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Purpose: Paclitaxel is an effective therapy for patients with solid tumors. While the albumin-bound formulation eliminates the hypersensitivity reaction caused by the Cremaphor solvent, significant peripheral neuropathy persists when given over the standard 30-min infusion time. We sought to determine if the incidence and severity of peripheral neuropathy could be reduced when the infusion time is lengthened to 2-h.Methods: This was an open-label, single-arm, phase 2 study of albumin-bound paclitaxel given over 2 h. Twenty-five patients with advanced non-small-cell lung cancer were enrolled to determine whether the longer infusion reduced the severity of neuropathy compared to data from an earlier cohort of 40 similar patients treated over 30 min Patients received 125 mg/m(2) of albumin-bound paclitaxel IV over 2 h without premedication on days 1, 8, and 15 of a 28-day cycle. Radiologic assessment was performed every 8 weeks.Results: There was a significant 0.45 grade decrease in average peripheral neuropathy experienced by patients in the 2-h group versus the 30-min group (90% CI, 0.03-0.87). There was, in addition, a significant decrease in grade ≥2 peripheral neuropathy in patients treated over 2 h versus 30 min (28% vs. 55%, 2-sided P = 0.04). A decrease in grade ≥2 neutropenia (20% vs. 48%, 2-sided P = 0.07) was also observed. The median survival, 11 months, was the same for both groups.Conclusion: Increasing the infusion time of albumin-bound paclitaxel from 30 min to 2 h resulted in a significant reduction in both average and grade ≥2 peripheral neuropathy without affecting survival. [ABSTRACT FROM AUTHOR]

Several cytokines have been reported to have hepatoprotective properties in animal models of acetaminophen toxicity. To investigate the relationships of cytokines and toxicity in acetaminophen overdose, blood samples were collected from patients following acute ingestions of acetaminophen. Samples for cytokine analysis were collected at the time of routine clinical monitoring in 111 patients (90 females; mean age 13.6 years). Plasma concentrations of interleukin 6, interleukin 8, interleukin 10, and monocyte chemoattractant protein 1 were analyzed by enzyme-linked immunosorbent assay. Patients were stratified by toxicity severity, defined by the maximal values of hepatic transaminase elevation. Levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 were higher in patients with serum alanine aminotransferase > 1000 IU/L, and monocyte chemoattractant protein 1 had the strongest association with toxicity. Monocyte chemoattractant protein 1 values were higher in patients with greater delays in N-acetylcysteine treatment and in patients with higher values of prothrombin time. Monocyte chemoattractant protein 1 elevation in acetaminophen overdose may represent an innate, immunomodulary response of the liver to earlier events in the toxicity. An understanding of the role of cytokine responses in acetaminophen overdose may be relevant to the future development of new therapies for acetaminophen toxicity. [ABSTRACT FROM AUTHOR]

Omeprazole is frequently used to treat gastroesophageal reflux in infants and children despite the lack of age-specific pharmacokinetic and dosing information in the approved product labeling. To address this challenge, the authors examined the potential influence of development and cytochrome P450 2C19 (CYP2C19) genotype on omeprazole disposition by conducting two pharmacokinetic (PK) studies in children and adolescents (ages 2-16 years) after a single oral 10- or 20-mg dose of the drug. Plasma omeprazole concentrations were determined by HPLC-MS from seven plasma samples obtained over a 6-hour postdose period. Pharmacokinetic parameters were determined by noncompartmental methods. Subjects were genotyped for CYP2C19 by PCR-RFLP. Data were available from 37 patients (19 female), 10 of whom were < or = 5 years of age. No drug-associated adverse events were observed. The numbers of functional CYP2C19 alleles per subject in the cohort were 2 (n = 25), 1 (n = 11), and 0 (n = 1). Pharmacokinetic parameters (mean +/- SD, range) were as follows: tmax (2.1 +/- 1.2, 1-6 h), Cmax (331.1 +/- 333.6, 20.8-885.8 ng/mL), AUC0-->infinity (809.5 +/- 893.8, 236.9-1330.9 ng/mL.h), t1/2 (0.98 +/- 0.22, 0.7-1.4 h), and CL/F (1.8 +/- 1.4, 0.3-5.8 L/h/kg). Comparison of mean AUC0-->infinity values normalized for dose (i.e., per 1 mg/kg) between subjects with one versus two functional CYP2C19 alleles revealed no statistically significant difference. In addition, the CL/F and apparent elimination rate constant (lambda z) for omeprazole were not significantly different for subjects with one versus two functional CYP2C19 alleles. No association between age and CL/F, t1/2, or lambda z was observed. The range of t1/2 values for omeprazole was similar to those reported in adults (1-1.5 h). CONCLUSIONS: (1) in children ages 2 to 16 years receiving 10 or 20 mg of omeprazole as a single oral dose, the PK are quite comparable to values reported for adults, and (2) in pediatric patients who are CYP2C19 extensive metabolizers, there was no association between genotype and the pharmacokinetics of omeprazole. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of intravenous famotidine (0.5 mg/kg, maximum 20 mg) were evaluated in 18 pediatric patients (ages 1-18 years) with stable, chronic renal insufficiency. Subjects were stratified by calculated creatinine clearance (Clcr) into mild (Clcr > or = 50 to < 90 mL/min/1.73 m2), moderate (Clcr > or = 25 to < 50 mL/min/1.73 m2), and severe (Clcr < or = 10 mL/min/1.73 m2) renal insufficiency groups. Significant differences between the mild, moderate, and severe groups were found for elimination rate (Kel), apparent elimination half-life (t1/2), area under the curve (AUC), and total plasma clearance (Clp) (p < 0.01). Famotidine renal clearance (Clr) was found to be significantly different between the mild and severe groups (p < 0.05). A linear relationship was observed between Clcr and Clp (p < 0.0001; R2 = 0.70). No significant differences in nonrenal clearance (Clnr) were found between groups; however, Clnr as a percentage of Clp was significantly different in the severe group (92.9% +/- 7.3% Clnr) compared to the combined mild and moderate groups (21.9% +/- 45.6% Clnr) (p < 0.05). It was concluded that the pharmacokinetics of famotidine are significantly altered in children with chronic renal insufficiency; accordingly, dosing should be based on glomerular filtration rate (i.e., Clcr). [ABSTRACT FROM AUTHOR]

OBJECTIVE. To compare the mean time to first stool, number of stools, and side effects of three commonly used cathartics in pediatric ingestions. DESIGN. This prospective clinical trial was a randomized, double-blinded comparison of sorbitol, magnesium citrate, magnesium sulfate, and water, administered with activated charcoal in the treatment of pediatric patients 1 to 5 years of age with acute ingestions. Outcome parameters were mean time to first stool, mean number of stools during 24 hours, and side effects. RESULTS. One hundred sixteen patients completed the study. Significant differences in mean time to the first stool were detected among cathartic agents (F = 9.29), with sorbitol-treated patients having a shortest mean time to the first stool (mean, 8.48 hours). Sorbitol produced a significantly higher number of stools (mean, 2.79) in the 24-hour follow-up period than other cathartics (F = 3.49). The most common side effect of cathartic administration was emesis, which occurred more commonly in sorbitol-treated patients. CONCLUSION. Sorbitol, when administered with activated charcoal in the treatment of children with acute ingestions, produced a shorter time to first stool and more stools than magnesium citrate, magnesium sulfate, or water. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Acetaminophen cysteine protein adducts are a widely recognized correlate of acetaminophen-mediated hepatic injury in laboratory animals. The objective of this study was to use a new assay for the detection of acetaminophen cysteine protein adducts in children with acute liver failure to determine the role of acetaminophen toxicity in acute liver failure of unknown cause. METHODS: Serum samples from children with acute liver failure were measured for acetaminophen cysteine protein adducts using high-performance liquid chromatography with electrochemical detection. For comparison, samples from children with well-characterized acetaminophen toxicity and children with known other causes of acute liver failure also were measured for acetaminophen cysteine protein adducts. The analytical laboratory was blinded to patient diagnoses. RESULTS: Acetaminophen cysteine protein adduct was detected in 90% of samples from children with acute liver failure that was attributed to acetaminophen toxicity, 12.5% of samples from children with acute liver failure of indeterminate cause, and 9.6% of samples from children with acute liver failure that was attributed to other causes. Adduct-positive patients from the indeterminate cause subgroup had higher levels of serum aspartate aminotransferase and alanine aminotransferase and lower levels of bilirubin. Adduct-positive patients also had lower rates of transplantation and higher rates of spontaneous remission. CONCLUSIONS: A small but significant percentage of children with acute liver failure of indeterminate cause tested positive for acetaminophen cysteine protein adducts, strongly suggesting acetaminophen toxicity as the cause of acute liver failure. An assay for the detection of acetaminophen cysteine protein adducts can aid the diagnosis of acetaminophen-related liver injury in children. [ABSTRACT FROM AUTHOR]

Background and Aims: Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis., Methods: Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication., Results: With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role., Conclusions: Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction/background: To assess racial/ethnic disparities in endocrine therapy (ET) adherence among women with breast cancer., Materials and Methods: A retrospective cohort study of Arkansas All-Payer Claims Database (APCD) linked to Arkansas Cancer Registry (ACR). Women with stages 0-3 HR+ breast cancer diagnosed in 2013-2017 were followed from cancer diagnosis for a year to determine ET initiation. Among women who initiated ETs within 1 year of diagnosis, we assessed first-year compliance (proportion of days covered ≥ 0.8) and followed them for 5 years, censoring at death, end of data availability (December 21, 2019), or disenrollment from insurance coverage, whichever occurred first, to determine time to discontinuation. Regression analysis was conducted to determine racial/ethnic disparities in ET use adjusting for patients demographic, clinical, tumor characteristics and county-level socioeconomic factors., Results: Among women with continuous insurance coverage, 81% initiated ET within 1 year of diagnosis; 80% were compliant in the first year of ET use and 27.4% discontinued ET by year 5 among those who initiated ET in the first year. There were no racial/ethnic differences in ET initiation or first-year compliance adjusting for covariates. NHB women were significantly less likely to discontinue ET within 5 years after ET initiation compared to NHW women after (HR, 95% CI, 0.76, 0.58-0.98; P = .035)., Conclusion: After adjusting for patients' and tumor characteristics, there were no racial/ethnic differences in ET initiation within 1 year of diagnosis and ET compliance within first year of ET use. However, NHB women were less likely to discontinue ET within 5 years of initiation., Competing Interests: Disclosure Li received research support for unrelated projects sponsored by University of Utah/AstraZeneca. Other authors have no conflicts of interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This investigation sought to determine industry perceptions of postgraduate strength and conditioning (S&C) degrees to understand whether graduates are equipped for the demands of sport performance service roles., Methods: Survey data were collected from 111 participants employed as performance staff or in a role that recruits and supervises performance staff. The survey consisted of 3 main sections: (1) perceptions of career-development opportunities in S&C, (2) perception of S&C postgraduate programs, and (3) perceptions of employability in S&C. Exploratory factor analysis was conducted to identify the key factors considered to be of greatest relevance to career progression in S&C., Results: A 2-factor solution was achieved for each of the 3 sections, resulting in 6 total factors. These factors are Academic and Professional Development, Mentorship and Sport Diversity, Student Preparation, Require Greater Emphasis, Testing and Training, and Personal and Professional Growth., Conclusions: Postgraduate S&C programs require a broad range of placement/internship opportunities to (1) provide diverse experiences, (2) allow students to build contacts and develop professional networks, (3) gain exposure to working in high-performance environments and multidisciplinary teams, and (4) access high-quality mentors. Alongside the ability to deliver training and testing, graduates should be equipped with strong organizational and relationship-building skills. Improved graduate capabilities can raise the standards of the profession and result in enhanced service provision to athletes.

Abstract: Geneau, MC, Carey, DL, Gastin, PB, Robertson, S, and James, LP. Classification of force-time metrics into lower-body strength domains. J Strength Cond Res 38(9): 1561-1567, 2024-The purpose of this study was to classify force-time metrics into distinct lower-body strength domains using a systematic data reduction analysis. A cross-sectional design was used, whereby competitive field sport athletes ( F = 39, M = 96) completed a series of drop jumps, squat jumps, countermovement jumps (CMJs), loaded CMJs, and 2 isometric tasks on portable force platforms, resulting in a total of 285 force-time performance metrics. The metrics were split into 4 test "families" and each was entered into a sparse principal component analysis (sPCA) model. A single metric from each component of each family-specific sPCA were selected based on the loading, reliability, and simplicity of the metric and entered into a second sPCA that included metrics across all tests. The final sPCA revealed 7 principal components each containing 2 metrics and explained a total of 53% variance of the dataset. The final principal components were interpreted as 7 lower-body strength domains: (a) dynamic force, (b) dynamic timing, (c) early isometric, (d) maximal isometric, (e) countermovement velocity, (f) reactive output, and (g) reactive timing. The findings demonstrate that a total of 7 metrics from a drop jump, CMJ, and isometric test can be used to represent ∼50% of variance in lower-body strength performance of field sport athletes. These results can help guide and simplify the lower-body strength diagnosis process in field sport athletes., (Copyright © 2024 National Strength and Conditioning Association.)

Abstract: Pairwise comparison of heavy dynamic strength and fast dynamic strength interventions on sprint performance: a systematic review and meta-analysis. J Strength Cond Res 38(9): 1675-1686, 2024-Previous studies have shown that both heavy dynamic strength (HDS) and fast dynamic strength (FDS) training can be used to improve sprint performance; however, a review and meta-analysis investigating pairwise studies that compare these two training interventions have not been performed. The aims of the study were to systematically review and analyze HDS and FDS training methodologies and evaluate their effect size difference, in pairwise comparison studies to determine and compare their effects on sprint performance. Databases were systematically searched using Boolean phrasing to identify eligible articles, and meta-analyses were performed on the extracted data. Seven studies met the inclusion criteria, which resulted in data from 138 subjects across 24 separate sprint assessments. Overall, there was a small effect in favor of FDS (standardized mean difference = 0.27, 95% confidence intervals [-0.07; 0.60], 95% prediction intervals [-1.01; 1.55]), but this was deemed not significant because of the wide-ranging prediction intervals. There is no distinguishable difference between HDS and FDS training on sprint performance. The wide-ranging prediction intervals suggest the variability is too great to determine whether one training type is more effective than the other. Practitioners should consider the individual needs of their athletes when deciding which training type to use for long-term sprint development., (Copyright © 2024 National Strength and Conditioning Association.)

Background: Australian Rules Football athletes complete long preseasons, yet injuries occur frequently at early stages of the competitive season. Little is known about the high-speed running (HSR) prescription during a preseason or whether players are adequately prepared for competition. This study described absolute and relative preseason and in-season HSR demands of 2 professional Australian football teams., Hypothesis: HSR and sprinting volumes are significantly lower in elite Australian Rules football athletes during in-season compared with preseason., Study Design: Cohort study., Level of Evidence: Level 3., Methods: During the 2019 season, HSR volume was collected for 2 professional Australian football teams (n = 55). Individual maximum speeds (V max ) were captured to calculate relative running speed thresholds, as reported in 5% increments from 70%V max to 100%V max ., Results: Weekly volume of running above 70%V max ( P = 0.01; r = 0.56) and 80%V max ( P = 0.01; r = 0.58) was significantly greater in the preseason than the in-season. The weekly volume completed above 90%V max was not significantly greater in the preseason than the in-season ( P = 0.10; r = 0.22). Individual variation in the distance completed at specific percentages of V max expressed as a coefficient of variation was reported as 51% at 71% to 80%V max , 39% at 81% to 90%V max , and 41% at 91% to 100%V max ., Conclusion: The volume of HSR completed by athletes is far greater in the initial 4 weeks of the preseason than in any other point in preseason or competitive phases. At the individual level, there is substantial variation in the distance covered. This supports the concept of a heavily individualized approach to high-speed prescription and monitoring., Clinical Relevance: Practitioners should carefully consider individual variation regarding sprinting volume during both preseason and in-season when prescribing and monitoring training to improve on-field performance and reduce the risk of injury., Competing Interests: The authors report no potential conflicts of interest in the development and publication of this article.

Pantoprazole is a proton pump inhibitor indicated for the treatment of gastroesophageal reflux disease, a condition that disproportionately affects children with obesity. Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. Physiologically-based PK (PBPK) models are an attractive alternative that can account for physiologic-, genetic-, and drug-specific changes without the need for extensive clinical trial data. In this study, we explored the effect of obesity on pantoprazole PK and evaluated label-suggested dosing in this population. An adult PBPK model for pantoprazole was developed using data from the literature and accounting for genetic variation in CYP2C19. The adult PBPK model was scaled to children without obesity using age-associated changes in anatomical and physiological parameters. Lastly, the pediatric PBPK model was expanded to children with obesity. Three pantoprazole dosing strategies were evaluated: 1 mg/kg total body weight, 1.2 mg/kg lean body weight, and US Food and Drug Administration-recommended weight-tiered dosing. Simulated concentration-time profiles from our model were compared with data from a prospective cohort study (PAN01; NCT02186652). Weight-tiered dosing resulted in the most (>90%) children with pantoprazole exposures in the reference range, regardless of obesity status or CYP2C19 phenotype, confirming results from previously published population PK models. PBPK models may allow for the efficient study of physiologic and developmental effects of obesity on PK in special populations where clinical trial data may be limited., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Acute viral hepatitis (AVH) comprises 11% of acute liver failure (ALF) in North America while acetaminophen (APAP) toxicity represents 46%. The use of APAP to treat prodromal hepatitis symptoms is common. It is unknown if concurrent APAP use impacts liver injury in AVH-induced ALF., Methods: In this prospective, multicenter cohort study, 356 patients meeting criteria for AVH including hepatitis A, B, Epstein-Barr virus, and herpes simplex virus, all leading to ALF (hepatic encephalopathy after acute illness, international normalized ratio ≥1.5), or acute liver injury (acute liver injury, international normalized ratio >2.0, no hepatic encephalopathy) were reviewed for evidence of APAP use: APAP ingestion history or measurement of serum APAP level or APAP-CYS adducts, a specific biomarker released into blood with APAP injury. Patients were grouped by APAP exposure level, from high (measurable APAP levels or toxic APAP-CYS), medium (therapeutic APAP-CYS), low (history of APAP ingestion only and/or barely detectable APAP-CYS), or no exposure recorded., Results: Two hundred five of 356 patients (57.5%) with AVH-ALF had evidence of APAP use: 87 out of 356 (24%) demonstrated high or medium exposures. The aminotransferase and bilirubin levels of high/medium group resembled a mixed APAP-viral injury. Mortality was the highest (51.6%, 21.4%, 28.8%, and 30.5%), and transplant-free survival was the lowest (22.6%, 44.6%, 41.5%, and 40.4%) in the high exposure group compared with medium, low, and no exposure groups. However, the specific comparisons of mortality and transplant-free survival between the high exposure and no exposure groups were not statistically different even after adjusting for baseline patient characteristics differences., Discussion: APAP use in AVH-ALF is common and may negatively impact outcomes compared with little or no APAP exposure. Prospective studies of the safest and effective dose of APAP to use in patients with AVH are needed., (Copyright © 2024 by The American College of Gastroenterology.)

Preparing athletes for competition requires the diagnosis and monitoring of relevant physical qualities (e.g., strength, power, speed, endurance characteristics). Decisions regarding test selection that attempt to measure these physical attributes are fundamental to the training process yet are complicated by the myriad of tests and measurements available. This article presents an evidenced based process to inform test measurement selection for the physical preparation of athletes. We describe a method for incorporating multiple layers of validity to link test measurement to competition outcome. This is followed by a framework by which to evaluate the suitability of test measurements based on contemporary validity theory that considers technical, decision-making, and organisational factors. Example applications of the framework are described to demonstrate its utility in different settings. The systems presented here will assist in distilling the range of measurements available into those most likely to have the greatest impact on competition performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 James, Haycraft, Carey and Robertson.)

Background: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST)., Methods and Findings: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics., Conclusions: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels., Competing Interests: JF has received grant funding from the Stop TB Partnership’s Global Drug Facility to support the roll out of child-friendly formulations of second-line TB drugs., (Copyright: © 2024 James et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Repeated-sprint training (RST) is a common training method for enhancing physical fitness in athletes. To advance RST prescription, it is important to understand the effects of programming variables on physical fitness and physiological adaptation., Objectives: This study (1) quantifies the pooled effects of running RST on changes in 10 and 20 m sprint time, maximal oxygen consumption (VO 2max ), Yo-Yo Intermittent Recovery Test Level 1 (YYIR1) distance, repeated-sprint ability (RSA), countermovement jump (CMJ) height and change of direction (COD) ability in athletes, and (2) examines the moderating effects of program duration, training frequency, weekly volume, sprint modality, repetition distance, number of repetitions per set and number of sets per session on changes in these outcome measures., Methods: Pubmed, SPORTDiscus and Scopus databases were searched for original research articles up to 04 July 2023, investigating RST in healthy, able-bodied athletes, between 14 and 35 years of age, and a performance calibre of trained or above. RST interventions were limited to repeated, maximal running (land-based) sprints of ≤ 10 s duration, with ≤ 60 s recovery, performed for 2-12 weeks. A Downs and Black checklist was used to assess the methodological quality of the included studies. Eligible data were analysed using multi-level mixed-effects meta-analysis, with standardised mean changes determined for all outcomes. Standardised effects [Hedges G (G)] were evaluated based on coverage of their confidence (compatibility) intervals (CI) using a strength and conditioning specific reference value of G = 0.25 to declare an improvement (i.e. G > 0.25) or impairment (i.e. G < - 0.25) in outcome measures. Applying the same analysis, the effects of programming variables were then evaluated against a reference RST program, consisting of three sets of 6 × 30 m straight-line sprints performed twice per week for 6 weeks (1200 m weekly volume)., Results: 40 publications were included in our investigation, with data from 48 RST groups (541 athletes) and 19 active control groups (213 athletes). Across all studies, the effects of RST were compatible with improvements in VO 2max (G 0.56, 90% CI 0.32-0.80), YYIR1 distance (G 0.61, 90% CI 0.43-0.79), RSA decrement (G - 0.61, 90% CI - 0.85 to - 0.37), linear sprint times (10 m: G - 0.35, 90% CI - 0.48 to - 0.22; 20 m: G - 0.48, 90% CI - 0.69 to - 0.27), RSA average time (G - 0.34, 90% CI - 0.49 to - 0.18), CMJ height (G 0.26, 90% CI 0.13-0.39) and COD ability (G - 0.32, 90% CI - 0.52 to - 0.12). Compared with the reference RST program, the effects of manipulating training frequency (+ 1 session per week), program duration (+ 1 extra training week), RST volume (+ 200 m per week), number of reps (+ 2 per set), number of sets per session (+ 1 set) or rep distance (+ 10 m per rep) were either non-substantial or comparable with an impairment in at least one outcome measure per programming variable., Conclusions: Running-based RST improves speed, intermittent running performance, VO 2max , RSA, COD ability and CMJ height in trained athletes. Performing three sets of 6 × 30 m sprints, twice per week for 6 weeks is effective for enhancing physical fitness and physiological adaptation. Additionally, since our findings do not provide conclusive support for the manipulation of RST variables, further work is needed to better understand how programming factors can be manipulated to augment training-induced adaptations., Study Registration: Open Science Framework registration https://doi.org/10.17605/OSF.IO/RVNDW ., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Abstract: Harrison, PW, James, LP, Jenkins, DG, Holmberg, PM, and Kelly, VG. Effects of repeated jump testing and diurnal changes on subsequent countermovement jump and squat jump output and force-time characteristics. J Strength Cond Res 38(1): 174-179, 2024-The aim of this brief study was to investigate the effects of repeated jump testing on performance over 2 consecutive days while considering the possibility of diurnal changes. Fourteen male subjects and 14 recreationally active female subjects completed countermovement jump (CMJ) and squat jump (SJ) testing on 5 occasions (baseline [0,800], 5 minutes [0,820], 8 hours [1,600], 24 hours [0,800], and 32 hours [1,600]) over 32 hours. An additional rested baseline test was conducted on a separate day in the afternoon (1,600) to compare jump performance between morning and afternoon baseline values. Excluding small decreases in CMJ height at 24 hours (p = 0.292, Cliff's delta = -0.225) in male subjects and similar decreases in CMJ height at 5 minutes (p = 0.034, Cliff's delta = -0.245) in addition to SJ height:contraction time at 32 hours (p = 0.126, Cliff's delta = 0.153) in female subjects, findings generally showed no changes in jump performance over multiple assessments. Squat jump metrics may have showed small improvements between morning and afternoon baseline values in male subjects (SJ height:contraction time [p = 0.030, Cliff's delta = 0.225]) and female subjects (SJ height [p = 0.013, Cliff's delta = 0.173] and SJ height:contraction time [p = 0.091, Cliff's delta = 0.163)]. As jump performance was largely unaffected by repeated jump testing, the present findings support the use of monitoring practices and research designs that require multiple jump assessments within acute periods (∼32 hours)., (Copyright © 2023 National Strength and Conditioning Association.)

Abstract: Harrison, PW, James, LP, Jenkins, DG, McGuigan, MR, Holmberg, PM, and Kelly, VG. The effects of low-load squat jump and maximal isometric priming exercise on muscular performance and perceptual state. J Strength Cond Res 38(1): 1-9, 2024-The aim of this study was to examine responses at 3 and 27 hours after low-load jump squat (LL) and maximal isometric half-squat (ISO) priming stimuli. Fifteen resistance-trained males performed LL (4 × 3 at 20% 1 repetition maximum [1RM]), ISO (4 × 3 seconds), and control (CON) activities (standardized warm-up) in a randomized and counterbalanced order. Countermovement jump (CMJ) and isometric midthigh pull tests were conducted to assess performance changes after priming and CON activities. No clear changes in CMJ measures were found after priming activities compared with CON. However, small effect size improvements were found after priming stimuli completed on the same day. A 2.9% decrease in concentric phase duration (CI = 0.3-5.9, p = 0.333, Cliff's delta = -0.156) and a 9.1% increase in RSImod (CI = 0.2-12.3, p = 0.151, Cliff's delta = -0.218) occurred at 3 hours after LL compared with CON. Braking phase duration (CI = 0.8-10.6, p = 0.333, Cliff's delta = -0.213) was 2.9% shorter at 3 hours after ISO compared with CON. No clear changes in isometric peak force occurred after priming activities compared with CON. Additionally, questionnaires were completed to assess perceptual state and perceived effectiveness of the priming stimulus to influence performance. An increase in the "effect of activity" was perceived at 3 hours after LL and ISO (p = 0.013-0.044, Cliff's delta = 0.578-0.6) and at 27 hours after ISO (p = 0.99, Cliff's delta = 0.173) compared with CON. An increase in "muscular heaviness" was also reported at 3 hours after ISO compared with CON (p = 0.199, Cliff's delta = 0.320). The collective findings suggest limited benefits over the day after LL and ISO priming stimuli. However, as there was substantial variation in individual responses, the relative nature of priming responses should be considered when prescribing similar strategies in practical environments., (Copyright © 2023 National Strength and Conditioning Association.)

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics., Competing Interests: J.S.B., J.L.G., L.P.J., and A.A. were investigators on this clinical study. B.K. and B.H.Y.G. are employees of Cumberland Pharmaceuticals.

Objective: Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this in vivo using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress., Methods: We used pharmacological and genetic approaches to inhibit MPC2 and alanine aminotransferase 2 (ALT2), individually and concomitantly, in mice and cell culture models and determined the effects on APAP hepatotoxicity., Results: We found that MPC inhibition sensitizes the liver to APAP-induced injury in vivo only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacological and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) significantly worsened APAP-induced liver damage. Further investigation indicated that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis, and these results were reproducible in vitro. Finally, induction of ALT2 and post-treatment with dichloroacetate both reduced APAP-induced liver injury, suggesting new therapeutic avenues., Conclusions: Increased susceptibility to APAP toxicity requires loss of both the MPC and ALT2 in vivo, indicating that MPC inhibition alone is insufficient to disrupt redox balance. Furthermore, the results from ALT2 induction and dichloroacetate in the APAP model suggest new metabolic approaches to the treatment of liver damage., Competing Interests: Declaration of Competing Interest LPJ is Chief Medical Officer of Acetaminophen Toxicity Diagnostics (ATD), LLC, which is developing a diagnostic test for APAP overdose. MR McGill is a consultant for ATD and has received research funding from GlaxoSmithKline which sells APAP. BNF is a shareholder and member of the scientific advisory board of Cirius Therapeutics, which is developing an MPC inhibitor to treat nonalcoholic steatohepatitis. The remaining authors declare that they have no conflicts related to the content of this article. These companies had no role whatsoever in the funding, conceptualization, design, execution, or reporting of the study., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Abstract: Harrison, PW, Kelly, VG, Jenkins, DG, McGuigan, MR, Holmberg, PM, and James, LP. Does moderate-load priming activity influence maximal upper-body performance and perceptual state?. J Strength Cond Res 37(11): e581-e587, 2023-The results of previous research indicate that resistance exercise "priming" may improve strength-power measures within 48 hours after their completion. Although researchers have primarily examined performance responses after lower-body priming stimuli, investigations examining the effects of upper-body resistance priming exercises are presently limited. Therefore, the aim of this study was to examine upper-body pushing and pulling performance in addition to perceptual responses 3 and 27 hours after moderate-load (ML) upper-body resistance priming exercise. Fourteen resistance-trained men were assigned to complete ML priming (4 × 3 bench press and bench pull at 65% 1RM [repetition maximum]) and control (rest) protocols in a randomized and counterbalanced order. Peak velocity during the bench throw and bench pull tests involving different loads (25, 50, and 75% 1RM) showed no practical change at 3 and 27 hours after the priming session (p = 0.216-0.99, Cliff's d = -0.041 to 0.225). Small effect size increases in perceptual measures ("physical feeling," "physical performance," "aggression" [p = 0.400-0.553, Cliff's d = 0.183-0.201], and "muscular heaviness" [p = 0.178, Cliff's d = 0.231]) were found at 3 hours postpriming. A moderate practical increase was observed in perceived "physical feeling" compared with control (p = 0.385, Cliff's d = 0.349) in addition to small effect size increases in perceived "physical performance" and "aggression" (Cliff's d = 0.243-0.290) at 27 hours after priming activities. These results indicate that upper-body strength-power changes within 27 hours after ML upper-body resistance exercise priming are not practically meaningful., (Copyright © 2023 National Strength and Conditioning Association.)

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission., (© 2023. Springer Nature Limited.)

Background: Maximal lower-body strength can be assessed both dynamically and isometrically; however, the relationship between the changes in these 2 forms of strength following resistance training is not well understood., Purpose: To systematically review and analyze the effects of resistance training on changes in maximal dynamic (1-repetition-maximum back squat, deadlift, and power clean) and position-matched isometric strength (isometric midthigh pull and the isometric squat). In addition, individual-level data were used to quantify the agreement and relationship between changes in dynamic and isometric strength., Methods: Databases were systematically searched to identify eligible articles, and meta-analysis procedures were performed on the extracted data. The raw results from 4 studies were acquired, enabling bias and absolute reliability measures to be calculated using Bland-Altman test of agreement., Results: Eleven studies met the inclusion criteria, which resulted in 29 isometric-dynamic change comparisons. The overall pooled effect was 0.13 in favor of dynamic testing; however, the prediction interval ranged from g = -0.49 to 0.75. There was no evidence of bias (P = .825) between isometric and dynamic tests; however, the reliability coefficient was estimated to be 16%, and the coefficient of variation (%) was 109.27., Conclusions: As a range of future effects can be expected when comparing isometric to dynamic strength changes following resistance training, and limited proportionality exists between changes in these 2 strength qualities, there is strong evidence that isometric and dynamic strength represent separate neuromuscular domains. These findings can be used to inform strength-assessment models in athlete populations.

Purpose: Ice hockey is a team invasion sport characterized by repeated high-intensity skating efforts, technical and tactical skill, physical contact, and collisions requiring considerable levels of muscular strength. The purpose of this study was to evaluate the relationships between lower-body vertical force-time metrics and skating qualities in subelite female ice hockey players., Methods: A cross-sectional cohort design was employed utilizing 14 athletes (body mass = 66.7 [1.8] kg; height = 171.6 [6.2] cm; age = 21.1 [1.7] y). The relationships between metrics of lower-body strength collected from a drop jump, squat jump, countermovement jump, loaded countermovement jump, and an isometric squat and 4 skating qualities collected from a linear sprint, repeated sprint test, and a multistage aerobic test were evaluated., Results: The regression models revealed a positive relationship between relative peak force in the isometric squat and skating multistage aerobic test performance (r2 = .388; P = .017) and a positive relationship between repeated-sprint ability and eccentric mean force during the loaded countermovement jump (r2 = .595; P = .001). No significant relationships were observed between strength metrics and skating acceleration or maximal velocity., Conclusions: These data suggest that skating ability is most affected by relative isometric strength in female ice hockey players. It is recommended that practitioners focus training on tasks that improve relative force output. It is also recommended that isometric relative peak force be used as a monitoring metric for this cohort.

Forensic laboratories need quick and simple technology to improve turnaround times, while delivering reliable results. The goal of this study is first to create a simplified workflow to meet new Academy Standards Board requirements for urine testing in drug-facilitated crime investigations and, second, to create "ready-to-go", "hands-free" testing technology to further streamline analytical procedures. A first of its kind, the ToxBox forensic test kit is used to validate a single analytical procedure for opioids, benzodiazepines, cannabinoids, antidepressants, and several other drug classes. Method performance indicators follow accreditation requirements and include accuracy, precision, measurement uncertainty, calibration models, reportable range, sensitivity, specificity, carryover, interference, ion suppression/enhancement, and analyte stability. "Hands-free" testing platforms require the use of new suspended-state technology to stabilize NIST-traceable standards premanufactured at precise concentrations in the presence of sample preparation reagents. By suspending all reaction components in the solid state, with air gaps between the phases, reference standards and process controls are built in a "ready-to-go" format and stabilized for long-term storage in the presence of a sample matrix, β-d-glucuronidase, and enzymatic buffers. "Hands-free" test kits are removed from storage, incubated at either ambient temperature or 60 °C, and assayed using validated methods. This is the first example of how complex forensic testing workflows can be streamlined with new "hands-free" testing strategies to meet analytical challenges associated with quantitative and confirmatory analyses.

Abstract: Freeman, BW, Talpey, SW, James, LP, Opar, DA, and Young, WB. Common high-speed running thresholds likely do not correspond to high-speed running in field sports. J Strength Cond Res 37(7): 1411-1418, 2023-The purpose of this study was to clarify what percentage of maximum speed is associated with various running gaits. Fifteen amateur field sport athletes (age = 23 ± 3.6 years) participated in a series of 55-meter running trials. The speed of each trial was determined by instructions relating to 5 previously identified gait patterns (jog, run, stride, near maximum sprint, and sprint). Each trial was filmed in slow motion (240 fps), whereas running speed was obtained using Global Positioning Systems. Contact time, stride angle, and midstance free-leg knee angle were determined from video footage. Running gaits corresponded with the following running speeds, jogging = 4.51 m·s -1 , 56%Vmax, running = 5.41 m·s -1 , 66%Vmax , striding = 6.37 m·s -1 , 78%Vmax, near maximum sprinting = 7.08 m·s -1 , 87%Vmax, and sprinting = 8.15 m·s -1 , 100%Vmax. Significant ( p < 0.05) increases in stride angle were observed as running speed increased. Significant ( p < 0.05) decreases were observed in contact time and midstance free-leg knee angle as running speed increased. These findings suggest currently used thresholds for high-speed running (HSR) and sprinting most likely correspond with jogging and striding, which likely underestimates the true HSR demands. Therefore, a higher relative speed could be used to describe HSR and sprinting more accurately in field sports., (Copyright © 2022 National Strength and Conditioning Association.)

Objective: Assess university students' SARS-CoV-2 antibody seroprevalence and mitigation behaviors over time. Participants: Randomly selected college students ( N  = 344) in a predominantly rural Southern state. Methods: Participants provided blood samples and completed self-administered questionnaires at three timepoints over the academic year. Adjusted odds ratios and 95% confidence intervals were estimated from logistic regression analyses. Results: SARS-CoV-2 antibody seroprevalence was 18.2% in September 2020, 13.1% in December, and 45.5% in March 2021 (21% for those with no vaccination history). SARS-CoV-2 antibody seroprevalence was associated with large social gatherings, staying local during the summer break, symptoms of fatigue or rhinitis, Greek affiliation, attending Greek events, employment, and using social media as the primary COVID-19 information source. In March 2021, seroprevalence was associated with receiving at least one dose of a COVID-19 vaccination. Conclusion: SARS-CoV-2 seroprevalence was higher in this population of college students than previous studies. Results can assist leaders in making informed decisions as new variants threaten college campuses.

Background: Gene therapy is a potential cure for sickle cell disease (SCD). Conventional cost-effectiveness analysis (CEA) does not capture the effects of treatments on disparities in SCD, but distributional CEA (DCEA) uses equity weights to incorporate these considerations., Objective: To compare gene therapy versus standard of care (SOC) in patients with SCD by using conventional CEA and DCEA., Design: Markov model., Data Sources: Claims data and other published sources., Target Population: Birth cohort of patients with SCD., Time Horizon: Lifetime., Perspective: U.S. health system., Intervention: Gene therapy at age 12 years versus SOC., Outcome Measures: Incremental cost-effectiveness ratio (ICER) (in dollars per quality-adjusted life-years [QALYs] gained) and threshold inequality aversion parameter (equity weight)., Results of Base-Case Analysis: Gene therapy versus SOC for females yielded 25.5 versus 15.7 (males: 24.4 vs. 15.5) discounted lifetime QALYs at costs of $2.8 million and $1.0 million (males: $2.8 million and $1.2 million), respectively, with an ICER of $176 000 per QALY (full SCD population). The inequality aversion parameter would need to be 0.90 for the full SCD population for gene therapy to be preferred per DCEA standards., Results of Sensitivity Analysis: SOC was favored in 100.0% (females) and 87.1% (males) of 10 000 probabilistic iterations at a willingness-to-pay threshold of $100 000 per QALY. Gene therapy would need to cost less than $1.79 million to meet conventional CEA standards., Limitation: Benchmark equity weights (as opposed to SCD-specific weights) were used to interpret DCEA results., Conclusion: Gene therapy is cost-ineffective per conventional CEA standards but can be an equitable therapeutic strategy for persons living with SCD in the United States per DCEA standards., Primary Funding Source: Yale Bernard G. Forget Scholars Program and Bunker Endowment., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3272.

Background: To address the high prevalence of health disparities and lack of research opportunities among rural and minority communities, the University of Arkansas for Medical Sciences (UAMS) developed the Rural Research Network in January 2020., Aim: The aim of this report is to describe our process and progress in developing a rural research network. The Rural Research Network provides a platform to expand research participation opportunities to rural Arkansans, many of whom are older adults, low-income individuals, and underrepresented minority populations., Methods: The Rural Research Network leverages existing UAMS Regional Programs family medicine residency clinics within an academic medical center., Results: Since the inception of the Rural Research Network, research infrastructure and processes have been built within the regional sites. Twelve diverse studies have been implemented with recruitment and data collection from 9248 participants, and 32 manuscripts have been published with residents and faculty from the regional sites. Most studies were able to recruit Black/African American participants at or above a representative sample., Conclusions: As the Rural Research Network matures, the types of research will expand in parallel with the health priorities of Arkansas., Relevance to Patients: The Rural Research Network demonstrates how Cancer Institutes and sites funded by a Clinical and Translational Science Award can collaborate to expand research capacity and increase opportunities for research among rural and minority communities., Competing Interests: The authors declared no conflicts of interest., (Copyright: © 2023 Author(s).)

Combined heavy- and light-load ballistic training is often employed in high-performance sport to improve athletic performance and is accompanied by adaptations in muscle architecture. However, little is known about how training affects muscle-tendon unit (MTU) kinematics during the execution of a sport-specific skill (e.g., jumping), which could improve our understanding of how training improves athletic performance. The aim of this study was to investigate vastus lateralis (VL) MTU kinematics during a countermovement jump (CMJ) following combined ballistic training. Eighteen young, healthy males completed a 10-week program consisting of weightlifting derivatives, plyometrics, and ballistic tasks under a range of loads. Ultrasonography of VL and force plate measurements during a CMJ were taken at baseline, mid-test, and post-test. The training program improved CMJ height by 11 ± 13%. During the CMJ, VL's MTU and series elastic element (SEE) length changes and velocities increased from baseline to post-test, but VL's fascicle length change and velocity did not significantly change. It is speculated that altered lower limb coordination and increased force output of the lower limb muscles during the CMJ allowed more energy to be stored within VL's SEE. This may have contributed to enhanced VL MTU work during the propulsion phase and an improved CMJ performance following combined ballistic training., (© 2022 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Background and study aims  Given the sizable number of patients with symptomatic gastroesophageal reflux disease (GERD) despite proton pump inhibitor (PPI) therapy, non-pharmacologic treatment has become increasingly utilized. The aim of this study was to analyze the cost-effectiveness of medical, endoscopic, and surgical treatment of GERD. Patients and methods  A deterministic Markov cohort model was constructed from the US healthcare payer's perspective to evaluate the cost-effectiveness of three competing strategies: 1) omeprazole 20 mg twice daily; 2) transoral incisionless fundoplication (TIF 2.0); and 3) laparoscopic Nissen fundoplication [LNF]. Cost was reported in US dollars with health outcomes recorded in quality-adjusted life years (QALYs). Ten-year and lifetime time horizons were utilized with 3 % discount rate and half-cycle corrections applied. The main outcome was incremental cost-effectiveness ratio (ICER) with a willingness-to-pay threshold of $ 100,000 per QALY. Probabilistic sensitivity analyses were also performed. Results  In our base-case analysis, the average cost of TIF 2.0 was $ 13,978.63 versus $ 17,658.47 for LNF and $ 10,931.49 for PPI. Compared to the PPI strategy, TIF 2.0 was cost-effective with an incremental cost of $ 3,047 and incremental effectiveness of 0.29 QALYs, resulting in an ICER of $ 10,423.17 /QALY gained. LNF was strongly dominated by TIF 2.0. Over a lifetime horizon, TIF 2.0 remained the cost-effective strategy for patients with symptoms despite twice-daily 20-mg omeprazole. TIF 2.0 remained cost-effective after varying parameter inputs in deterministic and probabilistic sensitivity analyses and for scenario analyses in multiple age groups. Conclusions  Based upon this study, TIF 2.0 was cost-effective for patients with symptomatic GERD despite low-dose, twice-daily PPI., Competing Interests: Competing interests Thomas R. McCarty has no conflicts to disclose. Pichamol Jirapinyo has the following disclosures: Apollo Endosurgery – Research Support, Fractyl – Research Support, GI Dynamics – Research Support, Endogastric Solutions – Consultant. Lyndon P. James has no conflicts to disclose. Sanchit Gupta has no conflicts to disclose. Walter W. Chan has the following disclosures: Ironwood – scientific advisory board. Christopher C. Thompson has the following disclosures: Apollo Endosurgery – Consultant/Research Support (Consulting fees/Institutional Research Grants), Aspire Bariatrics – Research Support (Institutional Research Grant), BlueFlame Healthcare Venture Fund – General Partner, Boston Scientific – Consultant (Consulting fees), Covidien/Medtronic – Consultant (Consulting Fees), EnVision Endoscopy (Board Member), Fractyl – Consultant/Advisory Board Member (Consulting Fees), GI Dynamics – Consultant (Consulting Fees)/ Research Support (Institutional Research Grant), GI Windows – Ownership interest, Olympus/Spiration – Consultant (Consulting Fees)/Research Support (Equipment Loans), Spatz – Research Support (Institutional Research Grant), USGI Medical – Consultant (Consulting Fees)/Advisory Board Member (Consulting fees)/Research Support (Research Grant)., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Solithromycin is a new macrolide-ketolide antibiotic with potential effectiveness in pediatric community-acquired bacterial pneumonia (CABP). Our objective was to evaluate its safety and effectiveness in children with CABP., Methods: This phase 2/3, randomized, open-label, active-control, multicenter study randomly assigned solithromycin (capsules, suspension or intravenous) or an appropriate comparator antibiotic in a 3:1 ratio (planned n = 400) to children 2 months to 17 years of age with CABP. Primary safety endpoints included treatment-emergent adverse events (AEs) and AE-related drug discontinuations. Secondary effectiveness endpoints included clinical improvement following treatment without additional antimicrobial therapy., Results: Unrelated to safety, the sponsor stopped the trial prior to completion. Before discontinuation, 97 participants were randomly assigned to solithromycin (n = 73) or comparator (n = 24). There were 24 participants (34%, 95% CI, 23%-47%) with a treatment-emergent AE in the solithromycin group and 7 (29%, 95% CI, 13%-51%) in the comparator group. Infusion site pain and elevated liver enzymes were the most common related AEs with solithromycin. Study drug was discontinued due to AEs in 3 subjects (4.3%) in the solithromycin group and 1 (4.2%) in the comparator group. Forty participants (65%, 95% CI, 51%-76%) in the solithromycin group achieved clinical improvement on the last day of treatment versus 17 (81%, 95% CI, 58%-95%) in the comparator group. The proportion achieving clinical cure was 60% (95% CI, 47%-72%) and 68% (95% CI, 43%-87%) for the solithromycin and comparator groups, respectively., Conclusions: Intravenous and oral solithromycin were generally well-tolerated and associated with clinical improvement in the majority of participants treated for CABP., Competing Interests: J.E.L. receives salary support for research from the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org), the American Lung Association, National Heart Lung and Blood Institute (NHLBI) (HL145415), University of Arkansas for Medical Sciences and Regeneron Pharmaceuticals; C.P.H. receives salary support for research from National Institute for Child Health and Human Development (NICHD) (1K23HD090239), the National Heart Lung and Blood Institute (NHLBI) (R61/R33HL147833), the US Food and Drug Administration (1R01-FD006099, PI Laughon; and 5U18-FD006298, PI: Benjamin), the U.S. government for his work in pediatric clinical pharmacology (Government Contract HHSN275201800003I, PI: Benjamin under the Best Pharmaceuticals for Children Act), the nonprofit Burrhoughs Wellcome Fund, and other sponsors for drug development in adults and children (https://dcri.org/about-us/conflict-of-interest/). M.C.-W. receives support for research from the National Institutes of Health (1R01-HD076676-01A1 and 1K24-AI143971), National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), NICHD (HHSN275201000003I), Federal Drug Administration (5U18-FD006298), and industry for drug development in adults and children. The other authors have no conflicts of interest to disclose. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: James, LP, Suchomel, TJ, Comfort, P, Haff, GG, and Connick, M. Rate of force development adaptations after weightlifting-style training: the influence of power clean ability. J Strength Cond Res 36(6): 1560-1567, 2022-This experiment examined changes to the rate of force development (RFD) expressed under loaded jump conditions between individuals with a higher (stronger) and lower (weaker) weightlifting performance (as assessed by the 1 repetition maximum [RM] power clean) after training with the weightlifting derivatives. Two groups of markedly different weightlifting ability undertook 10 weeks of training with the power clean variants, snatch pulls, and jump squats across heavy and light conditions. Testing was performed at baseline, after 5 weeks of training (mid-test) and after training (post-test). During testing, RFD was assessed under a series of loads (20-80% squat 1RM) through the jump squat. Furthermore, the force-velocity relationship, and unloaded jump strategy (through the force-time curve waveform), were also examined. Very large change (Hedge's g, 95% confidence interval [g] = 2.10, 1.24 to 4.16) in RFD at 20% 1RM at mid-test occurred within the stronger group. Conversely, a small increase (g = 0.27, 0.53-1.91) among the weaker subjects existed in this measure at mid-test, reaching a moderate increase at post-test (g = 0.71, -0.18 to 2.15). Limited improvements were seen by the stronger subjects in RFD at 60 and 80% 1RM at either mid-test (60%: g = 0.27, -0.75 to 1.33; 80% = 0.02, -1.01 to 1.00) or post-test (60%: g = 0.52, -0.38 to 1.80; 80% = -0.26, -1.23 to 0.77). The stronger group experienced a shift throughout the force-velocity relationship while a more force-dominant adaptation occurred in weaker subjects. Differences in jump strategy between groups were also noted. Such training will elicit practically different adaptations in rapid force production depending on the individual's baseline weightlifting ability., (Copyright © 2020 National Strength and Conditioning Association.)

The objective was to assess the cost-effectiveness of staging PET/CT in early-stage follicular lymphoma (FL) from the Canadian health-care system perspective. Methods: The study population was FL patients staged as early-stage using conventional CT imaging and planned for curative-intent radiation therapy (RT). A decision analytic model simulated the management after adding staging PET/CT versus using staging CT alone. In the no-PET/CT strategy, all patients proceeded to curative-intent RT as planned. In the PET/CT strategy, PET/CT information could result in an increased RT volume, switching to a noncurative approach, or no change in RT treatment as planned. The subsequent disease course was described using a state-transition cohort model over a 30-y time horizon. Diagnostic characteristics, probabilities, utilities, and costs were derived from the literature. Baseline analysis was performed using quality-adjusted life years (QALYs), costs (2019 Canadian dollars), and the incremental cost-effectiveness ratio. Deterministic sensitivity analyses were conducted, evaluating net monetary benefit at a willingness-to-pay threshold of $100,000/QALY. Probabilistic sensitivity analysis using 10,000 simulations was performed. Costs and QALYs were discounted at a rate of 1.5%. Results: In the reference case scenario, staging PET/CT was the dominant strategy, resulting in an average lifetime cost saving of $3,165 and a gain of 0.32 QALYs. In deterministic sensitivity analyses, the PET/CT strategy remained the preferred strategy for all scenarios supported by available data. In probabilistic sensitivity analysis, the PET/CT strategy was strongly dominant in 77% of simulations (i.e., reduced cost and increased QALYs) and was cost-effective in 89% of simulations (i.e., either saved costs or had an incremental cost-effectiveness ratio below $100,000/QALY). Conclusion: Our analysis showed that the use of PET/CT to stage early-stage FL patients reduces cost and improves QALYs. Patients with early-stage FL should undergo PET/CT before curative-intent RT., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

The purpose of this study was: i) to determine the reliability of alternate forms of the dynamic strength index (DSI) calculated over time-specific intervals that represent decisive actions in sport and ii) to assess the association between the original form of the DSI (DSI trad ) and its variants. Twenty-three resistance-trained males (BM = 80.4 ± 10.18 kg; age = 26.3 ± 10.2 y; 1-RM squat kg/kg/BM = 1.61 ± 0.37) performed trials of the countermovement jump (CMJ) and isometric squat. Several variations of the DSI were calculated by dividing the mean force in the CMJ by the mean force in the isometric squat calculated over the following epochs: 100 ms (DSI 100 ), 150 ms (DSI 150 ) and CMJ propulsive phase duration (DSI prop ). In the fourth method, mean force across the CMJ propulsive phase duration was divided by mean force in the isometric squat between initiation and peak force (DSI peak ). All alternate DSI measures achieved acceptable absolute reliability (CV < 10%), however they did not achieve at least a moderate relative reliability. DSI prop ( R 2  = 0.41), DSI 100 ( R 2  = 0.03) and DSI 150 ( R 2  = 0.14) demonstrated limited commonality with DSI trad . The alternate forms of DSI can cautiously be considered in strength assessment systems.

Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP-protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well-defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2-week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in-person at study initiation (day 1) and on days 3 and 5. APAP-protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full-length keratin 18 [K18], and total high-mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP-protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP-protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short-term administration of low-dose APAP (650 mg twice per day, <1 week) is likely safe in patients with compensated cirrhosis. These data provide a foundation for future studies to test higher doses, longer treatment, and subjects who are decompensated, especially in light of the remarkably delayed adduct clearance in subjects with cirrhosis., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)