Missed opportunities for earlier diagnosis of human immunodeficiency virus infection among adults presenting to Auckland District Health Board hospital services.

BACKGROUND: Earlier diagnosis of human immunodeficiency virus (HIV) infection improves health outcomes and reduces transmission. In New Zealand, half of new HIV diagnoses between 2005 and 2010 had a cluster of differentiation 4 count below 350 cells/mm3 . HIV screening is already offered in antenatal settings in New Zealand, but not universally in hospital settings. AIMS: To assess the impact of missed opportunities to diagnose HIV infection in adults presenting to hospital services at Auckland District Health Board (ADHB). METHODS: Retrospective cohort analysis of all new diagnoses of HIV infection in adults aged 15-64 years residing within the ADHB catchment area over a 7-year period. Those who had contact with hospital services prior to diagnosis, but within their estimated window of undiagnosed infection, were compared with those without such contact. RESULTS: Of 201 newly diagnosed patients, 68 had prior hospital contact within their estimated window of HIV infection, 68% of whom were men who have sex with men. These patients could potentially have been diagnosed earlier by a median of 12 months (range 1-84). Missed opportunity visits occurred across a wide range of hospital services, and included visits for conditions that indicated risk for, or actual, HIV infection. Thirteen patients had HIV-associated illnesses at the time of diagnosis that could have been prevented if diagnosed earlier. CONCLUSION: Our current risk-based HIV screening strategy commonly results in late diagnosis, negative health impacts and possibly avoidable transmissions. Further study is warranted to model the feasibility and potential impact of universal HIV screening at ADHB.

Physical Activity and Future Physical Function: Data From the Osteoarthritis Initiative.

Declining physical function is common among aging adults; however, physical activity may decrease the rate of functional loss among adults with or at risk of developing osteoarthritis. Previous studies on this topic used subjective measures of physical activity and were subject to higher selection bias. This study employed propensity score matching techniques to reduce selection bias when measuring the association between objectively measured physical activity and future physical function. Participants (n = 687) of the Osteoarthritis Initiative were included in either a physically active group (n = 280) or a physically inactive group (n = 407) according to baseline accelerometer data. Participants' performance on functional tests 4 years later was compared using both ordinary least squares linear regression and average treatment effects from propensity score matching. Analysis revealed physical activity to be associated with significantly better performance on a 400-m walk test, but not 20-m gait speed or chair stand tests.

Association of the HLA-B*53:01 Allele With Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome During Treatment of HIV Infection With Raltegravir.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, severe adverse event during treatment with raltegravir. The occurrence of DRESS syndrome during treatment with other drugs is strongly associated with particular HLA alleles. Methods: We performed HLA testing in 3 of the 5 patients previously reported to have developed raltegravir-induced DRESS syndrome and in 1 previously unreported patient. We then used virtual modeling to visualize interactions between raltegravir and the imputed HLA molecule. Results: Five of the 6 patients who developed raltegravir-induced DRESS syndrome were African, and 1 was Hispanic. HLA typing was performed in 4 patients, all of whom carried both the HLA-B*53 allele and the HLA-C*04 allele to which it is commonly haplotypic. No other HLA alleles were shared by all of the tested patients. Given the approximate prevalence of HLA-B*53 carriage in African (20%) and Hispanic (6%) populations, the probability of all 4 patients being HLA-B*53 carriers, and 2 of 3 African patients being homozygous for HLA-B*53:01, is approximately 0.00002. Conclusions: These data implicate the prevalent African allele HLA-B*53:01 in the immunopathogenesis of raltegravir-induced DRESS syndrome. Although the immunopathogenic mechanisms are currently unknown, virtual modeling suggests that raltegravir may bind within the antigen binding cleft of the HLA-B*53:01 molecule, but not within the closely related HLA-B*35:01 molecule. Further studies are necessary to confirm the strength of the association between carriage of the HLA-B*53:01 allele and raltegravir-induced DRESS syndrome, and the potential utility of HLA screening before raltegravir treatment.

Gastrocnemius Stretching Program: More Effective in Increasing Ankle/Rear-Foot Dorsiflexion When Subtalar Joint Positioned in Pronation Than in Supination.

CONTEXT: Stretching exercises are commonly prescribed for patients and healthy individuals with limited extensibility of the gastrocnemius muscle. OBJECTIVE: To determine if individuals demonstrate more dorsiflexion at the ankle/rear foot and less at the midfoot after a gastrocnemius-stretching program with the subtalar joint (STJ) positioned in supination compared with pronation. DESIGN: Randomized controlled trial. SETTING: Biomechanical laboratory. PARTICIPANTS: 22 volunteers with current or recent history of lower-extremity cumulative trauma and gastrocnemius tightness (10 women and 4 men, mean age 28 y) randomly assigned to stretching groups with the STJ positioned in either pronation (n = 11) or supination (n = 11). INTERVENTION: 3-wk home gastrocnemius-stretching program using a template to place the subtalar joint in either a pronated or a supinated position. MAIN OUTCOME MEASURES: A 7-camera Vicon motion-analysis system measured ankle/ rear-foot dorsiflexion and midfoot dorsiflexion of all participants during stretching with the STJ positioned in both pronation and supination before and after the 3-wk gastrocnemius-stretching program. RESULTS: A 2-way mixed-model ANOVA revealed a significant interaction (P = .019). At posttest, the group who performed the 3-week stretching program with the STJ positioned in pronation demonstrated more increased ankle/rear-foot dorsiflexion when measured with the STJ in pronation than the group who performed the 3-wk stretching program with the STJ positioned in supination. No significant main effect of stretching group or interaction for dorsiflexion at the midfoot was detected (P = .755 and P = .820, respectively). CONCLUSION: After a 3-wk gastrocnemius-stretching program, when measuring dorsiflexion with the STJ positioned in supination, the participants who completed a 3-wk gastrocnemius stretching program with the STJ positioned in pronation showed more increased dorsiflexion at the ankle/rear foot than participants who completed the stretching program with the STJ positioned in supination.

Generation of a C. elegans tdp-1 null allele and humanized TARDBP containing human disease-variants.

Clinical variants of TARDBP are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and other degenerative diseases. The predicted C. elegans ortholog of TARDBP is encoded by tdp-1 , but functional orthology has not been demonstrated in vivo. We undertook CRISPR/Cas9-based genome editing of the tdp-1 locus to create a complete loss of function allele; all tdp-1 exons and introns were deleted, creating tdp-1(tgx58) , which resulted in neurodegeneration after oxidative stress. Next, we undertook CRISPR-based genome editing to replace tdp-1 exons with human TARDBP coding sequences, creating humanized ( hTARDBP ) C. elegans expressing TDP-43 . Based on the efficiency of this genome editing, we suggest that iterative genome editing of the tdp-1 target locus using linked coCRISPR markers, like dpy-10 , would be a more efficient strategy for sequential assembly of the large engineered transgenes. hTARDBP decreased the neurodegeneration defect of tdp-1(tgx58) , demonstrating functional cross-species orthology. To develop C. elegans models of FTD and ALS, we inserted five different patient TARDBP variants in the C. elegans hTARDBP locus. Only one clinical variant increased stress-induced neurodegeneration; other variants caused inconsistent or negligible defects under these conditions. Combined, this work yielded an unambiguous null allele for tdp-1 , a validated, humanized hTARDBP, and multiple ALS/FTD patient-associated variant models that can be used for future studies.

Adolescent track and field injuries presenting to US emergency departments.

OBJECTIVES: Track and field (T&F) is a highly popular sport for adolescents. The diversity of running, jumping, and throwing events within the sport can result in unique injury patterns for adolescent track and field participants. The purpose of this study was to estimate injury risk in adolescent T&F and describe the types of injuries resulting in ED visits, classified by T&F events. METHODS: Emergency department (ED) data from the National Electronic Injury Surveillance System were obtained for a 20-year period from 2000 through 2019. Cases involving 14- to 18-year-olds participating in T&F were classified by sex, case severity, involved body region, and the T&F event patients were engaged in at the time of their injury. National estimates and Injury rates were calculated using national high school T&F participation data. Longitudinal trends in ED visits were measured using linear regression. Rate ratios (RRs) were used to compare the risk and severity of ED visits by sex. RESULTS: 8,060 track and field related ED encounters were observed, representing an estimated 272,227 encounters nationally over the 20-year study period. The rate of ED encounters increased significantly over the study period (p < 0.001). Adolescent females exhibited a higher rate of ED encounters (RR: 1.23, 95% CI: 1.22-1.24), but a lower rate of hospital admissions (RR: 0.68, 95% CI: 0.64-0.73) compared to males. The lower extremity was the most commonly injured body region for most T&F events, but this differed for sprinting, high jumping, shot put, and javelin events. Most T&F events resulted in unique injury patterns characteristic of their athletic demands. CONCLUSIONS: There was an increasing trend of ED visits from adolescent T&F participants throughout the 20-year study period with different injury patterns observed by sex and T&F event discipline.

The Problem of Recurrent Injuries in Collegiate Track and Field.

Background: As with most sports, participating in Track and Field (T&F) has inherent injury risks and a previous injury often predisposes athletes to a greater future injury risk. However, the frequency and burden of recurrent injuries in collegiate T&F have not been closely examined. Purpose: The purpose of this study was to describe the frequency and burden of recurrent injuries in collegiate T&F and compare differences in the time loss associated with initial and recurrent injuries by sex and T&F discipline. Study Design: Descriptive Epidemiology Study. Methods: Data from the NCAA Injury Surveillance Program were analyzed to describe the frequency and burden of recurrent injuries in collegiate T&F between 2009 and 2014. Comparisons of recurrent injury proportions by T&F discipline were made using Injury Proportion Ratios (IPR) and injury-associated time loss comparisons by injury type and sex were made using Negative Binomial Regression. Results: Four hundred and seventy-four injuries were reported, 13.1% of which were classified as recurrent injuries. T&F athletes who competed in jumps experienced a lower proportion of recurrent injuries (6.1%) than runners (14.6%) and throwers (19.2%) (Recurrent IPR 0.40, 95% CI 0.18-0.88, p<0.05). When controlling for sex and injury diagnosis, T&F athletes experienced 50% greater time loss from sport following a recurrent injury than an initial injury (95% CI 17%-107%, p<0.01). Conclusions: Recurrent injuries in T&F athletes account for greater time loss than initial injuries, despite sex or injury diagnosis. The current study indicates a need for further research to assess factors contributing to time loss. Level of Evidence: Level 3.

A Systematic Review of Factors Associated with Sport Participation among Adolescent Females.

Sport participation provides a direct means to attain health-enhancing physical activity; however, sport participation declines during adolescence, and over 85% of adolescent females fail to meet the recommended 60 min of moderate-vigorous physical activity daily. Given the importance of overcoming barriers to sport and increasing equity in women's sports, the purpose of this systematic review was to identify factors associated with sport participation among adolescent girls and operationalize those factors into theoretical constructs to guide future research. Six databases were systematically searched, and 36 records were included for review. Factors impacting girls' sport participation were categorized as personal, peer, family, socioeconomic, environmental, or other factors. Of these categories, personal factors, including self perceptions and desirable personal outcomes related to sport, were most frequently associated with sport participation. Most research on girls' sport participation lacks theoretical framework, so to aid future studies, this review categorized important participatory factors into the constructs of the theory of planned behavior. Future research would benefit from theory-driven prospective approaches to make clear and consistent predictions about factors impacting sport participation, as well as mixed-method approaches aimed to provide more robust understanding of girls' experiences with and perceptions of factors impacting their participation in sports.

Epidemiology of NCAA Track and Field Injuries From 2010 to 2014.

BACKGROUND: Track and field (T&F) athletes compete in a variety of events that require different skills and training characteristics. Descriptive epidemiology studies often fail to describe event-specific injury patterns. PURPOSE: To describe the epidemiology of injuries in National Collegiate Athletic Association (NCAA) T&F by sex, setting (practice vs competition), and time of season (indoor vs outdoor) and to compare injury patterns by events within the sport. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data were obtained from the NCAA Injury Surveillance Program for all indoor and outdoor T&F injuries during the academic years 2009-2010 to 2013-2014. Injury rates, injury rate ratios, and injury proportion ratios (IPRs) were reported and compared by sex, injury setting, season, and event. Analysis included time-loss as well as no-time loss injuries. RESULTS: Over the 5 seasons, the overall injury rate was 3.99 injuries per 1000 athletic-exposures (95% CI, 3.79-4.20). After controlling for injury diagnoses, women's T&F athletes experienced an 18% higher risk of injury (95% CI, 7% to 31%) and missed 41% more time after an injury (95% CI, 4% to 93%) when compared with men. Among all athletes, the injury risk during competition was 71% higher (95% CI, 50% to 95%) compared with practice and required 59% more time loss (95% CI, 7% to 135%). Distance running accounted for a significantly higher proportion of overuse injuries (IPR, 1.70; 95% CI, 1.40-2.05; P < .05) and required 168% more time loss (95% CI, 78% to 304%) than other events. The hip and thigh were the body regions most commonly injured; injury type, however, varied by T&F event. Sprinting accounted for the greatest proportion of hip and thigh injuries, distance running had the greatest proportion of lower leg injuries, and throwing reported the greatest proportion of spine and upper extremity injuries. CONCLUSION: Injury risk in NCAA T&F varied by sex, season, and setting. Higher injury rates were found in women versus men, indoor versus outdoor seasons, and competitions versus practices. The hip and thigh were the body regions most commonly injured; however, injury types varied by event. These findings may provide insight to programs aiming to reduce the risk of injury and associated time loss in collegiate T&F.

Atropine reduces aldicarb-induced sensitivity to C. elegans electroshock model.

Atropine has been used as an established anticonvulsant treatment for nerve agent intoxication. Atropine reduces electroshock recovery time among aldicarb-exposed wild-type C. elegans .

SGPL1 stimulates VPS39 recruitment to the mitochondria in MICU1 deficient cells.

OBJECTIVE: Mitochondrial "retrograde" signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated. METHODS: We performed transcriptomics, quantitative proteomics and lifespan assays to identify pathways that are mechanistically linked to mitochondrial network expansion and homeostasis in Caenorhabditis elegans lacking the mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To support our findings, we carried out biochemical and image analyses in mammalian cells and mouse-derived tissues. RESULTS: We report that micu-1(null) mutations impair the OXPHOS system and promote C. elegans longevity through a transcriptional program that is independent of the mitochondrial calcium uniporter MCU-1/MCU and the essential MCU regulator EMRE-1/EMRE. We identify sphingosine phosphate lyase SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit VPS-39/VPS39 as critical lifespan modulators of micu-1(null) mutant animals. Cross-species investigation indicates that SGPL1 upregulation stimulates VPS39 recruitment to the mitochondria, thereby enhancing mitochondria-lysosome contacts. Consistently, VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1 deficient cells. In mouse-derived muscles, we show that VPS39 recruitment to the mitochondria may represent a common signature associated with altered OXPHOS system. CONCLUSIONS: Our findings reveal a previously unrecognized SGPL1/VPS39 axis that stimulates intracellular organelle interactions and sustains autophagy and mitochondrial homeostasis in OXPHOS deficient cells.

The incidence of deep brain stimulator hardware infection: the effect of change in antibiotic prophylaxis regimen and review of the literature.

The complication of hardware infection related to deep brain stimulator implantation (or revision) varies between 0 and 15.2% in the literature. However, no national guidelines exist at present to define an average or acceptable rate of infection associated with, nor the preferred antibiotic prophylaxis required for, this procedure. The aim of this study was to examine the effect of changing the antibiotic prophylaxis regimen used in a single neurosurgical centre on the incidence and outcome of hardware infection. A prospective cohort of 38 patients undergoing deep brain stimulation (DBS) implantation or internal pulse generator (IPG) replacement and receiving perioperative vancomycin (including intravenous gentamicin on induction) and pouch-installed gentamicin, was compared to a historical cohort of 35 patients receiving perioperative cefuroxime in the same unit. The infection rate over 2 years in the prospective group for DBS surgery was 0 compared to 1 (5.6%) in the historical cohort (p = 0.11, χ(2)); the infection rate for IPG replacements was 1(3.6%) in the prospective cohort, versus 3 (17.6%) in the historical (p = 0.44, χ(2)). In this article, we have also systematically reviewed the literature to date and derived an average infection rate of 4.7% (PI 0.9-22%, Random Effects Meta-analysis, Stata) for 35 studies comprising 3550 patients. There is no significant difference in infection rates between DBS procedures that are primarily internalised (n = 9) compared to those in which there is a period of electrode externalisation (n = 23) (p = 0.9, Meta-regression analysis, Stata).

Structure of human brain fructose 1,6-(bis)phosphate aldolase: linking isozyme structure with function.

Fructose-1,6-(bis)phosphate aldolase is a ubiquitous enzyme that catalyzes the reversible aldol cleavage of fructose-1,6-(bis)phosphate and fructose 1-phosphate to dihydroxyacetone phosphate and either glyceral-dehyde-3-phosphate or glyceraldehyde, respectively. Vertebrate aldolases exist as three isozymes with different tissue distributions and kinetics: aldolase A (muscle and red blood cell), aldolase B (liver, kidney, and small intestine), and aldolase C (brain and neuronal tissue). The structures of human aldolases A and B are known and herein we report the first structure of the human aldolase C, solved by X-ray crystallography at 3.0 A resolution. Structural differences between the isozymes were expected to account for isozyme-specific activity. However, the structures of isozymes A, B, and C are the same in their overall fold and active site structure. The subtle changes observed in active site residues Arg42, Lys146, and Arg303 are insufficient to completely account for the tissue-specific isozymic differences. Consequently, the structural analysis has been extended to the isozyme-specific residues (ISRs), those residues conserved among paralogs. A complete analysis of the ISRs in the context of this structure demonstrates that in several cases an amino acid residue that is conserved among aldolase C orthologs prevents an interaction that occurs in paralogs. In addition, the structure confirms the clustering of ISRs into discrete patches on the surface and reveals the existence in aldolase C of a patch of electronegative residues localized near the C terminus. Together, these structural changes highlight the differences required for the tissue and kinetic specificity among aldolase isozymes.