Cognitive Functional Therapy compared with usual physiotherapy care in people with persistent low back pain: a mixed methods feasibility randomised controlled trial in the United Kingdom National Health Service.

OBJECTIVES: To determine the feasibility of completing a definitive randomised controlled trial (RCT), evaluating the clinical and cost-effectiveness of Cognitive Functional Therapy (CFT) in comparison to usual physiotherapy care (UPC), for people with persistent low back pain (LBP). DESIGN AND SETTING: A two-arm parallel feasibility RCT completed in a United Kingdom (UK) Secondary Care National Health Service (NHS) physiotherapy service. PARTICIPANTS: Sixty adult participants who reported LBP lasting for more than three months, that was not attributable to a serious (e.g. cancer) or specific (e.g. radiculopathy) underlying cause, were invited to participate. Participants were allocated at random to receive CFT or UPC. INTERVENTIONS: Cognitive Functional Therapy and Usual Physiotherapy Care for persistent LBP. MAIN OUTCOME MEASURES: The primary outcome was the feasibility of completing a definitive RCT, defined by recruitment of at least 5 participants per month, delivery of CFT per protocol and securing relevant and acceptable outcome measures. Data concerning study processes, resources, management and participant reported outcome measures were collected at baseline, 3, 6 and 12-month follow-up. RESULTS: Sixty participants (n = 30 CFT and n = 30 UPC) were recruited with 80% (n = 48), 72% (n = 43) and 53% (n = 32) retained at 3, 6 and 12-month follow-up respectively. NHS physiotherapists were trained to competence and delivered CFT with fidelity. CFT was tolerated by participants with no adverse events. Relevant and clinically important outcome data were collected at all time points (0.4%, 3%, 1% and 0.8% of data was missing from the returned outcome measure booklets at baseline and 3, 6 and 12-month follow-up respectively). The Roland-Morris disability questionnaire was considered the most suitable primary outcome measure with a proposed sample size of 540 participants for a definitive cluster RCT. CONCLUSION: It is feasible to conduct a randomised study of CFT in comparison to UPC for NHS patients. A future study should incorporate an internal pilot to address aspects of feasibility further, including participant retention strategies. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN12965286 CONTRIBUTION OF THE PAPER.

Deloading Practices in Strength and Physique Sports: A Cross-sectional Survey.

BACKGROUND: This study explored the deloading practices of competitive strength and physique athletes. A 55-item anonymised web-based survey was distributed to a convenience-based, cross-sectional sample of competitive strength and physique athletes (n = 246; males = 181 [73.6%], females = 65 [26.4%]; age = 29.5 ± 8.6 years) who had 8.2 ± 6.2 years of resistance training and 3.8 ± 3.1 years of competition experience. RESULTS: All athletes deloaded within training with energy and fatigue management being the main reasons to do so. The typical duration of a deload was 6.4 ± 1.7 days, integrated into the training programme every 5.6 ± 2.3 weeks. Deloading was undertaken using a proactive, pre-planned strategy (or in combination with an autoregulated approach) and undertaken when performance stalled or during periods of increased muscle soreness or joint aches. Athletes reported that training volume would decrease (through a reduction in both repetitions per set and sets per week), but training frequency would remain unchanged during deloads. Additionally, athletes reported that training intensity (load lifted) would decrease, and effort would be reduced (facilitated through an increase in repetitions in reserve). Athletes would generally maintain the same exercise selection during deloading. For athletes that supplemented deloading with additional recovery modalities (n = 118; 48%), the most reported strategies were massage, static stretching and foam rolling. CONCLUSION: Results from this research might assist strength and physique athletes and coaches to plan their deloading. Future research should empirically investigate the findings from this study to further evaluate the potential utility of deloading in strength and physique sports.

The Effect of Hormonal Contraceptive Use on Skeletal Muscle Hypertrophy, Power and Strength Adaptations to Resistance Exercise Training: A Systematic Review and Multilevel Meta-analysis.

BACKGROUND: Resistance exercise training is widely used by general and athletic populations to increase skeletal muscle hypertrophy, power and strength. Endogenous sex hormones influence various bodily functions, including possibly exercise performance, and may influence adaptive changes in response to exercise training. Hormonal contraceptive (HC) use modulates the profile of endogenous sex hormones, and therefore, there is increasing interest in the impact, if any, of HC use on adaptive responses to resistance exercise training. OBJECTIVE: Our aim is to provide a quantitative synthesis of the effect of HC use on skeletal muscle hypertrophy, power and strength adaptations in response to resistance exercise training. METHODS: A systematic review with meta-analysis was conducted on experimental studies which directly compared skeletal muscle hypertrophy, power and strength adaptations following resistance exercise training in hormonal contraceptive users and non-users conducted before July 2023. The search using the online databases PUBMED, SPORTDiscus, Web of Science, Embase and other supplementary search strategies yielded 4669 articles, with 8 articles (54 effects and 325 participants) meeting the inclusion criteria. The methodological quality of the included studies was assessed using the "Tool for the assessment of study quality and reporting in exercise". RESULTS: All included studies investigated the influence of oral contraceptive pills (OCP), with no study including participants using other forms of HC. The articles were analysed using a meta-analytic multilevel maximum likelihood estimator model. The results indicate that OCP use does not have a significant effect on hypertrophy [0.01, 95% confidence interval (CI) [- 0.11, 0.13], t = 0.14, p = 0.90), power (- 0.04, 95% CI [- 0.93, 0.84], t = - 0.29, p = 0.80) or strength (0.10, 95% CI [- 0.08, 0.28], t = 1.48, p = 0.20). DISCUSSION: Based on the present analysis, there is no evidence-based rationale to advocate for or against the use of OCPs in females partaking in resistance exercise training to increase hypertrophy, power and/or strength. Rather, an individualised approach considering an individual's response to OCPs, their reasons for use and menstrual cycle history may be more appropriate. REGISTRATION: The review protocol was registered on PROSPERO (ID number and hyperlink: CRD42022365677).

HIV-1 subtypes maintain distinctive physicochemical signatures in Nef domains associated with immunoregulation.

BACKGROUND: HIV subtype is associated with varied rates of disease progression. The HIV accessory protein, Nef, continues to be present during antiretroviral therapy (ART) where it has numerous immunoregulatory effects. In this study, we analyzed Nef sequences from HIV subtypes A1, B, C, and D using a machine learning approach that integrates functional amino acid information to identify if unique physicochemical features are associated with Nef functional/structural domains in a subtype-specific manner. METHODS: 2253 sequences representing subtypes A1, B, C, and D were aligned and domains with known functional properties were scored based on amino acid physicochemical properties. Following feature generation, we used statistical pruning and evolved neural networks (ENNs) to determine if we could successfully classify subtypes. Next, we used ENNs to identify the top five key Nef physicochemical features applied to specific immunoregulatory domains that differentiated subtypes. A signature pattern analysis was performed to the assess amino acid diversity in sub-domains that differentiated each subtype. RESULTS: In validation studies, ENNs successfully differentiated each subtype at A1 (87.2%), subtype B (89.5%), subtype C (91.7%), and subtype D (85.1%). Our feature-based domain scoring, followed by t-tests, and a similar ENN identified subtype-specific domain-associated features. Subtype A1 was associated with alterations in Nef CD4 binding domain; subtype B was associated with alterations with the AP-2 Binding domain; subtype C was associated with alterations in a structural Alpha Helix domain; and, subtype D was associated with alterations in a Beta-Sheet domain. CONCLUSIONS: Recent studies have focused on HIV Nef as a driver of immunoregulatory disease in those HIV infected and on ART. Nef acts through a complex mixture of interactions that are directly linked to the key features of the subtype-specific domains we identified with the ENN. The study supports the hypothesis that varied Nef subtypes contribute to subtype-specific disease progression.

Whole-genome sequencing of carbapenem-resistant Enterobacterales isolates in southeast Louisiana reveals persistent genetic clusters spanning multiple locations.

BACKGROUND: We investigated 51 g-negative carbapenem-resistant Enterobacterales (CRE) isolates collected from 22 patients over a five-year period from six health care institutions in the Ochsner Health network in southeast Louisiana. METHODS: Short genomic reads were generated using Illumina sequencing and assembled for each isolate. Isolates were classified as Enterobacter spp. (n = 20), Klebsiella spp. (n = 30), and Escherichia coli (n = 1) and grouped into 19 different multi-locus sequence types (MLST). Species and patient-specific core genomes were constructed representing ∼50% of the chromosomal genome. RESULTS: We identified two sets of patients with genetically related infections; in both cases, the related isolates were collected > 6 months apart, and in one case, the isolates were collected in different locations. On the other hand, we identified four sets of patients with isolates of the same species collected within 21 days from the same location; however, none had genetically related infections. Genes associated with resistance to carbapenem drugs (blaKPC and/or blaCTX-M-15) were found in 76% of the isolates. We found three blaKPC variants (blaKPC-2, blaKPC-3, and blaKPC-4) associated with four different Enterobacter MLST variants, and two blaKPC variants (blaKPC-2, blaKPC-3) associated with seven different Klebsiella MLST variants. CONCLUSIONS: Molecular surveillance is increasingly becoming a powerful tool to understand bacterial spread in both community and clinical settings. This study provides evidence that genetically related infections in clinical settings do not necessarily reflect temporal associations, and vice versa. Our results also highlight the regional genomic and resistance diversity within related bacterial lineages.

Integrating Deloading into Strength and Physique Sports Training Programmes: An International Delphi Consensus Approach.

BACKGROUND: Deloading is a ubiquitous yet under-researched strategy within strength and physique training. How deloading should be integrated into the training programme to elicit optimal training outcomes is unknown. To aid its potential integration, this study established consensus around design principles for integrating deloading in strength and physique training programmes using expert opinion and practical experience. METHODS: Expert strength and physique coaches were invited to an online Delphi consisting of 3 rounds. Thirty-four coaches completed the first round, 29 completed the second round, and 21 completed the third round of a Delphi questionnaire. In the first round, coaches answered 15 open-ended questions from four categories: 1: General Perceptions of Deloading; 2: Potential Applications of Deloading; 3: Designing and Implementing Deloading; and 4: Creating an Inclusive Deloading Training Environment. First-round responses were analyzed using reflexive thematic analysis, resulting in 138 statements organized into four domains. In the second and third rounds, coaches rated each statement using a four-point Likert scale, and collective agreement or disagreement was calculated. RESULTS: Stability of consensus was achieved across specific aspects of the four categories. Findings from the final round were used to develop the design principles, which reflect the consensus achieved. CONCLUSIONS: This study develops consensus on design principles for integrating deloading into strength and physique sports training programmes. A consensus definition is proposed: "Deloading is a period of reduced training stress designed to mitigate physiological and psychological fatigue, promote recovery, and enhance preparedness for subsequent training." These findings contribute novel knowledge that might advance the current understanding of deloading in strength and physique sports.

Comparing antimicrobial resistant genes and phenotypes across multiple sequencing platforms and assays for Enterobacterales clinical isolates.

INTRODUCTION: Whole genome sequencing (WGS) of bacterial isolates can be used to identify antimicrobial resistance (AMR) genes. Previous studies have shown that genotype-based AMR has variable accuracy for predicting carbapenem resistance in carbapenem-resistant Enterobacterales (CRE); however, the majority of these studies used short-read platforms (e.g. Illumina) to generate sequence data. In this study, our objective was to determine whether Oxford Nanopore Technologies (ONT) long-read WGS would improve detection of carbapenem AMR genes with respect to short-read only WGS for nine clinical CRE samples. We measured the minimum inhibitory breakpoint (MIC) using two phenotype assays (MicroScan and ETEST) for six antibiotics, including two carbapenems (meropenem and ertapenem) and four non-carbapenems (gentamicin, ciprofloxacin, cefepime, and trimethoprim/sulfamethoxazole). We generated short-read data using the Illumina NextSeq and long-read data using the ONT MinION. Four assembly methods were compared: ONT-only assembly; ONT-only assembly plus short-read polish; ONT + short-read hybrid assembly plus short-read polish; short-read only assembly. RESULTS: Consistent with previous studies, our results suggest that the hybrid assembly produced the highest quality results as measured by gene completeness and contig circularization. However, ONT-only methods had minimal impact on the detection of AMR genes and plasmids compared to short-read methods, although, notably, differences in gene copy number differed between methods. All four assembly methods showed identical presence/absence of the blaKPC-2 carbapenemase gene for all samples. The two phenotype assays showed 100% concordant results for the non-carbapenems, but only 65% concordance for the two carbapenems. The presence/absence of AMR genes was 100% concordant with AMR phenotypes for all four non-carbapenem drugs, although only 22%-50% sensitivity for the carbapenems. CONCLUSIONS: Overall, these findings suggest that the lack of complete correspondence between CRE AMR genotype and phenotype for carbapenems, while concerning, is independent of sequencing platform/assembly method.

Physical Match Demands of International Women's Rugby Union: A Three-Year Longitudinal Analysis of a Team Competing in The Women's Six Nations Championship.

There is a paucity of studies describing the physical match demands of elite international women's rugby union, which limits coaches' ability to effectively prepare players for the physical demands required to compete at the elite level. Global positioning system technologies were used to measure the physical match demands of 53 international female rugby union players during three consecutive Women's Six Nations Championships (2020-2022), resulting in 260 individual match performances. Mixed-linear modelling was used to investigate differences in physical match demands between positions. Significant effects (p < 0.05) of the position were observed for all variables, with the exception of relative distances (m.min-1) at velocities of 1.01-3.00 m·s-1 (p = 0.094) and 3.01-5.00 m·s-1 (p = 0.216). This study provides valuable data on the physical match demands of elite international women's rugby union match play that may aid practitioners in the physical preparation of players to compete at this level. Training methodologies for elite-level female rugby union players should consider the unique demands across positional groups with specific considerations of high-velocity running and collision frequency.

Clinical associations of patients with anti-3-hydroxy-3-methylglutaryl CoA reductase antibody-associated immune-mediated necrotising myopathy.

BACKGROUND: Anti-3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) antibodies are associated with a subtype of immune-mediated necrotising myopathy (IMNM). AIMS: To determine clinical associations of anti-HMGCR antibodies for anti-HMGCR-associated IMNM (HMGCR-IMNM) among a cohort of patients in Western Australia and to determine whether serial HMGCR antibody levels parallel disease activity. METHODS: Adult patients with positive anti-HMGCR antibodies detected by enzyme-linked immunosorbent assay between January 2015 and November 2019 were included. Symptoms, examination findings, imaging findings and blood test results were reviewed retrospectively using patient records and laboratory database results. RESULTS: Among 26 patients with positive anti-HMGCR antibodies, 23 were diagnosed with HMGCR-IMNM representing a positive predictive value (PPV) of 88%. Myopathy was frequently severe at diagnosis with limb weakness graded as Medical Research Council score 3 or below in 78% of patients, bulbar muscle weakness in 39% and an average creatine kinase (CK) at diagnosis of 7986 U/L. The majority (83%) required at least two therapies to maintain remission, 48% had at least one flare of disease and 57% did not achieve CK normalisation. Correlation between CK and anti-HMGCR antibody level at diagnosis was low (r = 0.04). Anti-HMGCR antibodies fell with treatment in 10 of 12 patients, but remained persistently positive in 83% of patients. CONCLUSIONS: The PPV of anti-HMGCR antibodies for HMGCR-IMNM in this Western Australian cohort is 88%. Patients typically present with proximal limb weakness, dysphagia and markedly elevated CK, and, despite multiagent immunosuppression, a significant number of patients have evidence of persistent biochemical myositis. Anti-HMGCR antibodies did not correlate with CK levels at diagnosis.

Editorial Commentary: Blood Flow Restriction Therapy Prior to Anterior Cruciate Ligament Reconstruction: Small Effects Require Accurate Measurements.

A recent research study showed that blood flow restriction (BFR) therapy was safe and well tolerated but failed to demonstrate efficacy as a modality that provides greater gains in quadriceps strength when added to a standard home program in patients awaiting anterior cruciate ligament (ACL) reconstruction. Despite employing a validated method of measurement, the results were highly variable, indicating the need for measurements with sufficient accuracy to detect the small, but potentially meaningful, gains in quadriceps strength that's been attributed to BFR. The results inform future investigations of BFR prior to ACL surgery by demonstrating the need for accurate methods of measurements when the anticipated effects are small.

Prevalence of hormonal contraceptive use and reported side effects of the menstrual cycle and hormonal contraceptive use in powerlifting and rugby.

OBJECTIVES: The prevalence of hormonal contraceptive (HC) use and the associated symptomology of use or nonuse are under-studied in athletic populations, and in particular, in strength and collision sports. This study aimed to investigate the prevalence of hormonal contraceptive use and reported side effects of the menstrual cycle and hormonal contraceptive use in powerlifters and rugby players. METHODS: Competitive female powerlifters and rugby players (aged ≥18 y), representing a strength and a collision sport respectively, completed an anonymous online questionnaire for the purpose of assessing self-reported prevalence of HC use, and symptoms of the menstrual cycle and HC use. Athletes were categorized by sport (powerlifters, n = 149; rugby players, n = 135) in order to conduct a stratified analysis. For open-ended questions, a content analysis was conducted to categorize responses, and frequency analyses were performed. RESULTS: Current HC use was reported by 51.1% of athletes, with similar prevalence for the two sports (powerlifting, 48.3% vs. rugby, 54.1%, P = 0.34). Side effects of the menstrual cycle were reported in 83.5% of non-HC users, with the most common being unspecified cramping (42.4%), headache/migraine (24.5%), and fatigue (24.5%). Side effects were reported in 40.0% of HC users, with the most common being mood changes (17.9%), stomach pain (8.3%) and headaches/migraines (6.9%). CONCLUSION: A large proportion of HC users and nonusers in this study experience negative side effects of HC use and the menstrual cycle, respectively. The symptoms experienced by both groups are wide-ranging, with a high degree of variation between individuals. The negative side-effects experienced by HC users and nonusers may have an influence on athletic performance, and this requires future investigation.

Long-Term Associations between Human Cytomegalovirus Antibody Levels with All-Cause Mortality and Cardiovascular Outcomes in an Australian Community-Based Cohort.

Human cytomegalovirus (HCMV) infection has been shown to increase the risk of cardiovascular events and all-cause death among individuals with clinically apparent cardiovascular disease (CVD). Whether this association exists in individuals with no history of CVD remains unclear. Serum levels of HCMV IgG antibody were measured using an ELISA in 2050 participants aged 40-80 years from the 1994/1995 Busselton Health Survey who did not have CVD at baseline. Outcomes were all-cause death, cardiovascular death, acute coronary syndrome (ACS) and major adverse coronary and cerebrovascular events (MACCE, composite of all-cause death, ACS, stroke and coronary artery revascularisation procedures). Cox proportional hazards regression analysis was used to investigate HCMV antibody levels as a predictor of death and cardiovascular outcomes during follow-up periods of 5, 10 and 20 years. At baseline, participants had a mean age of 56 years and 57% were female. During the 20-year follow-up, there were 448 (21.9%) deaths (including 152 from CVD), 139 (6.8%) participants had ACS and 575 (28.0%) had MACCE. In the fully adjusted model, levels of HCMV antibody at 20 years was associated with all-cause death (HR 1.04; 95% CI 1.00, 1.07, p = 0.037) but not with CVD death, ACS or MACCE. Levels of HCMV antibody are associated with all-cause death but not with cardiovascular outcomes in adults without pre-existing CVD.

The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi's Sarcoma Tumors during Antiretroviral Therapy.

Epidemic Kaposi's sarcoma (KS), defined by co-infection with Human Herpes Virus 8 (HHV-8) and the Human Immunodeficiency Virus (HIV), is a major cause of mortality in sub-Saharan Africa. Antiretroviral therapy (ART) significantly reduces the risk of developing KS, and for those with KS, tumors frequently resolve with ART alone. However, for unknown reasons, a significant number of KS cases do not resolve and can progress to death. To explore how HIV responds to ART in the KS tumor microenvironment, we sequenced HIV env-nef found in DNA and RNA isolated from plasma, peripheral blood mononuclear cells, and tumor biopsies, before and after ART, in four Ugandan study participants who had unresponsive or progressive KS after 180-250 days of ART. We performed immunohistochemistry experiments to detect viral proteins in matched formalin-fixed tumor biopsies. Our sequencing results showed that HIV diversity and RNA expression in KS tumors are maintained after ART, despite undetectable plasma viral loads. The presence of spliced HIV transcripts in KS tumors after ART was consistent with a transcriptionally active viral reservoir. Immunohistochemistry staining found colocalization of HIV Nef protein and tissue-resident macrophages in the KS tumors. Overall, our results demonstrated that even after ART reduced plasma HIV viral load to undetectable levels and restored immune function, HIV in KS tumors continues to be transcriptionally and translationally active, which could influence tumor maintenance and progression.

Characteristics and Future Direction of Tibialis Posterior Tendinopathy Research: A Scoping Review.

Background and Objectives: Tibialis posterior tendon pathologies have been traditionally categorized into different stages of posterior tibial tendon dysfunction (PTTD), or adult acquired flatfoot deformity (AAFD), and more recently to progressive collapsing foot deformity (PCFD). The purpose of this scoping review is to synthesize and characterize literature on early stages of PTTD (previously known as Stage I and II), which we will describe as tibialis posterior tendinopathy (TPT). We aim to identify what is known about TPT, identify gaps in knowledge on the topics of TPT, and propose future research direction. Materials and Methods: We included 44 studies and categorized them into epidemiology, diagnosis, evaluation, biomechanics outcome measure, imaging, and nonsurgical treatment. Results: A majority of studies (86.4%, 38 of 44 studies) recruited patients with mean or median ages greater than 40. For studies that reported body mass index (BMI) of the patients, 81.5% had mean or median BMI meeting criteria for being overweight. All but two papers described study populations as predominantly or entirely female gender. Biomechanical studies characterized findings associated with TPT to include increased forefoot abduction and rearfoot eversion during gait cycle, weak hip and ankle performance, and poor balance. Research on non-surgical treatment focused on orthotics with evidence mostly limited to observational studies. The optimal exercise regimen for the management of TPT remains unclear due to the limited number of high-quality studies. Conclusions: More epidemiological studies from diverse patient populations are necessary to better understand prevalence, incidence, and risk factors for TPT. The lack of high-quality studies investigating nonsurgical treatment options is concerning because, regardless of coexisting foot deformity, the initial treatment for TPT is typically conservative. Additional studies comparing various exercise programs may help identify optimal exercise therapy, and investigation into further nonsurgical treatments is needed to optimize the management for TPT.

Absence of antibody responses to SARS-CoV-2 N protein in COVID-19 vaccine breakthrough cases.

Understanding the risk factors for breakthrough coronavirus disease 2019 (COVID-19) (BC19) is critical to inform policy. Herein, we assessed Delta (Lineage B.1.617.2) variant-specific effectiveness of the BNT162b2 (Pfizer) vaccine and characterized Delta-driven BC19 cases (fully vaccinated individuals who get infected) with known-time-since-vaccination. In this longitudinal prospective study (January 21-October 30, 2021), 90 naïve and 15 convalescent individuals were enrolled at the initiation of vaccination. Samples from 27 unvaccinated individuals with previous laboratory-confirmed COVID-19 diagnosis were collected at a single time point. Longitudinal serology profile (antibodies against severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] S and N proteins) and live-virus-based neutralization capacities were assessed while controlling for age. Sex, age, history of reactions to the COVID-19 vaccine, and viral neutralization capacities were identified as significant risk factors for breakthrough COVID-19. At 8 months postvaccination, male sex, individuals ⩾65 years of age, and individuals who experienced noticeable side effects with the COVID-19 vaccine were at 5.47 (p-value = 0.0102), 4.33 (p-value = 0.0236), and 4.95 (p-value = 0.0159) fold greater risk of BC19 as compared to their peers, respectively. Importantly, every five-fold increase in viral neutralization capacities (by live-virus-based assays) was significantly associated with ~4-fold reduction in the risk occurrence of breakthrough COVID-19 (p-value = 0.045). Vaccine boosting remarkably increased these viral neutralization capacities by 16.22-fold (p- value = 0.0005), supporting the importance of the BNT162b2 booster in efforts to control the incursion of future variants into the population at large. Strikingly, BC19 cases exhibited a delayed/absent antibody response to the N protein, suggesting limited exposure to the virus. Since antibodies against N protein are widely used to evaluate the extent of virus spread in communities, our finding has important implications on the utility of existing serological diagnostic and surveillance for COVID-19.

Distinct HIV-1 Population Structure across Meningeal and Peripheral T Cells and Macrophage Lineage Cells.

HIV-1 sequence population structure among brain and nonbrain cellular compartments is incompletely understood. Here, we compared proviral pol and env high-quality consensus single-molecule real-time (SMRT) sequences derived from CD3+ T cells and CD14+ macrophage lineage cells from meningeal or peripheral (spleen, blood) tissues obtained at autopsy from two individuals with viral suppression on antiretroviral therapy (ART). Phylogenetic analyses showed strong evidence of population structure between CD3+ and CD14+ virus populations. Distinct env variable-region characteristics were also found between CD3+ and CD14+ viruses. Furthermore, shared macrophage-tropic amino acid residues (env) and drug resistance mutations (pol) between meningeal and peripheral virus populations were consistent with the meninges playing a role in viral gene flow across the blood-brain barrier. Overall, our results point toward potential functional differences among meningeal and peripheral CD3+ and CD14+ virus populations and a complex evolutionary history driven by distinct selection pressures and/or viral gene flow. IMPORTANCE Different cell types and/or tissues may serve as a reservoir for HIV-1 during ART-induced viral suppression. We compared proviral pol and env sequences from CD3+ T cells and CD14+ macrophage lineage cells from brain and nonbrain tissues from two virally suppressed individuals. We found strong evidence of viral population structure among cells/tissues, which may result from distinct selective pressures across cell types and anatomic sites.

Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension.

Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear. Here, we investigated whether Notch mechanosensitivity to strain may regulate arterial thickening in hypertension. We developed a multiscale computational framework by coupling a finite element model of arterial mechanics, including residual stress, to an agent-based model of mechanosensitive Notch signaling, to predict VSMC phenotypes as an indicator of growth and remodeling. Our simulations revealed that the sensitivity of Notch to strain at mean blood pressure may be a key mediator of arterial thickening in hypertensive arteries. Further simulations showed that loss of residual stress can have synergistic effects with hypertension, and that changes in the expression of Notch receptors, but not Jagged ligands, may be used to control arterial growth and remodeling and to intensify or counteract hypertensive thickening. Overall, we identify Notch mechanosensitivity as a potential mediator of vascular adaptation, and we present a computational framework that can facilitate the testing of new therapeutic and regenerative strategies.

SARS-CoV-2 genomic surveillance as an evidence-based infection control approach in an offshore petroleum employee population.

BACKGROUND: Industrial hygienists (IH) in the oil and gas business instituted an extraordinary number of safety protocols to limit spread of SARS-CoV-2 onto offshore platforms in the Gulf of Mexico. We used genomic surveillance to provide actionable information concerning the efficacy of their efforts. METHODS: Over 6 months, employees at a single company were serology and PCR tested during a 1-5 day predeployment quarantine and when postdeployment symptoms were reported. From each positive test (n = 49), SARS-CoV-2 genomes were sequenced. Phylogenetic analysis was used to investigate the epidemiology of transmissions. RESULTS: Genomic surveillance confirmed 2 viral strains were infecting 18 offshore workers. Genomic data combined with epidemiological data suggested that a change in quarantine protocols contributed to these outbreaks. A pre-deployment outbreak involved a WHO variant of interest (Theta) that had infected 4 international workers. Two additional predeployment clusters of infections were identified. CONCLUSIONS: Our findings support that IH quarantine/testing protocols limited viral transmissions, halted offshore outbreaks, and stopped the spread of a variant of interest. The study demonstrates how genomic data can be used to understand viral transmission dynamics in employee populations and evaluate safety protocols in the offshore oil and gas industry.

A Novel Targeted Amplicon Next-Generation Sequencing Gene Panel for the Diagnosis of Common Variable Immunodeficiency Has a High Diagnostic Yield: Results from the Perth CVID Cohort Study.

With the advent of next-generation sequencing (NGS), monogenic forms of common variable immunodeficiency (CVID) have been increasingly described. Our study aimed to identify disease-causing variants in a Western Australian CVID cohort using a novel targeted NGS panel. Targeted amplicon NGS was performed on 22 unrelated subjects who met the formal European Society for Immunodeficiencies-Pan-American Group for Immunodeficiency diagnostic criteria for CVID and had at least one of the following additional criteria: disease onset at age <18 years, autoimmunity, low memory B lymphocytes, family history, and/or history of lymphoproliferation. Candidate variants were assessed by in silico predictions of deleteriousness, comparison to the literature, and classified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology criteria. All detected genetic variants were verified independently by an external laboratory, and additional functional studies were performed if required. Pathogenic or likely pathogenic variants were detected in 6 of 22 (27%) patients. Monoallelic variants of uncertain significance were also identified in a further 4 of 22 patients (18%). Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG, including novel variants and variants with unexpected inheritance pattern. Targeted amplicon NGS is an effective tool to identify monogenic disease-causing variants in CVID, and is comparable or superior to other NGS methods. Moreover, targeted amplicon NGS identified patients who may benefit from targeted therapeutic strategies and had important implications for family members.

Self-Reported Prevalence, Magnitude, and Methods of Rapid Weight Loss in Male and Female Competitive Powerlifters.

ABSTRACT: Nolan, D, Lynch, AE, and Egan, B. Self-reported prevalence, magnitude, and methods of rapid weight loss in male and female competitive powerlifters. J Strength Cond Res 36(2): 405-410, 2022-Rapid weight loss (RWL) is common practice in weight category sports, but no empirical data exist documenting the weight-making practices of competitive strength athletes. This study investigated the self-reported prevalence, magnitude, and methods of RWL used by male and female powerlifters when preparing for competition. Competitive powerlifters (n = 321; M/F, 194/127) completed an anonymous online questionnaire previously validated for assessment of methods of RWL. Respondents were categorized by their federation's respective antidoping policy, weigh-in procedure, and degree of assistive equipment allowed, in addition to their use or not of RWL. Subgroup analyses were performed on the largest category of respondents (n = 200, M/F, 117/83; ≤2-hour weigh-in, drug-tested, "raw") based on sex, weight category, and competitive status. Prevalence of RWL was 85.8%, with an average RWL of 3.0 ± 1.9% body mass and an RWL score of 25.1 ± 7.4. Neither sex nor weight category influenced the RWL score, but in male athletes, a lower RWL score (22.7 ± 6.3) was reported in athletes in the lowest tertile of the Wilks score (p = 0.015). Frequencies of "always use" were reported as 54.0% for fluid restriction and 49.0% for water loading. Coaches (37.5%) and online resources (35.0%) were "very influential" on RWL practices in these athletes, while doctors (85.5%) and dieticians (63.0%) were reported to be "not influential." The prevalence of RWL is high in competitive powerlifting, and the methods used are akin to other weight category sports, but the reported RWL scores are lower than reported in combat sports with longer recovery periods after weigh-in.