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Abstract Objective To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations. Methods Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models. Results The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001‐0.01] and DBP: β = 0.01 [95% CI, 0.003‐0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes. Conclusion Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life.

Abstract INTRODUCTION Premenopausal bilateral oophorectomy (PBO) before the age of 46 years is associated with an increased risk of dementia. We investigated the long‐term effects of PBO performed before age 50 years on amyloid beta (Aβ), tau, and neurodegeneration imaging biomarkers of Alzheimer's disease (AD). METHODS Mayo Clinic Cohort Study of Oophorectomy and Aging‐2 participants were divided into early PBO (< 46 years; n = 61), and late PBO (46–49 years; n = 51) groups and were compared to referent women who did not undergo PBO ( n = 119). RESULTS Early PBO was associated with thinner entorhinal cortex ( p = 0.014), higher tau load at higher levels of Aβ load ( Pp = 0.005), higher Aβ load ( p = 0.026), and smaller temporal lobe cortical thickness ( p = 0.022), only at older ages compared to the referent group. DISCUSSION PBO before the age of 46 years is associated with entorhinal cortex thinning, elevated tau at higher Aβ levels, along with an AD‐like pattern of atrophy at older ages. CLINICAL TRIALS REGISTRATION NCT03821857 sex‐specific effects of endocrine disruption on aging and AD. Highlights Premenopausal bilateral oophorectomy (PBO) before the ages of 46 (early PBO) years and ages 46 to 49 (late PBO) years was studied. Early PBO was associated with reduced entorhinal cortex thickness later in life. Early PBO was associated with greater amyloid beta (Aβ) load at older ages. Early PBO was associated with greater Alzheimer's disease pattern of atrophy at older ages. Early PBO was associated with higher tau load at higher Aβ levels.

External (EL) and internal (IL) load are commonly used methods used to quantify training load in team sports. Playing time and playing position may influence the training loads for specific athletes throughout a season. The purpose of the current study was to evaluate the effect of athlete playing status and individual in-season practices on EL and IL across a collegiate women’s basketball season. Female basketball athletes were classified as high-minute (HMA; ≥15 min/game) or low-minute (LMA; <15 min/game) and wore microsensors during 53 practices for a total of 583 data points. EL was obtained via an inertial measurement unit (IMU) device that contained a triaxial accelerometer to obtain three-dimensional positioning data. IL and strength training (ST) load were determined via session rating of perceived exertion (sRPE) to create a daily summated value. Descriptive statistics indicate that athletes experienced individual differences in EL, ST, and IL throughout the season. A growth model showed that HMAs experienced higher EL than LMAs at the start of the season for practices (90.21 AU). Across all athletes, IL increased across the season (40.11 AU) and for each 1 unit of change in EL, IL increased by 1.04 AU. Repeated measures correlations identified a large relationship between IL and EL (r = 0.51, p < 0.001). A location-scale model indicated that the within-person variability of IL across all athletes was 3.29 AU but was not due to athlete playing status. It is recommended to base in-season training on individual loads and game demands to promote athlete readiness and improved sport performance.

Severe COVID-19 is a multisystem condition with thromboinflammation as a significant driver of morbidity and mortality. Cellular components involved in inflammatory and coagulation responses include platelets, endothelium, monocytes, and neutrophils. Thrombotic manifestations, such as arterial thrombosis, venous thromboembolism, and tissue microthrombosis, occur in at least 20% of ICU COVID-19 patients, possibly more based on postmortem studies. This study investigates the presence of prothrombotic antibodies similar to those found in heparin-induced thrombocytopenia (HIT), a condition caused by platelet-activating antibodies targeting platelet factor 4 (PF4) when complexed with heparin (PF4/H). In a study of samples from 130 hospitalized patients collected on average 3.6 days after COVID-19 diagnosis, 80% were found to have IgG antibodies recognizing PF4/H. This percentage is significantly lower than in 22 HIT patients (100%) but higher than in 51 non-COVID-19 patients with acute respiratory symptoms (ARS) (25%) and 12 healthy subjects (0%). Additionally, 41% of the 130 patients had antibodies inducing PF4-dependent P-selectin expression in CpG-treated normal platelets, a rate significantly lower than in 12 HIT patients (100%) but higher than in 51 non-COVID-19 ARS patients (20%) and 12 healthy subjects (0%). Significantly, platelet-activating antibodies in COVID-19 patients were associated with a specific elevation of platelet α-granule proteins in the plasma and correlated with inflammation and tissue damage markers, suggesting these antibodies' functionality in patients. Significantly, unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in COVID-19 patients regardless of recent heparin exposure, indicating different antigenic stimuli for these antibodies in COVID-19. Notably, certain antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 possessed sequence motifs, RKH and Y5, in the heavy-chain complementarity-determining region 3 (HCDR3) resembling those in pathogenic HIT antibodies identified in our previous studies, suggesting that these antibodies can activate platelets. Introducing exogenous RBD to COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. Furthermore, immunodepleting RBD-reactive antibodies from COVID-19 plasma or IgG purified from COVID-19 plasma using RBD-coated beads significantly reduced their ability to activate platelets. These findings demonstrate that some RBD-specific plasma IgG antibodies can activate platelets. To demonstrate the presence of RBD-specific, platelet-activating antibodies at the clonal level, we produced recombinant antibodies from 42 RBD-binding IgG+ B cells, tested their ability to activate platelets, and identified four that could do so. Interestingly, three antibodies possess HCDR3 sequences resembling RKH or Y5 motifs. Additionally, we identified RKH or Y5 motifs in RBD-specific antibodies reported by other groups, produced 15 such antibodies recombinantly, tested their ability to activate platelets, and identified four more that could do so. IgG+ B cells with these HCDR3 motifs were markedly expanded in severe COVID-19 patients, suggesting an expansion of B cells producing platelet-activating antibodies. The demonstration of functional and structural similarities between certain RBD-specific antibodies in COVID-19 patients and pathogenic HIT antibodies suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

Blood flow restriction (BFR) is a popular resistance exercise technique purported to increase metabolic stress and augment training adaptations over time. However, short-term use may lead to acute neuromuscular fatigue and higher exertion ratings. Objective: The purpose of the current study was to examine acute physiological responses to low-load resistance exercise utilizing BFR compared to higher-load, non-BFR resistance exercise. Methods: Recreationally trained males (n = 6) and females (n = 7) (mean ± standard deviation, age: 20 ± 1 yrs.; height: 172 ± 8 cm; weight: 73 ± 11 kg; BMI: 24.4 ± 2.2 kg·m−2; training experience: 4 ± 2 yrs.) had limb occlusion pressure determined (50%; right leg: 118 ± 11 mmHg; left leg: 121 ± 13 mmHg) using an automated, self-inflating cuff system during baseline testing. In subsequent sessions, using a randomized, cross-over design, participants completed one of two experimental conditions: (1) Low-load + BFR and (2) High load + non-BFR. In both conditions, participants completed one set of back squats at either 30% (BFR) or 60% (non-BFR) of an estimated 1RM for a max of 30 repetitions, followed by three additional sets with the same loads and a target of 15 repetitions per set. Blood lactate and countermovement jump (CMJ) height were measured pre- and post-back squat. Ratings of perceived exertion (RPE) were assessed following each set. Results: When collapsed across all sets, participants completed significantly more total repetitions in the BFR condition compared to non-BFR (75.0 ± 0.0 vs. 68.23 ± 9.27 reps; p = 0.015; ES: 1.03), but a lower training load volume (2380 ± 728 vs. 4756 ± 1538 kg; p < 0.001; ES: 1.97). There was a significant time-by-condition interaction (p < 0.001), with a greater increase in blood lactate occurring from baseline to post-back squat in the non-BFR condition (11.61 mmol/L, 95%CI: 9.93, 13.28 mmol/L) compared to BFR (5.98 mmol/L, 95%CI: 4.30, 7.65 mmol/L). There was another significant time-by-condition interaction (p = 0.043), with a greater reduction in CMJ occurring in the non-BFR condition (−6.01, 95%CI: −9.14, −2.88 cm; p < 0.001) compared to BFR (−1.50, 95%CI: −1.50, 4.51 cm; p = 0.312). Conclusions: Utilizing a low-load BFR protocol may allow for a higher training volume, yet lower metabolic stress and reduce neuromuscular fatigue compared to lifting at a higher load without the use of BFR.

Abstract Extracellular vesicles (EVs) are small membrane‐bound structures that originate from various cell types and carry molecular cargos to influence the behaviour of recipient cells. The use of EVs as biomarkers for diagnosis and as delivery vehicles for treatment in a wide range of human disease is a rapidly growing field in research and clinical practice. We hypothesized that electric fields (EFs) could influence the release and content of EVs. To examine this hypothesis, we developed a specialized bioreactor enabling cells to thrive in a three‐dimensional setting, replicating in‐vivo conditions amidst programmable EF environments. We established a three‐step EV purification protocol to achieve high‐density production of EVs. We also performed mass spectrometry‐based proteomics analysis on EV‐carrying proteins and used high‐resolution nanoparticle flowcytometry for single‐vesicle analysis. Findings from this report suggest that electrical stimulation, employing physiologically relevant amplitudes typical in therapeutic deep brain stimulation, influences the release of EVs and their cargo content in a frequency‐dependent fashion. This conclusion could carry significant implications for both fundamental biological understanding and medical advancements. First, it raises an intriguing question about how the endogenous electrical activity of neuronal and other cellular assemblies influence the production and composition of EVs. Second, it reveals a novel underlying mechanism of how therapeutic electrical stimulations can modulate EVs and treat human brain disorders. Third, it provides a novel approach to utilize electrical stimulation for generating desired EV cargos in a programmable setting.

Abstract Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG oligodeoxynucleotide–treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

The purpose of the study was to examine differences in body fat percentage (BF%) across groups stratified by resting metabolic rate (RMR) when normalized to body weight. National Collegiate Athletic Association Division III athletes (n = 190; Age: 19.8 ± 1.4 year; Body Mass: 79.3 ± 20.2 kg; Height: 175.0 ± 9.3 cm, Body Mass Index: 25.6 ± 4.9 kg/m2) participated in this cross-sectional mixed cohort study. Body composition was assessed using air displacement plethysmography. RMR was assessed using indirect calorimetry. For each sex, tertiles were determined and used to create low, moderate, and high relative RMR groups as follows: low (M: <26 kcal/kg; F: <24 kcal/kg), moderate (M: 26.1–29.0 kcal/kg; F: 24.1–27.0 kcal/kg), and high (M: >29.1 kcal/kg; F: >27.1 kcal/kg). The mean ± standard deviation RMR for male and female athletes was 27.9 ± 3.2 and 25.9 ± 2.8 kcals/kg when expressed relative to body weight. When stratified by sex, males in the low RMR group had significantly higher BF% values than those in the moderate (mean difference, [95% confidence intervals]) (7.2, [2.4, 12.0] kcal/kg; p < 0.01) and high RMR groups (7.7, [2.9, 12.5] kcal/kg; p < 0.001). Female athletes in the moderate RMR group had higher body fat percentages than those in the high RMR group (mean difference, [95% confidence intervals]) (5.8, [2.4, 9.2] kcal/kg; p < 0.01). Female athletes in the moderate relative RMR group had higher BF% values than those in the higher relative RMR group (3.3, [−0.1, 6.7] kcal/kg; p = 0.049). Both male and female athletes with a low relative RMR had a higher BF%.

ABSTRACT Women experience a higher rate of anterior cruciate ligament (ACL) injuries than men. Muscle imbalance, in particular hamstring-to-quadriceps (H:Q) strength ratio, is considered a risk factor for ACL injury. The purpose of this systematic review was to identify isokinetic H:Q strength ratios in women team sport athletes and determine whether cutoff values, determined from research with predominantly males, of >0.6 for conventional ratio (Hamstring concentric :Quadriceps concentric [CR]) and >1.0 for functional ratio (Hamstring eccentric :Quadriceps concentric [FR]) were met. The CR (0.6) was not met for team ([mean ± SD: 0.56 ± 0.08]), field (0.57 ± 0.08), and court (0.56 ± 0.08) sports. Handball presented the highest (0.58 ± 0.07), and softball presented the lowest CRs (0.47 ± 0.06). The FR (1.0) was not met for team (0.69 ± 0.14), field (0.85 ± 0.14), and court (0.65 ± 0.14) sports. Soccer presented the highest (0.85 ± 0.14) and handball the lowest (0.66 ± 0.13) FRs. When assessing hamstring and quadriceps strength balance, women team sport athletes did not meet CR or FR values, which may contribute to increased ACL injury risk. H:Q ratios below cutoff values may indicate compromised hamstring strength. It is recommended practitioners implement strength exercises aimed to improve H:Q ratios.