Mucosa-associated invariant T cells are systemically depleted in simian immunodeficiency virus-infected rhesus macaques

Mucosa-associated invariant T (MAIT) cells contribute to host immune protection against a wide range of potential pathogens via the recognition of bacterial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although bacterial products translocate systemically in human immunodeficiency virus (HIV)-infected individuals and simian immunodeficiency virus (SIV)-infected Asian macaques, several studies have shown that MAIT cell frequencies actually decrease in peripheral blood during the course of HIV/SIV disease. However, the mechanisms underlying this proportional decline remain unclear. In this study, we characterized the phenotype, activation status, functionality, distribution, and clonotypic structure of MAIT cell populations in the peripheral blood, liver, mesenteric lymph nodes (MLNs), jejunum, and bronchoalveolar lavage (BAL) fluid of healthy and SIV-infected rhesus macaques (RMs). Low frequencies of MAIT cells were observed in the peripheral blood, MLNs, and BAL fluid of SIV-infected RMs. These numerical changes were coupled with increased proliferation and a highly public T cell receptor alpha (TCRα) repertoire in the MAIT cell compartment without redistribution to other anatomical sites. Collectively, our data show systemically decreased frequencies of MAIT cells likely attributable to enhanced turnover in SIV-infected RMs. This process may impair protective immunit

Strength and Mobility Measures in Division I Female Volleyball Student Athletes Across Different Positions

Shoulder internal and external rotation and hand grip measures are commonly used to evaluate upper extremity mobility and strength in college athletes. However, positional differences and their impact on these scores are rarely considered, therefore further research is needed in sports such as volleyball where information on these potential trends is lacking. PURPOSE: The purpose of this study was to identify possible differences between strength and mobility measures in female volleyball student-athletes whose responsibilities include hitting (predominantly overhead roles) versus those who are primarily passers and diggers (non-overhead roles). METHODS: Thirteen Division I volleyball student-athletes who volunteered to participate in this study were divided into two groups - hitters (H; age = 19.6 ± 1.5 y, height = 180.7 ± 6.7 cm) and passers (P; age = 19.3 ± 1.2 y, height = 172.0 ± 10.0 cm). Players were tested on their shoulder range of motion (ROM) for internal rotation (IR), external rotation (ER), and flexion using a goniometer. Total ROM was identified as a sum of IR and ER. Hand grip strength was measured in the dominant hand using a hand grip dynamometer. All testing was completed by certified healthcare professionals prior to preseason following clearance by the team physician. Descriptive statistics were calculated as mean ± standard deviations. RESULTS: H had higher total ROM than P in both the right arm (158.6 ± 65.8° vs 144.1 ± 65.8°) and left arm (165.0 ± 67.8° vs 155.7 ± 69.7°). H had higher flexion than P in the right, dominant arm (176.9 ± 7.9° vs 171.5 ± 18.7°), but similar flexion in the left, nondominant arm (180.1 ± 5.6° vs 180.7 ± 3.4°). H and P both had higher than average values for shoulder ROM compared to published normative data. Hand grip strength was also higher in H compared to P (31.6 ± 6.2 kg vs 26.1 ± 2.5 kg). CONCLUSIONS: H displayed greater total ROM in both arms, a higher flexion ROM in their dominant arm than P as well as greater strength in their dominant arm. This emphasizes the importance of mobility and strength in their positional demands, and the need for shoulder stability. This information provides strength and conditioning coaches preliminary information on possible foci for training and areas where further research is still needed

Presence of early CKD-related metabolic complications predict progression of stage 3 CKD: a case-controlled study

Only a subset of patients who enter stage 3 chronic kidney disease (CKD) progress to stage 4. Identifying which patients entering stage 3 are most likely to progress could improve outcomes, by allowing more appropriate referrals for specialist care, and spare those unlikely to progress the adverse effects and costliness of an unnecessarily aggressive approach. We hypothesized that compared to non-progressors, patients who enter stage 3 CKD and ultimately progress have experienced greater loss of renal function, manifested by impairment of metabolic function (anemia, worsening acidosis and mineral abnormalities), than is reflected in the eGFR at entry to stage 3. The purpose of this case-controlled study was to design a prediction model for CKD progression using laboratory values reflecting metabolic status. Using data extracted from the electronic health record (EHR), two cohorts of patients in stage 3 were identified: progressors (eGFR declined >3 ml/min/1.73m2/year; n = 117) and non-progressors (eGFR declined <1 ml/min/1.73m2; n = 364). Initial laboratory values recorded a year before to a year after the time of entry to stage 3, reflecting metabolic complications (hemoglobin, bicarbonate, calcium, phosphorous, and albumin) were obtained. Average values in progressors and non-progressors were compared. Classification algorithms (Naïve Bayes and Logistic Regression) were used to develop prediction models of progression based on the initial lab data. At the entry to stage 3 CKD, hemoglobin, bicarbonate, calcium, and albumin values were significantly lower and phosphate values significantly higher in progressors compared to non-progressors even though initial eGFR values were similar. The differences were sufficiently large that a prediction model of progression could be developed based on these values. Post-test probability of progression in patients classified as progressors or non-progressors were 81% (73% − 86%) and 17% (13% − 23%), respectively. Our studies demonstrate that patients who enter stage 3 and ultimately progress to stage 4 manifest a greater degree of metabolic complications than those who remain stable at the onset of stage 3 when eGFR values are equivalent. Lab values (hemoglobin, bicarbonate, phosphorous, calcium and albumin) are sufficiently different between the two cohorts that a reasonably accurate predictive model can be developed

Lower Extremity Strength and Mobility in Division I Male Basketball Players Across Vertical Jump Performance

Vertical jump (VJ) performance is a commonly used assessment to measure explosive muscular power in collegiate strength and power athletes such as basketball players. However, research on the relationship between VJ performance and measures of lower extremity (LE) strength and mobility is inconsistent. PURPOSE: The purpose of this study was to analyze hip and ankle strength and mobility measures among collegiate male basketball players by comparing those with higher and lower VJ performance. METHODS: During pre-season screening, ten Division I male basketball players were assessed to determine VJ height by completing a countermovement VJ test. Players were divided into two groups based on VJ performance which were comprised of the top 5 performers (T; 20.8 ± 2.0 years, 186.4 ± 7.4 cm, 79.6 ± 8.6 kg; VJ: 70.4 ± 6.9 cm) and the bottom 5 performers (B; 20.0 ± 1.6 years, 197.4 ± 9.9 cm, 94.2.6 ± 19.7 kg; VJ: 56.9 ± 2.5 cm). Hip range of motion (ROM) was measured with a goniometer, and total hip ROM was calculated as the sum of internal and external rotation for each limb. Ankle dorsiflexion was assessed using a clinometer instrument. Hip abduction (ABD) and adduction (ADD) strength was measured using a dynamometer, and calculated relative to body weight. Players also self-reported LE injuries in the prior 12 months. Descriptive statistics were calculated as mean ± standard deviation. RESULTS: Compared to B, T had lower left leg hip ROM (69.4 ± 6.6° vs 72.6 ± 7.5°). T had higher right leg hip ROM (73.4 ± 5.0° vs 70.0 ± 11.9°) and left/right ankle ROM (36.8 ± 4.1° vs 33.2 ± 3.0° and 35.4 ± 2.4° vs 32.8 ± 4.0°, respectively). T had higher relative right/left leg ABD strength (43.5 ± 6.3 vs 37.5 ± 10.9 % and 37.8 ± 7.1 vs 36.8 ± 11.8 %, respectively), and right/left leg ADD strength (44.0 ± 21.4 vs 40.9 ± 6.1 % and 41.2 ± 10.5 vs 39.5 ± 12.3 %, respectively). However, only 20% of the T group compared to 60% of the B group reported experiencing a recent LE injury. CONCLUSION: Although the T group had higher right leg hip ROM, ankle ROM, and greater hip strength these were just trends, making it difficult to draw any inferences about the association between hip and ankle strength and mobility measures on VJ performance. It is also possible that the greater presence of recent LE injury in the B group may have impacted the findings of this study

Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach

Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases

Perceptions and impact of mandatory eLearning for foundation trainee doctors:a qualitative evaluation

BACKGROUND: Junior doctors in the UK must complete various educational components during their two year Foundation training programme. It is important that mandatory learning is informative and engaging. The aim of this study was to evaluate trainee doctors’ perceptions of a Technology Enhanced Learning (TEL) programme developed to improve prescribing competency. METHOD: Focus groups and interviews were conducted at three hospital sites in the West Midlands. Codes, sub-themes and themes were determined using deductive and inductive thematic analysis. RESULTS: Data were collected from 38 Foundation trainee doctors. Results revealed major themes relating to prescribing education, the user experience and user engagement. Key findings included the positive impact of preparedness following undergraduate education on the user experience of the TEL programme at the postgraduate level; the impact of content, structure, and individual learning needs and styles on the user experience; and the impact of motivation and time on engagement. Most trainees engaged with the programme owing to its mandatory nature; however, some trainees also used the programme voluntarily, for example, to acquire knowledge prior to starting a new placement. CONCLUSIONS: It is important to ensure that learners are willing to engage with mandatory TEL, and that they have the time and motivation to do so. It is also important to ensure that learners have a positive user experience and that in designing TEL individual differences in learning styles and needs are taken into account. These findings have implications for educators and system developers in the construction and design of mandatory eLearning programmes

Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium–Glucose Cotransporter 2 Inhibition

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication

Diversity and Complexity of the Large Surface Protein Family in the Compacted Genomes of Multiple Pneumocystis Species

Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multicopy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneurnocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins and provide a detailed description of the classification, unique characteristics, and phylogenetic relatedness of five Msg families. We further describe, for the first time, the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. coda from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests multiple functions for this superfamily rather than just conferring antigenic variation to allow immune evasion as previously believed. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology. IMPORTANCE Pneumocystis continues to be a major cause of disease in humans with immunodeficiency, especially those with HIV/AIDS and organ transplants, and is being seen with increasing frequency worldwide in patients treated with immunode-pleting monoclonal antibodies. Annual health care associated with Pneumocystis pneumonia costs similar to$475 million dollars in the United States alone. In addition to causing overt disease in immunodeficient individuals, Pneumocystis can cause subclinical infection or colonization in healthy individuals, which may play an important role in species preservation and disease transmission. Our work sheds new light on the diversity and complexity of the msg superfamily and strongly suggests that the versatility of this superfamily reflects multiple functions, including antigenic variation to allow immune evasion and optimal adaptation to host environmental conditions to promote efficient infection and transmission. These findings are essential to consider in developing new diagnostic and therapeutic strategies.Peer reviewe