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Youssef M Roman Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, VA, 23298, USACorrespondence: Youssef M RomanDepartment of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, VA, 23298, USAEmail romany2@vcu.edu I read with great interest and excitement the findings published in your journal by Takahashi1 and colleagues investigating the association between select pharmacogenetic variants and hospitalization and emergency department (ED) visits. However, I would like to share some comments regarding the study that have not been addressed in the original manuscript. View the original paper by Takahashi and colleagues

Background: Guideline-recommended strategies to interrupt chronic anticoagulation with warfarin or direct oral anticoagulants (DOAC) during the perioperative period of cardiac implantable electronic device (CIED) surgery differ worldwide. There is uncertainty concerning the benefits and harms of interrupted and uninterrupted anticoagulation in patients undergoing CIED surgery., Objectives: To assess the benefits and harms of interrupted anticoagulation (IAC) with either warfarin or DOAC in the perioperative period of CIED surgery versus uninterrupted anticoagulation (UAC), with or without heparin bridging, during an equivalent time frame, for CIED surgery., Search Methods: CENTRAL, MEDLINE, Embase, Web of Science, and two trials registers were searched on 26 November 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. We plan to update this review imminently., Selection Criteria: We included randomized controlled trials (RCTs) evaluating IAC vs. UAC in adults with a diagnosed cardiac rhythm disorder, who underwent elective CIED surgery and received at least one month of warfarin or DOAC anticoagulation. Comparisons of interest were: (1) continued warfarin vs. interrupted warfarin anticoagulation, with or without heparin bridging; and (2) continued DOAC (apixaban, betrixaban, dabigatran, edoxaban, or rivaroxaban) vs. interrupted DOAC, with or without heparin bridging., Data Collection and Analysis: Primary outcomes were composite thromboembolic events (transient ischemic attack, ischemic stroke, deep vein thrombosis, pulmonary embolism, peripheral embolism, or valve thrombosis) and device-pocket hematoma. Secondary outcomes included individual components of composite thromboembolic events, composite bleeding events, all-cause mortality, adverse events, quality of life and days of hospitalization. Two authors independently selected studies, extracted data, and assessed the risk of bias. We assessed the certainty of evidence using GRADE. The inverse variance random-effects model was used for meta-analyses, and the DerSimonian and Laird method was used for calculating the between-study variance Tau 2 . Dichotomous outcomes were calculated as risk ratios (RRs) and we used mean differences (MDs) for continuous outcomes, with respective 95% confidence intervals (95% CIs)., Main Results: We identified 10 eligible studies (2221 participants), of which one is ongoing. Of these 10 studies, six compared IAC vs. UAC with warfarin (1267 participants) and four compared IAC vs. UAC with DOAC (954 participants). Follow-up duration ranged between 0.5 to three months. The mean age of participants ranged from 68 to 76 years. Definitions of thromboembolic events, device-pocket hematoma, and bleeding events varied across studies. IAC vs. UAC with warfarin IAC with warfarin may result in little to no difference in composite thromboembolic events (RR 0.85, 95% CI 0.18 to 4.11; 5 RCTs, n = 1266; low-certainty evidence). The evidence is very uncertain about the effect of IAC on device-pocket hematoma (RR 1.87, 95% CI 0.83 to 4.22; 5 RCTs, n = 1266; very low-certainty evidence), ischemic stroke (RR 0.70, 95% CI 0.11 to 4.40; 5 RCTs, n = 1266; very low-certainty evidence) and composite bleeding events (RR 1.92, 95% CI 0.84 to 4.43; 5 RCTs, very low-certainty evidence). IAC with warfarin likely results in little to no difference in deep vein thrombosis or pulmonary embolism (0 events in both groups; 2 RCTs, n = 782; moderate-certainty evidence). IAC may result in a slight reduction of all-cause mortality (RR 0.35, 95% CI 0.04 to 2.93; 3 RCTs, n = 953; low-certainty evidence). IAC vs. UAC with DOAC IAC with DOAC may result in little to no difference in composite thromboembolic events (RR 0.98, 95% CI 0.06 to 15.63; 3 RCTs, n = 843; low-certainty evidence) and ischemic stroke (RR 0.98, 95% CI 0.06 to 15.63, 2 RCTs, n = 763; low-certainty evidence). The evidence is very uncertain about the effect of IAC with DOAC on device-pocket hematoma (RR 1.07, 95% CI 0.55 to 2.11; 4 RCTs, n = 954; very low-certainty evidence) and composite bleeding events (RR 1.07, 95% CI 0.55 to 2.06; 4 RCTs, n = 954; very low-certainty evidence). IAC may result in little to no difference in ischemic stroke (RR 0.98, 95% CI 0.06 to 15.63, 2 RCTs, low-certainty evidence). IAC likely results in little to no difference in deep vein thrombosis or pulmonary embolism (0 events in both groups; 2 RCTs, n = 763; moderate-certainty evidence). IAC may result in a slight reduction of all-cause mortality (RR 0.49, 95% CI 0.04 to 5.39; 2 RCTs, n = 763; low-certainty evidence)., Authors' Conclusions: Interrupted anticoagulation in people undergoing elective CIED surgery had similar outcomes to uninterrupted anticoagulation with either warfarin or DOAC medications. Certainty of evidence was judged to be low to very low for most of the assessed outcomes. Further RCTs are particularly needed to help identify whether IAC significantly impacts the risks of thromboembolic events and device-pocket hematoma., (Copyright © 2025 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves "dose-finding" studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases. The complexity arises from poorly understood pathophysiologies, scarcity of appropriate animal models, and limited natural history understanding. The inherent heterogeneity, coupled with challenges in defining clinical end points, poses substantial challenges, hindering the utility of available data. The small affected population, low disease awareness, and restricted healthcare access compound the difficulty in conducting dose-finding studies. This white paper delves into critical dose selection aspects, focusing on key therapeutic areas, such as oncology, neurology, hepatology, metabolic rare diseases. It also explores dose selection challenges posed by pediatric rare diseases as well as novel modalities, including enzyme replacement therapies, cell and gene therapies, and oligonucleotides. Several examples emphasize the pivotal role of clinical pharmacology in navigating the complexities associated with these diseases and emerging treatment modalities., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Introduction: We systematically assessed benefits and harms of the use of ivermectin in non-hospitalized patients with early COVID-19., Methods: Five databases were searched until October 17, 2023, for randomized controlled trials (RCTs) in adult patients with COVID-19 treated with ivermectin against standard of care (SoC), placebo, or active drug. Primary outcomes were hospitalization, all-cause mortality, and adverse events (AEs). Secondary outcomes included mechanical ventilation (MV), clinical improvement, clinical worsening, viral clearance, and severe adverse events (SAEs). Random effects meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. Pre-specified subgroup analyses (ivermectin dose, control type, risk of bias, follow-up, and country income) and trial sequential analysis (TSA) were performed., Results: Twelve RCTs (n = 7,035) were included. The controls were placebo in nine RCTs, SoC in two RCTs, and placebo or active drug in one RCT. Ivermectin did not reduce hospitalization (relative risk [RR], 0.81, 95% confidence interval [95% CI] 0.64-1.03; 8 RCTs, low QoE), all-cause mortality (RR 0.98, 95% CI 0.73-1.33; 9 RCTs, low QoE), or AEs (RR 0.89, 95% CI 0.75-1.07; 9 RCTs, very low QoE) vs. controls. Ivermectin did not reduce MV, clinical worsening, or SAEs and did not increase clinical improvement and viral clearance vs. controls (very low QoE for secondary outcomes). Subgroup analyses were mostly consistent with main analyses, and TSA-adjusted risk for hospitalization was similar to main analysis., Conclusions: In non-hospitalized COVID-19 patients, ivermectin did not have effect on clinical, non-clinical or safety outcomes versus controls. Ivermectin should not be recommended as treatment in non-hospitalized COVID-19 patients., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

The growing prevalence of cardiovascular diseases in the United States (US) has disproportionately affected minority populations more than their white counterparts. A population that is often overlooked is the Asian American population, particularly Southeastern Asian immigrants. Despite having relatively favorable socioeconomic indicators compared to the general US population, Asian Americans, specifically Southeast Asian individuals, face a significant burden of traditional cardiovascular risk factors and are considered a high cardiovascular disease risk group. In addition, most studies have aggregated Asian populations into one major racial group rather than analyzing the different ethnicities among the Asian categorization. While some studies suggest that the acculturation process has some degree of impact on cardiovascular health, there has not been a widely-used tool to measure or ascertain the totality of acculturation. Instead, multiple proxies have been used to measure acculturation, and prior studies have argued for more culturally-tailored acculturation proxies. This paper aims to assess the implications of different acculturation measures on cardiovascular health among Asian Americans, particularly Southeastern Asian immigrants. The following proxies were expanded on in this paper: English spoken at home, length of stay in the US, religiosity and spirituality, and admixed family structures. Previous studies showed that as the length of stay in the US increases, the burden of cardiovascular risk factors increases. However, the impact of English spoken at home, religiosity, and admixed family structure are still inconclusive given the extent of current studies. While most studies suggest that an increase in acculturation increases the risk of cardiovascular disease, it is critical to note that acculturation is a multifaceted process. Therefore, more studies are necessary to appropriately examine the implications of various acculturation processes on cardiovascular risk factors in Asians, specifically Southeastern Asian individuals in the US., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Participation of Black American older adults in community-engaged research remains challenging in health sciences. The objectives of this study were to describe the specific efforts, successes, and challenges in recruiting Black American older adults in research led by the Health and Wellness in Aging Across the Lifespan core, part of the Virginia Commonwealth University Institute for Inclusion, Inquiry, and Innovation (iCubed). We conducted a cross-case analysis of 6 community-engaged research projects using the community-engaged research continuum model. Successful recruitment strategies comprised a multifaceted approach to community-based collaboration, including a wellness program with a long standing relationship with the community, engaging key stakeholders and a community advisory board, and building a community-based coalition of stakeholders. Posting flyers and modest monetary compensation remain standard recruitment strategies. The cross-case analysis offered critical lessons on the community's nature and level of engagement in research. Relationship building based on trust and respect is essential to solving complex aging issues in the community., Competing Interests: All authors declare that they have no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU)., Methods: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model., Results: A one-compartment model with first-order absorption and elimination best described the oxypurinol concentration-time data. Inhibition of SU by oxypurinol was described with a direct inhibitory E max model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (-0.27 per A allele, 95% CI -0.38, -0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications., Conclusions: The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Uric acid is the final product of purine metabolism and is converted to allantoin in most mammals via the uricase enzyme. The accumulation of loss of function mutations in the uricase gene rendered hominoids (apes and humans) to have higher urate concentrations compared to other mammals. The loss of human uricase activity may have allowed humans to survive environmental stressors, evolution bottlenecks, and life-threatening pathogens. While high urate levels may contribute to developing gout and cardiometabolic disorders such as hypertension and insulin resistance, low urate levels may increase the risk for neurodegenerative diseases. The double-edged sword effect of uric acid has resurrected a growing interest in urate's antioxidant role and the uricase enzyme's role in modulating the risk of obesity. Characterizing both the effect of uric acid levels and the uricase enzyme in different animal models may provide new insights into the potential therapeutic benefits of uric acid and novel uricase-based therapy.

The promise of viral vector-based gene therapy (GT) as a transformative paradigm for treating severely debilitating and life-threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno-associated virus (AAV) vector-based gene therapies. Because of the irreversible mode of action and incomplete understanding of genotype-phenotype relationship and disease progression in rare diseases careful considerations should be given to GT product's benefit-risk profile. In particular, special attention needs to be paid to safe dose selection, reliable dose exposure response (including clinically relevant endpoints), or creative approaches in study design targeting small patient populations during clinical development. We believe that quantitative tools encompassed within model-informed drug development (MIDD) framework fits quite well in the development of such novel therapies, as they enable us to benefit from the totality of data approach in order to support dose selection as well as optimize clinical trial designs, end point selection, and patient enrichment. In this thought leadership paper, we provide our collective experiences, identify challenges, and suggest areas of improvement in applications of modeling and innovative trial design in development of AAV-based GT products and reflect on the challenges and opportunities for incorporating MIDD tools and more in rational development of these products., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Nonalcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease. The growing prevalence of NAFLD is strongly associated with the high incidence of metabolic syndrome. NAFLD affects as much as 19% of the US population with a disproportionate impact on minority racial groups such as Asian Americans. If not promptly managed, NAFLD may progress to more feared complications. Liver indices for NAFLD screening have been proposed but were often developed using study populations with different anthropometrics than patients of East Asian descent. This review compares the accuracy of five indices for NAFLD screening in Asian cohorts. The Fatty Liver Index performed well in multiple large-scale community studies, although other indices may be more suited for specific patient cohorts. This is important, as the utilization of liver indices could accelerate screening for NAFLD for early management and to reduce liver disease-related health disparities among Asian Americans.

Statins are among the most commonly prescribed medications worldwide. Rosuvastatin is a moderate- to high-intensity statin depending on the prescribed dose. Statin-associated muscle symptoms are the main side effects, contributing to low adherence to statins. The missense variant rs2231142 in ABCG2 affects the functionality of the ABCG2 transporter, altering the pharmacokinetics and pharmacodynamics of rosuvastatin. This special report aims to accentuate the importance of considering the ABCG2 genotype upon prescribing rosuvastatin in high cardiovascular disease risk subgroups, specifically Native Hawaiian and Pacific Islander populations. Based on the reported frequencies of rs2231142 in ABCG2 , it may be justifiable to initiate low-dose rosuvastatin in Samoans relative to Marshallese or Native Hawaiians. Interpopulation differences in pharmacogenetic allele frequencies underscore the need to disaggregate broad population categories to achieve health equity in treatment outcomes.

Statins are widely used medications for the primary and secondary prevention of cardiovascular diseases. Statin-induced musculoskeletal symptoms are the primary adverse drug events contributing to poor adherence to lipid-lowering therapy. Rosuvastatin is characterized by interindividual differences in systemic exposure among different patient population subgroups. The missense variant Q141K within ABCG2 , highly prevalent in some Asian subgroups, results in decreased transporter efflux function and increased exposure to rosuvastatin. We aim to highlight the implications of ABCG2 genotype in prescribing rosuvastatin and the ramifications of interpopulation differences in Q141K frequencies in the starting dose of rosuvastatin in major Asian subgroups, using the most recent genetic-based guidelines. The high frequency of Q141K in Filipinos could warrant a lower starting rosuvastatin dose versus non-Filipinos. The Q141K genotype frequencies in Asian subgroups suggest significant interpopulation differences, reinforcing the need to move beyond race-based to genotype-based rosuvastatin dosing.

Health disparities are well-documented among different racial and ethnic minority groups in the United States. Filipino Americans (FAs) are the third-largest Asian-American group in the USA and are commonly grouped under the Asian categorization. FAs have a higher prevalence of cardiometabolic disorders than non-Hispanic Whites and other Asian subgroups with rates comparable to African Americans. Although no major epidemiological studies have ascertained the prevalence of cardiometabolic diseases in FAs, limited reports suggest that FAs have a higher prevalence of dyslipidemia, hypertension, diabetes, metabolic syndrome, hyperuricemia, and gout than non-FAs. A recent genetic study has shown that FAs could have the highest prevalence of a genetic polymorphism strongly associated with the development of gout and gout-related comorbidities. While developing cardiometabolic disorders is a heterogeneous and multifaceted process, the overall prevalence of certain cardiometabolic disorders parallel the prevalence of population-level risk factors, including genetics, dietary lifestyles, health beliefs, and social determinants of health. Therefore, assessment of the Filipino cuisine, health behaviors among Filipinos, socio-cultural factors, and acculturation to living in the USA are equally critical. Ascertaining the contribution of the biological causes to disease onset and the different psychosocial factors that could modulate disease risk or disease management are needed. Ultimately, a multilevel research approach is critical to assess the role of biological and non-biological risk factors of cardiometabolic disorders in FAs to inform culturally appropriate health promotion, disease prevention strategies, and a personalized approach to health., (© 2021. W. Montague Cobb-NMA Health Institute.)

Background: We systematically assessed beneficial and harmful effects of monoclonal antibodies for coronavirus disease 2019 (COVID-19) treatment, and prophylaxis in individuals exposed to severe acute respiratory syndrome coronavirus 2., Methods: We searched 5 engines and 3 registries until November 3, 2021 for randomized controlled trials evaluating monoclonal antibodies vs control in hospitalized or non-hospitalized adults with COVID-19, or as prophylaxis. Primary outcomes were all-cause mortality, COVID-19-related death, and serious adverse events; hospitalization for non-hospitalized; and development of symptomatic COVID-19 for prophylaxis. Inverse variance random effects models were used for meta-analyses. Grading of Recommendations, Assessment, Development, and Evaluations methodology was used to assess certainty of evidence., Results: Twenty-seven randomized controlled trials were included: 20 in hospitalized patients (n = 8253), 5 in non-hospitalized patients (n = 2922), and 2 in prophylaxis (n = 2680). In hospitalized patients, monoclonal antibodies slightly reduced mechanical ventilation (relative risk [RR] 0.74; 95% confidence interval [CI], 0.60-0.9; I 2  = 20%, low certainty of evidence) and bacteremia (RR 0.77; 95% CI, 0.64-0.92; I 2  = 7%, low certainty of evidence); evidence was very uncertain about the effect on adverse events (RR 1.31; 95% CI, 1.02-1.67; I 2  = 77%, very low certainty of evidence). In non-hospitalized patients, monoclonal antibodies reduced hospitalizations (RR 0.30; 95% CI, 0.17-0.53; I 2  = 0%, high certainty of evidence) and may slightly reduce serious adverse events (RR 0.47; 95% CI, 0.22-1.01; I 2  = 33%, low certainty of evidence). In prophylaxis studies, monoclonal antibodies probably reduced viral load slightly (mean difference -0.8 log 10 ; 95% CI, -1.21 to -0.39, moderate certainty of evidence). There were no effects on other outcomes., Conclusions: Monoclonal antibodies had limited effects on most of the outcomes in COVID-19 patients, and when used as prophylaxis. Additional data are needed to determine their efficacy and safety., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic disrupted the landscape of primary care practice, creating new gaps in chronic disease management and worsening existing health disparities. Community-based pharmacy practices have played a critical role in responding to the pandemic; however, their role in promoting health equity and addressing existing health disparities has not been fully characterized. The objective of this commentary is to highlight some of the challenges and opportunities to cultivate an equitable plain field for communities to overcome significant health crises. Moreover, this commentary underscores the potential role of integrating community-based pharmacies into the public health infrastructure. It is uncommon to find an individual or an organization that has not been impacted by the pandemic. As painful as it has been to lose so many lives due to COVID-19 infection, it is critical to dedicate the time to reflect on how we arrived at this point. Compounding this global health crisis, the pandemic did not weigh equally on all community members, but rather some population groups carried the brunt of the pandemic more than others. The disproportionate burden of COVID-19 has uncovered significant gaps in our healthcare system and the global public health response. Understanding how we arrived at that point in the pandemic is a crucial first step toward achieving health equity. While many factors have led us onto the pandemic path, using national and global health frameworks to address health disparities and monitor health inequalities are worth discussing to delineate a roadmap to optimal population health. As these pandemic lessons challenge the status quo throughout communities, facing these new realities allows us to envision a roadmap for social justice, health equity, and innovative models to optimize health. Leveraging community-based pharmacy services could promote health equity, close growing health gaps, increase access to health care, and rapidly detect and respond to public health threats., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Gout is a metabolic disorder, and one of the most common inflammatory arthritic conditions, caused by elevated serum urate (SU). Gout is globally rising, partly due to global dietary changes and the growing older adult population. Gout was known to affect people of high socioeconomic status. Currently, gout disproportionately affects specific population subgroups that share distinct racial and ethnic backgrounds. While genetics may predict SU levels, nongenetic factors, including diet, cultural traditions, and social determinants of health (SDOH), need to be evaluated to optimize patient treatment outcomes. This approach would allow clinicians to assess whether certain cultural norms, or some SDOH, could be contributing to their patient's risk of developing gout or recurrent gout flares. A cultural assessment may inform the development of culturally tailored dietary recommendations for patients with gout. Causal and association studies investigating the interaction between diet, genetics, and gout, should be cautiously interpreted due to the lack of reproducibility in different racial groups. Optimal gout management could benefit from a multidisciplinary approach, involving pharmacists and nurses. While data on the effect of specific dietary recommendations on managing hyperuricemia and gout may be limited, counseling patients with gout on the role of a healthy diet to optimally control their gout flares and other comorbidities should be part of patient education. Future research investigating the role of a gene-diet interaction in the context of hyperuricemia and gout is needed. Optimal care for patients with gout needs to include a holistic assessment for gout and gout-related comorbidities. Additionally, addressing health beliefs and culture-specific lifestyle factors among patients with gout may reduce their risk of gout flare, improve adherence to urate-lowering therapy (ULT), and achieve health equity in gout management.

Aim: Prevalence of clinically actionable genetic variants of CYP2C19 is lacking in specific population subgroups. This study aims to assess the frequencies of CYP2C19*2 , *3 , and *17 in Asian, Native Hawaiian and Pacific Islander (NHPI) population subgroups compared with Europeans. Patients & methods: The study included repository DNA samples of 1064 women, 18 years or older, who self-reported as Filipino, Korean, Japanese, Native Hawaiian, Marshallese and Samoan. Results: The overall frequencies of CYP2C19*2 (25-36%) and CYP2C19*3 (2.5-10%) were significantly higher in all our subgroups than in Europeans (15 and 0.02%, respectively). The overall frequency of CYP2C19*17 was significantly lower in all our subgroups (1-6%) than in Europeans (21.7%). Conclusion: This is the first report on the frequencies of CYP2C19*2 , *3 , and *17 in women of Asian and NHPI descent with distinct population subgroup differences. Differential allele frequencies of CYP2C19 among population subgroups underscore the importance of increasing racial and ethnic diversity in pharmacogenetic research.

Introduction: We systematically assessed benefits and harms of tocilizumab (TCZ), which is an antibody blocking IL-6 receptors, in hospitalized COVID-19 patients., Methods: Five electronic databases and two preprint webpages were searched until March 4, 2021. Randomized controlled trials (RCTs) and inverse probability treatment weighting (IPTW) cohorts assessing TCZ effects in hospitalized, COVID-19 adult patients were included. Primary outcomes were all-cause mortality, clinical worsening, clinical improvement, need for mechanical ventilation, and adverse events (AE). Inverse variance random-effects meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology., Results: Nine RCTs (n = 7,021) and nine IPTW cohorts (n = 7,796) were included. TCZ significantly reduced all-cause mortality in RCTs (RR 0.89, 95%CI 0.81-0.98, p = 0.03; moderate QoE) and non-significantly in cohorts (RR 0.67, 95%CI 0.44-1.02, p = 0.08; very low QoE) vs. control (standard of care [SOC] or placebo). TCZ significantly reduced the need for mechanical ventilation (RR 0.80, 95%CI 0.71-0.90, p = 0.001; moderate QoE) and length of stay (MD -1.92 days, 95%CI -3.46 to -0.38, p = 0.01; low QoE) vs. control in RCTs. There was no significant difference in clinical improvement or worsening between treatments. AEs, severe AEs, bleeding and thrombotic events were similar between arms in RCTs, but there was higher neutropenia risk with TCZ (very low QoE). Subgroup analyses by disease severity or risk of bias (RoB) were consistent with main analyses. Quality of evidence was moderate to very low in both RCTs and cohorts., Conclusions: In comparison to SOC or placebo, TCZ reduced all-cause mortality in all studies and reduced mechanical ventilation and length of stay in RCTs in hospitalized COVID-19 patients. Other clinical outcomes were not significantly impacted. TCZ did not have effect on AEs, except a significant increased neutropenia risk in RCTs. TCZ has a potential role in the treatment of hospitalized COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist.

Global migration trends are accelerating population admixture. Increasing population diversity met with minority health disparities necessitates thoughtful training of health professional students. Health professional accreditation standards emphasize pharmacogenomics and clinical cultural competency (CCC); however, published studies focus on students' knowledge in pharmacogenomics alone. This report reviews considerations for integrating CCC into required pharmacogenomic education in pharmacy and other health disciplines. By coupling both topics during didactic training and active learning exercises repeated throughout the existing curriculum, students can become adept at these individualized patient care skills and retain their knowledge into their careers. Moving beyond race as a proxy for healthcare decision-making, the CCC of clinicians coupled with patients' genetic test results could empower clinicians to address health disparities and facilitate discussions about the role of race in clinical practice. Ultimately, an integrated approach of teaching pharmacogenomics and CCC could dismantle race-norming or race-based clinical practices.

Background: We systematically assessed benefits and harms of the use of ivermectin (IVM) in patients with coronavirus disease 2019 (COVID-19)., Methods: Published and preprint randomized controlled trials (RCTs) assessing the effects of IVM on adult patients with COVID-19 were searched until 22 March 2021 in 5 engines. Primary outcomes were all-cause mortality rate, length of hospital stay (LOS), and adverse events (AEs). Secondary outcomes included viral clearance and severe AEs (SAEs). The risk of bias (RoB) was evaluated using the Cochrane Risk of Bias 2.0 tool. Inverse variance random effect meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods., Results: Ten RCTs (n = 1173) were included. The controls were the standard of care in 5 RCTs and placebo in 5. COVID-19 disease severity was mild in 8 RCTs, moderate in 1, and mild and moderate in 1. IVM did not reduce all-cause mortality rates compared with controls (relative risk [RR], 0.37 [95% confidence interval, .12-1.13]; very low QoE) or LOS compared with controls (mean difference, 0.72 days [95% confidence interval, -.86 to 2.29 days]; very low QoE). AEs, SAEs, and viral clearance were similar between IVM and control groups (low QoE for all outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality rates in 3 RCTs at high RoB were reduced with IVM., Conclusions: Compared with the standard of care or placebo, IVM did not reduce all-cause mortality, LOS, or viral clearance in RCTs in patients with mostly mild COVID-19. IVM did not have an effect on AEs or SAEs and is not a viable option to treat patients with COVID-19., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Filipino Americans (FAs) are the third-largest Asian American subgroup in the United States (US). Some studies showed that FAs experience more cardiometabolic diseases (CMDs) than other Asian subgroups and non-Hispanic Whites. The increased prevalence of CMD observed in FAs could be due to genetics and social/dietary lifestyles. While FAs are ascribed as an Asian group, they have higher burdens of CMD, and adverse social determinants of health compared to other Asian subgroups. Therefore, studies to elucidate how FAs might develop CMD and respond to medications used to manage CMD are warranted. The ultimate goals of this study are to identify potential mechanisms for reducing CMD burden in FAs and to optimize therapeutic drug selection. Collectively, these investigations could reduce the cardiovascular health disparities among FAs., Rationale and Design: This is a cross-sectional epidemiological design to enroll 300 self-identified Filipino age 18 yrs. or older without a history of cancer and/or organ transplant from Virginia, Washington DC, and Maryland. Once consented, a health questionnaire and disease checklist are administered to participants, and anthropometric data and other vital signs are collected. When accessible, we collect blood samples to measure basic blood biochemistry, lipids, kidney, and liver functions. We also extract DNA from the blood or saliva for genetic and pharmacogenetic analyses. CMD prevalence in FAs will be compared to the US population. Finally, we will conduct multivariate analyses to ascertain the role of genetic and non-genetic factors in developing CMD in FAs. Virginia Commonwealth University IRB approved all study materials (Protocol HM20018500)., Summary: This is the first community-based study to involve FAs in genomics research. The study is actively recruiting participants. Participant enrollment is ongoing. At the time of this publication, the study has enrolled 97 participants. This ongoing study is expected to inform future research to reduce cardiovascular health disparities among FAs.

Introduction: No early treatment intervention for COVID-19 has proven effective to date. We systematically reviewed the efficacy of hydroxychloroquine as early treatment for COVID-19., Material and Methods: Randomized controlled trials (RCTs) evaluating hydroxychloroquine for early treatment of COVID-19 were searched in five engines and preprint websites until September 14, 2021. Primary outcomes were hospitalization and all-cause mortality. Secondary outcomes included COVID-19 symptom resolution, viral clearance, and adverse events. Inverse variance random-effects meta-analyses were performed and quality of evidence (QoE) per outcome was assessed with GRADE methods., Results: Five RCTs ( n = 1848) were included. The comparator was placebo in four RCTs and usual care in one RCT. The RCTs used hydroxychloroquine total doses between 1,600 and 4,400 mg and had follow-up times between 14 and 90 days. Compared to the controls, early treatment with hydroxychloroquine did not reduce hospitalizations (RR = 0.80, 95% CI: 0.47-1.36, I 2 = 2%, 5 RCTs, low QoE), all-cause mortality (RR = 0.77, 95% CI: 0.16-3.68, I 2 = 0%, 5 RCTs, very low QoE), symptom resolution (RR = 0.94, 95% CI: 0.77-1.16, I 2 = 71%, 3 RCTs, low QoE) or viral clearance at 14 days (RR = 1.02, 95% CI: 0.82-1.27, I 2 = 65%, 2 RCTs, low QoE). There was a larger non-significant increase of adverse events with hydroxychloroquine vs. controls (RR = 2.17, 95% CI: 0.86-5.45, I 2 = 92%, 5 RCTs, very low QoE)., Conclusions: Hydroxychloroquine was not efficacious as early treatment for COVID-19 infections in RCTs with low to very low quality of evidence for all outcomes. More RCTs are needed to elucidate the efficacy of hydroxychloroquine as early treatment intervention., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Termedia & Banach.)

There are no proven prophylactic interventions for COVID-19. We systematically reviewed the efficacy of prophylactic hydroxychloroquine for COVID-19. Studies evaluating hydroxychloroquine for prophylaxis of COVID-19 were searched in several engines until 8 December 2020. Primary outcomes included RT-PCR positivity, COVID-19 infections (positive RT-PCR or compatible COVID-19 symptoms), and all-cause mortality. Random effects meta-analyses were performed for all outcomes. Five randomized controlled trials (RCTs) ( n = 5579) and one cohort ( n = 106) were included. Placebo was the comparator in four RCTs, and usual care in one RCT. Compared to the controls, five RCTs showed that hydroxychloroquine prophylaxis did not reduce RT-PCR positivity (RR 1.01, 95% CI 0.88-1.16), COVID-19 infection (RR 0.98, 95% CI 0.78-1.22), or all-cause mortality (RR 0.73, 95% CI 0.27-1.99). There were no differences of effects by pre- or post-exposure prophylaxis. Prophylaxis with hydroxychloroquine increased the risk of diarrhea, abdominal pain, or vomiting (RR 4.56, 95% CI 1.58-13.19). There were no effects of hydroxychloroquine on other secondary outcomes. Quality of evidence was low to very low for all outcomes. Hydroxychloroquine was not efficacious as a prophylaxis for COVID-19 infections, defined either as RT-PCR positivity or as a composite of RT-PCR positivity or compatible symptoms. Hydroxychloroquine did not reduce all-cause mortality, clinical worsening, or adverse events.

We systematically reviewed the efficacy and safety of hydroxychloroquine as treatment for hospitalized COVID-19. Randomized controlled trials (RCTs) evaluating hydroxychloroquine as treatment for hospitalized COVID-19 patients were searched until 2nd of December 2020. Primary outcomes were all-cause mortality, need of mechanical ventilation, need of non-invasive ventilation, ICU admission and oxygen support at 14 and 30 days. Secondary outcomes were clinical recovery and worsening, discharge, radiological progression of pneumonia, virologic clearance, serious adverse events (SAE) and adverse events. Inverse variance random effects meta-analyses were performed. Thirteen RCTs ( n =18,540) were included. Hydroxychloroquine total doses ranged between 2000 and 12,400 mg; treatment durations were from 5 to 16 days and follow up times between 5 and 30 days. Compared to controls, hydroxychloroquine non-significantly increased mortality at 14 days (RR 1.07, 95%CI 0.92-1.25) or 30 days (RR 1.08, 95%CI 1.00-1.16). Hydroxychloroquine did not affect other primary or secondary outcomes, except SAEs that were significantly higher than the control (RR 1.24, 95%CI 1.05-1.46). Eleven RCTs had high or some concerns of bias. Subgroup analyses were consistent with main analyses. Hydroxychloroquine was not efficacious for treating hospitalized COVID-19 patients and caused more severe adverse events. Hydroxychloroquine should not be recommended as treatment for hospitalized COVID-19 patients.

Individuals of distinct Asian backgrounds are commonly aggregated as Asian, which could mask the differences in the etiology and prevalence of health conditions in the different Asian subgroups. The Hmong are a growing Asian subgroup in the United States with a higher prevalence of gout and gout-related comorbidities than non-Hmong. Genetic explorations in the Hmong suggest a higher prevalence of genetic polymorphisms associated with an increased risk of hyperuricemia and gout. History of immigration, acculturation, lifestyle factors, including dietary and social behavioral patterns, and the use of traditional medicines in the Hmong community may also increase the risk of developing gout and lead to poor gout management outcomes. Engaging minorities such as the Hmong population in biomedical research is a needed step to reduce the burden of health disparities within their respective communities, increase diversity in genomic studies, and accelerate the adoption of precision medicine to clinical practice.

Introduction: We systematically reviewed benefits and harms of convalescent plasma (CP) in hospitalized COVID-19 patients., Material and Methods: Randomized controlled trials (RCTs) and observational studies assessing CP effects on hospitalized, adult COVID-19 patients were searched until November 24, 2020. We assessed risk of bias (RoB) using Cochrane RoB 2.0 and ROBINS-I tools. Inverse variance random effect meta-analyses were performed. Quality of evidence was evaluated using GRADE methodology. Primary outcomes were all-cause mortality, clinical improvement, and adverse events., Results: Five RCTs ( n = 1067) and 6 cohorts ( n = 881) were included. Three and 1 RCTs had some concerns and high RoB, respectively; and there was serious RoB in all cohorts. Convalescent plasma did not reduce all-cause mortality in RCTs of severe (RR = 0.60, 95% CI: 0.33-1.10) or moderate (RR = 0.60, 95% CI: 0.09-3.86) COVID-19 vs. standard of care (SOC); CP reduced all-cause mortality vs. SOC in cohorts (RR = 0.66, 95% CI: 0.49-0.91). Convalescent plasma did not reduce invasive ventilation vs. SOC in moderate disease (RR = 0.85, 95% CI: 0.47-1.55). In comparison to placebo + SOC, CP did not affect all-cause mortality (RR = 0.75, 95% CI: 0.48-1.16) or clinical improvement (HR = 1.07, 95% CI: 0.82-1.40) in severe patients. Adverse and serious adverse events were scarce, similar between CP and controls. Quality of evidence was low or very low for most outcomes., Conclusions: In comparison to SOC or placebo + SOC, CP did not reduce all-cause mortality in RCTs of hospitalized COVID-19 patients. Convalescent plasma did not have an effect on other clinical or safety outcomes. Until now there is no good quality evidence to recommend CP for hospitalized COVID-19 patients., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Comparative efficacy and safety of renal denervation (RDN) interventions for uncontrolled (UH) and resistant hypertension (RH) is unknown. We assessed the comparative efficacy and safety of existing RDN interventions for UH and RH. Six search engines were searched up to 1 May 2020. Primary outcomes were mean 24-h ambulatory and office systolic blood pressure (SBP). Secondary outcomes were mean 24-h ambulatory and office diastolic blood pressure (DBP), clinical outcomes, and serious adverse events. Frequentist random-effects network meta-analyses were used to evaluate effects of RDN interventions. Twenty randomized controlled trials (RCTs) ( n = 2152) were included, 15 in RH ( n = 1544) and five in UH ( n = 608). Intervention arms included radiofrequency (RF) in main renal artery (MRA) ( n = 10), RF in MRA and branches ( n = 4), RF in MRA+ antihypertensive therapy (AHT) ( n = 5), ultrasound (US) in MRA ( n = 3), sham ( n = 8), and AHT ( n = 9). RF in MRA and branches ranked as the best treatment to reduce 24-h ambulatory, daytime, and nighttime SBP and DBP versus other interventions (p-scores: 0.83 to 0.97); significant blood pressure effects were found versus sham or AHT. RF in MRA+AHT was the best treatment to reduce office SBP and DBP (p-scores: 0.84 and 0.90, respectively). RF in MRA and branches was the most efficacious versus other interventions to reduce 24-h ambulatory SBP and DBP in UH or RH.

Objective: This systematic review evaluated the diagnostic accuracy of Xpert MTB/RIF to detect tuberculous meningitis (TBM)., Methods: PubMed and five other databases were systematically searched through March 2019. All studies evaluating diagnostic accuracy of Xpert MTB/RIF on cerebrospinal fluid (CSF) samples were included. Reference standards were definitive or definite plus probable TBM. The quality of studies was assessed by the QUADAS-2 tool. We performed bivariate random-effects meta-analysis and calculated summary diagnostic statistics., Results: We identified 30 studies (n = 3972 participants), including 5 cohort studies and 25 cross-sectional studies. Reference standards were definite TB (n = 28 studies) or definite plus probable TBM (n = 6 studies). The pooled Xpert MTB/RIF sensitivity was 85% (95% CI, 70-93%), and specificity was 98% (95% CI, 97-99%) with a negative likelihood ratio of 0.15 (95% CI, 0.04-0.27) for definite TBM. For probable TBM cases, pooled sensitivity was 81% (95% CI, 66-90%), and specificity was 99% (95% CI, 97-99%). For both reference standard types, meta-analyses showed a C-statistic area under the curve of 0.98. The QUADAS-2 tool revealed low risk of bias as well as low concerns regarding applicability. Methodological heterogeneity was high among studies., Conclusions: Xpert MTB/RIF showed high accuracy for TBM diagnosis, but a negative Xpert MTB/RIF test does not rule out TBM. Repeat Xpert testing may be necessary. In clinical practice, Xpert MTB/RIF adds speed and sensitivity when compared to classic TBM diagnostic methods or previous commercial nucleic acid amplification techniques. More studies and better strategies for rapidly confirming a diagnosis of TBM in children are urgently needed., (© 2020 John Wiley & Sons Ltd.)

Background: Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19., Methods: Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed., Results: We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed., Conclusions: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19., Competing Interests: The authors have read the journal’s policy and have the following potential competing interests: VP is a paid employee of MedErgy Health Group Inc., and PT is a paid employee of Hemex Health Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Background: The Agency for Healthcare Research and Quality (AHRQ) could devote resources to collate and assess quality improvement studies to support learning health systems (LHS) but there is no reliable data on the consistency of data extraction for important criteria., Methods: We identified quality improvement studies and evaluated the consistency of data extraction from two experienced independent reviewers at three time points: baseline, first revision (where explicit instructions for each criterion were created), and final revision (where the instructions were revised). Six investigators looked at the data extracted by the two systematic reviewers and determined the extent of similarity on a scale of 0 to 10 (where 0 represented no similarity and 10 perfect similarity). There were 42 assessments for baseline, 42 assessments for the first revision, and 42 assessments for the final revision. We asked two LHS participants to assess the relative value of our criteria., Results: The consistency of extraction improved from 1.17 ± 1.85 at baseline to 6.07 ± 2.76 after revision 1 (P < 0.001) and to 6.81 ± 1.94 out of 10 for the final revision (P < 0.001). However, the final revision was not significantly improved over the first revision (P = 0.14). One key informant rated the difficulty in finding and using quality improvement studies a 6 (moderately difficult) while the other a 4 (moderately difficult). When asked how valuable it would be if AHRQ found and collated the demographic information about the health systems and the interventions used in published quality improvement studies, they rated it a 9 (highly valuable) and a 6 (moderately valuable)., Conclusion: Creating explicit instructions for extracting data for quality improvement studies helps enhance the consistency of data extraction. This is important because it is difficult for LHS to vet these quality improvement studies on their own and they would value AHRQ's support in that regard.

Aims: Vascular calcification is common in diabetic patients. Warfarin has been associated with renovascular calcification and worsening renal function; rivaroxaban may provide renopreservation by decreasing vascular inflammation. We compared the impact of rivaroxaban and warfarin on renal outcomes in diabetic patients with non-valvular atrial fibrillation (NVAF)., Methods and Results: Using United States IBM MarketScan data from January 2011 to December 2017, we identified adults with both NVAF and diabetes, newly-initiated on rivaroxaban or warfarin with ≥12-month insurance coverage prior to anticoagulation initiation. Patients with Stage 5 chronic kidney disease (CKD) or undergoing haemodialysis at baseline were excluded. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weighting (IPTW) based on propensity scores (absolute standardized differences <0.1 achieved for all after adjustment). Outcomes included incidence rates of emergency department/hospital admissions for acute kidney injury (AKI) and the composite of the development of Stage 5 CKD or need for haemodialysis. Patients were followed until an event, index anticoagulant discontinuation/switch, insurance disenrollment, or end-of-data availability. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression. We assessed 10 017 rivaroxaban (22.6% received a reduced dose) and 11 665 warfarin users. In comparison to warfarin, rivaroxaban was associated with lower risks of AKI (HR = 0.83, 95% CI = 0.74-0.92) and development of Stage 5 CKD or need for haemodialysis (HR = 0.82, 95% CI = 0.70-0.96). Sensitivity and subgroup analyses had similar effects as the base-case analysis., Conclusion: Rivaroxaban appears to be associated with lower risks of undesirable renal outcomes vs. warfarin in diabetic NVAF patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objective: To review the 3 anti-inflammatory drugs, canakinumab, colchicine, and methotrexate, that have been investigated in major clinical trials for treating patients with atherosclerotic cardiovascular disease (ASCVD)., Data Sources: An Ovid MEDLINE literature search (1946 to February 2, 2020) was performed using search strategy [( C-reactive protein OR ASCVD OR cardiac disease OR cardiovascular disease) AND (canakinumab OR methotrexate OR Colchicine )]. Additional references were identified from the citations., Study Selection and Data Extraction: English-language studies assessing the impact of these 3 drugs on inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) or the association with reducing ASCVD events were included., Data Synthesis: Canakinumab and colchicine significantly reduced ASCVD events in high-risk patients with median baseline hs-CRP levels of ~4.0 mg/L. Methotrexate was ineffective at reducing ASCVD events in high-risk patients, but their baseline hs-CRP concentrations were a median of <2 mg/L. In subgroup analyses of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients whose baseline hs-CRP was 2 to 4 mg/L had benefits from canakinumab therapy similar to those with baseline levels exceeding 4., Relevance to Patient Care and Clinical Practice: Even with the best current drug therapies, patients with underlying inflammation can benefit from the addition of both colchicine and canakinumab to further lower CV events. Given its cost, colchicine is a more attractive option., Conclusions: Patients at high risk of recurrent cardiovascular disease events with an hs-CRP of 2 mg/L or greater can reduce the occurrence of ASCVD events with canakinumab or colchicine therapy. Colchicine is the preferable option, in particular for those with myocardial infarction, given its more reasonable cost.

Background: Hydroxychloroquine and chloroquine have antiviral effects in vitro against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Purpose: To summarize evidence about the benefits and harms of hydroxychloroquine or chloroquine for the treatment or prophylaxis of coronavirus disease 2019 (COVID-19)., Data Sources: PubMed (via MEDLINE), EMBASE (via Ovid), Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry from 1 December 2019 until 8 May 2020., Study Selection: Studies in any language reporting efficacy or safety outcomes from hydroxychloroquine or chloroquine use in any setting in adults or children with suspected COVID-19 or at risk for SARS-CoV-2 infection., Data Extraction: Independent, dually performed data extraction and quality assessments., Data Synthesis: Four randomized controlled trials, 10 cohort studies, and 9 case series assessed treatment effects of the medications, but no studies evaluated prophylaxis. Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. Several studies found that patients receiving hydroxychloroquine developed a QTc interval of 500 ms or greater, but the proportion of patients with this finding varied among the studies. Two studies assessed the efficacy of chloroquine; 1 trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy, was stopped owing to concern that the higher dose therapy increased lethality and QTc interval prolongation. An observational study that compared adults with COVID-19 receiving chloroquine phosphate, 500 mg once or twice daily, with patients not receiving chloroquine found minor fever resolution and virologic clearance benefits with chloroquine., Limitation: There were few controlled studies, and control for confounding was inadequate in observational studies., Conclusion: Evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting., Primary Funding Source: Agency for Healthcare Research and Quality.

When a review is performed following predefined steps (ie, systematically) and its results are quantitatively analyzed, it is called meta-analysis. Publication of meta-analyses has increased exponentially in pubmed.gov; using the key word "meta-analysis," 1,473 titles were yielded in 2007 and 176,704 on January 2020. Well-designed and reported meta-analyses provide valuable information for clinicians, researchers, and policymakers. The aim of this study was to provide CHEST peer reviewers, as well as authors and researchers in training, with tools that can help to improve the quality and timeliness of journal reviews, as well as the quality of the meta-analyses submitted. This article also is intended to be a practical guide to inform authors about the key features of meta-analyses to be considered when producing their review., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Older adults are at high risk for inappropriate prescribing, developing polypharmacy, adverse drug events and poor treatment outcomes due to multimorbidity and geriatric syndromes. Pharmacogenomics could allow healthcare professionals to provide optimal patient care while minimizing the risk of adverse drug events and simplifying complex medication regimens. The implementation of pharmacogenomics in geriatrics medicine requires a broad multilayered bottom-up approach. These include curriculum redesign, rethinking experiential education and patient and provider education. There are barriers associated with adopting pharmacogenomics into clinical practice. These barriers may include economic factors, workflow and informatics support. However, addressing these barriers primarily requires creating a culture of innovative practices in patient care, ongoing interprofessional continuing education and an interdisciplinary approach for patient care.

Background: There is a paucity of contemporary data assessing the implications of atrial fibrillation (AF) on major adverse cardiovascular events (MACE) in patients with or at high-risk for atherosclerotic disease managed in routine practice., Hypothesis: We sought to evaluate the 4-year incidence of MACE in patients with or at risk of atherosclerotic disease in the presence of AF., Methods: Using US MarketScan data, we identified AF patients ≥45 years old with billing codes indicating established coronary artery disease, cerebrovascular disease, or peripheral artery disease or the presence of ≥3 risk factors for atherosclerotic disease from January 1, 2013 to December 31, 2013 with a minimum of 4-years of available follow-up. We calculated the 4-year incidence of MACE (cardiovascular death or hospitalization with a primary billing code for myocardial infarction or ischemic stroke). Patients were further stratified by CHA 2 DS 2 -VASc score and oral anticoagulation (OAC) use at baseline., Results: We identified 625,951 patients with 4-years of follow-up, of which 77,752 (12.4%) had comorbid AF. The median (25%, 75% range) CHA 2 DS 2 -VASc score was 4 (3, 5) and 64% of patients received an OAC at baseline. The incidence of MACE increased as CHA 2 DS 2 -VASc scores increased (P-interaction<.0001 for all). AF patients receiving an OAC were less likely to experience MACE (8.9% vs 11.6%, P < .0001) including ischemic stroke (5.4% vs 6.7%, P < .0001)., Conclusion: Comorbid AF carries a substantial risk of MACE in patients with or at risk of atherosclerotic disease. MACE risk increases with higher CHA 2 DS 2 -VASc scores and is more likely in patients without OAC., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

The Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) of the Seguro Social de Salud (EsSalud) has completed seven brief reports by means of rapid reviews of evidence regarding the potentially effective therapies against SARS-CoV-2 in order to provide current and relevant information for decision makers, clinicians, researchers and the academic community in Peru. The therapeutic agents evaluated were chloroquine/hydroxychloroquine, lopinavir/ritonavir, tocilizumab, oseltamivir, interferon, atazanavir and anti SARS-CoV-2 serum. Evidence identification included the review of PubMed and Cochrane Library electronic databases. Additionally, manual search was carried out on websites from groups dedicated to research and education on health, as well as in the main specialized societies or institutions, such as, the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC). Furthermore, in order to reduce publication bias, the websites: www.clinicaltrials.gov and http://apps.who.int/trialsearch were searched to identify in-progress or unpublished clinical trials. Finally, a "snowball" strategy was performed by reviewing the reference lists of the systematic reviews, primary studies and selected narrative reviews to identify relevant information. The latest review (March 27, 2020) showed that there is no evidence to recommend any medication for patients´ treatment with COVID-19. More evidence, preferably high-quality randomized clinical trials, is needed for decision-making against SARS-CoV-2.

Allopurinol, a common medication to treat gout, is associated with severe cutaneous adverse reactions, and the occurrence is highly predicted by an individual's HLA-B*58:01 carrier status. Guidelines endorse preemptive testing in select Asian populations before initiating allopurinol. The Hmong, an Asian subpopulation originally from China who now live dispersed around the world, have a 2.5-fold higher risk of gout when compared to non-Hmong in Minnesota. Given the concern for severe cutaneous adverse reactions when prescribing allopurinol, we quantified the carrier status of HLA-B*58:01 in Hmong from two independent cohorts in Minnesota. Using a community-based participatory research approach, HLA-B*58:01 carrier status was determined in 49 US-born Hmong without a history of gout or allopurinol use. Further, 47 Hmong patients undergoing clinical evaluation to receive gout pharmacotherapy were also tested. The frequency of HLA-B*58:01 positive carrier status in these two cohorts were compared to published data from a Han Chinese (n = 2910) and a Korean cohort (n = 485) using a Fisher's exact test with a Bonferroni-corrected P-value <0.025 for significance. With one uninterpretable result, we identified two out of 95 people (2.1%) who carried HLA-B*58:01. This 2.1% incidence in these Hmong adults is notably lower than Han Chinese (19.6%, P < 0.0001) and Korean (12.2%, P = 0.0016) populations. Though commonly understood to be of Chinese descent, the lower prevalence within the Hmong underscores the risk of generalizing genotypic findings from Chinese to Asian subpopulations. We suggest no change to the current guidelines recommending which populations should be tested for HLA-B*58:01 before allopurinol use until further validation.

Background There is a paucity of contemporary data estimating the incidence of major adverse cardiovascular events (MACE) in patients with established atherosclerotic disease or multiple risk factors managed in routine practice. We estimated 1- and 4-year incidences of MACE and the association between MACE and vascular beds affected in these patients. Methods and Results Using US IBM MarketScan data from January 1, 2013 to December 31, 2017, we identified patients ≥45 years old with established coronary artery disease, cerebrovascular disease, peripheral artery disease, or the presence of ≥3 risk factors for atherosclerosis during 2013 with a minimum of 4 years of follow-up. We calculated 1- and 4-year incidences of MACE (cardiovascular death or hospitalization for myocardial infarction or ischemic stroke). A Cox proportional hazards regression model adjusted for age and sex was used to evaluate the association between vascular bed number/location(s) affected and MACE. We identified 1 302 856 patients with established atherosclerotic disease or risk factors for atherosclerosis. Coronary artery disease was present in 16.9% of patients, cerebrovascular disease in 7.6%, peripheral artery disease in 13.6%, and risk factors for atherosclerosis only in 66.0%. The 1- and 4-year incidences of MACE were 1.4% and 6.9%, respectively. At 4 years, MACE was more frequent in patients with atherosclerotic disease in a single (hazard ratio=1.51, 95% CI=1.48-1.55), 2-(hazard ratio=2.35, 95% CI=2.27-2.44), or all 3 vascular beds (hazard ratio=3.30, 95% CI=2.97-3.68) compared with having risk factors for atherosclerosis. Conclusions Patients with established atherosclerotic disease or who have multiple risk factors and are treated in contemporary, routine practice carry a substantial risk for MACE at 1- and 4- years of follow-up. MACE risk was shown to vary based on the number and location of vascular beds involved.

Objective: To evaluate the association between preeclampsia (PE) and eclampsia (E) on subsequent metabolic and biochemical outcomes., Methods: Systematic review and meta-analysis of observational studies. We searched five engines until November 2018 for studies evaluating the effects of PE/E on metabolic and biochemical outcomes after delivery. PE was defined as presence of hypertension and proteinuria at >20 weeks of pregnancy; controls did not have PE/E. Primary outcomes were blood pressure (BP), body mass index (BMI), metabolic syndrome (MetS), blood lipids and glucose levels. Random effects models were used for meta-analyses, and effects reported as risk difference (RD) or mean difference (MD) and their 95% confidence interval (CI). Subgroup analyses by time of follow up, publication year, and confounder adjustment were performed., Results: We evaluated 41 cohorts including 3300 PE/E and 13,967 normotensive controls. Women were followed up from 3 months after delivery up to 32 years postpartum. In comparison to controls, PE/E significantly increased systolic BP (MD = 8.3 mmHg, 95%CI 6.8 to 9.7), diastolic BP (MD = 6.8 mmHg, 95%CI 5.6 to 8.0), BMI (MD = 2.0 kg/m 2 ; 95%CI 1.6 to 2.4), waist (MD = 4.3 cm, 95%CI 3.1 to 5.5), waist-to-hip ratio (MD = 0.02, 95%CI 0.01 to 0.03), weight (MD = 5.1 kg, 95%CI 2.2 to 7.9), total cholesterol (MD = 4.6 mg/dL, CI 1.5 to 7.7), LDL (MD = 4.6 mg/dL; 95%CI 0.2 to 8.9), triglycerides (MD = 7.7 mg/dL, 95%CI 3.6 to 11.7), glucose (MD = 2.6 mg/dL, 95%CI 1.2 to 4.0), insulin (MD = 19.1 pmol/L, 95%CI 11.9 to 26.2), HOMA-IR index (MD = 0.7, 95%CI 0.2 to 1.2), C reactive protein (MD = 0.05 mg/dL, 95%CI 0.01 to 0.09), and the risks of hypertension (RD = 0.24, 95%CI 0.15 to 0.33) and MetS (RD = 0.11, 95%CI 0.08 to 0.15). Also, PE/E reduced HDL levels (MD = -2.15 mg/dL, 95%CI -3.46 to -0.85). Heterogeneity of effects was high for most outcomes. Risk of bias was moderate across studies. Subgroup analyses showed similar effects as main analyses., Conclusion: Women who had PE/E have worse metabolic and biochemical profile than those without PE/E in an intermediate to long term follow up period., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To systematically evaluate the effects of bone anabolic therapies (BATs) - specifically, drug therapy with teriparatide, abaloparatide or romosozumab - on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis., Methods: Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome., Results: Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments., Conclusions: Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Intermittent dieting may be an alternative to continuous dieting for weight reduction., Objective: To evaluate the effect of intermittent dieting versus continuous dieting on weight and body composition in overweight or obese adults., Design: A systematic review and meta-analysis of randomized controlled trials (RCTs). Five databases were searched until February 2018 for RCTs comparing intermittent versus continuous dieting. Intermittent dieting consisted of two types: regular intermittent was caloric restriction interspersed with days of weight maintenance or ad libitum eating; intensified intermittent was caloric restriction interspersed with days of even lower caloric restriction. Continuous was continual caloric restriction. Primary outcomes were weight, body fat, lean mass, waist circumference, hip circumference, and energy expenditure. Data were pooled by the inverse variance method using random-effects models and expressed as mean differences (MD) and their 95% confidence intervals (CI)., Results: Nine trials met the inclusion criteria (n = 782), six comparing regular intermittent vs continuous (n = 553), and three comparing intensified intermittent vs continuous (n = 229). Populations were heterogeneous: obese only in five studies, and overweight or obese (mixed) in four studies. Lean mass was significantly lower in regular intermittent vs continuous (MD -0.86 kg; 95% CI -1.62 to -0.10; p = 0.03). No differences were found for the remaining outcomes for both comparisons (regular intermittent or intensified intermittent vs continuous). There was low heterogeneity of effects across trials. Subgroup effects by time to follow-up, gender, per-protocol versus intention-to-treat, enforced exercise, and diabetes were similar to main analyses., Conclusions: This systematic review in obese and overweight individuals showed that regular intermittent dieting decreased lean mass compared to continuous dieting. There were no differences in effects for either intermittent vs continuous interventions across all other outcomes. In contrast to previous systematic reviews, this study suggested that lean mass is better preserved in continuous dieting compared to regular intermittent dieting.

Background: Evidence-based Practice Center (EPC) reports are lengthy and difficult for health systems to navigate. A quality measure index was created to allow health systems to more efficiently access information relevant to their needs., Methods: Two tables were embedded in an EPC report. The first identified quality measures covered by the report with descriptive information. The second contained page numbers in the report's executive summary addressing these quality measures, with hyperlinks to navigate to those pages. The researchers received feedback on the tables from four health system representatives and enhanced the tables. An exercise with two health system-targeted scenarios was then created. Three trainees (one medical fellow and two pharmacy students) and two health system representatives from a large community and a small rural health system completed the exercise, with and without the enhanced tables. They timed how long it took to find answers to scenario questions and provided general feedback., Results: It took 63.4% less time to find quality measure information when the hyperlinked quality measure indexing tables were used (11.0 ± 5.0 vs. 4.0 ± 3.5 minutes; p = 0.002). The health system representatives stated that the quality measure indexed tables were very easy to use and that if these tables were used in future reports they were "somewhat" or "very likely" to use quality measure-indexed EPC reports in the future., Conclusion: A unique concept that can allow EPC reports to be more user friendly to health systems was identified. The refined quality measure-indexed tables enhanced the efficiency of finding information and the overall likability of the report., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Turmeric extract or active component curcumin may have anti-inflammatory effects in people with chronic inflammatory diseases. The effect of turmeric or curcumin on a wide range of inflammatory markers has not been evaluated in a systematic review. We performed a systematic review of randomized controlled trials (RCTs) evaluating the effects of oral turmeric or curcumin on inflammatory markers (CRP, hsCRP, IL-1, IL-6, TNF) in patients with a wide range of chronic inflammatory diseases. Pubmed, EMBASE, Scopus, the Web of Science, and the Cochrane library were evaluated until June 2018. Random effects meta-analyses with inverse variance methods and stratified by turmeric or curcumin were performed. Effects were expressed as mean differences (MD) and their 95% confidence intervals (CI). Risk of bias of RCTs was evaluated with the Cochrane tool. Nineteen RCTs were identified; included patients had rheumatic diseases, advanced chronic kidney disease with hemodialysis, metabolic syndrome, and cardiovascular diseases. Turmeric was the intervention in 5 RCTs (n = 356) and curcumin/curcuminoids in 14 RCTs (n = 988). Follow up times ranged between 4 and 16 weeks. One RCT had high risk of bias. In comparison to controls, turmeric or curcumin did not significantly decrease levels of CRP (MD -2.71 mg/L, 95%CI -5.73 to 0.31, p = 0.08, 5 studies), hsCRP (MD -1.44 mg/L, 95%CI -2.94 to 0.06, p = 0.06, 6 studies), IL-1 beta (MD -4.25 pg/mL, 95%CI -13.32 to 4.82, p = 0.36, 2 studies), IL-6 (MD -0.71 pg/mL, 95%CI -1.68 to 0.25, p = 0.15), and TNF alpha (MD -1.23 pg/mL, 95%CI -3.01 to 0.55, p = 0.18, 7 studies). There were no differences between turmeric and curcumin interventions. High heterogeneity of effects was observed for all markers across studies, except hsCRP. Other inflammatory markers such as IL-1 alpha, TNF beta, IL-17, and IL-22 had scarce data. Turmeric or curcumin did not decrease several inflammatory markers in patients with chronic inflammatory diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: A systematic review and meta-analysis was conducted to assess the efficacy of low-sodium salt substitutes (LSSS) as a potential intervention to reduce cardiovascular (CV) diseases., Methods: Five engines and ClinicalTrials.gov were searched from inception to May 2018. Randomised controlled trials (RCTs) enrolling adult hypertensive or general populations that compared detected hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), overall mortality, stroke and other CV risk factors in those receiving LSSS versus regular salt were included. Effects were expressed as risk ratios or mean differences (MD) and their 95% CIs. Quality of evidence assessment followed GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology., Results: 21 RCTs (15 in hypertensive (n=2016), 2 in normotensive (n=163) and 4 in mixed populations (n=5224)) were evaluated. LSSS formulations were heterogeneous. Effects were similar across hypertensive, normotensive and mixed populations. LSSS decreased SBP (MD -7.81 mm Hg, 95% CI -9.47 to -6.15, p<0.00001) and DBP (MD -3.96 mm Hg, 95% CI -5.17 to -2.74, p<0.00001) compared with control. Significant increases in urinary potassium (MD 11.46 mmol/day, 95% CI 8.36 to 14.55, p<0.00001) and calcium excretion (MD 2.39 mmol/day, 95% CI 0.52 to 4.26, p=0.01) and decreases in urinary sodium excretion (MD -35.82 mmol/day, 95% CI -57.35 to -14.29, p=0.001) were observed. Differences in detected hypertension, overall mortality, total cholesterol, triglycerides, glucose or BMI were not significant. Quality of evidence was low to very low for most of outcomes., Conclusions: LSSS significantly decreased SBP and DBP. There was no effect for detected hypertension, overall mortality and intermediate outcomes. Large, long-term RCTs are necessary to clarify salt substitute effects on clinical outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)