A precision engineered interleukin-2 (IL-2) for bolstering CD8+ T- and NK-cell activity without eosinophilia and vascular leak syndrome in non-human primates.

We have created a precisely pegylated IL-2 [SAR-444245 (SAR'245) or pegenzileukin, previously THOR- 707] designed for proliferation of target CD8+ T and NK cells for anti-cancer activity, with minimal expansion of anti-target regulatory CD4+ T cells (Tregs) that counter their action, or eosinophils that trigger vascular leak syndrome (VLS). We performed in vivo studies in non-human primate (NHP) to monitor SAR'245's safety, pharmacokinetic profile, and pharmacodynamic parameters including expansion of peripheral CD8+ T and NK cells, and effects on Tregs and eosinophils. Studies included multiple ascending dosing and repeat dosing with different regimens (QW, Q2W, Q3W and Q4W). We also conducted ex vivo studies using human primary cells to further evaluate SAR'245 stimulation of target cells alone and in combination with PD-1 checkpoint inhibitors. The pharmacokinetic profile of SAR'245 in NHP demonstrated dose-proportional exposure that was comparable with redosing. It elicited expansion of peripheral CD8+ T and NK cells that was comparable with each dose and with multiple dosing regimens. Once-weekly dosing showed no significant adverse effects, including no hallmark signs of VLS at dosing levels up to 1 mg/kg. Ex vivo, SAR'245 enhanced T-cell receptor responses alone and in combination with PD-1 inhibitors without inducing cytokines associated with cytokine release syndrome or VLS. Results support the clinical development of SAR'245 as a drug candidate for the treatment of solid tumors, alone or in combination with PD-1 inhibitory agents.

Environmental stress reduces shark residency to coral reefs.

Coral reef ecosystems are highly threatened and can be extremely sensitive to the effects of climate change. Multiple shark species rely on coral reefs as important habitat and, as such, play a number of significant ecological roles in these ecosystems. How environmental stress impacts routine, site-attached reef shark behavior, remains relatively unexplored. Here, we combine 8 years of acoustic tracking data (2013-2020) from grey reef sharks resident to the remote coral reefs of the Chagos Archipelago in the Central Indian Ocean, with a satellite-based index of coral reef environmental stress exposure. We show that on average across the region, increased stress on the reefs significantly reduces grey reef shark residency, promoting more diffuse space use and increasing time away from shallow forereefs. Importantly, this impact has a lagged effect for up to 16 months. This may have important physiological and conservation consequences for reef sharks, as well as broader implications for reef ecosystem functioning. As climate change is predicted to increase environmental stress on coral reef ecosystems, understanding how site-attached predators respond to stress will be crucial for forecasting the functional significance of altering predator behavior and the potential impacts on conservation for both reef sharks and coral reefs themselves.

Creating cell-specific computational models of stem cell-derived cardiomyocytes using optical experiments.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have gained traction as a powerful model in cardiac disease and therapeutics research, since iPSCs are self-renewing and can be derived from healthy and diseased patients without invasive surgery. However, current iPSC-CM differentiation methods produce cardiomyocytes with immature, fetal-like electrophysiological phenotypes, and the variety of maturation protocols in the literature results in phenotypic differences between labs. Heterogeneity of iPSC donor genetic backgrounds contributes to additional phenotypic variability. Several mathematical models of iPSC-CM electrophysiology have been developed to help to predict cell responses, but these models individually do not capture the phenotypic variability observed in iPSC-CMs. Here, we tackle these limitations by developing a computational pipeline to calibrate cell preparation-specific iPSC-CM electrophysiological parameters. We used the genetic algorithm (GA), a heuristic parameter calibration method, to tune ion channel parameters in a mathematical model of iPSC-CM physiology. To systematically optimize an experimental protocol that generates sufficient data for parameter calibration, we created in silico datasets by simulating various protocols applied to a population of models with known conductance variations, and then fitted parameters to those datasets. We found that calibrating to voltage and calcium transient data under 3 varied experimental conditions, including electrical pacing combined with ion channel blockade and changing buffer ion concentrations, improved model parameter estimates and model predictions of unseen channel block responses. This observation also held when the fitted data were normalized, suggesting that normalized fluorescence recordings, which are more accessible and higher throughput than patch clamp recordings, could sufficiently inform conductance parameters. Therefore, this computational pipeline can be applied to different iPSC-CM preparations to determine cell line-specific ion channel properties and understand the mechanisms behind variability in perturbation responses.

Muscle microvascular oxygen delivery limitations during the contraction phase of intermittent maximal effort contractions.

PURPOSE: The end-test torque (ETT) during intermittent maximal effort contractions reflects the highest contraction intensity at which a muscle metabolic steady-state can be attained. This study determined if ETT is the highest intensity at which the contraction phase of intermittent exercise does not limit the matching of microvascular oxygen delivery to muscle oxygen demand. METHODS: Microvascular oxygenation characteristics of the biceps brachii muscle were measured in sixteen young, healthy individuals (8M/8F, 22 ± 3 years, 80.9 ± 20.3 kg) by near-infrared spectroscopy during maximal effort elbow flexion under control conditions (CON) and with complete circulatory occlusion (OCC). RESULTS: Increases in total-[heme] were blunted during OCC compared to CON (225 ± 87 vs. 264 ± 88 µM, p < 0.001) but OCC did not elicit a compensatory increase in deoxygenated-[heme] at any timepoint (108 ± 62 vs. 101 ± 61 µM, p > 0.05). Deoxygenated-[heme] was significantly elevated during contraction, relative to relaxation, above ETT (107 ± 60 vs. 98.8 ± 60.5 µM, p < 0.001), but not at ETT (91.7 ± 54.1 vs. 98.4 ± 62.2 µM, p = 0.174). Total-[heme] was significantly reduced during contraction, relative to relaxation, at all contraction intensities during CON (p < 0.05) and OCC (p < 0.05). CONCLUSION: These data suggest that ETT may reflect the highest contraction intensity at which contraction-induced increases in intramuscular pressures do not limit muscle perfusion to a degree that requires further increases in fractional oxygen extraction (i.e., deoxygenated-[heme]) despite limited microvascular diffusive conductance (i.e., total-[heme]).

Clinical Features and HLA Genetics Differ in Children at Type 1 Diabetes Onset by Hispanic Ethnicity.

CONTEXT: Type 1 diabetes incidence continues to increase in children, especially among Hispanic Whites (HW). OBJECTIVE: We investigated the clinical, immunologic, and genetic characteristics of HW and Non-Hispanic White (NHW) children that presented at type 1 diabetes diagnosis. METHODS: In this single-center, observational study, children who were diagnosed with type 1 diabetes (<20 years old) and tested for islet autoantibodies within 1 year of diagnosis were included in the study and divided into two groups by Hispanic ethnicity. RESULTS: Of 1297 children, 398 HW children presented with a younger age at diabetes onset (10.2 ± 3.9 vs. 11.1 ± 4.1 years, p<0.001) and more diabetic ketoacidosis (62.4% vs. 51.9%, p<0.001) compared to NHW children (n=899). There was no difference in sex, A1c levels, or the number and prevalence of islet autoantibodies between the two cohorts. A subset of our cohort was HLA typed as specific alleles confer strong genetic risk for type 1 diabetes (e.g., HLA-DR4 and DQ8). Among 637 HLA-typed children, HW children had a significantly higher prevalence of the DR4-DQ8 haplotype compared to NHW children (79.1% vs. 60.1%, p<0.001), and this frequency was much higher than a reference Hispanic population (OR = 6.5, 95% CI 4.6-9.3). CONCLUSIONS: Hispanic White children developing type 1 diabetes have a high prevalence of HLA DR4-DQ8, which can be utilized to select individuals for immune monitoring with islet autoantibodies to lessen diabetic ketoacidosis and potentially prevent diabetes onset.

A Moderate Blood Flow Restriction Pressure Does Not Affect Maximal Strength or Neuromuscular Responses.

ABSTRACT: Lubiak, SM, Lawson, JE, Gonzalez Rojas, DH, Proppe, CE, Rivera, PM, Hammer, SM, Trevino, MA, Dinyer-McNeely, TK, Montgomery, TR, Olmos, AA, Sears, KN, Bergstrom, HC, Succi, PJ, Keller, JL, and Hill, EC. A moderate blood flow restriction pressure does not affect maximal strength or neuromuscular responses. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this study was to examine the acute effects of blood flow restriction (BFR) applied at 60% of total arterial occlusion pressure (AOP) on maximal strength. Eleven college-aged female subjects completed two testing sessions of maximal unilateral concentric, isometric, and eccentric leg extension muscle actions performed with and without BFR. Separate 3 (mode [isometric, concentric, eccentric]) × 2 (condition [BFR, no BFR]) × 2 (visit [2, 3]) repeated-measures analysis of variances were used to examine mean differences in maximal strength, neuromuscular function, rating of perceived exertion (RPE), and pain. For maximal strength (collapsed across condition and visit), isometric (128.5 ± 22.7 Nm) and eccentric (114.5 ± 35.4 Nm) strength were greater than concentric maximal strength (89.3 ± 22.3 Nm) (p < 0.001-0.041). Muscle excitation relative (%) to isometric non-BFR was greater during the concentric (108.6 ± 31.5%) than during the eccentric (86.7 ± 29.2%) (p = 0.045) assessments but not different than isometric (93.4 ± 17.9%) (p = 0.109) assessments, collapsed across condition and visit. For RPE, there was an interaction such that RPE was greater during non-BFR (4.3 ± 1.7) than during BFR (3.7 ± 1.7) (p = 0.031) during the maximal concentric strength assessments. Furthermore, during maximal strength assessments performed with BFR, isometric RPE (5.8 ± 1.9) was greater than concentric (3.7 ± 1.7) (p = 0.005) and eccentric (4.6 ± 1.9) (p = 0.009) RPE. Finally, pain was greater during the isometric (2.8 ± 2.1 au) than during the concentric (1.8 ± 1.5 au) (p = 0.016), but not eccentric, maximal strength assessments (2.1 ± 1.6 au) (p = 0.126), collapsed across condition and visit. The application of BFR at 60% AOP did not affect concentric, isometric, or eccentric maximal strength or neuromuscular function. Trainers, clinicians, and researchers can prescribe exercise interventions relative to a restricted (when using a moderate AOP) or nonrestricted assessment of maximal strength.

Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance.

Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D, and this haplotype carries the single nucleotide variant rs3184504*T in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cell-intrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient CD8+T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival post-transfer compared to control cells despite a similar proliferation profile in the same host. Next, we created a spontaneous NOD .Sh2b3 -/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens. Article Highlights: The rs3184504 polymorphism, encoding a hypomorphic variant of the negative regulator SH2B3, strongly associates with T1D.SH2B3 deficiency results in hypersensitivity to cytokines, including IL-2, in murine CD4+ and CD8+ T cells.SH2B3 deficient CD8+ T cells exhibit a comparable transcriptome to wild-type CD8+ T cells at baseline, but upon antigen stimulation SH2B3 deficient cells upregulate genes characteristic of enhanced JAK/STAT signaling and effector functions.We found a T-cell intrinsic role of SH2B3 leading to severe islet destruction in an adoptive transfer murine T1D model, while global SH2B3 deficiency accelerated spontaneous NOD diabetes across sexes.

Management Approaches in WHO Grade III Meningioma: A National Oncology Trainees' Collaborative for Healthcare Research (NOTCH) UK Multi-Centre Retrospective Study.

AIMS: WHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years. MATERIALS AND METHODS: Patients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival. RESULTS: 84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection. Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27-1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27-0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy-60Gy), 45.8% of adjuvant RT was delivered using IMRT. At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT. CONCLUSION: Surgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

Influence of Blood Flow Restriction on Neuromuscular Function and Fatigue During Forearm Flexion in Men.

ABSTRACT: Montgomery, TR Jr, Olmos, A, Sears, KN, Succi, PJ, Hammer, SM, Bergstrom, HC, Hill, EC, Trevino, MA, and Dinyer-McNeely, TK. Influence of blood flow restriction on neuromuscular function and fatigue during forearm flexion in men. J Strength Cond Res 38(7): e349-e358, 2024-To determine the effects of blood flow restriction (BFR) on the mean firing rate (MFR) and motor unit action potential amplitude (MUAPAMP) vs. recruitment threshold (RT) relationships during fatiguing isometric elbow flexions. Ten men (24.5 ± 4.0 years) performed isometric trapezoidal contractions at 50% maximum voluntary contraction to task failure with or without BFR, on 2 separate days. For BFR, a cuff was inflated to 60% of the pressure required for full brachial artery occlusion at rest. During both visits, surface electromyography was recorded from the biceps brachii of the dominant limb and the signal was decomposed. A paired-samples t test was used to determine the number of repetitions completed between BFR and CON. ANOVAs (repetition [first, last] × condition [BFR, CON]) were used to determine differences in MFR vs. RT and MUAPAMP vs. RT relationships. Subjects completed more repetitions during CON (12 ± 4) than BFR (9 ± 2; p = 0.012). There was no significant interaction (p > 0.05) between the slopes and y-intercepts during the repetition × condition interaction for MUAPAMP vs. MFR. However, there was a main effect of repetition for the slopes of the MUAPAMP vs. RT (p = 0.041) but not the y-intercept (p = 0.964). Post hoc analysis (collapsed across condition) indicated that the slopes of the MUAPAMP vs. RT during the first repetition was less than the last repetition (first: 0.022 ± 0.003 mv/%MVC; last: 0.028 ± 0.004 mv/%MVC; p = 0.041). Blood flow restriction resulted in the same amount of higher threshold MU recruitment in approximately 75% of the repetitions. Furthermore, there was no change in MFR for either condition, even when taken to task failure. Thus, BFR training may create similar MU responses with less total work completed than training without BFR.

Novel CTD tag establishes shark fins as ocean observing platforms.

Animal-borne tags are effective instruments for collecting ocean data and can be used to fill spatial gaps in the observing network. We deployed the first conductivity, temperature, and depth (CTD) satellite tags on the dorsal fin of salmon sharks (Lamna ditropis) to demonstrate the potential of sharks to monitor essential ocean variables and oceanographic features in the Gulf of Alaska. Over 1360 km and 36 days in the summer of 2015, the salmon shark collected 56 geolocated, temperature-salinity profiles. The shark swam through a plume of anomalously salty water that originated from the "Blob" and encountered several mesoscale eddies, whose subsurface properties were altered by the marine heatwave. We demonstrate that salmon sharks have the potential to serve as submesoscale-resolving oceanographic platforms and substantially increase the spatial coverage of observations in the Gulf of Alaska.

Cell-to-cell heterogeneity in ion channel conductance impacts substrate vulnerability to arrhythmia.

Determining whether an ectopic depolarization will lead to a self-perpetuating arrhythmia is of critical importance in determining arrhythmia risk, so it is necessary to understand what factors impact substrate vulnerability. This study sought to explore the impact of cell-to-cell heterogeneity in ion channel conductance on substrate vulnerability to arrhythmia by measuring the duration of the vulnerable window in computational models of one-dimensional cables of ventricular cardiomyocytes. We began by using a population of uniform cable models to determine the mechanisms underlying the vulnerable window phenomenon. We found that in addition to the known importance of GNa, the conductances GCa,L and GKr also play a minor role in determining the vulnerable window duration. We also found that a steeper slope of the repolarizing action potential during the vulnerable window correlated with a shorter vulnerable window duration in uniform cables. We applied our understanding from these initial simulations to an investigation of the vulnerable window in heterogeneous cable models. The heterogeneous cables displayed a great deal of intra-cable variation in vulnerable window duration, highly sensitive to the cardiomyocytes in the local environment of the ectopic stimulus. Coupling strength modulated not only the magnitude of the vulnerable window duration but also the extent of intra-tissue variability in vulnerable window duration.NEW & NOTEWORTHY We investigate the impact of cell-to-cell heterogeneity in ion channel conductance on substrate vulnerability to arrhythmia by measuring the vulnerable window duration in computational cardiomyocyte cable models. We demonstrate a wide range of intra-cable variability in vulnerable window duration (VWD) and show how this is changed by ion channel block and coupling strength perturbations.

A CD25-biased interleukin-2 for autoimmune therapy engineered via a semi-synthetic organism.

BACKGROUND: Natural cytokines are poorly suited as therapeutics for systemic administration due to suboptimal pharmacological and pharmacokinetic (PK) properties. Recombinant human interleukin-2 (rhIL-2) has shown promise for treatment of autoimmune (AI) disorders yet exhibits short systemic half-life and opposing immune responses that negate an appropriate therapeutic index. METHODS: A semi-synthetic microbial technology platform was used to engineer a site-specifically pegylated form of rhIL-2 with enhanced PK, specificity for induction of immune-suppressive regulatory CD4 + T cells (Tregs), and reduced stimulation of off-target effector T and NK cells. A library of rhIL-2 molecules was constructed with single site-specific, biorthogonal chemistry-compatible non-canonical amino acids installed near the interface where IL-2 engages its cognate receptor ßγ (IL-2Rßγ) signaling complex. Biorthogonal site-specific pegylation and functional screening identified variants that retained engagement of the IL-2Rα chain with attenuated potency at the IL-2Rßγ complex. RESULTS: Phenotypic screening in mouse identifies SAR444336 (SAR'336; formerly known as THOR-809), rhIL-2 pegylated at H16, as a potential development candidate that specifically expands peripheral CD4+ Tregs with upregulation of markers that correlate with their suppressive function including FoxP3, ICOS and Helios, yet minimally expands CD8 + T or NK cells. In non-human primate, administration of SAR'336 also induces dose-dependent expansion of Tregs and upregulated suppressive markers without significant expansion of CD8 + T or NK cells. SAR'336 administration reduces inflammation in a delayed-type hypersensitivity mouse model, potently suppressing CD4+ and CD8 + T cell proliferation. CONCLUSION: SAR'336 is a specific Treg activator, supporting its further development for the treatment of AI diseases.

Interleukin-2 (IL-2) is a protein that functions as a master regulator of immune responses. A key function of IL-2 is the stimulation of immune-regulatory cells that suppress autoimmune disease, which occurs when the body's immune system mistakenly attacks healthy tissues. However, therapeutic use of IL-2 is limited by its short duration of action and incomplete selectivity for immune-suppressive cells over off-target immune-stimulatory cells. We employ a platform that we have previously developed, which is a bacterial organism with an expanded DNA code, to identify a new version of IL-2, SAR444336 (SAR'336), with an extended duration of activity and increased selectivity for immune-suppressive cells. In mice and monkeys, SAR'336 was a specific activator of immune suppression, with minimal effect on immune cells that stimulate autoimmunity. Our results support further development of SAR'336 for treatment of autoimmune disorders.

The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.

Creating cell-specific computational models of stem cell-derived cardiomyocytes using optical experiments.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have gained traction as a powerful model in cardiac disease and therapeutics research, since iPSCs are self-renewing and can be derived from healthy and diseased patients without invasive surgery. However, current iPSC-CM differentiation methods produce cardiomyocytes with immature, fetal-like electrophysiological phenotypes, and the variety of maturation protocols in the literature results in phenotypic differences between labs. Heterogeneity of iPSC donor genetic backgrounds contributes to additional phenotypic variability. Several mathematical models of iPSC-CM electrophysiology have been developed to help understand the ionic underpinnings of, and to simulate, various cell responses, but these models individually do not capture the phenotypic variability observed in iPSC-CMs. Here, we tackle these limitations by developing a computational pipeline to calibrate cell preparation-specific iPSC-CM electrophysiological parameters. We used the genetic algorithm (GA), a heuristic parameter calibration method, to tune ion channel parameters in a mathematical model of iPSC-CM physiology. To systematically optimize an experimental protocol that generates sufficient data for parameter calibration, we created simulated datasets by applying various protocols to a population of in silico cells with known conductance variations, and we fitted to those datasets. We found that calibrating models to voltage and calcium transient data under 3 varied experimental conditions, including electrical pacing combined with ion channel blockade and changing buffer ion concentrations, improved model parameter estimates and model predictions of unseen channel block responses. This observation held regardless of whether the fitted data were normalized, suggesting that normalized fluorescence recordings, which are more accessible and higher throughput than patch clamp recordings, could sufficiently inform conductance parameters. Therefore, this computational pipeline can be applied to different iPSC-CM preparations to determine cell line-specific ion channel properties and understand the mechanisms behind variability in perturbation responses.

Blood flow restriction increases necessary muscle excitation of the elbow flexors during a single high-load contraction.

PURPOSE: To investigate the effects of blood flow restriction (BFR) on electromyographic amplitude (EMGRMS)-force relationships of the biceps brachii (BB) during a single high-load muscle action. METHODS: Twelve recreationally active males and eleven recreationally active females performed maximal voluntary contractions (MVCs), followed by an isometric trapezoidal muscle action of the elbow flexors at 70% MVC. Surface EMG was recorded from the BB during BFR and control (CON) visits. For BFR, cuff pressure was 60% of the pressure required to completely occlude blood at rest. Individual b (slope) and a terms (gain) were calculated from the log-transformed EMGRMS-force relationships during the linearly increasing and decreasing segments of the trapezoid. EMGRMS during the steady force segment was normalized to MVC EMGRMS. RESULTS: For BFR, the b terms were greater during the linearly increasing segment than the linearly decreasing segment (p < 0.001), and compared to the linearly increasing segment for CON (p < 0.001). The a terms for BFR were greater during the linearly decreasing than linearly increasing segment (p = 0.028). Steady force N-EMGRMS was greater for BFR than CON collapsed across sex (p = 0.041). CONCLUSION: BFR likely elicited additional recruitment of higher threshold motor units during the linearly increasing- and steady force-segment. The differences between activation and deactivation strategies were only observed with BFR, such as the b terms decreased and the a terms increased for the linearly decreasing segment in comparison to the increasing segment. However, EMGRMS-force relationships during the linearly increasing- and decreasing-segments were not different between sexes during BFR and CON.

Serum osmolality measured in fingertip capillary blood is comparable to serum osmolality measured in venous blood.

Blood osmolality is considered the gold standard hydration assessment, but has limited application for technical and invasive reasons. Paired antecubital-venous blood and fingertip-capillary blood were collected pre- and 30 min post-drinking 600 mL water in 55 male/female participants. No bias (0.2 mOsmo/kg, limits of agreement = -2.5 to 2.8 mOsmo/kg) was found between sampling methods, with high linear correlation (Spearman's r = 0.95, P < 0.001). Capillary blood sampling offers an accurate less-invasive method for determining serum osmolality than venous blood sampling.

Sex differences in muscle contraction-induced limb blood flow limitations.

PURPOSE: To determined sex differences in absolute- and %-reductions in blood flow during intermittent muscular contractions as well as relationships between blood flow reductions and time to task failure (TTF). METHODS: Thirteen males (25 ± 4 years) and 13 females (22 ± 5 years) completed intermittent isometric trapezoidal forearm flexion at 50% maximal voluntary contraction until task failure. Doppler ultrasound was used to measure brachial artery blood flow (BABF) during the 12-s plateau phase and 12-s relaxation phase. RESULTS: Target torque was less in females than males (24 ± 5 vs. 42 ± 7 Nm; p < 0.001); however, TTF was not different between sexes (F: 425 ± 187 vs. M: 401 ± 158 s; p = 0.72). Relaxation-phase BABF at end-exercise was less in females than males (435 ± 161 vs. 937 ± 281 mL/min; p < 0.001) but contraction-phase BABF was not different (127 ± 46 vs. 190 ± 99 mL/min; p = 0.42). Absolute- and %-reductions in BABF by contraction were less in females than males (309 ± 146 vs. 747 ± 210 mL/min and 69 ± 10 vs. 80% ± 6%, respectively; both p < 0.01) and were associated with target torque independent of sex (r = 0.78 and 0.56, respectively; both p < 0.01). Absolute BABF reduction per target torque (mL/min/Nm) and TTF were positively associated in males (r = 0.60; p = 0.031) but negatively associated in females (r = - 0.61; p = 0.029). CONCLUSIONS: This study provides evidence that females incur less proportional reduction in limb blood flow from muscular contraction than males at a matched relative intensity suggesting females may maintain higher levels of muscle oxygen delivery and metabolite removal than males across the contraction-relaxation cycle of intermittent exercise.

A Qualitative Study of Racial, Ethnic, and Cultural Experiences of Minority Clinicians During Agitation Care in the Emergency Department.

STUDY OBJECTIVE: Racial and ethnic bias in health care has been documented at structural, organizational, and clinical levels, impacting emergency care, including agitation management in the emergency department (ED). Little is known about the experiences of racial and ethnic minority ED clinicians caring for racial and ethnic minority groups, especially during their agitated state. The objective of this study was to explore the lived experiences of racial and ethnic minority ED clinicians who have treated patients with agitation in the ED. METHODS: We performed semistructured individual interviews of Black, Latino, and multiracial clinicians who worked at 1 of 3 EDs from an urban quaternary care medical center in the Northeast United States between August 2020 and June 2022. We performed thematic analysis through open coding of initial transcripts and identifying additional codes through sequential iterative rounds of group discussion. Once the codebook was finalized and applied to all transcripts, the team identified key themes and subthemes. RESULTS: Of the 27 participants interviewed, 14 (52%) identified as Black, 9 (33%) identified as Hispanic/Latino, and 4 (15%) identified as multiracial and/or other race and ethnicity. Three primary themes emerged from racial and ethnic minority clinician experiences of managing agitation: witness of perceived bias during clinical interactions with patients of color who bear racialized presumptions of agitation, moral injury and added workload to address perceived biased agitation management practices while facing discrimination in the workplace, and natural advocacy and allyship for agitated patients of color based on a shared identity and life experience. CONCLUSIONS: Our study found that through their shared minority status, racial and ethnic minority clinicians had a unique vantage point to observe perceived bias in the management of agitation in minority patients. Although they faced added challenges as racial and ethnic minority clinicians, their allyship offered potential mitigation strategies for addressing disparities in caring for an underserved and historically marginalized patient population.