Bioequivalence of a new coated 15 mg primaquine formulation for malaria elimination.

BACKGROUND: With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. METHODS: A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18-45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5-30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration-time (AUC0-t) were within 80.00 to 125.00%. RESULTS: 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92-111.96%); the corresponding GM AUC0-t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76-112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0-t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. CONCLUSION: IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699.

Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial.

In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance. BACKGROUND: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. METHODS: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]), assessed in a modified intention-to-treat population (mITT). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial was registered at ClinicalTrials.gov (NCT05041907) on 13/09/2021. RESULTS: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients given favipiravir and patients receiving no study drug; a -1% (95% credible interval: -14 to 14%) difference. High dose favipiravir was well-tolerated. INTERPRETATION: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19. The viral clearance rate estimated from quantitative measurements of oropharyngeal eluate viral densities assesses the antiviral efficacy of drugs in vivo with comparatively few studied patients.

Robotic-assisted total knee arthroplasty is associated with the use of thinner polyethylene liners compared to navigation-guided and manual techniques.

PURPOSE: The purpose of this study was to examine the effects of intraoperative technology use on the rate of using polyethylene liners 15 mm or greater during primary total knee arthroplasty (TKA). METHODS: There were 103,295 implants from 16,386 primary unilateral TKAs performed on 14,253 patients at a single institution between 1 January 2018, and 30 June 2022, included in the current study. Robotic assistance and navigation guidance were used in 1274 (8%) and 8345 (51%) procedures, respectively. The remaining 6767 TKAs (41%) were performed manually. Polyethylene liners were manually identified and further subcategorised by implant thickness. Patients who underwent robotic-assisted TKA were younger (p < 0.001) and more likely to be male (p < 0.001) compared to patients who underwent navigation-guided or manual TKAs. RESULTS: Average polyethylene liner thickness was similar between groups (10.5 ± 1.5 mm for robotic-assisted TKAs, 10.9 ± 1.8 mm for navigation-guided TKAs and 10.8 ± 1.8 mm for manual TKAs). The proportions of polyethylene liners 15 mm or greater used were 4.9%, 3.8% and 1.9% for navigation-guided, manual and robotic-assisted procedures, respectively (p < 0.001). Multivariate regression analyses demonstrated that navigation-guided (odds ratio [OR]: 2.6, 95% confidence Interval [CI]: [1.75-4.07], p < 0.001) and manual (OR: 2.0, 95% CI: [1.34-3.20], p = 0.001) procedures were associated with an increased use of polyethylene liners 15 mm or greater. CONCLUSION: Robotic-assisted TKA was associated with a lower proportion of polyethylene liners 15 mm or greater used compared to navigation-guided and manual TKA. These findings suggest that robotic assistance can reduce human error via a more precise cutting system, limit over-resection of the tibia and flexion-extension gap mismatch and ultimately allow for more appropriately sized implants. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

An Artificial Intelligence Chatbot is an Accurate and Useful Online Patient Resource Prior to Total Knee Arthroplasty.

BACKGROUND: Online information is a useful resource for patients seeking advice on their orthopaedic care. While traditional websites provide responses to specific frequently asked questions (FAQs), sophisticated artificial intelligence tools may be able to provide the same information to patients in a more accessible manner. Chat Generative Pretrained Transformer (ChatGPT) is a powerful artificial intelligence chatbot that has been shown to effectively draw on its large reserves of information in a conversational context with a user. The purpose of this study was to assess the accuracy and reliability of ChatGPT-generated responses to FAQs regarding total knee arthroplasty. METHODS: We distributed a survey that challenged arthroplasty surgeons to identify which of the 2 responses to FAQs on our institution's website was human-written and which was generated by ChatGPT. All questions were total knee arthroplasty-related. The second portion of the survey investigated the potential to further leverage ChatGPT to assist with translation and accessibility as a means to better meet the needs of our diverse patient population. RESULTS: Surgeons correctly identified the ChatGPT-generated responses 4 out of 10 times on average (range: 0 to 7). No consensus was reached on any of the responses to the FAQs. Additionally, over 90% of our surgeons strongly encouraged the use of ChatGPT to more effectively accommodate the diverse patient populations that seek information from our hospital's online resources. CONCLUSIONS: ChatGPT provided accurate, reliable answers to our website's FAQs. Surgeons also agreed that ChatGPT's ability to provide targeted, language-specific responses to FAQs would be of benefit to our diverse patient population.

The Financial Burden of Aspirin versus Oral Factor Xa Inhibitors for Thromboprophylaxis Following Total Knee Arthroplasty.

BACKGROUND: Aspirin and oral factor Xa inhibitor thromboprophylaxis regimens are associated with similarly low rates of venous thromboembolism following total knee arthroplasty (TKA). However, the rate of prosthetic joint infection (PJI) is lower with aspirin use. This study aimed to compare the cost differential between aspirin and factor Xa inhibitor thromboprophylaxis with respect to PJI management. METHODS: We used previously published rates of PJI following aspirin and factor Xa inhibitor thromboprophylaxis in primary TKA patients at a single, large institution. Prices for individual drugs were obtained from our hospital's pharmacy service. The cost of PJI included that of 2-stage septic revision, with or without the cost of 1-year follow-up. National data were obtained to determine annual projected TKA volume. RESULTS: The per-patient costs associated with a 28-day course of aspirin versus factor Xa inhibitor thromboprophylaxis were $17.36 and $3,784.20, respectively. Including cost of follow-up, per-patient costs for a 28-day course of aspirin versus factor Xa inhibitors increased to $73,358.76 and $77,125.60, respectively. The weighted average per-patient costs for a 28-day course were $237.38 and $4,370.93, respectively. The annual cost difference could amount to over $14.1 billion in the United States by 2040. CONCLUSIONS: The per-patient cost associated with factor Xa inhibitor thromboprophylaxis is as much as 1,980.6% higher than that of an aspirin regimen due to increased costs of primary treatment, differential PJI rates, and high costs of management. In an era of value-based care, the use of aspirin is associated with major cost advantages.

Changes in Body Composition and Athletic Performance in National Collegiate Athletic Association Division I Female Field Hockey Athletes Throughout a Competitive Season.

ABSTRACT: Summer, LC, Cheng, R, Moran, JT, Lee, M, Belanger, AJ, TaylorIV, WL, and Gardner, EC. Changes in body composition and athletic performance in National Collegiate Athletic Association Division I female field hockey athletes throughout a competitive season. J Strength Cond Res 38(1): 146-152, 2024-The purposes of this study were (a) to analyze the changes in total and regional body composition measurements in a National Collegiate Athletic Association (NCAA) Division I female field hockey team throughout a 17-game competitive season using dual X-ray absorptiometry (DXA); (b) to examine improvements, if any, in athletic performance measures after a season; and (c) to report on the relationship between these body composition changes and changes in athletic performance. Preseason and postseason dual-energy DXA and performance data from the 2019-2020 season were retrospectively identified for 20 field players (forwards, midfielders, and defenders). Body composition data included total and regional fat mass, lean mass, and body fat percentage, whereas athletic performance measures included the vertical jump, 10-yard dash, and pro-agility (5-10-5) shuttle run. All variables were quantitative and analyzed using paired t -tests or its nonparametric equivalent and an alpha level of p < 0.05 was used to determine significance. After a competitive season, athletes had significant decreases in fat mass and increases in lean mass in their arms, legs, trunks, gynoids, and total body measurements. Android fat mass and body fat percentage also decreased. Athletes performed significantly better on the pro-agility shuttle run at the end of the season, but no significant differences were observed in other performance metrics. Moderate correlations were observed between changes in body composition (total fat mass and total lean mass) and changes in athletic performance. Our study provides a novel, longitudinal assessment of body composition and athletic performance for elite female field hockey athletes that will help trainers and coaches better understand how these variables change throughout a season and allow them to better prepare their players for competitive success.

Total knee arthroplasty survivorship and outcomes in young patients: a review of the literature and 40-year update to a longitudinal study.

INTRODUCTION: Growing numbers of younger patients are electing to undergo total knee arthroplasty (TKA) for end-stage osteoarthritis. The purpose of this study was to compare established literature regarding TKA outcomes in patients under age 55, to data from an ongoing longitudinal young patient cohort curated by our study group. Further, we aimed to provide a novel update on survivorship at 40 years post-TKA from our longitudinal cohort. METHODS: A literature search was conducted using the electronic databases PubMed, Embase, and Cochrane Library, using terms related to TKA, patients under age 55, and osteoarthritis. Demographic and outcome data were extracted from all studies that met the inclusion criteria. Data were divided into the "longitudinal study (LS) group," and the "literature review (LR) group" based on the patient population of the study from which it came. RESULTS: After screening, 10 studies met the inclusion criteria; 6 studies comprised the LR group, and 4 studies comprised the LS group. 2613 TKAs were performed among the LR group, and 114 TKAs were longitudinally followed in the LS group. The mean patient ages of the LR and LS groups were 46.1 and 51, respectively. Mean follow-up was 10.1 years for the LR group. Mean postoperative range of motion was 113.6° and 114.5° for the LR and LS groups, respectively. All-cause survivorship reported at 10 years or less ranged from 90.6% to 99.0%. The LS cohort studies reported survivorship ranges of 70.1-70.6% and 52.1-65.3% at 30 and 40 years, respectively. CONCLUSIONS: Young TKA patients demonstrated improved functionality at each follow-up time point assessed. Survivorship decreased with increasing lengths of follow-up, ultimately ranging from 52.1-65.3% at 40 years post-TKA. The paucity of literature on long-term TKA outcomes in this patient population reinforces the necessity of further research on this topic.

Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV).

BACKGROUND: Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. METHODS: In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). RESULTS: The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%-73%). CONCLUSIONS: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.

Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low-dose primaquine or placebo.

BACKGROUND: Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status. METHODS: This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively. RESULTS: One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo). CONCLUSIONS: In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa. TRIAL REGISTRATION: The trial is registered at ISRCTN 11594437.

Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. METHODS: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. RESULTS: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001. CONCLUSION: Reduced adherence, including less supervision, increases the risk of vivax recurrence.

Cardiovascular concentration-effect relationships of amodiaquine and its metabolite desethylamodiaquine: Clinical and preclinical studies.

AIMS: Amodiaquine is a 4-aminoquinoline used extensively for the treatment and prevention of malaria. Orally administered amodiaquine is largely converted to the active metabolite desethylamodiaquine. Amodiaquine can cause bradycardia, hypotension, and electrocardiograph QT interval prolongation, but the relationship of these changes to drug concentrations is not well characterized. METHODS: We conducted a secondary analysis of a pharmacokinetic study of the cardiac safety of amodiaquine (10 mg base/kg/day over 3 days) in 54 Kenyan adults (≥18 years) with uncomplicated malaria. Nonlinear mixed effects modelling was used to assess amodiaquine and desethylamodiaquine concentration-effect relationships for vital sign (pulse rate, blood pressure) and electrocardiograph interval (QT, QRS, PR) outcomes. We also measured the spontaneous beating heart rate after cumulative dosing of amodiaquine and desethylamodiaquine in isolated mouse atrial preparations. RESULTS: Amodiaquine and desethylamodiaquine caused concentration-dependent mean decreases in pulse rate (1.9 beats/min per 100 nmol/L; 95% confidence interval: 1.5-2.4), supine systolic blood pressure (1.7 mmHg per 100 nmol/L; 1.2-2.1), erect systolic blood pressure (1.5 mmHg per 100 nmol/L; 1.0-2.0) and erect diastolic blood pressure (1.4 mmHg per 100 nmol/L; 1.0-1.7). The mean QT interval prolongation was 1.4 ms per 100 nmol/L irrespective of correction factor after adjustment for residual heart rate dependency. There was no significant effect of drug concentration on postural change in blood pressure or PR and QRS intervals. In mouse atria, the spontaneous beating rate was significantly reduced by amodiaquine (n = 6) and desethylamodiaquine (n = 8) at 3 µmol/L (amodiaquine: 10 ± 2%; desethylamodiaquine: 12 ± 3%) and 10 µmol/L (amodiaquine: 50 ± 7%; desethylamodiaquine: 46 ± 6%) concentrations with no significant difference in potency between the 2 compounds. CONCLUSION: Amodiaquine and desethylamodiaquine have concentration-dependent effects on heart rate, blood pressure, and ventricular repolarization.

The heterogeneity of symptom reporting across study sites: a secondary analysis of a randomised placebo-controlled multicentre antimalarial trial.

INTRODUCTION: Symptoms reported following the administration of investigational drugs play an important role in decisions for registration and treatment guidelines. However, symptoms are subjective, and interview methods to quantify them are difficult to standardise. We explored differences in symptom reporting across study sites of a multicentre antimalarial trial, with the aim of informing trial design and the interpretation of safety and tolerability data. METHODS: Data were derived from the IMPROV trial, a randomised, placebo-controlled double blinded trial of high dose primaquine to prevent Plasmodium vivax recurrence conducted in eight study sites in Afghanistan, Ethiopia, Indonesia and Vietnam. At each follow up visit a 13-point symptom questionnaire was completed. The number and percentage of patients with clinically relevant symptoms following the administration of primaquine or placebo, were reported by study site including vomiting, diarrhoea, anorexia, nausea, abdominal pain and dizziness. Multivariable logistic regression was used to estimate the confounder-adjusted site-specific proportion of each symptom. RESULTS: A total of 2,336 patients were included. The greatest variation between sites in the proportion of patients reporting symptoms was for anorexia between day 0 and day 13: 97.3% (361/371) of patients in Arba Minch, Ethiopia, reported the symptom compared with 4.7% (5/106) of patients in Krong Pa, Vietnam. Differences attenuated slightly after adjusting for treatment arm, age, sex, day 0 parasite density and fever; with the adjusted proportion for anorexia ranging from 4.8% to 97.0%. Differences between sites were greater for symptoms graded as mild or moderate compared to those rated as severe. Differences in symptom reporting were greater between study sites than between treatment arms within the same study site. CONCLUSION: Despite standardised training, there was large variation in symptom reporting across trial sites. The reporting of severe symptoms was less skewed compared to mild and moderate symptoms, which are likely to be more subjective. Trialists should clearly distinguish between safety and tolerability outcomes. Differences between trial arms were much less variable across sites, suggesting that the relative difference in reported symptoms between intervention and control group is more relevant than absolute numbers and should be reported when possible. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01814683; March 20th, 2013.

Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population.

BACKGROUND: A strong predictor for the development of alcohol use disorder (AUD) is altered sensitivity to the intoxicating effects of alcohol. Individual differences in the initial sensitivity to alcohol are controlled in part by genetic factors. Mice offer a powerful tool to elucidate the genetic basis of behavioral and physiological traits relevant to AUD, but conventional experimental crosses have only been able to identify large chromosomal regions rather than specific genes. Genetically diverse, highly recombinant mouse populations make it possible to observe a wider range of phenotypic variation, offer greater mapping precision, and thus increase the potential for efficient gene identification. METHODS: We have taken advantage of the Diversity Outbred (DO) mouse population to identify and precisely map quantitative trait loci (QTL) associated with ethanol sensitivity. We phenotyped 798 male J:DO mice for three measures of ethanol sensitivity: ataxia, hypothermia, and loss of the righting response. We used high-density MegaMUGA and GigaMUGA to obtain genotypes ranging from 77,808 to 143,259 SNPs. We also performed RNA sequencing in striatum to map expression QTLs and identify gene expression-trait correlations. We then applied a systems genetic strategy to identify narrow QTLs and construct the network of correlations that exists between DNA sequence, gene expression values, and ethanol-related phenotypes to prioritize our list of positional candidate genes. RESULTS: We observed large amounts of phenotypic variation with the DO population and identified suggestive and significant QTLs associated with ethanol sensitivity on chromosomes 1, 2, and 16. The implicated regions were narrow (4.5-6.9 Mb in size) and each QTL explained ~4-5% of the variance. CONCLUSIONS: Our results can be used to identify alleles that contribute to AUD in humans, elucidate causative biological mechanisms, or assist in the development of novel therapeutic interventions.

Prevalence and associated risk factors of soil-transmitted helminth infections in Kandahar, Afghanistan.

BACKGROUND: Soil-transmitted helminth (STH) infections are still a major health problem, especially in resource-limited countries. The community-based prevalence of STH is unknown in Afghanistan. Main objectives of this study were to estimate the prevalence and associated factors of STH among children in Daman district of Kandahar province in Afghanistan. METHODS: This was a community-based cross-sectional study, with data collected during five months (June-October, 2020) from children living in five villages of Daman district in Kandahar, Afghanistan. All the stool samples were examined by saline wet mount method. Data were analyzed by using descriptive statistics, Chi square test, and multivariate logistic regression. RESULTS: A total of 1426 children were studied, with majority (61.8%) of males and the mean age of 6.3 years. The overall prevalence of any intestinal parasitic infection was 39.8%. The overall prevalence of STH infection was 22.7%, with Ascaris lumbricoides (18.7%) as the most prevalent STH species, followed by hookworm (7.5%) and Trichuris trichiura (1.4%). Single, double, and triple STH infections were present in 14.9%, 7.2%, and 0.6% of the children, respectively. Multivariate logistic regression revealed that not washing hands after defecating/before eating (AOR 7.0, 95% CI 3.4-14.0), living in mud house (AOR 3.5, 95% CI 1.6-7.4), walking barefoot (AOR 2.2, 95% CI 1.6-3.1), living in overcrowded house (AOR 1.6, 95% CI 1.1-2.3), and practicing open defecation (AOR 1.4, 95% CI 1.1-2.0) as the risk factors associated with the predisposition of rural children for getting STH in Daman district of Afghanistan. CONCLUSIONS: Prevalence of STH is high among children of Daman district in Afghanistan. Most of the risk factors are related to poverty, decreased sanitation, and improper hygiene. Improvement of socioeconomic status, sanitation, and health education to promote public awareness about health and hygiene together with periodic mass deworming programs are better strategies for the control of STH infections in Afghanistan. Also, government and international donor agencies in Afghanistan should help in improving socio-economic status of the rural areas through provision of basic facilities such as piped water, electricity, good housing, and proper toilets.

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.

BACKGROUND: Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. METHODS AND FINDINGS: Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS: While caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.

Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria.

BACKGROUND: In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. METHODS: The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. RESULTS: The proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day. CONCLUSION: The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Isolation and Structure Elucidation of Additional Alkaloids from the Tropical Rainforest Tree Galbulimima baccata.

The structures of five new natural products (GB 27-GB 31, 1-5), isolated as minor components from the bark of Galbulimima baccata, have been determined by 2D NMR spectroscopy in combination with DFT calculations. Among the alkaloids, GB 31 (5) belongs to Class I, GB 27 (1) and 28 (2) belong to Class II, and GB 30 (4) belongs to Class III GB alkaloids. GB 31 is the first non-nitrogen-containing GB "alkaloid", being a biosynthetic oxidation product of himbacine, himandravine, or himbeline. GB 29 (3) has an entirely new natural product scaffold but belongs to Class IV (miscellaneous alkaloids). The isolation of a new Galbulimima scaffold has revealed a new pathway in the biosynthesis of the GB alkaloids. The new molecules isolated have shed further light on the biogenetic relationship among these structurally unique and complex groups of alkaloids. We present, for the first time, a unified biogenesis for the GB alkaloids that were first isolated in the 1950s and now number over 40 examples. This work also brings full circle the story of Galbulimima alkaloids. A life-long project of Wal Taylor involving one of his first students (Lew Mander) and one of his last students (Peter Karuso), a story stretching over six decades, has come to a final conclusion.

Factors Associated With Half- and Full-Marathon Race-Related Injuries: A 3-Year Review.

OBJECTIVE: To better evaluate the relationships between training, demographics, and injury, this study sought to define race-related injury risk factors for half- and full-marathon runners. DESIGN: This 3-year, observational cross-sectional study included adults who participated in a half or full marathon. Prerace and 2-week postrace surveys collected data on demographics, training factors, and injuries. SETTING: This study took place during a nationally recognized marathon affiliated with a local hospital. PARTICIPANTS: Runners were recruited during the Expo in the days before the race. Postrace surveys were returned by 1043 half marathoners and 624 full marathoners (response rate, 83%). INTERVENTIONS: This was an observational study; independent variables included demographic data and race year. MAIN OUTCOME MEASURE: The primary outcome was race-related injury that occurred during the race or within 2 weeks after the race. RESULTS: Race-related injuries were reported by 24% of half marathoners and 30% of full marathoners. For half and full marathoners, respectively, significant factors for injuries were previous injury, lower peak weekly training mileage, and lower weekly mileage before race training. Factors significant for only half-marathon injuries were younger age, female sex, shorter distance of longest training run, and no formal training program. Factors significant for only full-marathon injuries were higher body mass index, fewer days running per week, and fewer years of running experience. CONCLUSIONS: Previous running injuries, undertraining, and inexperience increased race-related injury risk; women had higher risk than men. Decreased risk of injury was associated with training loads of greater than 23 miles/week for half marathoners and 40 miles/week for full marathoners.

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

BACKGROUND: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. CONCLUSIONS: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

Significant Efficacy of a Single Low Dose of Primaquine Compared to Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant Plasmodium falciparum Malaria.

Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (∼6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at ClinicalTrials.gov under identifier NCT02434952.).