Neuromechanical Differences between Pronated and Supinated Forearm Positions during Upper-Body Wingate Tests.

Arm-cycling is a versatile exercise modality with applications in both athletic enhancement and rehabilitation, yet the influence of forearm orientation remains understudied. Thus, this study aimed to investigate the impact of forearm position on upper-body arm-cycling Wingate tests. Fourteen adult males (27.3 ± 5.8 years) underwent bilateral assessments of handgrip strength in standing and seated positions, followed by pronated and supinated forward arm-cycling Wingate tests. Electromyography (EMG) was recorded from five upper-extremity muscles, including anterior deltoid, triceps brachii lateral head, biceps brachii, latissimus dorsi, and brachioradialis. Simultaneously, bilateral normal and propulsion forces were measured at the pedal-crank interface. Rate of perceived exertion (RPE), power output, and fatigue index were recorded post-test. The results showed that a pronated forearm position provided significantly (p < 0.05) higher normal and propulsion forces and triceps brachii muscle activation patterns during arm-cycling. No significant difference in RPE was observed between forearm positions (p = 0.17). A positive correlation was found between seated handgrip strength and peak power output during the Wingate test while pronated (dominant: p = 0.01, r = 0.55; non-dominant: p = 0.03, r = 0.49) and supinated (dominant: p = 0.03, r = 0.51; don-dominant: p = 0.04, r = 0.47). Fatigue changed the force and EMG profile during the Wingate test. In conclusion, this study enhances our understanding of forearm position's impact on upper-body Wingate tests. These findings have implications for optimizing training and performance strategies in individuals using arm-cycling for athletic enhancement and rehabilitation.

The Duration of Non-Local Muscle Fatigue Effects.

Non-local muscle fatigue (NLMF) refers to a transient decline in the functioning of a non-exercised muscle following the fatigue of a different muscle group. Most studies examining NLMF conducted post-tests immediately after the fatiguing protocols, leaving the duration of these effects uncertain. The aim of this study was to investigate the duration of NLMF (1-, 3-, and 5-minutes). In this randomized crossover study, 17 recreationally trained participants (four females) were tested for the acute effects of unilateral knee extensor (KE) muscle fatigue on the contralateral homologous muscle strength, and activation. Each of the four sessions included testing at either 1-, 3-, or 5-minutes post-test, as well as a control condition for non-dominant KE peak force, instantaneous strength (force produced within the first 100-ms), and vastus lateralis and biceps femoris electromyography (EMG). The dominant KE fatigue intervention protocol involved two sets of 100-seconds maximal voluntary isometric contractions (MVIC) separated by 1-minute of rest. Non-dominant KE MVIC forces showed moderate and small magnitude reductions at 1-min (p < 0.0001, d = 0.72) and 3-min (p = 0.005, d = 0.30) post-test respectively. The KE MVIC instantaneous strength revealed large magnitude, significant reductions between 1-min (p = 0.021, d = 1.33), and 3-min (p = 0.041, d = 1.13) compared with the control. In addition, EMG data revealed large magnitude increases with the 1-minute versus control condition (p = 0.03, d = 1.10). In summary, impairments of the non-exercised leg were apparent up to 3-minutes post-exercise with no significant deficits at 5-minutes. Recovery duration plays a crucial role in the manifestation of NLMF.

Inclusion of a skeletal model partly improves the reliability of lower limb joint angles derived from a markerless depth camera.

A single depth camera provides a fast and easy approach to performing biomechanical assessments in a clinical setting; however, there are currently no established methods to reliably determine joint angles from these devices. The primary aim of this study was to compare joint angles as well as the between-day reliability of direct kinematics to model-constrained inverse kinematics recorded using a single markerless depth camera during a range of clinical and athletic movement assessments.A secondary aim was to determine the minimum number of trials required to maximize reliability. Eighteen healthy participants attended two testing sessions one week apart. Tasks included treadmill walking, treadmill running, single-leg squats, single-leg countermovement jumps, bilateral countermovement jumps, and drop vertical jumps. Keypoint data were processed using direct kinematics as well as in OpenSim using a full-body musculoskeletal model and inverse kinematics. Kinematic methods were compared using statistical parametric mapping and between-day reliability was calculated using intraclass correlation coefficients, mean absolute error, and minimal detectable change. Keypoint-derived inverse kinematics resulted in significantly smaller hip flexion (range = -9 to -2°), hip abduction (range = -3 to -2°), knee flexion (range = -5° to -2°), and greater dorsiflexion angles (range = 6-15°) than direct kinematics. Both markerless kinematic methods had high between-day reliability (inverse kinematics ICC 95 %CI = 0.83-0.90; direct kinematics ICC 95 %CI = 0.80-0.93). For certain tasks and joints, keypoint-derived inverse kinematics resulted in greater reliability (up to 0.47 ICC) and smaller minimal detectable changes (up to 13°) than direct kinematics. Performing 2-4 trials was sufficient to maximize reliability for most tasks. A single markerless depth camera can reliably measure lower limb joint angles, and skeletal model-constrained inverse kinematics improves lower limb joint angle reliability for certain tasks and joints.

Evaluation of the EMA Log Kow Trigger for Fish BCF Testing Based on Data for Several Human Pharmaceuticals.

In the European Medicines Agency (EMA) "Guideline for Environmental Risk Assessment of Medicinal Products for Human Use," a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow > 4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation ('B') potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3Rs principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

Emergency Medical Planning for an Ultramarathon Open Water Swim: A Case Review of "Swim Tuff".

ABSTRACT: Ultramarathon open water swimming (OWS) events are one of the toughest endurance challenges in the world. The sport has gained notoriety with athletes swimming across the English Channel, Diana Nyad swimming from Cuba to Florida, and the 5- and 10-km OWS in the Olympic schedule. The athletes who participate are exposed to dangerous conditions that expose risks inherent to the sport. The optimal time to prepare for an emergency is before it happens. The aim of this paper is to present an emergency action plan (EAP) designed for the "Swim Tuff" event, a record-breaking ultramarathon swim that took place in Rhode Island, United States. This article identifies an overview of Swim Tuff, the challenges experienced, and how the team designed and implemented risk mitigation strategies. The professionals looking over athletes completing an OWS should be educated and aware of the unique circumstances inherent to the sport.

Impact of maternal posture on fetal physiology in human pregnancy: a narrative review.

In numerous medical conditions, including pregnancy, gravity and posture interact to impact physiology and pathophysiology. Recent investigations, for example, pertaining to maternal sleeping posture during the third trimester and possible impact on fetal growth and stillbirth risk highlight the importance and potential clinical implications of the subject. In this review, we provide an extensive discussion of the impact of maternal posture on fetal physiology from conception to the postpartum period in human pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 242 studies from 1991 through 2021, inclusive, that met our inclusion criteria. Herein, we provide a synthesis of the resulting literature. In the first section of the review, we group the results by the impact of maternal posture at rest on the cervix, uterus, placenta, umbilical cord, amniotic fluid, and fetus. In the second section of the review, we address the impact on fetal-related outcomes of maternal posture during various maternal activities (e.g., sleep, work, exercise), medical procedures (e.g., fertility, imaging, surgery), and labor and birth. We present the published literature, highlight gaps and discrepancies, and suggest future research opportunities and clinical practice changes. In sum, we anticipate that this review will shed light on the impact of maternal posture on fetal physiology in a manner that lends utility to researchers and clinicians who are working to improve maternal, fetal, and child health.

Time series of freshwater macroinvertebrate abundances and site characteristics of European streams and rivers.

Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Genetic influence on vascular smooth muscle cell apoptosis.

Vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis play important roles in many physiological processes and pathological conditions. To identify genetic influences on VSMC behavior, we measured these traits and undertook genome-wide association studies in primary umbilical artery-derived VSMCs from >2000 individuals. Although there were no genome-wide significant associations for VSMC proliferation or migration, genetic variants at two genomic loci (7p15.3 and 7q32.3) showed highly significant associations with VSMC apoptosis (P = 1.95 × 10-13 and P = 7.47 × 10-9, respectively). The lead variant at the 7p51.3 locus was associated with increased expression of the GSDME and PALS2 genes in VSMCs. Knockdown of GSDME or PALS2 in VSMCs attenuated apoptotic cell death. A protein co-immunoprecipitation assay indicated that GSDME complexed with PALS2. PALS2 knockdown attenuated activated caspase-3 and GSDME fragmentation, whilst GSDME knockdown also reduced activated caspase-3. These findings provide new insights into the genetic regulation of VSMC apoptosis, with potential utility for therapeutic development.

RNA adapts its flexibility to efficiently fold and resist unfolding.

Recent studies have demonstrated that the mechanisms through which biopolymers like RNA interconvert between multiple folded structures are critical for their cellular functions. A major obstacle to elucidating these mechanisms is the lack of experimental approaches that can resolve these interconversions between functionally relevant biomolecular structures. Here, using a nano-electronic device with microsecond time resolution, we dissect the complete set of structural rearrangements executed by an ultra-stable RNA, the UUCG stem-loop, at the single-molecule level. We show that the stem-loop samples at least four conformations along two folding pathways leading to two distinct folded structures, only one of which has been previously observed. By modulating its flexibility, the stem-loop can adaptively select between these pathways, enabling it to both fold rapidly and resist unfolding. This paradigm of stabilization through compensatory changes in flexibility broadens our understanding of stable RNA structures and is expected to serve as a general strategy employed by all biopolymers.

qPCR assay for detection of Woodchuck Hepatitis Virus Post-Transcriptional Regulatory Elements from CAR-T and TCR-T cells in fresh and formalin-fixed tissue.

As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells-such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells-in patients' tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product. Herein, we developed a WPRE-targeted qPCR assay that is broadly applicable for detection of engineered cell products in both fresh and archival formalin-fixed paraffin embedded (FFPE) tissues. Using both traditional PCR and SYBR Green PCR protocols, we demonstrate the use of this WPRE-targeted assay to successfully detect two CAR-T cell and two TCR-T cell products in FFPE tissue. Standard curve analysis reported a reproducible limit of detection at 100 WPRE copies per 20µL PCR reaction. This novel and inexpensive technique could provide better understanding of tissue abundance of engineered therapeutic T cells in both tumor and second-site toxicity tissues and provide quantitative assessment of immune effector cell trafficking in archival tissue.

A novel echocardiographic parameter considering left ventricular afterload during V-A ECMO support.

BACKGROUND: Left ventricular stroke work index (LVSWI) and cardiac power index (CPI) account for the haemodynamic load of the left ventricle and are promising prognostic values in cardiogenic shock. However, accurately and non-invasively measuring these parameters during veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is challenging and potentially biased by the extracorporeal circulation. This study aimed to investigate, in an ovine model of cardiogenic shock, whether Pressure-Strain Product (PSP), a novel speckle-tracking echocardiography parameter, (1) can correlate with pressure-volume catheter-based LVSWI and CPI, and (2) can be load-independent during the flow modification of V-A ECMO. METHODS: Nine Dorset-cross ewes (51 ± 4 kg) were included. After cardiogenic shock was induced, full support V-A ECMO (X L/min based on 60 mL/kg/min) commenced. At seven time points during 24-h observation, echocardiographic parameters as well as pressure-volume catheter-based LVSWI and CPI were simultaneously measured with X and following X-1 L/min of ECMO flow. PSP was calculated by multiplying global circumferential strain or global radial strain, and mean arterial pressure, for PSPcirc or PSPrad, respectively. RESULTS: PSPcirc showed a stronger correlation with LVSWI (correlation coefficient, CC = .360, p < .001) and CPI (CC = .283, p < .001) than other echocardiographic parameters. The predictability of PSPcirc for pressure-volume catheter-based LVSWI (AUC .82) and CPI (AUC .80) was also higher than other echocardiographic parameters. No statistically significant differences were identified between the two ECMO flow variations in PSPcirc (p = .558). CONCLUSIONS: A novel echocardiographic parameter, PSP, may non-invasively predict pressure-volume catheter-based LVSWI and CPI in a load-independent manner in a cardiogenic shock supported by V-A ECMO.

What question are we trying to answer? Embracing causal inference.

This study summarizes a presentation at the symposium for the Calvin Schwabe Award for Lifetime Achievement in Veterinary Epidemiology and Preventive Medicine, which was awarded to the first author. As epidemiologists, we are taught that "correlation does not imply causation." While true, identifying causes is a key objective for much of the research that we conduct. There is empirical evidence that veterinary epidemiologists are conducting observational research with the intent to identify causes; many studies include control for confounding variables, and causal language is often used when interpreting study results. Frameworks for studying causes include the articulation of specific hypotheses to be tested, approaches for the selection of variables, methods for statistical estimation of the relationship between the exposure and the outcome, and interpretation of that relationship as causal. When comparing observational studies in veterinary populations to those conducted in human populations, the application of each of these steps differs substantially. The a priori identification of exposure-outcome pairs of interest are less common in observational studies in the veterinary literature compared to the human literature, and prior knowledge is used to select confounding variables in most observational studies in human populations, whereas data-driven approaches are the norm in veterinary populations. The consequences of not having a defined exposure-outcome hypotheses of interest and using data-driven analytical approaches include an increased probability of biased results and poor replicability of results. A discussion by the community of researchers on current approaches to studying causes in observational studies in veterinary populations is warranted.

Factors affecting 12-month unplanned readmissions for chronic obstructive pulmonary disease patients: the effect of mental disorders in an Australian cohort.

BACKGROUND: Many individuals with chronic obstructive pulmonary disease (COPD) experience frequent hospitalization and readmissions, which is burdensome on the health system. This study aims to investigate factors associated with unplanned readmissions and mortality following a COPD-related hospitalization over a 12-month period in Australia, focusing on mental disorders and accounting for the acute phase of the COVID-19 pandemic. METHODS: A retrospective cohort study using linked hospitalization and mortality records identified individuals aged ≥40 years who had at least one hospital admission with a principal diagnosis of COPD between 2014 and 2020 in New South Wales, Australia. A semi-competing risk analysis was conducted to examine factors associated with unplanned readmission and mortality. RESULTS: Adults with a mental disorder diagnosis, specifically anxiety, had a higher risk of 12-month unplanned readmission. Individuals with anxiety and dementia also had a higher risk of mortality pre- and post-unplanned readmission. Individuals who were admitted during the acute phase of the COVID-19 pandemic period had lower risk of unplanned readmission, but higher risk of mortality without unplanned readmission. CONCLUSION: Interventions aimed at reducing admissions should consider adults living with mental disorders such as anxiety or dementia to improve healthcare delivery and health outcomes for individuals living with COPD.

Telomeric RNA (TERRA) increases in response to spaceflight and high-altitude climbing.

Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA's role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors.

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation.

BACKGROUND: LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson's disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. METHODS: Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. RESULTS: pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil degranulation, antigenic responses, and suppressed platelet activation. CONCLUSIONS: The extracellular serum ratio of pT73-Rab10 to total Rab10 is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics that mitigate associated deleterious immunological responses.

Haemophagocytic Lymphohistiocytosis Following the anti-PD-1 Nivolumab in a Patient with Gastric Cancer and Ankylosing Spondylitis.

Background: Autoimmune diseases are not contraindications for immune checkpoint inhibitors (ICI) therapy in patients with cancer. However, immune-related adverse events (irAEs) are frequently observed in patients receiving ICIs including dermatitis, thyroiditis, colitis, and pneumonitis. Thrombocytopenic purpura, aplasia, and haemophagocytic lymphohistiocytosis (HLH) are rarely observed during ICIs. Case description: We report the case of a male patient with pre-existing untreated HLA B27 and ankylosing spondylitis with gastric cancer and liver metastases. The 79-year-old man was treated with anti-HER2 trastuzumab and anti-PD-1 nivolumab. Seventeen days after the seventh cycle of treatment, he presented at the emergency department with acute fever, confusion, and hypotension. Laboratory results showed pancytopenia, and elevation of ferritin and triglyceride. No infections were detected. Although not seen in a bone marrow biopsy, clinical presentation, and absence of infection, together with an H-score of 263, indicated HLH. The patient was treated with dexamethasone for four days and discharged on a tapering dose of steroids. At the two-month follow-up, clinical presentation was normal and blood test almost normalised. At 8 months, no liver metastases were observed. Conclusions: In a patient with a pre-existing autoimmune condition, immunotherapy led to the development of HLH, which was controlled by glucocorticoid. Absence of the feature of haemophagocytosis in the bone marrow biopsy did not exclude the diagnosis, as HLH can occur in the spleen or in the liver. Glucocorticoid therapy did not prevent the anti-cancer effect of ICIs, and liver metastases disappeared 8 months post-HLH. This case warrants further research on the interplay between autoimmunity and ICI response, as well as ICI-induced irAEs. LEARNING POINTS: Haemophagocytic lymphohistiocytosis (HLH) post seventh cycle of trastuzumab (anti-HER2) and nivolumab (anti-PD-1) was controlled with glucocorticoid.Breach of tolerance was due to immunotherapy-induced HLH in a patient with pre-existing autoimmune condition (HLA B27- positive ankylosing spondylitis).There was a complete disappearance of liver metastases 8 months post-HLH.

Serologic Cross-reactivity of Murine Parvovirus Capsid Antigens.

Genomic sequence analysis of autonomous parvoviruses within the genus Protoparvovirus generates 2 groups that are principally of mouse origin: the minute virus of mice (MVM) strains (MVMp, MVMi, MVMc, MVMm) and the mouse parvovirus (MPV)-like strains (MPV-1, MPV-2, MPV-3, MPV-4, MPV-5, HaPV, LuIII). Baculovirus-expressed recombinant capsid protein (rVP2) from each of these 11 parvovirus strains were produced, purified, and demonstrated to form virus-like particles. Each rVP2 preparation was then used as antigen in a multiplex fluorescent immunoassay and to immunize 5 different strains of mice. Sera from immunized mice, mice experimentally monoinfected with various MVM or MPV isolates, and mice naturally infected with murine parvoviruses were evaluated with the multiplex fluorescent immunoassay rVP2 panel. Results for sera from immunized mice indicate that homologous antigen-antisera interactions produced the strongest seroreactivity. All MVM antigens were highly cross-reactive with heterologous MVM antisera, while more variability was observed in heterologous antigen-antisera reactions among the MPV-like strains. MPV-1, MPV-3, HaPV, and LuIII were highly cross-reactive with each other, MPV-2 and MPV-5 were highly cross-reactive with each other, and MPV-4 displayed modest cross-reactivity with certain MPV-like strains. Serologic cross-reactivity patterns similar to those in immunized mice were observed in mice experimentally infected with MVMp, MVMm, MPV-1, MPV-5, or HaPV, and in sera from mice naturally infected with MVM and MPV. Serologic cross-reactivity spectrums suggest a small panel of rVP2 antigens (MVM, MPV-1, MPV-2, MPV-4) combined with the generic murine parvovirus recombinant nonstructural protein 1 (rNS1) antigen are sufficient for qualitative detection of currently known MVM and MPV-like strains.