Counterfeit drugs: A major issue for vulnerable citizens throughout the world and in the United States.

Instruct clinicians on counterfeit drugs and their implications for patient health. Counterfeit drugs imperil patients around the globe, and their penetration into the United States, Canada, and Western Europe is only increasing over time. In addition to inserting counterfeit drugs in the legitimate drug supply, rogue Internet pharmacies and consumer purchases while traveling abroad allow counterfeit drugs to endanger patients. Pharmacists need to understand the nature and severity of the issue and directly counter it through personal actions to secure a legitimate drug supply, such as by using verified distributors and examining the shipment packaging, product packaging, the bottle, and the label for evidence to determine if it is counterfeit or has been tampered with. They can also indirectly counter it through patient education and by working with other key stakeholders in the health care system. Given the risk to patients, pharmacists have an important role to play in limiting patient use of counterfeit drugs.

Rapid Detection of COVID-19 by Serological Methods and the Evaluation of Diagnostic Efficacy of IgM and IgG.

BACKGROUND: In December 2019, a novel coronavirus (SARS-CoV-2) causing symptomatic illness (COVID-19) occurred in Wuhan, China. Travel-associated cases were reported in many other countries leading to epidemic transmission. The number of cases has increased rapidly but laboratory diagnosis is limited. METHODS: We collected samples from two groups of patients diagnosed with COVID-19 for experiments. In one group, 63 serum samples were analyzed IgG and IgM antibodies by enzyme-linked immunosorbent assay (ELISA) and 35 healthy serum samples were served as controls. In the other group, 91 plasma samples were analyzed by colloidal gold-immunochromatographic assay (GICA) for IgG and IgM antibodies and 35 healthy plasma samples were served as controls. Throat swab samples for nucleic acids retest were collected from 81/91 of these participant. RESULTS: The sensitivity of the combined ELISA IgM and IgG detection was 55/63 (87.3%). Sensitivity of the com-bined GICA IgM and IgG detection was 75/91 (82.4%). Both methods were negative for healthy controls and had a specificity of 100%. In 81 cases, the follow up throat swab samples were retested by RT-PCR, showing that 42 cases were positive. The sensitivity was 51.9% (42/81). The area under the receiver operating characteristic (ROC) curve for IgG (AUC(IgG)) was 0.934. The area under the ROC curve for IgM (AUC(IgM)) was 0.812. The area under the ROC curve for IgG + IgM (AUC(IgG+IgM)) was 0.983. CONCLUSIONS: The serological test of SARS-CoV-2 can be used as an important supplement to the existing RT-PCR test for the specific and rapid diagnosis of COVID-19. AUC(IgG) > AUC(IgM) indicates that IgG has better classification performance than IgM. AUC(IgG + IgM) > AUC(IgG) indicates that the combination of IgG and IgM has better classification performance than IgG alone.

Elemental impurities (heavy metals) in kratom products: an assessment of published individual product analyses.

INTRODUCTION: Kratom is commonly used by consumers, and the elemental impurity exposure that consumers would have at different kratom ingestion doses has been determined. METHODS: This assessment used original data from independent third-party laboratory testing of kratom products to identify the percentage of products that exceeded permissible daily exposure limits for lead (5 µg/day), nickel (200 µg/day), arsenic (15 µg/day), and cadmium (5 µg/day), the interim reference level for lead in adults (12.5 µg/day), and the tolerable upper intake level for manganese (11 mg/day) and nickel (1 mg/day). We assessed all products regardless of type and then evaluated non-extract products, extract products, and a soda preparation separately for elemental impurities. RESULTS: Three assessments of elemental impurities in kratom products have been published, totaling 68 products. Assessing all products and assuming a 3 g daily dose of kratom, 7.4% would exceed the permissible daily exposure limits for lead, 0% for nickel, 3.1% for arsenic, and 0% for cadmium. At a kratom dose of 25 g daily, 70.6% would exceed the permissible daily exposure limits for lead, 20.6% for nickel, 9.4% for arsenic, and 0% for cadmium. The interim reference level for lead would be exceeded by 1.5% of products at a kratom daily dose of 3 g and 33.8% of products at 25 g. The tolerable upper intake level for manganese would be exceeded by 12.5% of products at a kratom daily dose of 3 g and 41.7% of products at 25 g. Non-extract products generally contain greater concentrations of elemental impurities than extract products or the soda preparation. DISCUSSION: Apart from their concentrations in a gram of product, assessing the amount of exposure to elemental impurities at different kratom ingestion doses is also important. Elemental impurities exceeding regulatory permissible concentrations for many products, especially with greater daily kratom ingestion doses, may impact human health. CONCLUSIONS: Some kratom products contain excessive concentrations of elemental impurities of toxicological concern, such as lead and arsenic. Non-extract products (powders, capsules, tablets) generally contain greater concentrations of elemental impurities than extract products or the soda preparation. Daily use of these products can result in exposures exceeding regulatory thresholds and adverse health effects.

A kinetic threshold between negative and positive selection based on the longevity of the T cell receptor-ligand complex.

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II- restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64-76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR-ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR-ligand complexes.

Relationships between physical activity and muscular strength among healthy adults across the lifespan.

The purpose of this study was to examine relationships between objective and self-report measures of physical activity and muscle strength among healthy adults ranging in age from 20 to 91 years. Participants (n = 412) were mostly Caucasian men (48 %) and women (52 %) 43.9 ± 16.1 year of age with a body mass index (BMI) of 26.4 ± 4.8 kg/m(2). Physical activity was measured objectively with an accelerometer and by self-report with the Paffenbarger Physical Activity Questionnaire. Upper and lower body muscle strength were measured with an isokinetic dynamometer and handgrip strength with a static dynamometer. Multivariate regression assessed relationships between physical activity and muscle strength. The strongest correlates of upper body strength including handgrip strength were gender (r = -0.861 to -0.716), age (r = -0.445 to -0.241), BMI (r = 0.134-0.397), and physical activity (r = 0.093-0.186). The strongest correlates of lower body strength were gender (r = -0.772 to -0.634), age (r = -0.663 to -0.445), BMI (r = 0.160-0.266), and physical activity (r = -0.139 to 0.151). The strongest correlates of muscle strength were gender (explaining 40-74 % of the variance), age (6-44 %), and BMI (2-16 %), while physical activity correlations were weaker (1-3 %). Conflict surrounding the influence of a physically active lifestyle on muscle strength with age may be due to the stronger influences of other factors that supersede those of physical activity whether measured objectively or by self-report methods.

How MDMA's pharmacology and pharmacokinetics drive desired effects and harms.

3,4-Methylenedioxymethamphetamine (MDMA) is an agent of abuse that has been used by over 16 million Americans. Increased energy, elevated mood, bonding with others, and psychedelic effects are desired effects while liver damage, extended depressed mood, sexual assault, rhabdomyolysis, serotonin syndrome, multiorgan failure, cardiovascular events, arrhythmias, and death are possible adverse effects. These desirable and adverse effects of MDMA are extensions of its fascinating pharmacologic and pharmacokinetic profile. In addition to methamphatemine like effects, MDMA also has mescaline like effects and increases the release of cortisol, oxytocin, and antidiuretic hormone. The desirable effects of MDMA are accentuated by the rave or electronic dance music scene where warm temperatures, vigorous dancing, loud music, and light shows accentuate some of the responses. However, the same environment increases the risk of certain harms. Knowledge of the constellation of these factors is needed for education, prevention of harm, and treatment.

Mobility, walking and physical activity in persons with multiple sclerosis.

OBJECTIVE: The effect of differing levels of mobility and walking disability on level of physical activity (PA) performed in persons with multiple sclerosis (PwMS) is unknown. We aimed to quantify the association between mobility and walking impairment and PA levels in PwMS. METHODS: We assessed mobility and walking impairment in >3000 North American Research Committee on Multiple Sclerosis registrants using the Patient Determined Disease Steps scale (score of 0-2 = no, 3-6 = moderate, ≥7 = severe impairment) and 12-Item Multiple Sclerosis Walking Scale (MSWS-12) score (divided into quartiles, score of 0-25 = least walking impairment, 76-100 = most). Level of PA performance (metabolic equivalent [MET] minutes/week) was estimated using the Godin Leisure-Time Exercise Questionnaire. Multivariable regression and general linear models were used to assess the impact of walking and mobility impairment on PA levels. RESULTS: Moderate and severe mobility impairment was associated with performance of 183 and 319 fewer MET minutes/week and a 65% and 90% reduced odds of performing ≥500 MET minutes/week of PA compared to no impairment (mean ± SD: 447 ± 413 MET minutes/week) (p < 0.05 for all). Compared to the first quartile of MSWS-12 score (mean ± SD: 475 ± 401), the second, third and fourth quartiles were associated with performance of 127, 216 and 268 fewer MET minutes/week and 51%, 71% and 77% reduced odds of achieving ≥ 500 MET minutes/week of PA (p < 0.05 for each). Limitations of our study include possible recall bias, use of a patient-reported rather than objective outcome and assumptions made when calculating MET minutes. CONCLUSION: Mobility and walking impairment are associated with less physical activity in PwMS.

Atorvastatin increases exercise leg blood flow in healthy adults.

OBJECTIVES: We sought to examine the effect of atorvastatin therapy on exercise leg blood flow in healthy middle-aged and older-men and women. BACKGROUND: The vasodilatory response to exercise decreases in humans with aging and disease and this reduction may contribute to reduced exercise capacity. METHODS: We used a double-blind, randomly assigned, placebo-controlled protocol to assess the effect of atorvastatin treatment on exercising leg hemodynamics. We measured femoral artery blood flow (FBF) using Doppler ultrasound and calculated femoral vascular conductance (FVC) from brachial mean arterial pressure (MAP) before and during single knee-extensor exercise in healthy adults (ages 40-71) before (PRE) and after (POST) 6 months of 80 mg atorvastatin (A: 14 men, 16 women) or placebo (P: 14 men, 22 women) treatment. FBF and FVC were normalized to exercise power output and estimated quadriceps muscle mass. RESULTS: Atorvastatin reduced LDL cholesterol by approximately 50%, but not in the placebo group (p < 0.01). Atorvastatin also increased exercise FBF from 44.2 ± 19.0 to 51.4 ± 22.0 mL/min/W/kg muscle whereas FBF in the placebo group was unchanged (40.1 ± 16.0 vs. 39.5 ± 16.1) (p < 0.01). FVC also increased with atorvastatin from 0.5 ± 0.2 to 0.6 ± 0.2 mL/min/mmHg/W/kg muscle, but not in the placebo subjects (P: 0.4 ± 0.2 vs. 0.4 ± 0.2) (p < 0.01). CONCLUSIONS: High-dose atorvastatin augments exercising leg hyperemia. Statins may mitigate reductions in the exercise vasodilatory response in humans that are associated with aging and disease.

Mechanistic modeling of SARS-CoV-2 immune memory, variants, and vaccines

The functional relationship between neutralizing antibodies (NAbs) and protection against SARS-CoV-2 infection and disease remains unclear. We jointly estimated protection against infection and disease progression following natural infection and vaccination from meta-study data. We find that NAbs are strongly correlated with prevention of infection and that any history of NAbs will stimulate immune memory to moderate disease progression. We also find that natural infection provides stronger protection than vaccination for the same level of NAbs, noting that infection itself, unlike vaccination, carries risk of morbidity and mortality, and that our most potent vaccines induce much higher NAb levels than natural infection. These results suggest that while sterilizing immunity may decay, we expect protection against severe disease to be robust over time and in the face of immune-evading variants.

Efficacy and harms of remdesivir for the treatment of COVID-19: a systematic review and meta-analysis

BackgroundWe evaluated the efficacy and safety of remdesivir for the treatment of COVID-19. MethodsSystematic review in five engines, pre-print webpages and RCT registries until May 22, 2020 for randomized controlled trials (RCTs) and observational studies evaluating remdesivir on confirmed, COVID-19 adults with pneumonia and/or respiratory insufficiency. Primary outcomes were all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAE). Secondary outcomes included length of hospital stay, progression of pneumonia, and adverse events (AE). Inverse variance random effects meta-analyses were performed. ResultsTwo placebo-controlled RCTs (n=1300) and two case series (n=88) were included. All studies used remdesivir 200mg IV the first day and 100mg IV for 9 more days, and followed up until 28 days. Wang et al. RCT was stopped early due to AEs; ACTT-1 was preliminary reported at 15-day follow up. Time to clinical improvement was not decreased in Wang et al. RCT, but median time to recovery was decreased by 4 days in ACTT-1. Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28) and need for invasive ventilation at 14 days (RR 0.57, 95%CI 0.23 to 1.42), but had fewer SAEs (RR 0.77, 95%CI 0.63 to 0.94). AEs were similar between remdesivir and placebo arms. Risk of bias ranged from some concerns to high risk in RCTs. InterpretationThere is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in adult, hospitalized COVID-19 patients. Remdesivir should not be recommended for the treatment of severe COVID-19.

Changes in eating habits and lifestyles in Peruvian population during social isolation by the COVID-19 pandemic

BackgroundThe COVID-19 pandemic caused that some governments have implemented house confinement measures with probable consequences on lifestyle, particularly affecting eating habits, physical activity, sleep quality, and mental health. ObjectivesThe aim of this study was to assess the frequency of lifestyles, physical activity and sleep characteristics, as well as changes in eating habits in the Peruvian population during COVID-19 pandemic. MethodsA Cross-sectional descriptive study was performed. We analyzed adults from Peru between July to August 2020 based on an online self-administered questionnaire divided into sociodemographic, anthropometrics and COVID-19 diagnostic reported, lifestyle habits and frequency of consumption of foods. FindingsDuring confinement by COVID-19, 1176 participants were studied, 39% were student, 37.5% were workers and 46% were assert not to work. The population asserted gain weight (1 to 3 Kg) and 35.7% were overweight. The lifestyles habits showed that 54.8% affirmed to doing physical activity and a large proportion (37.2%) asserted sleep less. The Peruvian population presented a main feeding patter of breakfast (95.7%), lunch (97.5%), dinner (89.1%) and brunch (44.9%). Likewise, feeding habits before and during COVID-19 pandemic showed that vegetables (OR:1.56, CI95% 1.21 - 200), fruit (OR: 1.42, CI95% 1.10 - 1.81), legumes (OR:1.67, CI95% 1.23 - 2.28) and eggs (OR: 2.00, CI95% 1.52 - 2.65) presented significantly consumption increase during social isolation, while bakery products (OR: 0.74, CI95% 0.56 - 0.97), meat, snack, refreshment and fast-food decrease consumption. Other food no significant differences were presented. ConclusionThis study in a Peruvian population showed an important frequency of overweight and sleep disorders. There was a slight increase in physical activity despite the social isolation measures and an increase in health eating habits, nevertheless a majority reported gaining weight.

Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies.

A large proportion of SARS-CoV-2 infected individuals remains asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyzed antibody functions in 52 asymptomatic infected individuals, 119 mild and 21 hospitalized COVID-19 patients. We measured anti-Spike antibody levels with the S-Flow assay and mapped SARS-CoV-2 Spike- and N-targeted regions by Luminex. Neutralization, complement deposition and Antibody-Dependent Cellular Cytotoxicity (ADCC) were evaluated using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC and trigger complement deposition. Antibody levels and activities are slightly lower in asymptomatic individuals. The different functions of the antibodies are correlated, independently of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction, with minor variations. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells. - Sera from convalescent COVID-19 patients activate the complement and kill infected cells by ADCC. - Asymptomatic and symptomatic SARS-CoV-2-infected individuals harbor polyfunctional antibodies. - Antibody levels and functions are slightly lower in asymptomatic individuals - The different antiviral activities of anti-Spike antibodies are correlated regardless of disease severity. - Functions of anti-Spike antibodies have similar kinetics of induction and contraction.

Humoral Immunity to SARS-CoV-2 and Inferred Protection from Infection in a French Longitudinal Community Cohort

Population-level immunity to SARS-CoV-2 is growing through vaccination as well as ongoing circulation. Given waning immunity and emergence of new variants, it is important to dynamically determine the risk of re-infection in the population. For estimating immune protection, neutralization titers are most informative, but these assays are difficult to conduct at a population level. Measurement of antibody levels can be implemented at high throughput, but has not been robustly validated as a correlate of protection. Here, we have developed a method that predicts neutralization and protection based on variant-specific antibody measurements to SARS-CoV-2 antigens. This approach allowed us to estimate population-immunity in a longitudinal cohort from France followed for up to 2 years. Participants with a single vaccination or immunity caused by infection only are especially vulnerable to COVID-19 or hospitalization due to SARS-CoV-2. While the median reduced risk to COVID-19 in participants with 3 vaccinations was 96%, the median reduced risk among participants with infection-acquired immunity only was 42%. The results presented here are consistent with data from vaccine-effectiveness studies indicating robustness of our approach. Our multiplex serological assay can be readily optimized and employed to study any new variant and provides a framework for development of an assay that would include protection estimates.

SARS-CoV-2 Omicron neutralization and risk of infection among elderly after a booster dose of Pfizer vaccine

BackgroundThe protective immunity against Omicron following a BNT162b2 Pfizer booster dose among elderly is not well characterized. MethodsThirty-eight residents from three nursing homes were recruited for the study. Antibodies targeting the Spike protein of SARS-CoV-2 were measured with the S-Flow assay. Neutralizing activities in sera were measured as effective dilution 50% (ED50) with the S-Fuse assay using authentic isolates of Delta and Omicron. ResultsAmong the 38 elderly included in the study, with median (inter-quartile range, IQR) age of 88 (81-92) years, 30 (78.9%) had been previously infected. The ED50 of neutralization were lower against Omicron than Delta, and higher among convalescent compared to naive residents. During an Omicron epidemic affecting two of the three nursing homes in December 2021-January 2022, 75% (6/8) of naive residents got infected, compared to 25% (6/24) of convalescents (P=0.03). Antibody levels to Spike and ED50 of neutralization against Omicron after the BNT162b2 booster dose were lower in those with breakthrough infection (n=12) compared to those without (n=20): median of 1256 vs 2523 BAU/mL (P=0.02) and median ED50 of 234 vs 1298 (P=0.0004), respectively. ConclusionThis study confirmed the importance of receiving at least three antigenic exposures to the SARS-CoV-2 Spike protein for achieving satisfactory neutralizing antibody levels. In this population, protection against Omicron infection was increased in individuals who had been previously infected in addition to the three vaccine doses. Thus, a fourth antigenic exposure may be useful in the elderly population to prevent infection with Omicron, a variant known for its high escape immunity properties.