25 mg and she also received clarithromycin orally at the dose of 500 mg twice-daily and two days after clarithromycin administration she developed profound weakness associated with nausea, vomiting, dizziness and dyspnoea. Clarithromycin inhibits CYP3A4 which metabolizes digoxin thus the serum concentration of digoxin became high and caused toxicity [38], a woman was maintained on digoxin orally at the daily dose of 0.25 mg and she also received clarithromycin orally at the dose of 500 mg twice-daily and three days after clarithromycin administration she developed nausea, vomiting, and diarrhoea [39]. In conclusion, Clarithromycin is a macrolide antibiotic and has good activity against Moraxella catarrhalis, Chlamydia species, Helicopter pylori, Borrelia burgdorferi, Legionella pneumonia, Mycoplasma leprae, non-tuberculous mycobacteria, and some protozoa such as Toxoplasma gondii, Cryptosporidium, and Plasmodium species. The efficacy and safely of clarithromycin, the prevention and treatment of bacterial infections with clarithromycin have been reviewed. The trials conducted with clarithromycin and the metabolism of clarithromycin have been reviewed. Clarithromycin in metabolized into the microbiologically active 14-hydroxy-(R)-clarithromycin and into the inactive 14-hydroxy-(S)-clarithromycin and clarithromycin is also N-demethylated. The pharmacokinetics of clarithromycin have been reviewed. After a single oral dose of 250 mg of clarithromycin, the elimination half-life of clarithromycin in plasma is 1.09±0.35 hours and following the oral administration of clarithromycin at the dose of 500 mg twice-daily the elimination halflie of clarithromycin in plasma is 3.7±0.6 hours. The metabolism of clarithromycin is saturable thus longer half-life is observed following the administration of high doses. The penetration of clarithromycin and 14-hydroxy-(R)-clarithromycin into human tissues has been reviewed. Clarithromycin interacts with drugs and when clarithromycin is co-administered with colchicine, carbamazepine, or with digoxin causes toxicity. The aim of this study is to review the clinical pharmacology of clarithromycin.

Conflict of Interests

The authors declare no conflicts of financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employments, gifts, and honoraria. This article is a review and drugs have not been administered to men or animals.

Acknowledgments

The author thanks Dr. Patrizia Ciucci and Dr. Francesco Varricchio, of the Medical Library of the University of Pisa, for retrieving the scientific literature.

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A Case Report of High-Grade Endometrial Stromal Sarcoma in a 32-Year-Old Woman

Endometrial stromal sarcoma (ESS) represents a rare neoplasm of endometrial stromal lineage, constituting a mere 0.2% of all uterine malignancies and comprising 10% of uterine sarcomas [1,2]. It predominantly manifests in the premenopausal demographic. Highgrade endometrial stromal sarcoma (HG-ESS) is prevalent among individuals of advanced age, with an average age approximating 60 years, displaying a proclivity for heightened aggressiveness [3,4]. Common presenting manifestations of HG-ESS encompass irregular vaginal bleeding, discernible masses, and pelvic discomfort. The occurrence of HG-ESS in adolescents and young women is exceedingly uncommon, with scant documented cases in the extant literature [5]. Therefore, an amalgamation of documented instances of this exceptional clinical entity is imperative for a more comprehensive understand of its inherent trajectory. This study delineates a singular case of HG-ESS in a 32-year-old woman, whose presentation featured hypermenorrhea and the presence of a pelvic mass.

Case Report

A 32-year-old nulligravida woman presented with a six-month history of hypermenorrhea, accompanied by a palpable mass in the lower abdomen exhibiting rapid enlargement. Her medical history was devoid of noteworthy events. Transvaginal ultrasonography revealed an enlarged uterus, surpassing 10 cm in overall size, hosting a heterogenous mass within the endometrial cavity. Magnetic resonance imaging (MRI) disclosed an enlarged and well-defined uterine border with heterogeneous thickening in the endometrial cavity, encompassing the entire uterine corpus and cervix (Figure 1). A biopsy from the endometrial cavity was procured, and its histopathological examination indicated the potential presence of undifferentiated carcinoma with a heterogeneous component. The clinical suspicion pointed towards an advanced-stage malignancy of the cervix. At surgery, the uterus exhibited enlargement, and multiple nodules were identified in the cul-de-sac. The uterine serosa displayed diffuse involvement, harboring numerous tumor plaques. Neither the adnexae nor the omentum manifested any remarkable features. The surgical interventions encompassed total abdominal hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy, and resections of enlarged pelvic lymph nodes.

Figure 1

The postoperative phase transpired without incidents, and the final histopathological report delineated high-grade endometrial stromal sarcoma with a heterologous element, characterized by more than 10 mitoses per 10 high-power fields (Figure 2). Additional immunohistochemistry studies unveiled positive diffuse staining for CD34 and vimentin. The tumor exhibited negative staining for estrogen receptor, and progesterone receptor, melan A, c-kit, and EMA. A diagnosis of stage IIIC high-grade endometrial stromal sarcoma was established based on these investigative outcomes. During a twoweek deliberation concerning the diagnosis of high-grade ESS and the life-threatening nature of the condition, the patient encountered rapid disease progression, accompanied by vaginal bloody discharge emanating from the exophytic polypoid mass (1 x 1 cm) on the vaginal stump while undergoing adjuvant radiotherapy. Despite being slated to initiate adjuvant chemotherapy involving adriamycin, her employer and social supporters were diligently working towards facilitating her further treatment in her home country.

Figure 2

Comment

Due to the low incidence of HG-ESS, a dearth of distinct clinical manifestations and imaging features exists. A comprehensive literature review revealed eight singular case reports detailing highgrade endometrial stromal sarcoma occurrences in adolescents and young adults [5]. These instances often manifest as abnormal uterine bleeding, acute abdominal pain, and the presence of a pelvic mass, and hypermenorrhea in the current case. All previously documented cases were diagnosed at advanced stages (III and IV) during the initial assessment. Notably, three cases were reported in teenage girls [6-8], with one of them experiencing menarche at the age of 14 and commencing oral contraception at 15 [6]. HG-ESS exhibits significantly distinct biological characteristics from its low-grade counterpart: while low-grade ESS may manifest as estrogen-dependent, the investigation into HG-ESS occurrences in adolescents is ongoing [9]. Transvaginal ultrasonography and endometrial curettage, although beneficial in diagnosing endometrial polyps, uterine leiomyomas, or adenomyosis, prove unpredictable in diagnosing ESS. Magnetic Resonance Imaging (MRI) may identify ESS through the presence of heterogeneous areas within the lesion caused by aggressive tumor permeations into the myometrium. When coupled with contrast-enhanced Computed Tomography (CT), these modalities contribute to the preoperative diagnosis of potential extents, as seen in the current case. Treatment protocols encompass debulking surgery, followed by total hysterectomy with bilateral salpingo-oophorectomy and omentectomy [1,10,11].

The contentious nature of pelvic and para-aortic lymphadenectomy stems from its uncertain role [12]. Given the heightened risk of recurrence and metastasis associated with HG-ESS, postoperative adjuvant therapy assumes a pivotal role. To date, chemotherapy and pelvic external radiotherapy have been widely employed as adjuvant measures for HG-ESS. Notably, anthracyclines exhibit specific efficacy against sarcomas. Amant et al. [13] chronicled a case of transperitoneal HG-ESS complicating a pregnancy at 15 weeks, exploring diverse avenues to sustain the pregnancy, including anthracycline-based chemotherapy and cytoreductive surgery, even during gestation. Unfortunately, the patient succumbed to the disease six weeks post-diagnosis. In summary, we elucidated the clinical and imaging findings of a rare case involving a 32-year-old woman afflicted by HG-ESS. Despite the ongoing intensive adjuvant chemotherapy, the bleak prognosis associated with this disease underscores the imperative to maintain a high degree of suspicion for HG-ESS in the evaluation of any case presenting with abnormal uterine bleeding and the presence of a rapid growth of a pelvic mass.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Laboratory Use of Information Technology to Monitor Real-Time Challenges in the Pre-Analytical Phase

Introduction

Laboratory information aids healthcare professionals make proper diagnostic or therapeutic decisions, assisting with a prompt disposition for their patients (Eaton, et al. [1]). Accurate and timely reporting of laboratory analytes to ordering providers plays a significant role in hospital care quality (Cavallo, et al. [2,3]). Critical areas such as the ED rely on laboratory analytes’ expedited results to confirm an initial diagnosis that leads to a shorter length stay. It is essential to monitor the entire laboratory testing workflow’s efficiency because 60% to 70% of the objective information on the patient’s chart is laboratory information (Holland, et al. [4]). However, hospitals currently spend less than 5% of the hospital budget on clinical laboratory services (Eaton, et al. [1]). The hospital laboratory testing workflow is a multi-disciplinary process that begins with computer entry, specimen collection, and specimen transportation (the pre-analytical phase) by various HCW immediately followed by the laboratory procedures to detect and measure biologic substances (the analytical phase) and ends with the electronic transmission of the final laboratory results to the hospital information system (HIS) (the post-analytical phase) (Dasgupta, et al. [5]).

Historically, errors were more predominant in the analytical phase due to all the manual laboratory procedures such as pipetting, titrating, colorimetric readings, and reagent preparation that require frequent troubleshooting. Nowadays, technological advances in laboratory instrumentation, improved reagent stability, and computerized reporting of laboratory results have steadily streamlined the specimen workflow and significantly decreased errors in both analytical and post-analytical phases (Bickley, et al. [6,7]). However, the pre-analytical phase’s error rate remains relatively high (Hammerling, et al. [8-10]). Hammerling [8] studied the laboratory quality assessment and reported that the pre-analytical phase of the total specimen workflow is where the majority of the errors occurred. Plebani [10] also reported that almost 70% of all laboratory diagnostics mistakes are pre-analytical errors that arise from problems in patient preparation, sample collection, transportation, specimen preparation, and specimen storage. According to Hammerling [8], types of errors at the pre-analytical phase could include: inappropriate test request, order entry errors, misidentification of patient, improper container, sample collection and transport inadequate, inadequate sample/anticoagulant volume ratio, insufficient sample volume, sorting and routing errors, and labeling errors.

In general, there are four categories of pre-analytical variability, including:
1) Test ordering,
2) Patient preparation,
3) Specimen collection, and
4) Specimen processing, transportation, and storage (Ghaedi, et al. [11,12]).

Unlike the other two phases in the specimen workflow, due to the nature of tasks involved in the pre-analytical phase, such as computer entry of appropriate lab tests, blood collection, patient preparation in some cases, and specimen transportation, it is hard to utilize automation technology to decrease the number of errors (Hammerling, et al. [8-10,13]). Furthermore, it should be noted that common sources of pre-analytical errors occur in settings outside the laboratory’s jurisdiction. Often, the chaotic conditions in the ED sidetrack personnel from routine tasks, which impede the timely submission of collected samples to the laboratory and increase the possibility of making errors (Hawkins [14]). A study on ED physicians and nurses reported a mean rate of 7.51 interruptions per hour with ED colleagues’ interruptions, and telephone/beepers accounted for almost 75% of all interruptions (Weigl, et al. [13]). Proper specimen collection using positive patient identification immediately followed by timely submission to the laboratory for testing are major pre-analytical concerns outside the laboratory’s jurisdiction (Plebani, et al. 2014). Delays on specimen collection and transport could potentially prolong a provider’s time to make a disposition, especially in ED, where multi-tasking nurses are distracted continuously (Lou, et al. [15]).

Currently, the literature search did not reveal any solutions to effectively decrease the errors at the pre-analytical phase and identify and intervene on delayed specimen collection and submission to the laboratory (outliers) in real-time. Thus, this field experiment was designed to identify the common sources of delays in specimen delivery from ED to the lab in the pre-analytical phase. In addition, given that interruption is often listed as a cause for fallouts on other tasks such as specimen collection and specimen transport and assuming a higher level of activities during the day shift compared with the night shift, the study also evaluated the impact of work schedule or shift on the delays by comparing the frequency of negative outcomes between day and night shift. Finding the major sources of delays from the specimen collection at the ED to delivery to the laboratory is the main purpose of this field experiment so that inter-disciplinary leadership teams can plan an applicable system change. Collaborative input from healthcare professionals and laboratory professionals helps identify the major challenges and, at the same time, discuss a resolution to prevent a recurrence.

Materials and Methods

Research Design

A fast-paced ED environment surrounded by interruptions can generate unintended outliers in the specimen collection process, causing delays in the total turn-around time. In order to identify the common causes of specimen delays, a field experiment was conducted at the laboratory and the ED of the Mount Sinai Hospital at Queens (MSQ), New York, from August to November 2018 (4 months) using real-time data posted in HIS by the Epic Rover once ED HCWs collected the specimens. MSQ is a community hospital in a middle-class, commercial neighborhood of western Queens, NY. MSQ joins six other hospitals and one renowned medical school forming the Mount Sinai Health System, one of the country’s largest nonprofit systems. MSQ recently increased the ED throughput at the new state-of-the-art Emergency Department that opened its doors in May 2016 and cared for 60,000 visits in that year compared to 51,737 in the previous year (Epic). ED visits at MSQ still steadily increases through the years with 63,563, 67,406, and 68,553 from 2017, 2018, and 2019, respectively.

Instruments

This field experiment utilized a combination of existing technological devices, including the Epic Rover, the computer systems starting with the laboratory information system (LIS) which is the Specialist Computer Centres (SCC), interfacing with the hospital information system (HIS) which is Epic, the pneumatic tube system (PTS) manufactured by Swisslog, and the Vocera phones, to study the effects of laboratory interventions.

The Epic Rover

Epic Systems loaded a mobile device (Epic Rover) with accessories such as scanners for barcode validations and software applications that allow a variety of healthcare workers to access and update patient charts directly to HIS (Gramling [16]). The Epic Rover shows applicable medication advisories at the point of care, supports recording vitals, and provides a clinical summary of allergies, labs, and current medications, allowing clinicians to update administrative details such as dose, route, or site. ED nurses at MSQ used the Epic Rover to electronically document every specimen collection that transmitted all the information to the HIS in real-time. Epic Rover relays all the updates in HIS, in which the hospital Information Technology (IT) department interfaced with different computer systems such as the LIS. Specifically, the Epic Rover device requires scanning wristbands from patients for positive identification that eliminated mislabeling, which is a fatal type of pre-analytical error. Mislabeled specimens led to medical errors when laboratory data from one patient was used by a provider to treat another patient. Epic Rover can help HCWs positively identify patients for blood collection and other tasks in patient care such as documentation of vital signs, the performance of pointof- care testing, and administration of medication.

The laboratory can monitor the specimen collection information sent by Epic Rover to HIS and LIS during the pre-analytical phase. It is available for iPhone Operating System (IOS), Android, and other mobile platforms that connect to HIS, allowing access to clinical data but, most importantly, for the positive patient and specimen identification (Gramling [16]). The specimen collectors use Epic Rover to scan the patient’s wristband, displaying all of the patient’s uncollected laboratory orders requested by the provider. The specimen barcode label, which contains patient demographics and a list of tests, prints after selecting all tests to be collected, which the specimen collectors used to confirm patient identification before initiating the specimen collection. Completing the required steps in the specimen collection using Epic Rover sends accurate information to HIS including the user code of the person who collected the specimen, the site of collection (which arm), method of collection (arterial, venipuncture, or fingerstick), and the date and time of collection. Occasionally, HCW’s revert to paper requisitions instead of the Epic Rover during computer downtime. The manual process of paper requisitions is prone to mistakes, primarily due to illegible HCW’s handwriting.

Incorrect entry of the collection time, mostly when HCWs failed to use military time, and laboratory clerks were unable to recognize the error, erroneously displays the results in the wrong sequence on the patient’s flowchart in HIS that could contribute to medical error. Epic Rover automatically transmits the specimen collector’s user code and current date and time to HIS and LIS eliminating any risk of incorrect flowchart sequence.

The Laboratory Information System and Hospital Information System

The Specialist Computer Centres (SCC) is the LIS that enabled a flatscreen to display all collected samples waiting for arrival in the CPA. CPA clerks monitored the flatscreen that refreshed every three minutes. There are several advantages of utilizing the LIS. First, it helped ED nurses to promptly collect specimens with required collection kits and proper collection techniques, including the full utilization of the Epic Rover. Through LIS, the CPA clerks were able to capture the real-time collection information from the Epic Rover through the wall-mounted flatscreen and connect to more nurses as they frequently checked the order status monitor (OSM) displayed on a wall-mounted flatscreen inside the CPA workstation for a specimen collected but not received (outliers). The LIS also streamlined the information delivery to HIS. After CPA clerks processed all specimens received, which they delivered to the workstations of the clinical laboratory technologist (CLT) team for analysis using either manual or automated methodologies, CLTs reviewed all laboratory instrument output and finalized test result interpretations, which were then sent over by interface from the LIS to HIS. Epic is the HIS used mainly by the rest of the hospital HCWs. Epic stores all patient information needed by providers and other HCWs to deliver safe and quality patient care.

The Pneumatic Tube System

MSQ used the pneumatic tube system (PTS) manufactured by Swisslog Healthcare, Westerstede, Germany, an efficient and cost-effective mode of specimen transport from the ED to the laboratory. PTS canisters contain inner foam inserts and travel at a constant speed of approximately 20 ft/sec with a distance of about 200 feet between the lab and the ED stations. According to Swisslog, a study by the Ohio State Medical University concluded that the PTS could save 160 work hours each day. Using the PTS allowed ED nurses and other HCWs to perform additional clinical functions instead of spending time transporting specimens to the laboratory. However, several features of PTS, such as speed, distance, and packing material that might contribute to hemolysis, so Phelan, et al. (2017) conducted a study to prove the acceptability of using PTS regarding hemolysis. The research of Phelan, et al. (2017) showed a minimal variation of the hemolysis rate between the use of PTS (12.6%) and hand-delivery (14.6%). A similar study conducted by Cui, et al. [17] concluded that using PTS canisters without the foam inserts had a statistical effect on both the lactate dehydrogenase (LDH) and the potassium levels. Another study conducted by Cakirca, et al. [18] also concluded that the samples transported using PTS without the foam inserts showed a significantly higher hemolysis rate (47%) compared to hand-delivered specimens (10%) and PTS using canisters with foam inserts (8%). Users must properly use PTS to reap the benefits of a faster and cost-effective mode of specimen delivery without compromising specimen integrity through hemolysis. Institutions must also have an effective contingency plan when PTS malfunctions because any instrumentation is prone to meet intermittent operational disruptions, a dilemma that happens several times a year. Some PTS malfunctions were resolved remotely by the manufacturer, but there were 29 instances since the July 2016 installation that MSQ hospital reached out to Swisslog to restore service.

The Vocera Phones

Vocera phones are handsfree wearable communication devices that enhanced the hospital system’s mode of interaction (Mack [19]). Vocera phones offer hospitals and health systems communication services by creating hospital-specific smartphones featuring medical alarms and text messaging capabilities (Mack [19]). Vocera phones were assigned to the ED nurses and served as the direct line of communication between ED nurses and CPA clerks. These phones eliminate the CPA clerks’ wasted time calling the nursing station and asking clerical staff to search for the nurse and put him/her on the line. The laboratory’s accessibility to Vocera phones quickly links the nurse with the laboratory technologists during the notification of suboptimal specimens in the pre-analytical phase.

Procedures

We conducted a field experiment that turned out to be a joint process improvement project (PIP) between ED and laboratory for four months on the challenges of timely specimen collection and transport from the ED nursing station to the CPA of the laboratory. The field experiment involved multiple HCWs with specific roles using respective tools and technology to work in a system centered on patient care, as shown in Table 1. During the study period, leaders of ED and the laboratory collaborated on the field experiment to maximize the use of the Epic Rover in the specimen collection process and using paper requisitions only during systemwide computer downtime. The hospital information technology department assisted in installing a large wall-mounted flatscreen that computer analysts interfaced with software to monitor specimen activity. The ED treatment team, led by providers, initiated the specimen workflow through appropriate laboratory orders entered in the HIS. ED nurses use an electronic device similar to a smartphone (Epic Rover) retrofitted by the Epic company with a scanner and software for identification of patients and document various tasks such as vital signs and specimen collection. The entire hospital facility’s specimen collection activities were filtered to capture high priority laboratory tests sent over by the Epic Rover collection devices that interfaced with HIS and LIS.

The implementation of pre-analytical devices such as the Epic Rover enabled laboratories to see incoming specimens and monitor specimen collection and transport progress. Epic Rover registered the date, time, and user code of the person who collected the specimens then transmits all the information to both the HIS and the LIS in real-time. The Epic Rover provided the solution for patient identification problems using scanning technology from a smartphone-like device interfaced with HIS that prevents processing information on misidentified patients. Epic Rover also allowed HCWs to safely simplify and manage their daily tasks using positive patient identification while securely protecting PHI (Talukder, et al. [20]). Meanwhile, laboratory clerks monitored the order status monitor (OSM) linked to HIS that displays all specimens collected by ED HCWs with three minutes of update time. The color-coded notification system under the TAT column (TAT is the abbreviation of “turnaround time”) changes the status to yellow when the laboratory has not received that specimen on the 11th minute and turns red on the 21st minute, as shown in Figure 1. Any specimens collected but not received after 21 minutes were considered outliers and turned red on the OSM, which prompted the CPA clerks to initiate the intervention by calling the HCW who collected the specimens using Vocera phones to inquire about the submission delay.

Figure 1

Vocera phones assigned to every nurse served as a direct link between the laboratory clerks and the ED HCW and enhanced the communication between CPA clerks and ED nurses by eliminating the traditional calls to the nursing station, usually staffed by ED clerks who had to search for the ED nurses. Each phone call represented the laboratory intervention that CPA clerks documented in a PIP log, as illustrated in Figure 2. The PIP log allowed the laboratory to document all communications with the ED personnel for future analysis. The field experiment utilized information from the Epic Rover to open the line of communication via Vocera phones between laboratory clerks and ED nurses regarding specimens that were collected but not received, which then allowed the CPA clerks to intervene by calling the specimen collector if the collected specimens never reached the laboratory within 21 minutes. Non-laboratory personnel performed several activities in the pre-analytical phase that affected the total TAT of the specimen workflow. Specimen collection and transport to the laboratory were major concerns that affected the total TAT of the specimen workflow in the pre-analytical phase. The laboratory can only monitor the department’s pre-analytical activities and are completely incognizant of the status of the collected specimen from other departments until the arrival of the Epic Rover. Using this technology, the laboratory now knows who collected the specimens and at what time but are still vulnerable to delays when multi-tasking ED nurses fail to timely submit the specimens to the laboratory.

Figure 2

Participants

Nurses, physician assistants, medical assistants, and doctors at the ED joined CPA clerks of the laboratory in the completion of activities related to the pre-analytical phase. Several HCWs at the ED, like physician assistants, medical assistants, and doctors, occasionally helped the nurses with specimen collection and transport. The major participants of this interdisciplinary field experiment at MSQ were a) The ED providers, who initiated the specimen workflow by electronically submitting the appropriate orders in HIS,
b) ED nurses, who collected the specimens then transported the specimens to the laboratory on time, and
c) CPA clerks, who processed the specimens for laboratory testing by the CLT.

MSQ ED nurses worked 12-hour shifts from 7 AM to 7 PM (Day shift) and 7 PM to 7 AM (Night shift) while CPA clerks worked 7.5- hour shifts from 7 AM to 2:30 PM (day shift), 4 PM to 11:30 PM (Evening shift), and 11:30 PM to 7 AM (Night shift). There was another CPA clerk who worked from 8:30 AM to 4 PM to keep pace with the higher workload and to ensure a seamless transition between day and evening shifts.

The Conceptual Model

The Systems Engineering Initiative for Patient Safety (SEIPS) model is the conceptual model used for this PIP to identify the common sources of delays in the work system of laboratory testing. We used the SEIPS model approach to evaluate and improve the specimen workflow processes to incorporate the pre-analytical activities outside the laboratory. The SEIPS model has six elements, and the interactions between interdepartmental HCWs represented the activities in the external environment illustrated in Figure 3. The first element is the person, which includes the patient, treatment team, and allied health professionals such as medical assistants, phlebotomists, and respiratory therapists. Tasks are the second element, which are activities related to the collection processes. Technologies and tools are the third element, which includes the Epic Rover collection documentation device, HIS and LIS computer software, flatscreen, and Vocera cell phones. The organization is the fourth element, which provides for institutional culture, protocols, and managerial approaches. The physical environment is the fifth element, which includes structural design and surrounding necessities, such as lights, ventilation, noise control, and privacy. The external environment is the sixth element, which provides delivery of care and the reporting system. The work system activities or external environment played a significant role in initiating the testing process to achieve favorable patient outcomes (Figure 4).

Figure 3

Figure 4

Outcome Measures

This field experiment was designed to identify the common sources of delays in specimen delivery from ED to the laboratory. The following outcome measures were collected:

1) Number of laboratory interventions: Number of laboratory interventions represented the number of phone calls made by CPA clerks to the collector of specimens that were not submitted to the lab after 21 minutes of collection to inquire about the submission delay.
2) Outcome of specimens: Outcome of specimens represented the specimens’ final status that was not submitted to the lab after 21 minutes of collection. Outcome of the specimens was a categorical variable with two levels: received (delayed specimen received after the intervention) vs. canceled (no specimens received prompting the lab to cancel).
3) Reasons for the specimens that were not submitted to the lab after 21 minutes of the collection were also collected. 4) TAT (in minutes) from intervention call to the ED collector to the time the laboratory received the specimens.
In addition to the outcomes, information of work shift, when the submission delay occurred, was also obtained from a respective set of HCW rosters in the day and night shift.

Statistical Analysis

Data were entered into and analyzed using SPSS version 23 for Windows (IBM Corp., Armonk, NY). Number of laboratory interventions (number of phone calls made by CPA clerks to the collector of specimens that were not submitted to the lab after 21 minutes of collection to inquire about the submission delay) was derived from the PIP log and divided into two groups based on the outcome of specimens (received vs. canceled). Frequency tables were used to summarize

a) Outcome of specimens by work shift, and
b) Causes of submission delay.

Descriptive statistics were used to summarize TAT (in minutes) from intervention call to the ED collector to the time the laboratory received the specimens. A chi-square test of independence (Field [21]) was used to determine if there was an association between work shift and outcome of specimens. To ensure the validity of the analysis results, we examined the following two assumptions on the Chi-square test

a) Independence of observations, and
b) All cells should have expected counts greater than five (Field [21]).

Both assumptions were satisfied. The collected data were from two different intervention outcomes (Cancelled vs. Received), and hence it was reasonable to assume observations were independent. A p-value of less than 0.05 indicated significance.

Results

The four-month field experiment generated a total of 133 laboratory interventions (calls made by CPA clerks to the collector of specimens that were not submitted to the lab after 21 minutes of collection to inquire about the submission delay) that involved 60 nurses. Table 1 showed the frequency table of the outcome of specimens by work shift. Of the 133 specimens that required laboratory interventions, 82 (61.7%) were submitted after the CPA clerks called the collector of specimens to inquire about the submission delay and 51 (38.3%) were canceled. Furthermore, of the 133 laboratory interventions, 105 (78.9%) occurred during the day shifts, and 28 (21.1%) occurred during the night shifts. The results of the chi-square test of independence indicated that there was no statistically significant association between shift and outcome of specimens (χ₂ (N = 133, 1) = 0.104, p = 0.747). Several unavoidable causes of delays were identified, including difficult veins, patients unable to void urine, malfunctioning Epic Rover devices, and unavailability of patients due to procedures at other ancillary services such as Radiology and Dialysis. Notably, of the 133 specimens that required laboratory interventions, nearly half of them (46.6%) were not given specific reasons for the delay (Table 2).

Table 1: Work System Model.

Note: CLT = Clinical laboratory technologist; CPA = Central processing area; ED = Emergency department; HIS = Hospital information system; LIS = Laboratory information system; TAT = turnaround time.

Table 2: Frequency of the Outcomes Recorded on the Laboratory Intervention Log.

Note: Outcome of specimens: received (delayed specimen received after the intervention) vs. canceled (no specimens received prompting the lab to cancel). Others = included Epic Rover printer issues encountered by ED nurses and CPA workload issues.

The unspecified reasons for the delay may indicate that the ED collectors were distracted after collecting the specimens during the four-month field experiment. The study also found that 14 of the outliers (10.5%) were unavoidable due to difficult collection; 4.5% were caused by the combination of the challenges faced by nurses with Epic Rover (N = 4) and overwhelming workflow faced by CPA clerks (N = 2) (Table 2). The specimens received after difficult collections had the highest mean TAT in minutes from intervention call to the ED collector to the time the laboratory received the specimens (M = 119.0, SD = 132.8), followed by the other specimens that involved barcode label printer issues in ED combined with workload issues at the laboratory (M = 32.0, SD = 18.2), and finally, the specimens received without explanation (M=19.6, SD = 26.0) as detailed in Table 3. We also determined that the laboratory received overdue specimens within 20 minutes after calling the collector in over half (58.5%) of the total number of received specimens (Table 4). Table 4 also showed that 61% of specimens received after intervention were received over one hour from the collection time, potentially generating inaccurate lab results (Table 5).

Table 3: Summary Statistics of TAT in Minutes from Intervention Call to the ED Collector to the Time the Laboratory Received the Specimens.

Table 4: Frequency Table on Specimen Receive Time

Note: The lab monitored the time it took for the ED nurse to send the collected specimens after calling (intervention).

Table 5: Frequency Counts (%) of Outcome of Specimens by Shift.

Note: Outcome of specimens: received (delayed specimen received after the intervention) vs. canceled (no specimens received prompting the lab to cancel).

Figure 5

Figure 6

The common reason for the missing collection information is when the collector fails to document in the HIS either through the application of Epic Rover or from a computer on the nursing station or workstation on wheels (WOW). For example, Epic Rover users may fail to follow step four of the Epic Tip Sheet for PCAs (Figure 6). HCWs who chose not to use the Epic Rover can still document the collection information by following step 3 of the Epic Tip Sheet in Hyperspace (Figure 7). The Epic Rover, which replaced an older system called Data Fusion on November 27, 2017, is a major device technological upgrade that transmits specimen collection information to HIS. The early stages of Epic Rover implementation were when several HCWs submitted the specimens to the lab using the downtime paper requisitions without barcoded labels on the specimens instead of the expected electronic transmission of collection information from a HIS to LIS. CPA clerks had to either manually order the tests and manually input the collection information if such information is available in the requisition.

Figure 7

The second limitation of the study was the staffing issue in the laboratory. In addition to monitor the process of specimen collection, CPA clerks also had to respond to other critical areas like the operating room, ICU, and chemotherapy departments. Staffing issues in the laboratory limited the ability to call the ED nurse who failed to submit collected samples to the laboratory in a timely fashion. Working understaffed limited the sample size down to 133 interventions. The study’s third limitation was that Vocera phones may mal-function and the pneumatic tube system may occasionally break down. Mal-functioned Vocera phones prevented instant connection between the CPA clerks to the ED nurse who collected the specimens that were not submitted within the required timeframe. The pneumatic tube system’s occasional breakdown caused specimen transport delays because the ED staff had to hand-deliver the specimens. ED HCWs batched the specimens before sending to the lab instead of hand delivering every sample after collection. The fourth and final limitation of the study was the amount of time for the field experiment, which was only four months from August to November of 2018. This limitation exists due to a doctoral program’s time constraints and very difficult to overcome unless a researcher devotes personal time for future research. Data from different seasons of the year would provide a better understanding if a particular pattern exists on the different reasons for delays in specimen delivery.

Conclusion

The study showed that distracted HCWs from the ED were the leading causes of delays between specimen collection and specimen delivery to the laboratory. More importantly, the study proved that the laboratory interventions helped decrease the TAT from specimen collection to specimen received, which helped move the average time from patient arrival to provider disposition. The methodology implemented to monitor all collected samples also served as a safety net that the laboratory can use for other departments such as clinics and nursing stations that routinely faced the risk-of leaving the collected specimens behind and exceeding the stability period before delivering to the laboratory. Maximizing the potential of technological devices such as the Epic Rover and the Vocera phones improves the TAT in the pre-analytical phase and enhances the professional relationships between ED and laboratory team members. We also concluded that all HCWs faced the same types of distractions and patient conditions that cause delays regardless of the time of day and the set of the roster on duty.

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Bleb and Blister-Cystic Lymphangioma

Introduction

Cystic lymphangioma represents as a benign vascular lesion constituted of an amalgamation of distended lymphatic channels. The essentially benign proliferation of lymphatic vessels may configure superficial or deep seated lesions or may diffusely incriminate various organs and physiological systems. Initially scripted by Rodender in 1828, tumefaction appears immune reactive to CD31 and D2-40. Contingent to site of origin, neoplasm is additionally designated as lymphatic malformation, lymphangioma circumscriptum, superficial cutaneous lymphangioma, cavernous lymphangioma, deep lymphangioma, cystic hygroma, cystic lymphangioma, intra-abdominal cystic lymphangioma, hemangiolymphangioma or lymphangiomatosis, generalized lymphangioma and systemic angiomatosis. Cystic lymphagioma preponderantly appears within paediatric subjects or young adults. Majority (~90%) of lesions occur at birth or within first 2 years. Exceptionally, neoplasm may emerge within older adults and frequently represent as mesenteric lesions. Intra- abdominal neoplasms exhibit a mild male predominance [1,2]. Cystic hygroma is posited to concur with Turner’s syndrome. Splenic lymphangiomas appear concordant with Klippel-Trenaunay syndrome.

Neoplasm is associated with a variant of Maffucci syndrome. Cystic lymphagioma is associated with trisomy 13, trisomy 18, trisomy 21 and various genetic syndromes as Noonan’s syndrome [1,2]. Genomic mutations within VEGFR3, FLT4, PROX1, FOXC2 and SOX18 gene may contribute to disease occurrence. Somatic mutations within PIK3CA gene are documented. Cystic lymphangioma occurring within superficial cutaneous sites frequently implicates proximal extremities or limb girdles. Commonly, deep seated lesions appear within head and neck region, pre- eminently upon tongue or floor of mouth followed in frequency by upper and lower extremities, axilla, groin or abdominal region [1,2]. Cystic hygroma is preponderantly confined to sites within head and neck region as posterior triangle of neck. Intra-abdominal lesions may appear within mesentery, omentum or retroperitoneum. Lymphangiomatosis may incriminate multiple visceral sites as pulmonary parenchyma, hepatic parenchyma or bone [1,2]. Cystic lymphangioma is posited to arise from anomalous development of the lymphatic system. Genetic triggers as genomic mutations within PIK3CA gene and diverse chromosomal mutations induce neoplastic genesis through various endothelial growth receptor pathways.

Preliminary, congenital lesions emerge as developmental malformations wherein sequestered lymphatics lack contiguity with normal lymphatic and vascular channels. Majority of neoplasms are contemplated to be malformations or hamartomas. However, genetic anomalies significantly contribute to disease emergence [2,3]. Clinically, superficial lesions may represent as aggregates of multiple, miniature vesicular lesions implicating diverse cutaneous surfaces. Lesions confined to tongue manifest as a tumour mass superimposed with pebbly, vesicle-like nodules, akin to ‘frog eggs’. Commonly, cystic hygroma represents as a unilateral, painless, diffuse, non pulsatile tumefaction confined to posterior triangle of neck. Deep seated lesions emerge as enlarged, painless, gradually progressive tumefaction. Intra-abdominal lesions may displace diverse visceral organs and induce intestinal obstruction [2,3]. Grossly, neoplasm manifests as a multi-cystic, spongy, translucent, reddish brown tumefaction. Cystic spaces are incorporated with watery, viscous or milky fluid [2,3]. Upon microscopy, tumefaction is composed of thin walled, distended lymphatic vessels of variable magnitude. Lymphatic articulations are layered by flattened endothelium with occasional configuration of papillary projections.

Lumina of the cystic cavity may be pervaded with eosinophilic, amorphous proteinaceous fluid commingled with infrequent lipid laden macrophages and lymphocytes. Lesions of extended duration exhibit interstitial fibrosis. Enlarged lymphatic vessels exemplify smooth muscle within the walls [2,3]. The cystic tumefaction is encompassed with lymphoid aggregates which may occasionally configure reactive germinal centres. Intervening stroma frequently enunciates aggregates of mast cells and hemosiderin pigment deposits [2,3]. Generally, lymphangiomatosis is associated with anastomosing pattern of neoplastic evolution which dissects and circumscribes normal anatomical structures. Neoplasm may induce extensive granulation tissue and an inflammatory exudate, features which may obscure lymphatic genesis of the neoplasm [3,4]. Ultrastructural examination aids in confirming endothelial origin of neoplastic cells layering cystic cavities. Features as Weibel-Palade bodies or storage granules permeating endothelial cells may be observed [3,4]. Mitotic count is predominantly calculated from mitotically active areas, devoid of tumour necrosis. Mitosis may be quantified within 10 consecutive high power fields (HPF) upon 40x objective or 1 HPF x 400 = 0.1734 mm2 area wherein appropriate high power fields encompassing 1 mm2 area is contingent to individual microscope (Figures 1 & 2) (Tables 1 & 2).

Figure 1

Figure 2

Table 1: CT Exam Protocol.

Note: HPF: high power field

Table 2: CT Exam Protocol.

Note: Tumour necrosis is appropriately evaluated upon cogent gross examination and categorized upon histological sections.

Cystic lymphangioma appears immune reactive to podoplanin (D2-40), PROX1, vascular endothelial growth factor receptor 3(VEGFR3), lymphatic endothelial hyaluron receptor 1 (LYVE1), CD31, CD34, smooth muscle actin (SMA) or Factor VIII related antigen. Neoplastic cells expound enhanced expression of VEGFR3. Neoplastic cells appear immune non reactive to GLUT1, human herpes virus 8(HHV8) or c-MYC [4,5]. Cystic lymphangioma requires segregation from neoplasms as haemangioma, vascular malformation, atypical vascular lesion, acquired progressive lymphangioma, secondary lymphangiectasia, cystic lymphangioma-like adenomatoid tumour, parasitic cyst (echinococcal cyst), mesothelial cyst or soft tissue sarcomas. Besides, lesions as hematoma, abscess or lymphocele necessitate a distinction [4,5]. Cystic lymphangioma appears as a swollen, soft tissue mass which may be discerned with trans-illumination assay. Plain radiographs of abdominal lesions frequently demonstrate a soft tissue tumefaction which displaces loops of small and large intestine. Ultrasonography may be appropriately adopted to confirm the cystic or multi-cystic lesion and delineates a unilocular or multilocular, anechoic tumefaction. Cystic or multi-cystic lesions may be sharply demarcated and traversed by intrinsic septa.

Tumour may be aptly discerned upon prenatal ultrasonography [4,5]. Computerized tomography (CT) depicts a cystic lesion of variable magnitude traversed by septa and devoid of image enhancement. The cystic mass is pervaded with homogeneous fluid and may displace adjacent organs or viscera. Upon T1 weighted magnetic resonance imaging (MRI), a hypo-intense or hyper-intense tumefaction is permeated with proteinaceous substance or extravasation of red blood cells. T2 weighted imaging expounds a multi-loculated tumefaction with hyper-intense areas. Cogent ascertainment of the pre-eminently cystic lesion may be challenging upon assessment of miniature tissue samples on account of demonstrable bland cytological features [4,5]. Enlarged, symptomatic lesions may be optimally subjected to surgical extermination. Additionally, intralesional injection of sclerosing agents as bleomycin and OK-432 may be beneficially adopted. Neoplasm may be eradicated by radiofrequency ablation [4,5]. The pre-eminently benign lesion is associated with excellent prognostic outcomes. Inadequate surgical excision is associated with enhanced possible tumour reoccurrence. Deep seated lesions confined to various tissue planes delineate tumour relapse in up to 20% instances. Cystic lymphangioma is associated with complications as infection, haemorrhage, tumour rupture or intestinal obstruction. Diffuse lymphangiomatosis occurring within mediastinal organs or diverse viscera is accompanied by tumour associated mortality. Malignant metamorphosis remains undocumented [4-8].

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Biotechnology Application in Medicine

Introduction

In this paper, I have reviewed the technology of Bio.lectronics. This science nowadays in many branches of technology has influenced specially in Medicine and electronics technology that in continue I illustrate. For this paper from article has been helped that in references has come [1].

Bio. Sensors

The name is a group of sensors designed to react only with a specific substance called analyte that can react chemicals, toxins, toxic gases, etc. Biosensor technology is a combination of biochemistry, molecular biology, chemistry, physics, chemistry, physics, electronics and computers [2]. It is used in various medical sciences, chemical industry, food industry, environmental monitoring, pharmaceutical and health care products, etc. The definition of the International Union of Chemistry (IUPAC), a biosensor is a device that, by means of specific biochemical reactions or through isolated enzymes, tissues, or cellules, detects chemical elements of the material in question, usually electronically, lightly, or thermally. The first biosensor is made to measure blood sugar. DNA-based biosensors with the aim of detecting people’s DNA are useful tools to detect mutations and genetic defects as well as pathogens [3]. In my view, Bio. Technology , Bio. Chemistry and Genetics can solve Bio. Molecular tecniques. In this method Bio. Farming can be solved. In fact, Theory by help computer Programming and Bio. Informatics is a solution for many sides of science.

Gen.Generation . and Gen.Correction

Bio.informatics has a big relation to genetics engineering. By coding gene and translate, change or creat code, we can play cureness [4]. Also, for cure each illness that is related to correct gene, by codes in program we can correct gene to initiate gene and remove the illness for ever. This is my mind, you can do proof it.

Assessment of Alzheimer Illness

It is obviouse there is relation between gene and protein brain nerves. Main cause of this illness or demance is abnormal build. up protein in and around brain cells plaques are deposits fragment called beta_amyloid that build up in the spaces between nerve cells [5]. In my idea for cureness, we are related to correct protein that polted as beta_amyloid between proteins can have connect. Maybe correction gene by Help bio. informatics methods helps this idea. or other methods of drugs to correct gen in protein and illuminate beta [6]. amyloid for cureness of gen and protein brain, solve thid illness.

Bio. Chemistry and Bio. Informatics

For cure many dangerous illnesses such as cancer and genetical illnesses , combination of Bio. Informatics science and new forms of Bio.Chemistry would be helpful. Even for Enzym.thrapy and Hormon [7]. Therapy has been mixed by Bio.Informatics and Pharmacology chemistry.

Various Type Learning Algorithms and Applications

Deep. learning in my idea, can be use a for Neural Language Processibng, also Computer. Vision and Image Processing and …. There are tools for deep.learning such as CAFFE, TENSOR, TORCH, FLOW(Python, C++) and … .CNN is convolutional neural networks.

Neural Signalling

The brain is adapted at information about body and its environment. Such information must be proceed within illnesses, also it can be stored as memories that endure for years. Neurons perform this function by generating electrical and chemical signals. These signals are generated at synaptic connections between nerve cells. The cellular and molecular mechanism this unique signaling abilities are targets deep poisenes that compromise the function of the nervous system Function of the nervoussystem neurvos employ several different types of electrical signals to encode and transfer information. The voltage clamp technique is an electrical feedback method that allows control of neurons membrane potential and, simultanteosly, direct measurement of the voltage dependent fluxes of Na+ and K+ that produce the action potential. The flow of Ions through single open channels can be detected as tiny eelectrical currents, and the synchronous opening of many channels, generate the macroscopic currents that produce action potential and other elecgtrical signals.

Deep. Learning for Neurons

Neural Network is a network of interconnected of interconnected neurves. Neurons can be biological(that there is in human brain) or Artifitual. Some forms of Neural Networks can not be mapped to function of human brain and biological Neurons, Because biological Neurons have only two output: on and off.

There are three main components :

1) The dandrits that receive the input signals,
2) The cell body where the signal is processed in some forms,
3) The tail-like axon through which is transform the signal out to the next neurons.

The goal of all supervised machine learning algorithms is to best estimate target function(f) that maps input data(X) onto output ariable( Y). Different algorithms will be used to form machine larning from X to Y. Common algorithm by using gradient descent are Linear Regression and Logestic Regression. Neurologists have long recognized that patients who suffer injuriesin brain region can be covered a repair in brain neurons. In some sampels, we applied this category and 80% of brain got healthy state in patient.

Conclusion

There are types of Neural Repair, but in my openion, signaling of healthy brain toward damaged brain neuros by help a algorithm that we leant in before lines for machine learning is a method to injured neurons to recover themselves. It means by mapping of healthy brain signals to patient we behave machine. learning for injured neurons to get healthy.

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Incorporating Qigong into a Western Medical Practice: A Study in Artificial Intelligence

Introduction

Qigong [pronounced chee gong] has been a tool in the toolbox of Traditional Chinese Medicine (TCM) for thousands of years. Basically, it consists of a series of exercises that awaken the bio-electromagnetic fields in the human body. These activated energy fields serve to strengthen the body’s immune system, thus preventing disease, as well as healing the human body of existing diseases. Qigong exercises can also be used to alleviate or reduce the side-effects of numerous ailments. They are often used as supplementary treatments in medical practices. Numerous studies found qigong produced significant positive effects in patients having a wide variety of ailments. Many of these studies were done in China and a few other Asian countries. However, in recent years, similar studies have been conducted in other parts of the world [1-57]. Medical professionals who want to obtain detailed information about these studies can find what they need in the PubMed [58] database. However, the focus of the present study is different. This paper is intended to provide more of an introduction to the use of qigong in an easy-to-read format that both professionals and nonprofessionals can find useful. It also introduces the use of artificial intelligence (AI) to find useful information on qigong. Artificial intelligence has become an increasingly useful tool in medical research in recent years [59-84]. It has many applications in both research and diagnosis.

Using Artificial Intelligence

There are a number of good AI bots that can be used to conduct medical and other kinds of research. This study will use Microsoft Copilot [85] because it is currently being widely used, and it is easy to use even for nonprofessionals. It is too early to tell whether it is the “best” bot to use for medical research, since the AI market is changing so rapidly. Even if Copilot were the best bot to use for medical research today, it might not be the best bot a few weeks after the present article is written. Things are really changing that fast. To start things off, the instruction below was given to generate some basic information. Since the focus is on applications in Western medicine, the instruction was written to focus on that subtopic of qigong medical research and practice.

INSTRUCTION: List some recent studies where qigong has been used as a supplement to Western medicine. Provide references.

REPLY

Certainly! Here are some recent studies where qigong has been explored as a supplement to Western medicine:

1. “Qigong and the Treatment of Illness: Recent Case Studies”:

o This paper reviews several studies that have used qigong to treat various illnesses, including back pain, cancer, cognitive impairment, depression and anxiety, fatigue, muscle strength, posture, and Parkinson’s Disease [86].

o Reference: Qigong and the Treatment of Illness: Recent Case Studies

2. “Qigong Exercise Balances Oxygen Supply and Acid-Base to Modulate…”:

o A study suggests that qigong exercise can help balance oxygen supply and acid-base levels, potentially benefiting health [87].

o Reference: Qigong Exercise Balances Oxygen Supply and Acid- Base to Modulate…

3. “The Future of Qigong in Western Medicine”:

o This analysis explores the ancient history of qigong in China, scientific explanations of bio-electromagnetic fields found in Qi, and measurable medical applications for self-healing and medical assisted-healing. It highlights qigong as an emerging technique in Western medicine, emphasizing integrative medicine and biophysical care [88].

o Reference: The Future of Qigong in Western Medicine

These studies provide valuable insights into the potential benefits of qigong as a complementary approach alongside Western medicine. Integrating traditional practices like qigong with evidence-based medicine can enhance overall well-being and promote holistic health [89-95].

Concluding Comments

Copilot provided a nice, but very brief summary of what qigong is all about and how it may be used in Western medical practices. Actually, the summary might have been too brief for medical practitioners who would have liked more depth or breadth. Fortunately, Copilot also provided nine references and links to other articles and blogs on the subject, which fill in many of the gaps. The references it provided are also written in mostly nontechnical language, making it easy for medical professionals and others to obtain a basic understanding of what qigong is all about it what it is capable of doing. For those who wish to read some studies that have more depth, PubMed [58] would be a good place to go, since this database has many studies on the health benefits of qigong, mostly as a supplement to traditional Western medicine. In fact, a word search of titles and abstracts that included the word “qigong” got 1095 hits.

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The Production of Turmeric (Curcuma Longa) as Affected by Variety and Nutrient Source Grown in Jos, Nigeria

Introduction

Turmeric is believed to be originated from south Asia around Vietnam, China, and west India (Kew, et al. 2016) the crop has been known as a domestic plant and not found in the wild, it is sterile but grows vigorously from rhizomes. The horizontal roots Is important, rhizome is both planting material and use commercially as source of money to the farmer. The crop is long duration crop 8-9 months and produces different sizes of propagules from the mother (shoot base) to daughter rhizome which are used as spice The daughter rhizomes don’t develop at the same time as the shoot base. In the last few years as awareness of its many uses continues to increase, many farmers have begun to grow it as cash crop especially in the ginger growing areas of southern part of Kaduna State. Turmeric is a cross-pollinated, triploid species (2n =3x = 63), which can be vegetative propagated using its underground rhizomes (Sasikumar [1]). Curcuminoids and essential oils are the major active constituents in turmeric, crucial for the quality of both the plant and its processed products (He, et al, [2,3]). The demand for the crop is increasing due to its medicinal and nutritional value hence the need to come up with variety and organic nutrient source in cultivation of turmeric. In Nigeria about 19 States are prominent in turmeric production and it’s given many names de­pending on the locality (Olojede, et al [4]) organic manure remain one of the most effective tool in improving the fertility status tilt and soil productivity, organic manure out weight the inorganic fertilizer in terms of having wide range of essential nutrients and organic matter needed by plants, since nutrients are held in organic form, it is there­fore important to supply nutrients most especially organic nutrient to the soil to boost plant growth and yield Akanbi et al. (2015).

Consumers tend to use organic products continuously, and this has become a global trend due to health challenges and cheaper ways to source it. In response to consumer demand, organic food products are quickly growing (Peng, 2019). All countries around the world report a trend of continual growth in the organic food and beverage market (Golijan and Dimitrijević, 2018). The demand for organic products has been reported to be increasing in both local and inter­national markets (Declaro-Ruedas, 2019), and is expected to contin­ue growing, especially in both developed and developing countries, while the supply of organic products is limited and still cannot pro­duce enough organic products to meet the market demand. The fer­tility of a soil and the level of acidity or alkalinity play an important role in determining the yield of the crops, which can be affected by intensive farming, hence the reason why proper soil quality manage­ment is required to sustain high yield in sorrel production (Talpur, et al. 2013). It is necessary to know the best practice and nutrient source and verity which could help in increasing the production of turmeric hence the need for this work. The objectives of the work therefore are to determine the effects of variety and nutrient source that influences growth and yield of turmeric in study.

Material and Methods

The experiment was carried out at Jos at (9° 31’- 9o 50`N Latitude and 10° 41’N-11o 09`E Longitude above sea level in of Nigeria to in­vestigate the productivity of Turmeric (Curcuma longa) as influenced by nutrients and variety grown in Jos, Plateau State. The experiment was laid in a Randomized Complete Block Design (RCBD) with three replications. Treatment were two varieties (UT25 and UT30) and or­ganic sources of nutrients (compost 10t/ha, (Dry matter 11%, Organ­ic Material 10%, Total Nitrogen 10.0%, Total Phosphorus 0.2% and Total Potassium 0.4%), dung site 10t/ha(Dry matter 34%, Organic Material 12%, Total Nitrogen 3.5%, Total Phosphorus 1.0% and To­tal Potassium 1.3%), poultry droppings 10t/ha and Poultry dropping (100% Dry Matter, Organic Material 65%, Total Nitrogen 5.9%, Total Phosphorus 1.41% and Total Potassium 2.72%) and control), rhi­zome size of (2-3cm) where collected from both and cattle that where kept under intensive management, where the organic manure where kept/stored to undergo partial decomposition for five months fol­lowing the recommendation of (Bello, 2015) with 10tones/ha before incorporation into the soil Agronomic practice such as wedding was done manually at 2weeks after sowing and earthing-up at 6 weeks after planting. Data collected were number of leaves, plant height, Number leaves, rhizome length, rhizomes diameter, rhizomes weight, number of rhizomes per plant, number of primary rhizomes, number of secondary rhizomes and yield weight was taken during harvest all the data were collected within the net plot of 4m2 where a total of 10 plants were tagged for data collection within each net plot.

The data collected were analyzed using (ANOVA) while least sig­nificant difference (LSD) at 5% level of probability was used in sepa­rating the means. Table 1 presents data on the effect of different va­rieties and nutrient sources on the plant height of turmeric grown in Jos, Nigeria, at various weeks after transplanting (WAT). Varietal Effect: Varieties (UT25 and UT30) and Nutrient Sources (Compost, Dung site, Poultry dropping, Control) where significant difference was observed (P<0.05) Plant height increases as the weeks progress for both varieties at each time point, UT25 consistently shows taller plants compared to UT30. UT25 tends to produce taller plants com­pared to UT30 across all weeks, this is not far from the assertion of Olojede and Nwokocha [5] who stated that most variation in vege­tative growth is caused by genetic make-up, environmental factors and probably cultural practice. On nutrient source effect, plant height tends to increase with weeks for all nutrient sources. Poultry drop­ping consistently results in the tallest plants at each time point Poul­try dropping is the most effective nutrient source for promoting plant height, this could be so because poultry dropping release its nutrient faster than other source of organic source, followed by compost and dung site, with the control group being the least effective. The Control group consistently shows the shortest plants. This findings collabo­rate with the work of (Miyakoshi, et al. [6]) who stated that poultry dropping releases it nutrient fast and through-out the plant cycle in the field, he added that residual effects could be experience if plant are planted in the same land in subsequent year.

Table 1: Effect of Variety and Nutrient Source on Plant Height of Turmeric Grown in Jos, Nigeria Weeks After Transplanting (WAT).

Note: LSD= Least Significant Differences at 5% Level of Probability.

This study provides valuable insights into the influence of variet­ies and nutrient sources on turmeric plant height in the given region and can guide farmers in making informed decisions for optimizing crop growth Olojede, et al. [5]. Table 2 investigates the impact of different turmeric varieties and nutrient sources on the number of leaves in turmeric plants grown in Jos, Nigeria. The experiment spans various weeks after transplanting (WAT), providing a comprehensive view of the development of leaves over time. Two turmeric varieties, UT25 and UT30, were subjected to different nutrient sources, in­cluding compost, dung site, poultry droppings, and a control group. The analysis of this work incorporates the leaf area as an additional metric for assessing overall plant development according to (Njoku, et al. [7]). The results reveal distinct patterns in leaf development in­fluenced by both variety and nutrient source. Varietal Influence, UT25 consistently exhibits a lower number of leaves compared to UT30 at each WAT point. Leaf area is higher for UT25 than UT30, suggesting a potential trade-off between leaf number and individual leaf size which could be linked to genetic variability as reported by Ukpabi, et al. [8]. Nutrient source effect shows Poultry dropping stands out as the most effective nutrient source, consistently promoting a higher number of leaves across all WAT points. Compost and dung site also positively influence leaf development but to a lesser extent.

Table 2: Effect of Variety and Nutrient Source on Number of Leaves of Turmeric Grown in Jos, Nigeria.

Note: LSD= Least Significant Differences at 5% Level of Probability.

The control group consistently shows the lowest number of leaves, emphasizing the importance of nutrient supplementation this could be related to the ability of poultry dropping having high con­tent of uric acid which in turn lead to leaf initiation and production through the process of photosynthetic activities, assimilation and dis­tribution of absorb solute, this finding agree with the work of Onuoha, et al. [9] who reported same trend in his work on ginger he added that beside fast release of nutrient in poultry dropping it has ability to improve soil organic matter, binding soil colloids for sustainable cultivation of crops . This study contributes valuable insights into the nuanced relationship between turmeric varieties, nutrient sources, and leaf development Madina et al (2023). The findings can inform agricultural practices, guiding farmers in the selection of optimal va­rieties and nutrient management strategies for enhancing leaf initi­ation and production in turmeric cultivation (Akinpelu, et al. [10]). The provided data in Table 3 explores the impact of different turmeric varieties and nutrient sources on yield-related parameters of turmer­ic cultivated in Jos, Nigeria. The parameters analyzed include rhizome length, rhizome diameter, and rhizome weight per plant. The statis­tical significance is evaluated using the Least Significant Differences (LSD) at a 5% level of probability.

Table 3: Effect of Variety and Nutrient Source on Some Yield Related Parameters of Turmeric Grown in Jos, Nigeria.

Note: LSD= Least Significant Differences at 5% Level of Probability.

Rhizome Length

Varietal Effect: UT25 exhibits a longer rhizome length (6.87 mm) compared to UT30 (5.78 mm), on nutrient source Poultry dropping as a nutrient source results in the longest rhizomes (6.83 mm), followed by dung site (5.34 mm), compost (5.00 mm), and control (4.02 mm) this finding correspond with the report of Jiang [3] who stated that variety and nutrients plays an important role in rhizome length and over all yield.

Rhizome Diameter

UT25 has a larger rhizome diameter (4.54 mm) compared to UT30 (3.32 mm) this could be as the result inherent trads which had caused the variability, this finding is in line with the work of Ohaeri and Olajede (2001) who reported that growth and yield related char­acter is influence by crop inherent ability, cultural practice and also rainfall pattern, on nutrient source, Poultry dropping leads to the largest rhizome diameter (5.01 mm), followed by compost (4.21 mm), dung site (3.12 mm), and control (2.87 mm) this is a facts that yield character is largerly affected by nutrient absortion and utilization as reported by (Olife, et al. [11]).

Rhizome Weight per Plant

UT25 results in a higher rhizome weight per plant (40.21 g) com­pared to UT30 (36.11 g) UT25 tends to produce larger and heavier rhizomes compared to UT30, and on nutrient source Poultry drop­ping as a nutrient source lead to the highest rhizome weight per plant (41.73 g), followed by dung site (38.00 g), compost (34.33 g), and con­trol (28.20 g). Poultry dropping as a nutrient source generally leads to better rhizome development; weight is a product of nutrient assimi­lation, utilization, and varietal influence same is reported by the find­ing of Amadi et al. [12] who agreed with the above accretion adding that method and timing of nutrient application influences rhizomes weight and over-all yield. This study provides valuable insights into the combined effects of turmeric varieties and nutrient sources on key yield-related parameters, offering practical implications for farm­ers in Jos, Nigeria Madina et al., (2023) farmers may consider UT25 and poultry dropping for optimizing rhizome length and weight. Ta­ble 4 presents data on the influence of turmeric varieties and nutrient sources on yield and yield-related characteristics of crops cultivated in Jos, Nigeria. The parameters analyzed include the number of rhi­zomes per plant, the number of primary and secondary rhizomes, and the overall yield per hectare. Statistical significance is determined us­ing the Least Significant Differences (LSD) at a 5% level of probability.

Table 4: Effect of Variety and Nutrient Source on Yield and Yield Related Characters of Turmeric Grown in Jos, Nigeria.

Note: LSD= Least Significant Differences at 5% Level of Probability.

Number of Rhizomes per Plant

On varietal UT25 exhibits a higher number of rhizomes per plant (5.23) compared to UT30 (4.14). On nutrient Source Poultry drop­ping as a nutrient source result in the highest number of rhizomes per plant (5.62), followed by dung site (4.28), compost (3.43), and control (3.00). These findings contribute valuable insights for Tur­meric cultivation in the study area emphasizing the need for tailored nutrient management strategies based on specific turmeric varieties and growth stages Onwubiko, et al. [13].

Number of Primary Rhizomes

On varietal UT25 has a higher number of primary rhizomes (2.07) compared to UT30 (1.14). On nutrient Source Poultry dropping as a nutrient source leads to the highest number of primary rhizomes (1.63), followed by dung site (2.00), compost (1.20), and control (1.40), this could be true with poultry droppings due to its ability to release the needed nutrient fast and consistently at every stage of growth, development and initiating rhizomes production as reported by Ravindra, et al. [14].

Number of Secondary Rhizomes

On varietal effect, there is a minor difference in the number of secondary rhizomes between UT25 (3.16) and UT30 (3.00). On nutri­ent source Poultry dropping as a nutrient source result in the highest number of secondary rhizomes (3.01), followed by dung site (2.28), compost (2.23), and control (1.60). this true because secondary rhi­zomes are influenced by variety and nutrients source as reported by Nwokocha, et al. [4] that variety and nutrient plays a very important role in both growth, reproductive and yield parameters of plants he added that nutrients gotten from organic source mostly poultry drop­ping release their nutrient through-out the crop life cycle, improving secondary rhizomes, over all yield and soil organic matter.

Yield Per Hectare on Varietal Effect

UT25 produces a higher yield per hectare (4.53 t/ha) compared to UT30 (3.82 t/ha) UT25 generally outperforms UT30 in terms of the number of rhizomes, primary rhizomes, secondary rhizomes, and yield per hectare. Cattapedhyay, et al. [15]. On nutrient source, poultry dropping as a nutrient source results in the highest yield per hectare (4.73 t/ha), followed by dung site (3.67 t/ha), compost (3.00 t/ha), and control (2.12 t/ha) Poultry dropping as a nutrient source appears to be highly effective in promoting all measured yield-related parameters, this study provides valuable insights into the combined effects of turmeric varieties and nutrient sources on key yield and yield-related characteristics, offering practical guidance for optimiz­ing turmeric cultivation in the study area. Verma, et al. [16] reported that variety and poultry dropping affects yield and yield related char­acters he added that poultry dropping affects tumeric reproductive stage positively due to nitric acid availability which translate to repro­duction and yield characters, this poultry dropping could be needed in appreciable quantity at the growing stage and also reproductive stage to affect the over-all yield. Table 5 presents the interaction be­tween turmeric varieties (UT25 and UT30) and nutrient sources on various yield and yield-related parameters in Jos, Nigeria. The param­eters analysed include the number of rhizomes per plant, rhizome weight per plant, and overall yield per hectare. The statistical signifi­cance is determined using the Least Significant Differences (LSD) at a 5% level of probability.

Table 5: Interaction Between Variety and Nutrient Source on the Yield and Yield Related Character of Turmeric Grown in Jos, Nigeria.

Note: LSD= Least Significant Differences at 5% Level of Probability.

Number of Rhizomes per Plant

Variety and Nutrient Interaction, For both UT25 and UT30, the number of rhizomes per plant varies with the nutrient source. UT25 generally produces more rhizomes compared to UT30. Amadi, et al. [12] who stated that nutrient and cultivars/varieties influences yield related characters and overall yield positively, the fast mineralization and decomposition of poultry manure released slowly throughout the growing period might have contributed to the overall yield as stated by

Rhizome Weight per Plant

Variety and Nutrient Interaction: The weight of rhizomes per plant varies between UT25 and UT30 across different nutrient sourc­es. Poultry dropping as a nutrient source tends to result in higher rhizome weights per plant for both varieties. Jiang [3] who reported that rhizomes weight is obtainable when variety, nutrient source and the environment favours the plant in terms of uptake of nutrients, utilization of such nutrients for both plant growth, and yield-related components.

Yield per Hectare

Variety and Nutrient Interaction: The overall yield per hectare is influenced by both variety and nutrient source. Poultry dropping as a nutrient source consistently leads to higher yields for both UT25 and UT30. Amadi, et al. [17] who stated that high nitric acid which is utilized for photosynthetic activities in plants with an adoptable va­riety, good cultural practice and optimum climatic conditions could lead over all yield. This study emphasizes the significant interaction between turmeric varieties and nutrient sources on crucial yield-re­lated parameters. The findings provide practical insights for farmers, guiding them in selecting optimal combinations of varieties and nu­trient sources for enhancing turmeric yield in the specific agricultural context of the study area Ohaeri, et al. [18-23] [24-32].

Recommendations

UT₂₅ generally outperforms UT₃₀ in terms of the number of rhi­zomes, rhizome weight, and yield per hectare across different nutri­ent sources. Poultry dropping emerges as the most effective nutrient source for promoting higher rhizome numbers, weights, and overall yield, irrespective of the variety. Farmers may consider using UT₂₅ and implementing poultry dropping as a preferred nutrient source for maximizing turmeric yield in the given region.

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Seroprevalence of Cytomegalovirus, Epstein-Barr Virus, and Herpes Simplex Viruses in Children Born HIV Positive at the Yaounde University Teaching Hospital, Cameroon After 12 Months of Follow-Up: A Cross Sectional Study

Introduction

Since its discovery, Human Immunodeficiency Virus (HIV) infec­tion remains a real health problem, and particularly in sub-Saharan Africa, and according to the data of the National AIDS Control Com­mittee (NACC), Cameroon in 2021, the prevalence of HIV infection was 3.1% [1]. HIV infection promotes exogenous infections or reacti­vation of solely controlled infections, with the LT CD4+ lynphopenia. With the weakening of the immune system, the reactivations concern more tuberculosis and the oncogenic viruses such as herpes virus­es [2]. Herpesviridae are among the few known causes of cancer and contribute to a variety of malignancies worldwide. The agents con­sidered here, termed Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV–human herpesvirus 8 [HHV8]), are members of the gamma-herpesvirus subfamily [3]. And are a family of managerial viruses such as Kaposi Sarcoma and lymphomas, opportunistic infec­tions of HIV/AIDS [4]. The Herpes simplex virus (HSV), responsible for a contagious disease affecting the skin and mucous membranes, is characterized by a vesicular eruption of grouped pimples [5].

A disease long considered begining in immunocompetent sub­jects; it can be very severe in subjects with immunodeficiency. [6,7]. The Epstein-Barr virus (EBV) and cytomegalovirus (CMV) is com­mon in HIV-infected individuals. Pathogenic gene products enhance the replication of HIV by transactivation of HIV long terminal repeats (LTRs) and are involved in infectious mononucleosis and associated lymphomas, while the type 8 human herpes virus (HHV8) enters in the occurrence of Kaposi sarcoma (KS) and associated lymphomas. The immunosuppression of the individual, obesity, excessive alco­hol, and smoking considers as risk factors for the emergence of these viruses, [8-10]. Although Cameroon is an endemic zone for human herpes virus, and the work done by Njiki et al., In 2015 showing that there is very little information on the epidemiology of HHV8 infec­tion particularly that associated with HIV infection [11], the finding remains with other viruses of the same family. The aim of this study was to determine the seroprevalence of four viruses HSV-1, HSV-2, EBV and CMV in patients born HIV positive at the Yaounde University Teaching Hospital (YUTH).

Methods

Study Design and Setting

It was a prospective cross-sectional study, conducted from No­vember 2020 to October 2021, in YUTH, on patients who came for consultation or were followed at the Approved Treatment Center (ATC).

Participants Enrolment

For every participant who completed the inclusion criteria, a written informed consent was obtained from the parents, and a tech­nical sheet had to be filled by each participant, providing the socio-de­mographic and clinical status as age sex and HIV infection. These data were completed and/or confirmed by the patient’s medical record.

Laboratory Methods

Then a sampling of venous blood into an EDTA tube of 5ml was made and the samples taken then transported to the Microbiology Laboratory of the Faculty of Science. At the laboratory, after centrif­ugation (at 1300 rpm for 10 min, between 18-24 °C), the plasma ob­tained was kept in a freezer at -25 °C, for the later serological research of the infectious agents [12]. According to the manufacturer’s instruc­tions, the kits and samples to be tested were first brought to room temperature. For the detection of IgM and IgG antibodies directed against CMV, HSV-1 and HSV-2, the One Step TORCH IgM/IgG kit (TOX IgM/IgG, RV IgM/IgG, CMV IgM/IgG, HSV-I /2IgM/IgG (Bioneavan co.LTD., NO.18 Ke YuanLu, GongYeKaiFaQu, Huang Cun Zhen AaXing County, Beijing) was used, and for the detection of IgM antibodies di­rected against EBV, the Epstein Barr Rapid Diagnostic kit (EB) -IgM antibody was used according to the kit manufacturer’s instructions (Bioneavan co.LTD., Beijing). The test card was placed on a dry hori­zontal work surface, then 30μl of sample plasma added on top. When the sample migration was found to be difficult, 20μl of sample dilu­tion solution was added immediately, and an additional 50μl of the same solution 5 minutes later. 15 to 20 minutes after the addition of the plasma, the different results were observed [13].

Data Management and Analysis

For each participant, data on parameters of interest gathered through interviews and by blood analysis were recorded and pro­cessed using Excel 2016, and the statistical analysis was done using IBM Statistical Package for Social Science Version 22.0. On one hand, we used the Fischer exact and the Chi-square tests to compare quali­tative variables between groups, while on the other hand, we used the Mann–Whitney test to compare quantitative variables. All p values below 0.05 were considered significant.

Ethical Considerations

The study was approved by the Regional Ethics Committee for Research in Human Health (N°0082/CRERSHC/2023) and received authorization from the Yaounde University and Teaching Hospital (N°494/AR/CHUY/DG/DGA/CAPRC). The Microbiology Laboratory allowed the laboratory analyses. Patients signed consent forms re­garding the use of their plasma and the collection of their medical data.

Results

Sociodemographic and Clinical Parameters

The average age in the study was 9.05±5.09 years, the children were in majority (56.76%, n=42/74) under 10 years old and of female gender (68.92%, n=51/74). 18/74 children (24.32%) smoked and 17/74 concerned by alcohol consumption (22.97%). HIV-1 infection was the most encountered in our cohort, with 94.60% of participants at WHO stage I of the disease. According to medical records, the most commonly used protocol was Tenofovir-Lamivudine-Efavirenz (TD­F/3TC/EFV) with 79.73% of participants (Table 1).

Seroprevalence of Herpesviridae

The seroprevalence of CMV was 95.95% (n=71/74), that of HSV-1 at 93.24% (n=69/74), that of HSV-2 at 93.24% (n=69/74) that of EBV was 22.97% (n=17/74). Seropositivity for HSV-2, HSV-1 and CMV was statically associated with HIV infection (p<0.05) (Table 2). Our partic­ipants presented multi-infections to herpesviridae. Most co-infections found was CMV/HSV-1/HSV-2 63.51%, (n=43) (Table 3). The co-in­fections found affected all age groups (Table 3). Ages ranging from 10 to 19 years concentrate the greatest number of all the consumption of alcohol (n=25/74) and tobacco (n=18/74) (Table 4) and Ages ranging from 0 to 14 years concentrate the greatest number of co-infections (Table 5).

Table 1: Baseline characteristics of the participants.

Table 2: Distribution of participants according to IgG/IgM antibodies against HSV-1, HSV-2, CMV, and IgM against EBV results.

Table 3: Distribution of participants according to Herpesviridae co-infections.

Note: HSV-1/-2: Herpes simplex Virus-1/-2. HIV-1: Human immunodeficiency virus type 1. HIV-2: Human immunodeficiency virus type 2. CMV: Cytomegalovirus. EBV: Epstein-Barr virus, RV: Rubella virus.

Table 4: Frequency of HIV infection according to age group and alcohol, Tobacco, Alcohol and Tobacco consumption.

Table 5: Frequency of herpesviridae infection according to age group and alcohol, Tobacco, Alcohol and Tobacco consumption.

Discussion

Epidemiological data for herpesviridae in Cameroon is not well documented [11]. Among the opportunistic infections of viral origin, infections caused by Herpesviridae, are often responsible for a conta­gious disease affecting the skin and mucous membranes, is character­ized by a vesicular eruption of grouped pimples but also cancers [14]. Both human immunodeficiency virus (HIV) and human herpesvirus (HHV) infections persist lifelong, and almost all individuals infect­ed with HIV are also infected with ≥1 HHV [15]. Our study revealed a female predominance (68.92%, n=51/74) with an average age of 9.05±5.09 years, the majority of participants were under 10 years. A study conducted by Njimbam et al., at the Cité Verte Subdivision­al Medical Center of Yaoundé in 2016, reported 66% of women [16]. This observation corroborates the feminization of the HIV pandem­ic, which is a major trend. Currently 50% of people living with HIV in the world are women, with this rate reaching 59% in sub-Saharan Africa, the region most affected by the epidemic. Certainly, the risk of contamination during sexual intercourse is greater among them, but they are also in a situation of greater social and economic vulnerabil­ity, and therefore greater exposure to risks, particularly in relation to AIDS [17].

The age groups obtained during our study follow the concerned population trend of PLHIV in Cameroon [18]. Most of our participants were under TDF/3TC/EFV treatment protocol (79.73%), a first-line regimen. This protocol is a preferred option in countries with limited resources, because it is simple, inexpensive, in combined form and can be used in HIV/HBV, HIV/BK and in pregnant and breastfeed­ing women [1]. In our study, IgG seroprevalences were 95.95% for CMV, 93.24% for HSV-1, 93.24% for HSV-2, IgM seroprevalence was 22.97% for EBV. This high antibody seroprevalence demonstrates the widespread circulation of these viruses in the population, confirming the status of an endemic area for herpes viruses [14]. Also, to date, the population changes its sexual practices, such as oral sex associated with sociocultural changes, may explain the increasing trend of these infections [11]. The majority of co-infections between herpesviridae found concerned HSV-1 and HSV-2 with a prevalence of 47(63.51) this result is high compared to that reported by Njimbam et al (2016) which was 34% [16]. It is becoming urgent to sensitize young people born HIV positive because the HIV-HSV interaction would be the cause of several resistances to antiretrovirals with the formation of pseudo­typed viruses (i.e. viral particles comprising the HIV genome envel­oped in surface glycoproteins derived from other viruses) [19,20].

EBV and CMV co-infections appear to be more frequent in the literature. A possible explanation is that most of the patients in this cohort, although hospitalized, were seen in outpatient care [21]. Testing for the presence of CMV infection is particularly important for HIV-positive patients to assess disease severity and monitor re­sponse to treatment. The influence of factors not investigated in this study such as genetics, nutritional status, socio-economic conditions could explain these a priori weight results concerning the prevalence of CMV [22]. Ages ranging from 0 to 15 years concentrate the greatest number of co-infections, and ages ranging from 10 to 19 yers concen­trate the risk factors for the occurrence of these co-infections (alcohol and tobacco consumption). If alcohol acts as a behavioral risk factor in acquisition of HIV, it also acts at the biological level through its immu­nosuppressive role increasing susceptibility to infections by reducing the inflammatory response [23], thus finding the smoking which is also associated with the metabolic complications of certain antiret­rovirals [4]. These data underline the need to implement preventive actions, particularly with regard to the consumption of alcohol and increased dietary support when stopping smoking [24]. The present study confirmed that herpesviridae prevalence among children born hiv positive at the yaounde university teaching hospital, Cameroon after 12 months of follow-up was high and this might increase risk of cancers. Our study has strengths including that it was carried out on children who were born HIV positive to HIV-positive mothers and had an undetectable viral load; the study provided information on the epidemiology of herpesviridae in young people. HIV infected born HIV positive. Furthermore, our study has limitations due to its monocen­tric and transversal nature. The absence of molecular analyzes would make it possible to confirm infections or even co-infections.

Conclusion

Our study aimed to determine the seroprevalence of herpesviri­dae in children born HIV with an undetectable viral load at the Hos­pital and University Center of Yaounde. Our study allowed us to eval­uate the co-infection of four herpesviridae (EBV, CMV, HSV-1 and 2) in children born HIV positive at the YUTH. This study highlighted a high risk of herpesvirus infections among PLHIV born HIV positive, in ages ranging from 3 to 19 years, especially among women. The seropreva­lences of these viruses were high and their association with children clinical profile highlights their risk factors. HSV-1, HSV-2 and CMV se­roprevalences were higher in coinfection than in monoinfection. The prevalence of these viruses demonstrates their high endemicity in Cameroon.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

Riwom E.S. Honorine, Njiki B. Jacky designed and set up the re­search project. Mbongué M.C. André, collected the samples, with Njiki B. Jacky and Mbaga D. Serge, led the technical aspects at the Micro­biology Laboratory. The analysis of the data and the writing of this article saw the collaboration of all authors.

Acknowledgment

The authors would like to acknowledge all the participants who contributed to this research. The authors would also like to acknowl­edge the staff of the Yaoundé University Teaching Hospital, Cameroon.

Funding/Support

The authors received no funding support for the research, author­ship, and publication of this article.

Data Availability Statement

The data supporting the results of this study are available on re­quest from the corresponding author. The data is not publicly avail­able because it contains information that could compromise the con­fidentiality of research participants.

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Examining Healthcare Accessibility: A Qualitative Review of Health Disparity, Medical Inequity, and Discrimination

Introduction

For the purpose of this study, participants were asked to describe some of their experiences accessing healthcare, healthcare related services, and/or pharmaceuticals specifically in the United States as a means of obtaining a phenomenography of how they experience aspects of the medical community [2]. Qualitative data was also anatomized following informed consent and respondents were given pseudonyms associated with the crux of their narratives.

Interviews

Interviews lasted one hour to one hour and fifteen minutes each and were digitally recorded. Respondent narratives were then transcribed verbatim, cross tabulated, and analyzed using atlas.ti qualitative data analysis software and a language tonal analyzer. Qualitative data analysis software was used to examine themes present in respondent narratives. The qualitative tonal analyzer assessed the occurrence of anger, disgust, fear, joy, and sadness present in the participant responses. It also examined the analytical, tentative and confidence level of the data (based on its linguistic style). Note, however, that the tonal analyzer evaluated each emotion categorically as opposed to comparatively.

Respondents

Participants for this study were recruited from the Houston and Galveston metropolitan areas through convenience sampling and snowballing. The target population sample for this study were adults of any sex, gender, or race who wanted to discuss their experiences accessing care related services. Unfortunately, several people did not feel that they qualified for participation in the study. They assumed, even after repeated conversations to the contrary, that senior citizens, people with chronic medical conditions, or individuals who had experienced a trauma (physical, psychological, physiological or otherwise) were the most valid respondents for research on one’s medical experiences. As such, a few individuals referred me to someone they perceived as better fitting my criteria. More specifically, for the interested but self-perceived unqualified individual, they had only been to see a doctor a few times (and for “minor” reasons) in their lives and thus their experiences were not relevant. As such, several individuals referred me to people who had more frequent physician-patient interactions due to chronic or reoccurring diseases or illnesses. Thus, of the twenty people recruited for this study, four people were self-excluded. Sixteen people felt that their narratives were fitting and thus continued participation in the study [3].

Qualitative Data

In cognitive narratology, the significance of one’s narrative chronology lies at the intersection between fabula (the chronological sequence of events in a narrative) and sjuzet (the re-presentation of events through narrative) which act as a gauge of one’s perception of his or her quality of life and lived experience [4]. Understanding the significance of fabula and sjuzet within the qualitative data of this study provides insight into respondent’s health care experiences, self-perceived quality of life, and how that phenomenology situates within health disparities, medical inequities, and various forms of discrimination.

As such, it is valid and interesting to note that all of the respondents’ narratives had similar properties. Not only were they all self-reflective—a necessary component for most qualitative interviews— but they were also comparative appraisals of the study participant’s perceived social expectations and personal agency. Specifically, the chronology of each respondent’s narrative either compared their present situation with that of the past or vice versa. Their recollections also all began in a time when the individual experienced the least amount of direct agency or when he or she relied heavily on proxy agency or via one’s parents and one’s parents’ applicable insurance. No one was prompted to do this, and it occurred contrary to the age of the research participant.

According to Albert Bandura’s agentic perspective of social cognitive theory, human agency is characterized by self-reflectiveness which distinguishes between one’s ability to have and apply direct personal agency, rely on a kind of proxy agency (agency via the help of other people), or rely on collective agency which is actualized by socially coordinative and interdependent means [5]. Within the context of the qualitative data obtained for this study, an individual’s ability to either obtain and use private insurance, obtain and use governmental insurance or that of a proxy’s (such as a parent or guardian), or one’s need to seek health care via a community health facility or clinic, for example, was discussed in the respondent’s narrative chronology by first articulating a period in time in which the individual seemed to lack direct personal agency. This chronological structure represented a time when they had what Bandura described as a reduced “capacity to exercise control over the nature and quality of their own lives”- hence the need to begin each narrative from a point in which he or she had (or has) the least amount of agency.

Thus, respondents were comparing their past and present experiences based on how they perceived their ability to take care of themselves relative to the standards, expectations and/or norms of American society. This could be better understood by asking oneself at what age or in what period of life you are responsible for yourself and your own well-being? The answers you may come up with are a part of a larger social and cognitive process. Such answers were communicated by respondents via the structure and content of the initial chronological structure (fabula), and the specific elements and re-presentation of their narratives (sjuzet). For example, respondent M.P. began her narrative by stating that: [6]

Well, recently it hasn’t been so good with the (pauses) I am on government insurance. I am actually finding it really difficult to find a doctor to see me when they find out that I have the discounted or subsidized plan. So, currently, I do not have a Primary Care Provider. I have only recently found a gynecologist who would take my insurance after calling about seven or eight different offices. So, it’s not going super well lately, and I have only recently become interested in (pauses) I have been keeping up with my health. I turned twenty-seven in September and so now I’m like I’m getting older, and I have to start taking care of myself because mommy and daddy aren’t going to be like “go to the doctor” anymore. So, I have to take care of myself and find the resources myself and it is proving difficult.

M. P. began her narrative by articulating her contemporary inability to access health care using governmental assistance and related it to her perception of what she felt she should be capable of given her age and degree of autonomy. For example, she stated that she was twenty-seven years old, that she was getting older, and that she should be able to take care of herself. Her need to use a kind of proxy agency- previously through her parents but currently through the use of governmental insurance was not in tuned with the kind of agency she believed she should be able to exercise [7]. Given her health care situation, however, she lacked the agency to do that. Thus, as noted via a tonal analysis of her narrative, the retelling of her experiences indicated high levels of anger, sadness, fear, tentativeness, and conscientiousness at 63%, 43%, 26% as well as 10% and 23%, respectively [8].

Similarly, respondent V.A., began her narrative by stating the following: When my parents came over and I don’t remember what earlier forms of health care were like, but I always went to the doctor every year. I always went to the dentist. I don’t remember having an ID, but I am pretty sure that my dad had some form of health insurance like maybe a gold card. Then one day he was like “Go to the doctor! Go to the dentist before it runs out. Go to the eye doctor!” because we had optometry care too. And I didn’t I don’t know why I guess I was busy with school and then things started going not downhill but going typical, I guess. Like I had teeth problems and then eye problems and then I think that the first time that it finally sunk in that we didn’t have insurance was right before we got government healthcare, it was I think I had to get my eye examined and I had to pay out-of-pocket and it really hurt having to pay for like your own glasses and paying for the check-up and the eye drops or whatever. You realize that other people didn’t have what you have or had and you didn’t take advantage of it. So, for me at this point, I am just paying everything out of pocket, and I haven’t been to the doctor in a while and like the dentist either. Like, I had a really bad fever two weeks ago and I think that maybe one of my teeth was falling out and I have to think about saving up money and not going out and doing all of this stuff that I have been so accustomed to. Like, I need to save up and go to the dentist. I might just have to pull the tooth out. So, yeah, that’s where I am right now. I am just having to think long term about my health and just eating better and all of that.

V. A.’s narrative is also a comparative of her previous health and health acquisition status with her current experiences. According to a tonal analysis, the syntax and prosody of her narrative depict high levels of anger, fear, and tentativeness, at 74%, 43%, and 94%, respectively. Like M.P., the interaction between V. A.’s narratives’ fabula and sjuhet with her linguistic structure and tone are indicative of her perceived quality of life and agency via self-reflection. More specifically, V.A. perceived herself as having a quality of life that negatively compared to her previous healthcare-related experiences. It was perhaps these elements of her narrative that facilitated the production anger, fear and tentativeness identified in her narrative retelling.

Another respondent, B.D., noted a similarly structured, comparative phenomenology as well as a transition from proxy agency to a reduction in her ability to take care of herself. She stated that:

I was living with my mom, and I was under her insurance and back in the day, I guess maybe I didn’t know enough, but insurance was great. It was not a problem to go to the doctor and it was not a problem to get medication. But as I got older I would say that it all stayed that way through college when I left home and got my own job. I was fortunate enough to get a job that had insurance. So, I was actually able to go to the doctor when I needed it and I could go and get medication. Then I started a new job and I just noticed that maybe insurance was free before then and now they wanted to charge me for it. I am not really sure how that went. Then suddenly, you start to be more aware of everything. You are wondering like how much co-pays are and just wanting to know the cost of everything, my medications, and strips and everything just suddenly became this huge burden.

Like many of the other study participants, B.D.’s story was laced with fear (57%), sadness (45%), and tentativeness (86%). She also acknowledged a generally decreased ability to take care of herself relative to the cost and accessibility of health care and health care related services. Narrative snippets such as M.P.’s, B.D., and V.A. not only speak to some of the economic and health related hardships faced by some impoverished peoples, but also how that positionality affects one’s self-perception and well-being, and his or her intrapersonal and interpersonal engagement. These are socio-medical affects that have stemmed from one’s difficulty accessing health care and/ or health care related services and can instigate medical inequities downstream.

Generally, medical inequity is facilitated by the unequal accessibility and/or affordability of health care and health care related services. Disparity is normalized through thanatopolitical systems which favor the wealthy. Thus, the kinds of narrative descriptions noted by M.P., V.A., and B.D. are significant because they provide context for understanding and forecasting the interplay between medical inequity and disparity by describing some of the contemporary hindrance’s individuals experience relative to health care accessibility. Furthermore, contemporary health care trends are not leaning towards greater accessibility and affordability for indigent families. So, the inequitable access of health care and health care related services facilitated by neoteric medical technologies that do not account for pre-existing disparities, healthcare biases, and racialized medicine, for example, may increase the disparate nature of the healthcare system. Thus, cost and access become significant indicators of actual or perceived health outcomes.

Cost and Access

Within respondent narratives, cost and access were discussed as dynamic concerns with specific issues being the price of pharmaceuticals and private insurance, the amount of time (relative to cost-benefit) one spends searching for a physician that will take government subsidized insurance, one’s ability to directly and immediately access health care, and issues of care continuity [9]. Self-medicating was also a recurring theme within respondent narratives relative to cost-albeit with much less frequency. The plight of M.P. is an elaboration of such an issue. She stated in the following excerpt of her narrative that:

I think everyone should have access to health care. So, it’s frustrating to kind of run into all of these roadblocks and it’s interesting too because I have had doctors make the appointment and they take that kind of health insurance but then they’ll call back about a day or so later like “Is this a government plan?” Then, they say that they can see me, but I would have to pay out of pocket. So, yeah. They can see you but it will be about four or five hundred dollars. I started calling around because my insurance sent me a list of approved providers. So this is actually going off of their website’s list in my area that take that insurance but then, again, when you go down the list it’s something different. I found (pauses) I think it was like the seventh or eighth person who would finally see me and I had to wait a month [emphasis hers] I think before they had an available time slot. And they were actually very sympathetic and were saying that like “we’re very booked because a lot of people have this problem.” So, I self-medicate. It can get to a point where, you know, I am relatively healthy. So, I haven’t (pauses) it hasn’t gotten to a point where I needed to see a doctor in a short amount of time. So, luckily it hasn’t really gotten to the point where I have to really try to figure it out. But like, if you get the flu or a cold, I don’t go to the doctor I just self-treat it with some Theraflu or something [else] unfortunately. But it is scary knowing that you don’t really have that resource that you need if something did get bad. It’s like you have the illusion of having it because a part of actually having it is being able to access it. It is almost like it is kind of like a mask to avoid the tax penalty. So, it’s like you have insurance so you avoid the tax issue, but you don’t have any of the benefits from it.

Unfortunately, as noted by M.P., having insurance does not necessarily equate to being able to access healthcare-related services in any meaningful way or timely manner. In these instances, the individual tax mandate acts as a negative, biopolitical sanction applied to the American populace in the name of public health [10]. M.P.’s narrative is thereby a depiction of biopolitics and a reiteration of the ways in which poorer health outcomes are facilitated by persisting inaccessibility to health care or health care related services. Yes, she technically has health insurance but if one has to wait a month or more to be seen by a physician it is logical for them to feel that they do not actually have entrée to that benefit. Also, given that most viral and bacterial infections may only last about two weeks, by the time M.P. is likely able to get in to see her doctor her sickness may have already subsided. Such a situation is analogous to a fictive idea of someone who owns a car but can only drive it once every month or two. Eventually, that person may begin to feel that the car is not actually his or her property. Occasional access to the car would also have no major impact on his or her daily transportation needs, his or her ability to access locations beyond the vicinity of public transportation and could potentially compound costs relative to the need for vehicle maintenance and bus, Uber, or taxi services. Similarly, according to respondent M.P., having governmental health coverage provides a miniscule amount of assurance and does not account for the costs of self-medicating [11].

Respondent W.Y.’s health care phenomenology was also fraught with systemic health care accessibility issues, disparities, and discriminations. For her, however, the decreased ability to access regular doctor’s appointments for therapeutic treatment of her chronic illness and prophylactic treatment of other more acute sicknesses, caused her symptoms to worsen over time. W.Y.’s difficulty accessing healthcare also negatively affected her continuity of care. During our interview she stated that:

Unfortunately, I don’t have health care coverage (pauses) per se. So, I have been left, basically, to navigate the Harris County Health System (long pause). I had some health issues and ended up with pneumonia and was unable to get rid of it and ended up with a lung mass. So, I was going to [name omitted] hospital and they basically (pauses) after I returned a few times (pauses) urged me to get care under the Harris Health System because I didn’t have private insurance. Eventually, I was fortunate enough to find out that I didn’t have lung cancer or breast cancer, because I was tested for both. and that my lung (pauses) the lung mass was granulated so it would just basically dissolve over time. Eventually though, I ended up with (pauses) my home had mold in it which I suspected but I ended up having some more serious health concerns from the mold. And so that [emphasis hers] issue dealing with that with the Harris County Health System was well (pauses) different because I was not an immediate concern and so care was, at that point, so-so at best. I would say it was average at best. One of the problems I had was that there was no continuity of care. So, when I would receive or rather go to my appointments, I would see one resident at this place on this day and I would see somebody different on the next visit. So, the continuity of care and with the health issues I was having (pauses) I was having lung problems (pauses) so the care just was not adequate.

I’m forty-six years old (pauses) almost forty-six years old so I feel like I know my body and I know when something’s not right and so, you know, being that I don’t have a long history of care with this certain provider, they pretty much don’t know you and know your body. It’s like when I go in and I have a complaint or a concern it really was sometimes kind of brushed off. I would go in there and I would tell them “This is what’s happening” and that it was the same way that I felt when I had pneumonia. I’d say, “My body feels exactly the same during that time that I had the lung mass.” But, you know, they still just kind of did what they wanted to do. At one point I feel like I am having, well, I know that I am having, some memory loss right now and I have had a terrible time trying to convince them that I need to see a neurologist and then right now, see, I am waiting since when (pauses) I want to say December but it may have been October to see a rheumatologist for a diagnosis. I have some positive Lupus tests and I have some arthritis that has started but all they do is basically give me pain meds and say well we think that it is possible that you may have this but it is also possible that you don’t and until you see a neurologist (pauses) I mean until to see the rheumatologist we won’t have a definite diagnosis. But, I won’t see (pauses) I can’t see a rheumatologist until July which is about six months out. So, I am still waiting to see a rheumatologist.

According to respondent W.Y., when she needed immediate, emergency care she was able to get it. She went to the emergency room. She received all applicable testing, medications, and follow-up appointments. However, when her lung condition went from acute to chronic the immediacy and continuity of her care shifted dramatically. At the time of our interview, she had already waited four months to see a rheumatologist and would need to wait another six months before being able to get in for an appointment. That is almost a year of waiting for a doctor’s appointment. Meanwhile, over the counter ibuprofen and steroids have been suggested as a means of dealing with her pain. This matter further problematizes her plight in that some of the adverse effects of uncontrolled pain include the loss of physical strength, immune system impairment, and increased susceptibility to disease- issues which could potentially irritate her preexisting conditions while simultaneously increasing her susceptibility to other diseases and/or sicknesses [12]. Additionally, although she pays very little for her health insurance, the costs for her prescriptions were double that of retail pharmacies. To an individual who earns less than 150% of the federal poverty level of $21,983 a year for two people, the differences in pharmaceutical costs could be astronomical [13].

Additionally, narratives such as W.Y.’s outline the relationship between one’s socioeconomic status and the inability to access consistent care or otherwise afford health care related services. They also evidence the reality that access to care and care continuity are not mutually exclusive. Instead, they bleed into each other and reveal how one’s poor health becomes a consequence of his or her level of poverty (or perhaps a lack of private insurance) [14]. More specifically, according to Becker and Newson’s article on the interplay of one’s socioeconomic status and dissatisfaction of care, “low socioeconomic status has potentially deadly consequences for several reasons: its associations with other determinants of health status, its relationship to health insurance or the absence thereof, and the constraints on care at sites serving people who have low incomes.”Consequently, the burden of illness is defined by the tautological, inextricable link between poverty and poor health-an issue that Western society has known about for decades and that does not seem to be changing in the foreseeable future.

According to respondent C.C., one’s inability or difficulty to pay for medications is a reoccurring plight witnessed by many people in the pharmaceutical industry. She stated in her interview that: People would get prescriptions filled (pauses) they’d find out the price and then the prescriptions would get left behind. So, they wouldn’t get their prescription. Sometimes it would be because of a high co-pay. Sometimes it would be something that was just a couple of dollars that they would need to pay for their mother’s prescription, but they can’t pay the couple of dollars for their mother’s prescription. So, the item would get left behind. So, price is some issue. Price or paying for prescriptions was an issue for a number of people. They may just go without their medicine, or they may have to wait until their check comes in or put it off or wait until next month or whatever. Depending on the pharmacy those prescriptions would be returned to stock within seven to fourteen days. But, the prescription is good for a year; unless it is a controlled substance and then it’s only good for six months. So, it would be returned to stock, and they could just call back and have it refilled. It’s not like they lose it or they [are] penalized by their insurance or something or rebilled or something. There are times like, for instance, there was a guy and his mother had just been released from the hospital, I think, and she needed these medications and (pauses) a lot of times with Medicaid you have a zero- dollar co-pay. It’s free. But with certain medications that may not be covered by Medicaid and they’re over the counter they have to pay out of pocket for it. So, she had a pain medication that was zero dollars, but the pain medication caused constipation. The constipation medication was considered over the counter and wasn’t covered, and it was just two dollars and he left it behind. And, I let him know what the purpose of that medication was and why it was important for his mother and he just said that he would have to come back and get it. Well, it was eventually returned to stock. The kinds of issues described by study participants W.Y. and C.C. are further compounded by institutionalized racism inherent in many of the ideologies, epistemologies, and praxis of medicine.

Access and Discrimination

According to Kelly H. Hoffman et al, “individuals with at least some medical training hold and may use false beliefs about biological differences between blacks and whites to inform medical judgments, which may contribute to racial disparities [15].” Such beliefs stem from normalized and legitimized ideologies of the molecularization and biologization of race and racialization that have persisted through history. Socialized ideas of the kind of Black/White dichotomies also inform medical students’ perceptions—and thus their treatments—of African American and White people. For example, in a study published in the Proceeding of the National Academy of Sciences, some of the racially biologized ideas existing amongst medical professionals included beliefs that the nerve endings of African Americans were less sensitive than their White counterparts; the notion that the blood of African Americans coagulated more slowly than Whites; that White people had larger brains than African Americans (and thus greater intellect); that the skin of African Americans was thicker than their White counterparts; that African Americans were more fertile than White people; that African Americans had more efficient respiratory systems than Whites; and that African Americans had stronger immune systems than Whites [16]. These assumptions are culturally malignant in that they not only influence physician prescribing tendencies but also the general doctor-patient engagement as a whole.

As varied medical technologies such as AI or machine learning continue to be developed without healthcare biases or normalized structural violences in mind, the kinds of racially biologized concepts referenced in the preceding paragraph will be further mapped on to and into the epistemologies, interpretations, and process of the scientific and medical endeavor. As with many other such instances that have occurred through time, those ideologies will be legitimized, socialized, and heralded as objective within scientific and medical communities. According to Gorgio Agamben and Zygmat Bauman “to the conscious understanding of agents, such as researchers, medical doctors, or lawyers, these [kind of] phenomena will appear more as blind zones and un-intended consequences than as intended action [17].” Nonetheless, to those individuals who are directly and indirectly affected by racial and racialized molecular and biological supposition, the individual intentionality of the researcher or physician is surpassed by institutionalized thanatopolitical medical systems that facilitate and perpetuate inequity and disparity.

One of the most pervasive examples of this is the overrepresentation of minority peoples in the inadequate treatment for acute and chronic pain management. According to a recent study published in the Journal of Clinical Orthopedics and Related Research, for example, the undertreatment of pain for minority populations is largely due to physicians who are unaware of their own cultural beliefs, subjectivities, and/or stereotypes regarding minority peoples, pain management, and the use of narcotic analgesics [18]. Persisting stereotypes feed the kinds of medical inequities discussed by many of the respondents of this study. For example, according to respondent C.C., stereotypes regarding the African American threshold for pain and/or the abuse of controlled substances (such as pain medications) create disparities in pain management between racial groups. During her interview, she provided the following perspective:

I have actually had to correct one of my Techs who (pauses) ok, so there is an issue with people abusing pain medications, or narcotics or sedatives, oxycodone or whatever and an issue of people selling those things on the street. So, the Tech was just turning people away and wouldn’t fill their prescriptions for those kinds of things. So, I was noticing that if it was a Black person that she would just turn them away, but she would fill those prescriptions for people of other races. She would just turn the Black people away. But when you can look at their profile you can see how often they get it filled in. Now there is this thing out here where you can log into it and (pauses) say if I pull up your name, I can see all of the controlled substances that you’ve gotten filled at different pharmacies. People would get away with filling out a prescription at one retail pharmacy and they don’t know that the person also just got one filled at another retail pharmacy because they don’t have access to each other’s systems. The person may even have gotten them filled the same day—two different doctors with two different prescriptions. So with this new system, it will get rid of that issue. I can go in and see that someone just got one filled two days ago. Another way is to look for trends. Are they doctor shopping? Are they on all these different kinds of controls? So, there are a lot of different red flags.

So, I said “um, what’s the problem with that?” She didn’t really have a good reason. So, I said “before they leave let me see the prescription. Let me be the judge of what happens here.” So, she was the gatekeeper whereas I would be the person that needs to decide, and I needed to see if there was an issue or if there was something that made me think that there was a problem. So, I was just realizing that if it was a Black person that she was more likely to treat them like they were a drug abuser or whatever and thus their prescription didn’t need to be filled. It was her personal bias. This was a Hispanic young lady, and I already knew that she has certain biases toward people because she would outwardly say things that were very critical without knowing that she’s saying things that were very critical or inappropriate. So, based on my observations I realized that she didn’t even know that she was feeling those things necessarily. So, I just basically took away her ability to make that judgment—I took away her ability to make that decision.

Again, preconceived notions of race and racialized behaviors (such stereotypes regarding the abuse of controlled substances) work as primary agents prohibiting an individual’s access to medical goods and resources. Such issues, in addition to those of cost and access were repeatedly articulated in respondent narratives. Respondents’ healthcare phenomenographies also depicted a lack of confidence in the health care system, decreased feelings of agency, decreased quality of care, decreased continuity of care, anger, and fear. These experiences and feelings are significant to understanding the broader medical and socio-medical effects of varied health care systems on poor and minoritized peoples. Aspects of these experiences were captured in the tonal analysis.

Tonal Analysis

An aggregate tonal analysis of the interviews showed that 72.5% of participants expressed anger within their narrative retelling. An additional 28% of respondents were fearful. Disgust and sadness were equally indicated in approximately 6.5% of the experiences articulated by participants, and 10% of participant narratives indicated feelings of joy. The most prevalent aspect of the interviews, however, was the feeling of tentativeness, at 92%. What is most telling, however, is that none of the participant narrative experiences indicated feelings of confidence (see table 4). Note that these percentages total more than 100% because they are analyzed by the software as independent variables (Figure 1). Creating a dialogue between respondent narrative fabula and sjuzet with the aforenoted aggregate tonal analysis allowed for the critical analysis and nuance of participants’ phenomenology. Many of their subjective realities were underlined by a lack of confidence in their ability to access health care and/or pharmaceuticals. This sense was compounded by feelings of tentativeness and fear—the latter of which to a much lesser degree. A further analysis of respondent interviews indicated that their feelings were likely in response to the intersection of increasing or unstable health care costs with an inability (or decreased ability) to actually access care or applicable medications. Discrimination (based on race and/or insurance type held) was a peripheral issue that also affected the timorous sensibility of respondent narratives.

Figure 1

Conclusion

And, while discourses on the medical, and social implications of race, racism, and discrimination in general continue to be intellectualized amongst a variety of medical and academic disciplines, their impacts have yet to effectively penetrate the epistemologies and praxis of the medical and biomedical industries [19]. This is perhaps due to the centuries of scientific racism that worked to legitimize health disparities, medical inequities, and discrimination. However, we cannot begin to discuss the prevalence and perpetuation of these issues if we are unable to first acknowledge that they exist. Instead, we (members of the academic, medical, and scientific community) have reified biological reductionism and genetic essentialism and used their bases as the most relevant and meaningful proxies for medical and social scientific research and practice. This further victimizes racialized and minoritized people within the framework of medical progress and continues to muddy the reality of how progress is experienced by all people-as noted by the narratives told in this article.

Conflict of Interest

The authors have no conflicts of interest associated with the material presented in this paper.

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