Comparison of etonogestrel bioanalytical assay results in plasma and serum within and across laboratories.

OBJECTIVES: To compare performance characteristics of etonogestrel bioanalytical assays across laboratories. STUDY DESIGN: We conducted a blinded, six laboratory study: five academic laboratories and one contracted commercial laboratory (reference). Etonogestrel was quantitated at each laboratory in both prepared serum and/or plasma samples of six known etonogestrel concentrations, and in 60 clinical samples from participants using etonogestrel-containing contraceptive methods. Per regulatory guidance, laboratory accuracy (percent bias) and precision (coefficient of variation; CV) were defined as ±15% of the nominal prepared concentration. We compared inter- and intra-laboratory agreement using a Kendall's Tau-B and Passing-Bablok regression. RESULTS: For prepared samples, six laboratories analyzed serum and three laboratories analyzed plasma. All etonogestrel results were within ±15% for accuracy across all concentrations at four labs, including the reference laboratory. All labs demonstrated high precision, with only one occurrence of CV >15%. We found a positive association between prepared plasma and serum etonogestrel results (Kendall's Tau-B 0.80-0.88). For clinical samples, five laboratories analyzed serum and three laboratories analyzed plasma. Compared to the reference laboratory, inter-laboratory serum etonogestrel concentrations were positively correlated (Kendall's Tau-B 0.76-0.95). Proportional bias was observed, meaning individual lab etonogestrel results were consistently higher (slope estimates 0.78-0.95) or lower (slope estimates 1.05-1.10) than the reference laboratory. In clinical samples, intra-laboratory results were well associated between plasma and serum (Kendall's Tau-B 0.92-0.96). CONCLUSIONS: There was good intra-laboratory agreement, irrespective of sample matrix; however, there was inter-laboratory variability in etonogestrel results. Differences between laboratory results should be considered when comparing etonogestrel pharmacokinetics across studies. IMPLICATIONS: Etonogestrel concentrations were highly precise within each laboratory and were comparable between serum and plasma. Results varied between laboratories (5-28% higher to 5-9% lower compared to the Organon commercial laboratory). To minimize variability, we recommend utilizing a single laboratory that conducts routine proficiency testing for etonogestrel analysis within a study.

Reliability of Wearable Technology to Monitor Core Temperature Among Helicopter-Based EMS Crews.

BACKGROUND: Excessive heat stress led to more than 400 deaths in the United States from 2011 to 2021. Common methods for heat injury prevention revolve around measurements of the environment and fail to account for the unique individual response to stressors. METHODS: An observational approach was utilized with nine helicopter-based emergency medical services personnel during emergency flights to compare core temperature readings obtained from an ingestible temperature monitoring pill and the estimated core temperature reading of the Slate Safety Band V2 wearable device. Comparison of data was conducted within Microsoft Excel programming to determine the mean square error (MSE), root mean square error (RMSE), mean absolute error (MAE), mean biased error (MBE), and Bland-Altman plot development. FINDINGS: A significant bias (t = 17.58, p < .001) toward the Slate Safety device reading higher with an average difference of -0.48°C (-0.86°F) was found, meaning the average temperature reading is 0.48°C (-0.86°F) higher with the Slate Safety device. A significant correlation of .26 (p < .001) was noted between the ingestible pill and the wearable device with a 95% confidence interval of 0.23 to 0.29. Aggregate core temperature data demonstrated an MSE of 0.43, an RMSE of 0.65, an MAE of 0.54, and an MBE of -0.48. CONCLUSIONS/APPLICATION TO PRACTICE: The ability to monitor the physiological parameters of a worker remotely adds safety tools relative to the risks of heat stress. The slightly higher reading associated with the Slate Safety wearable device provides an added safety margin to protect our workers.

The Effect of Resisted Sprint Training on Acceleration: A Systematic Review and Meta-Analysis.

Resisted sprint (RS) training, such as sled or parachute towing, is commonly used for sprint training among field sport athletes. While RS training is frequently employed by athletes and coaches, there is little research on its benefits, especially compared to unresisted running (UR) training programs with similar training volumes. This systematic review and meta-analysis compared the effectiveness of RS training on acceleration compared to UR training. Potential sources were limited to peer-reviewed articles published in English prior to June 12, 2022, and gathered from the EBSCOhost, PubMed, and Web of Science online databases identified using combinations of the following terms: towing, sled, "resisted sprint," "sprint acceleration," "sprint performance," and "sprint speed." The search returned 1,159 sources, from which 15 were eligible for inclusion. Fifty effects were used to estimate the impact of RS training on initial sprint speed. Based on the cumulative results from these studies, RS training yielded a small improvement in acceleration but was not different from same volume of UR training (Hedges' d Effect Size=0.11, 95% CI: -0.01 to 0.23; p=0.08). These results do not support the use of RS training over UR training for improving initial sprint speed; however, further research should be conducted.

Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates.

Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving the life expectancy of people living with HIV; however, they also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the effect of preexisting metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4+ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.

In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19.

BACKGROUND: Bemnifosbuvir (AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of persons with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. OBJECTIVES: This Phase 1 study in healthy subjects aimed to assess the bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of bemnifosbuvir. METHODS: A total of 24 subjects were assigned to receive bemnifosbuvir twice daily at doses of 275, 550 or 825 mg for up to 3.5 days. RESULTS: AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550 mg twice daily. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4-5 h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. Bemnifosbuvir was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. CONCLUSIONS: The favourable pharmacokinetics and safety profile of bemnifosbuvir demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19.

The anti-HIV drug abacavir stimulates ß-catenin activity in osteoblast lineage cells.

Bone mineral density (BMD) loss in people living with HIV occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/ß-catenin in bone formation, we further investigated ARV effects on the Wnt/ß-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic ß-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) ß-catenin staining, and ß-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/ß-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/ß-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton.

Validity of Using the Load-Velocity Relationship to Estimate 1 Repetition Maximum in the Back Squat Exercise: A Systematic Review and Meta-Analysis.

ABSTRACT: LeMense, AT, Malone, GT, Kinderman, MA, Fedewa, MV, and Winchester, LJ. Validity of using the load-velocity relationship to estimate 1 repetition maximum in the back squat exercise: a systematic review and meta-analysis. J Strength Cond Res 38(3): 612-619, 2024-The one repetition maximum (1RM) test is commonly used to assess muscular strength. However, 1RM testing can be time consuming, physically taxing, and may be difficult to perform in athletics team settings with practice and competition schedules. Alternatively, 1RM can be estimated from bar or movement velocity at submaximal loads using the minimum velocity threshold (MVT) method based on the load-velocity relationship. Despite its potential utility, this method's validity has yielded inconsistent results. The purpose of this systematic review and meta-analysis was to assess the validity of estimated 1RM from bar velocity in the back squat exercise. A systematic search of 3 electronic databases was conducted using combinations of the following keywords: "velocity-based training," "load-velocity profiling," "mean velocity," "mean propulsive velocity," "peak velocity," "maximal strength," "1RM," "estimation," "prediction," "back squat," and "regression." The search identified 372 unique articles, with 4 studies included in the final analysis. Significance was defined as a p level less than 0.05. A total of 27 effects from 71 subjects between the ages of 17-25 years were analyzed; 85.2% of effects were obtained from male subjects. Measured 1RMs ranged from 86.5 to 153.1 kg, whereas estimated 1RMs ranged from 88.6 to 171.6 kg. Using a 3-level random effects model, 1RM back squat was overestimated when derived from bar velocity using the MVT method (effect sizes [ES] = 0.5304, 95% CI: 0.1878-0.8730, p = 0.0038). The MVT method is not a viable option for estimating 1RM in the free weight back squat. Strength and conditioning professionals should exercise caution when estimating 1RM from the load-velocity relationship.

Lower limb blood flow occlusion increases systemic pressor response without increasing brachial arterial blood flow redistribution in women.

This study was conducted to investigate the systemic hemodynamic and vascular changes in women during and after two commonly used clinical blood flow restriction (BFR) pressures at rest. There are minimal data regarding the independent effects of BFR on hemodynamic and systemic vascular changes due to pressor response, particularly among women. Therefore, this study investigated BFR-induced alterations in pressor response and systemic flow redistribution at rest during two commonly used pressures (50% and 80% limb occlusion pressure [LOP]). Fifteen women (22.1 ± 4.2 years) completed two randomised sessions involving 8-min of bilateral, lower limb restriction at 50% or 80% LOP followed by 8-min of recovery post-deflation. Changes in vascular (arterial diameter [DIA], time-averaged mean velocity [TAMV], volume flow [VF], and area) and hemodynamic (heart rate [HR] and blood pressure) measures over time (pre-, during, post-occlusion) and by session (50% vs. 80% LOP) were tested using repeated measures analysis of variance. Repeated measures correlations (rrm) quantified common intraindividual associations between BFR-induced hemodynamic and vascular responses. HR increased from baseline during 50% LOP and remained elevated during recovery (p < 0.05). HR increased from baseline during 80% LOP, while tibial VF and TAMV decreased (p < 0.03 for all). HR and TAMV values returned to baseline during recovery, while brachial artery VF decreased (p < 0.05). Changes in HR, brachial VF, and brachial TAMV were similar between 50% and 80% LOP (rrm = 0.32-0.70, p < 0.05 for all). At 80% LOP, changes in HR were positively correlated with brachial VF (rrm = 0.38) and TAMV (rrm = 0.43) and negatively correlated with tibial VF (rrm = -0.36) and TAMV (rrm = -0.30) (p < 0.05 for all). Results suggest that BFR at 80% LOP elicits an acute systemic pressor reflex without concomitant increases in brachial arterial flow, while 50% LOP elicits a subdued response.

Body composition estimates using a 2D image analysis system across different environmental conditions: An agreement study.

PURPOSE: This study examined the agreement between %Fat measurements using a smartphone-based application (IMAGE) across different environmental conditions. METHODS: A single reference image was obtained using an 8 MP smartphone camera under Ambient Light in front of a white background. Additional photos were obtained using a 0.7 MP, 5 MP, and 12 MP smartphone cameras; low-, moderate-, and bright-lighting conditions; and various color backgrounds including black, green, orange, and gray. RESULTS: %Fat measured using the 0.7 MP camera (27.8 ± 6.2 %Fat) was higher than the reference (26.8 ± 6.1 %Fat) (p < 0.001). The black (32.0 ± 12.0 %Fat), green (27.5 ± 6.3 %Fat), and gray (27.8 ± 6.3 %Fat) backgrounds yielded higher %Fat than the white (p = 0.03, 0.01, and 0.001). All camera, lighting, and background conditions were strongly correlated with the reference (all intraclass correlation coefficient [ICC] >0.98, all standard error of the estimate [SEE] <1.5 %Fat, all p < 0.001), except the black background which yielded poorer agreement with the white background (ICC = 0.69, SEE = 4.5%, p < 0.001). CONCLUSION: %Fat from IMAGE were strongly correlated across various environmental conditions.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV replication in M3+ Mauritian cynomolgus macaques initiated on ART two weeks post-infection.

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). None of the MCMs possessed MHC haplotypes previously associated with SIV control. For six months after ART withdrawal, we observed undetectable or transient viremia in seven of the eight MCMs, despite detecting replication competent SIV using quantitative viral outgrowth assays. In vivo depletion of CD8α+ cells induced rebound in all animals, indicating the observed PTC was mediated, at least in part, by CD8α+ cells. With intact proviral DNA assays, we found that MCMs had significantly smaller viral reservoirs two wpi than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. We found a similarly small viral reservoir among six additional SIV+ MCMs in which ART was initiated at eight wpi, some of whom exhibited viral rebound. These results suggest that an unusually small viral reservoir is a hallmark among SIV+ MCMs. By evaluating immunological differences between MCMs that did and did not rebound, we identified that PTC was associated with a reduced frequency of CD4+ and CD8+ lymphocyte subsets expressing exhaustion markers. Together, these results suggest a combination of small reservoirs and immune-mediated virus suppression contribute to PTC in MCMs. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.

Disparities in physical activity between sexual minority and heterosexual women: A systematic review and meta-analysis.

Research examining potential differences in physical activity (PA) between sexual minority women (SMW) and heterosexual women have yielded inconsistent results. OBJECTIVE: Therefore, the purpose of this systematic review and meta-analysis is to examine potential differences in PA between SMW and heterosexual women and to identify potential moderators that may partially explain observed differences in PA. METHODS: All studies were peer reviewed, published in English, and included a continuous measure of PA for SMW and heterosexual women. A standardized mean difference effect size (ES) was used to compare groups, with random effects models used to estimate a mean ES and 95% CI using a 3-level meta-analysis model to adjust for the correlation between effects nested within studies. RESULTS: The cumulative results of 24 effects gathered from 7 studies indicated there was no difference in PA between SMW (n = 1619) and heterosexual women (n = 103,295) (ES = -0.038, 95%CI -0.179 to 0.102, p = 0.576). Despite no mean differences, moderate-high heterogeneity was observed, indicating that the results were not consistent across effects (I2 = 64.8%, Q23 = 36.7, p = 0.035). The difference in PA was associated with age (ß = -0.018, 95%CI -0.034 to -0.003, p = 0.022) and BMI (ß = -0.145, 95%CI -0.228 to -0.061, p = 0.002), with a quadratic relationship observed for both variables. CONCLUSIONS: Although the results of the current analysis did not indicate significant differences in PA behaviors between SMW and heterosexual women, age and BMI modify the association and are curvilinear in nature; such that smaller differences in PA were observed between SMW and heterosexual women when samples were middle-aged and overweight.

Cardiovascular Responses During Light-intensity Aerobic Exercise with Varying Levels of Limb Occlusion Pressures.

The study aimed to assess cardiovascular responses to low-intensity aerobic exercise with varying levels of limb occlusion pressures (LOP) in a healthy population of men and women 30 to 60 years. The study was a single-session repeated measures design. Thirty individuals completed the study. All subjects participated in a single bout of low-intensity cycling (30-39% HRR) with bilateral lower extremity (LE) BFR for four 5-minute stages [0% (No BFR), 40%, 60%, and 80% LOP] with a 2-minute active rest between stages (BFR pressure released). The subjects' systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), oxygen saturation (SpO2), and ratings of perceived exertion (RPE) were measured at rest, peak, immediately post, post-15 minutes, and post-30 minutes. Peak SBP (no BFR 160.7 ±19.1 mmHg; 40% LOP 173.6 ± 18.7 mmHg; 60 % LOP; 182.5 ± 21.1 mmHg; 80% LOP 193.5± 23.3 mmHg ; p<0.001; ηP2=.747), DBP (no BFR 74.9 ± 8.5 mmHg; 40% LOP (83.0 ± 9.0 mmHg;60 % LOP 90.4 ± 8.7 mmHg; 80% LOP 97.7 ± 9.5 mmHg ;p<0.001; ηP2=.924), MAP (no BFR 103.5 ± 10.1 mmHg; 40% LOP 113.2 ± 10.5 mmHg; 60% LOP 121.1 ± 11.7 mmHg; 80% LOP 129.7 ± 12.9 mmHg; p<0.001; ηP2=.960), and RPE (No BFR 10.0 ± 2.0; 40 % LOP 11.5 ± 2.3; 60% LOP 13.2 ± 2.6; 80% LOP 14.5 ± 3.; p<0.001; ηP2=.826) were significantly higher with each progressing stage. The results indicate that low-intensity cycling with bilateral LE BFR for each LOP stage resulted in elevated SBP, DBP, MAP, and RPE despite maintaining a fixed HR.

Quantification of nine antiretroviral drugs in cerebrospinal fluid: An approach to overcome sample collection tube adsorption.

A highly sensitive LC-MS/MS methods were developed and validated to quantify nine antiretrovirals (atazanavir [ATV], tenofovir [TFV], emtricitabine [FTC], darunavir [DRV], dolutegravir [DTG], efavirenz [EFV], lamivudine [3TC], raltegravir [RAL], and ritonavir [RTV]) in human cerebral spinal fluid (CSF). The approach remedies adsorption issues caused by polypropylene based sample collection tubes. 1% ammonium hydroxide in methanol was added in an amount equal to the volume of each quality control (QC) or patient sample. Protein precipitation was utilized with a CSF sample volume of 100 µL and a 100 µL of methanol:ACN and vortexed. Chromatographic separation was achieved with a 3 × 100 ACE® C18 column for ATV, DRV, DTG, EFV, RTV and RAL, and a 2 × 100 Polar RP column for TFV/FTC/3TC. Mobile phase was methanol:water:formic acid (70:30:0.1, v/v/v) for ATV, DRV, DTG, EFV and RTV (10 uL injection, flow rate: 1.00 mL/min), ACN:water:formic acid (35:65:0.1, v/v/v) for RAL (50 uL injection, flow rate: 1.00 mL/min), ACN:water:formic acid (2:98:0.1, v/v/v) for TFV, FTC and 3TC (50 uL injection, flow rate: 0.35 mL/min). Column temperature was 40° C across all assays. The mass spectrometer was operated in positive, multiple-reaction-monitoring (MRM) mode with electrospray ionization (ESI) for all analytes with the exception of EFV, which was operated in negative, MRM mode with ESI. The assay was linear over the calibration range of 1 to 250 ng/mL for all analytes. The addition of 1% ammonium hydroxide in sample tubes overcame up to 44% negative bias in QC samples and allowed the methods to meet full validation criteria.

Agreement between ultrasound protocols for the estimation of body fat percentage: Comparison to a four-compartment model.

The purpose of this study was to examine the agreement between body fat percentage (%Fat) estimates derived from a standardized ultrasound protocol (%FatIASMS ), a commonly used skinfold (SKF)-site-based ultrasound protocol (%FatJP ), and a criterion four-compartment (4C) model (%Fat4C ). For the ultrasound protocols, all measurement sites were marked, measured and analyzed by the same evaluator. Subcutaneous adipose tissue (SAT) thickness was measured manually at the region where the muscle fascia was parallel to the skin and the average value per measurement site was used to calculate body density and subsequently %Fat. A repeated-measures analysis of variance with a priori planned contrasts was used to compare %Fat values between the 4C criterion and both ultrasound methods. Small nonsignificant mean differences were observed between %FatIASMS (18.82 ± 14.21%Fat, effect size [ES] = 0.25, p = 0.178), %FatJP (18.23 ± 13.32%Fat, ES = 0.32, p = 0.050) and the %Fat4C criterion (21.70 ± 7.57%Fat); however, %FatIASMS did not yield a smaller mean difference than the %FatJP (p = 0.287). Additionally, %FatIASMS (r = 0.90, p < 0.001, standard error of the estimate [SEE] = 3.29%) and %FatJP (r = 0.88, p < 0.001, SEE = 3.60%) were strongly correlated with the 4C criterion, however, %FatIASMS did not yield better agreement than %FatJP (p = 0.257). Despite slightly underestimating %Fat, both ultrasound techniques demonstrated Good-Very Good agreement with the 4C criterion, with comparable mean differences, correlations, and SEE. The International Association of Sciences in Medicine and Sports (IASMS) standardized protocol using manual calculations of SAT was comparable to the SKF-site-based ultrasound protocol when compared to the 4C criterion. These results indicate that the IASMS (with manually measured SAT) and SKF-site-based ultrasound protocols may be of practical use to clinicians.

Acute Blood Flow Responses to Varying Blood Flow Restriction Pressures in the Lower Limb.

The purpose of this study was to investigate lower limb blood flow responses under varying blood flow restriction (BFR) pressures based on individualized limb occlusion pressures (LOP) using a commonly used occlusion device. Twenty-nine participants (65.5% female, 23.8 ± 4.7 years) volunteered for this study. An 11.5cm tourniquet was placed around participants' right proximal thigh, followed by an automated LOP measurement (207.1 ± 29.4mmHg). Doppler ultrasound was used to assess posterior tibial artery blood flow at rest, followed by 10% increments of LOP (10-90% LOP) in a randomized order. All data were collected during a single 90-minute laboratory visit. Friedman's and one-way repeated-measures ANOVAs were used to examine potential differences in vessel diameter, volumetric blood flow (VolFlow), and reduction in VolFlow relative to rest (%Rel) between relative pressures. No differences in vessel diameter were observed between rest and all relative pressures (all p < .05). Significant reductions from rest in VolFlow and %Rel were first observed at 50% LOP and 40% LOP, respectively. VolFlow at 80% LOP, a commonly used occlusion pressure in the legs, was not significantly different from 60% (p = .88), 70% (p = .20), or 90% (p = 1.00) LOP. Findings indicate a minimal threshold pressure of 50%LOP may be required to elicit a significant decrease in arterial blood flow at rest when utilizing the 11.5cm Delfi PTSII tourniquet system.

An Efficient Humanized Mouse Model for Oral Anti-Retroviral Administration.

HIV anti-retrovirals (ARVs) have vastly improved the life expectancy of people living with HIV (PLWH). However, toxic effects attributed to long-term ARV use also contribute to HIV-related co-morbidities such as heart disease, bone loss and HIV-associated neurocognitive disorders (HAND). Unfortunately, mouse models used to study the effects of ARVs on viral suppression, toxicity and HIV latency/tissue reservoirs have not been widely established. Here, we demonstrate an effective mouse model utilizing immune-compromised mice, reconstituted with infected human peripheral blood mononuclear cell (PBMCs). ARVs areincorporated into mouse chow and administered daily with combination ARV regimens includingAtripla (efavirenz, tenofovir disoproxil fumarate, and emtricitabine) and Triumeq (abacavir, dolutegravir and lamivudine). This model measures HIV-infected human cell trafficking, and ARV penetration throughout most relevant HIV organs and plasma, with a large amount of trafficking to the secondary lymphoid organs. Furthermore, the HIV viral load within each organ and the plasma was reduced in ARV treated vs. untreated control. Overall, we have demonstrated a mouse model that is relatively easy and affordable to establish and utilize to study ARVs' effect on various tissues, including the co-morbid conditions associated with PLWH, such as HAND, and other toxic effects.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV in Mauritian cynomolgus macaques.

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). For six months after ART withdrawal, we observed undetectable or transient viremia in seven of eight MCMs. In vivo depletion of CD8α+ cells induced rebound in all animals, indicating the PTC was mediated, at least in part, by CD8α+ cells. We found that MCMs had smaller acute viral reservoirs than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. The mechanisms by which unusually small viral reservoirs and CD8α+ cell-mediated virus suppression enable PTC can be investigated using this MHC-haplomatched MCM model. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.

Acute Responses to High-Intensity Back Squats with Bilateral Blood Flow Restriction.

This study examined the acute effects of high-intensity resistance exercise with blood flow restriction (BFR) on performance and fatigue, metabolic stress, and markers of inflammation (interleukin-6 (IL-6)), muscle damage (myoglobin), angiogenesis (vascular endothelial growth factor (VEGF)). Thirteen resistance-trained participants (four female, 24.8 ± 4.7 years) performed four sets of barbell back-squats (75% 1RM) to failure under two conditions: blood flow restriction (BFR, bilateral 80% occlusion pressure) and control (CTRL). Completed repetitions and pre-post-exercise changes in maximal voluntary isometric contractions, countermovement jump, barbell mean propulsive velocity, and surface electromyography were recorded. Pre-post blood lactate (BLa) and venous blood samples for analysis of IL-6, myoglobin, and VEGF were collected. Ratings of perceived exertion (RPE) and pain were recorded for each set. Fewer repetitions were performed during BFR (25.5 ± 9.6 reps) compared to CTRL (43.4 ± 14.2 reps, p < 0.001), with greater repetitions performed during sets 1, 2, and 4 (p < 0.05) in CTRL. Although RPE between conditions was similar across all sets (p > 0.05), pain was greater in BFR across all sets (p < 0.05). Post-exercise fatigue was comparable between conditions. BLa was significantly greater in CTRL compared to BFR at two minutes (p = 0.001) but not four minutes post-exercise (p = 0.063). IL-6 was significantly elevated following BFR (p = 0.011). Comparable increases in myoglobin (p > 0.05) and no changes in VEGF were observed (p > 0.05). BFR increases the rate of muscular fatigue during high-intensity resistance exercise and acutely enhances IL-6 response, with significantly less total work performed, but increases pain perception, limiting implementation.

Effect of double-dose levonorgestrel subdermal implant in women taking efavirenz-based antiretroviral therapy: The DoubLNG pharmacokinetic study.

OBJECTIVE: We evaluated the pharmacokinetics of double-dose levonorgestrel (LNG) implants to overcome the drug-drug interaction with efavirenz-based antiretroviral therapy (ART). STUDY DESIGN: We conducted a nonrandomized, open-label, parallel-group, longitudinal pharmacokinetic study among Ugandan women ages 18-45 years. Participants with HIV on ART containing efavirenz 600 mg received 300 mg of LNG implants (Jadelle®, Bayer, New Zealand): 300LNG+ART group. We compared our outcomes with women without HIV using standard dose, 150 mg of LNG implants: 150LNG group. The implant was placed on day zero in both groups, and we quantified plasma LNG concentrations over 48 weeks post implant insertion. LNG pharmacokinetic parameters were estimated using noncompartmental techniques. Our primary outcome was the geometric mean ratio with 90% confidence intervals of LNG area under the concentration-time curve over 24 weeks (AUC0-24w) between groups. Demographic data were described as median (interquartile range). A secondary outcome compared between-group percent of LNG concentrations ≥300 pg/mL, a minimum threshold selected a priori based on observed pregnancies in Ugandan women on standard-dose LNG implants plus efavirenz. RESULTS: We enrolled 27 women in the 300LNG+ART group (34 [28.0 to 40.5] years and 61.0 [49.8-66.0] kg) and 19 women in the 150LNG group (33 [30.0 to 34.5] years and 64.9 [59.0 to 74.5] kg). LNG AUC0-24w was 34% lower for 300LNG+ART versus 150LNG (geometric mean 9998 vs. 15,231 pg*week/mL, respectively [geometric mean ratio 0.66 (90% confidence intervals, 0.54 to 0.80)]). The percentage of participants with LNG concentrations ≥300 pg/mL was not statistically different between groups at week 24 (300LNG+ART: 74.1%; 150LNG: 89.5%; p = 0.27). CONCLUSION: Double-dose LNG implant did not completely overcome the drug-drug interaction with efavirenz. IMPLICATION: In women using ART containing efavirenz, placing two implant systems (300 mg) did not normalize LNG pharmacokinetics compared with the standard-dose implant (150 mg), and some women had evidence of ovulatory activity. Alternative ART without drug-drug interactions, such as dolutegravir, is recommended with contraceptive implants.