A BIOMECHANICAL COMPARISON BETWEEN STRONGMAN EVENTS AND TECHNICALLY SIMILAR TRADITIONAL WEIGHT TRAINING EXERCISES: A NARRATIVE REVIEW

A literature search was conducted to identify studies comparing biomechanical parameters of strongman events and technically similar traditional weight training exercises. While many similarities were identified, the farmers walk may result in reduced stress placed on the lumbar spine due to the more vertical trunk than when performing the deadlift under identical loading conditions, the heavy sled pull may be used to better develop anterior force production than the back squat, and the log lift may be used to better develop forceful hip extension during a triple extension movement than the clean and jerk. The identification of biomechanical similarities and differences between strongman and traditional weight training exercises may be used by strength and conditioning coaches to better prescribe exercises suited to an individual athletes’ conditioning requirements

Expression of the ???6 integrin promotes migration and invasion in squamous carcinoma cells

The integrin αvβ6 is a fibronectin receptor whose expression is not detectable on normal oral epithelium but is increased significantly in healing and in oral epithelial dysplasia and oral squamous cell carcinoma, suggesting it may promote changes associated with tumor development. To study whether αvβ6 may drive invasive behavior we have used transfection and retroviral infection to create a panel of epithelial cell lines expressing various levels of αvβ6. We report that increased expression of αvβ6 in malignant keratinocytes promotes invasion and leads to an increased capacity for migration towards fibronectin. αvβ6 expression may have a significant role in contributing to the malignant behavior of epithelial cells

Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a

Background Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. Methods and Findings We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. Conclusions Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge

Scaling matters: incorporating body composition into Weddell seal seasonal oxygen store comparisons reveals maintenance of aerobic capacities

Adult Weddell seals (Leptonychotes weddellii) haul-out on the ice in October/November (austral spring) for the breeding season and reduce foraging activities for ~4 months until their molt in the austral fall (January/February). After these periods, animals are at their leanest and resume actively foraging for the austral winter. In mammals, decreased exercise and hypoxia exposure typically lead to decreased production of O2-carrying proteins and muscle wasting, while endurance training increases aerobic potential. To test whether similar effects were present in marine mammals, this study compared the physiology of 53 post-molt female Weddell seals in the austral fall to 47 pre-breeding females during the spring in McMurdo Sound, Antarctica. Once body mass and condition (lipid) were controlled for, there were no seasonal changes in total body oxygen (TBO2) stores. Within each season, hematocrit and hemoglobin values were negatively correlated with animal size, and larger animals had lower mass-specific TBO2 stores. But because larger seals had lower mass-specific metabolic rates, their calculated aerobic dive limit was similar to smaller seals. Indicators of muscular efficiency, myosin heavy chain composition, myoglobin concentrations, and aerobic enzyme activities (citrate synthase and β-hydroxyacyl CoA dehydrogenase) were likewise maintained across the year. The preservation of aerobic capacity is likely critical to foraging capabilities, so that following the molt Weddell seals can rapidly regain body mass at the start of winter foraging. In contrast, muscle lactate dehydrogenase activity, a marker of anaerobic metabolism, exhibited seasonal plasticity in this diving top predator and was lowest after the summer period of reduced activity

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Characterisation of pituitary melatonin target cells under photoperiod changes by single cell RNAseq

Anticipation and adaptation of behaviour and physiology to the season changes are essential for animals to survive. Recent studies have defined that the melatonin rhythms responding to photoperiodic input acts on thyrotroph cells of pituitary pars tuberalis (PT), leading to seasonal activation of thyroid hormone converting pathways in the brain. In turn this activates reproductive and metabolic neurones driving fertility and metabolism. Action in the PT is mediated by activation of the developmental regulator EYA3, which is driven by the circadian clock in response to melatonin. It is unclear which downstream transcriptional switches drive these changes at the single cell level in the several complex cell types of the PT. To address this, we performed single cell RNA sequencing (using ICELL8 single-cell system) with PT tissue collected from a series of sheep housed over short (winter) photoperiods to long (summer) photoperiods. We observed in single PTs unique populations of cells exclusively expressing marker genes for short photoperiods (hormone processing chromogranin, CHGA) or long photoperiods (TSHB, EYA3), as well as the thyrotroph cell marker (aGSU) and folliculostellate cell marker (S100). These results indicate that single cell RNAseq offers the opportunity to define complex programmed switching mechanisms driving seasonal neuroendocrine responses in multiple cell types in the PT. Importantly, it suggests that timing mechanisms exist in one of 2 binary states (winter or summer-like), with rapid conversion of individual cells within the PT from one state to another. Single cell analysis is thus essential to define these mechanisms, as tissue based approaches can only provide an overall mean value for complex populations of timing cells

Single Cell RNA Sequencing Defines Cellular Binary Switching Mechanism Driving Circadian Regulation of Mammalian Photoperiodism in Melatonin-Target Calendar Cells.

Background/Objectives Recent studies define thyrotoph cells of the pituitary pars tuberalis (PT) as key mammalian seasonal calendar cells, driving photoperiodic responses to melatonin via thyroid stimulating hormone, TSH, which in turn regulates hypothalamic thyroid hormone conversion pathways. In the PT, long photoperiods activate the developmental regulator, EYA3 that drives TSH. We have shown previously that PT cells operate as binary switches driving accumulation of increasing numbers of TSH positive cells on long photoperiods. We do not know how this transcriptional switch drives cellular re-modelling within single thyrotroph cells nor do we know how the EYA3/TSH circuit is engaged by the circadian clockwork. Methods/Results We performed single nuclei RNA sequencing (iCELL8) of PT tissue collected from sheep housed in controlled artificial short photoperiods and in transition to long photoperiods (LP days 3, 10, 35). This revealed single PTs unique populations of endocrine cells exclusively expressing marker genes for short photoperiods (hormone processing chromogranin, CHGA) or long photoperiods (TSHB). Importantly, we show that the molecular repertoire characterising short or long photoperiods exist in one of 2 binary states (winter or summer-like). The proportion of cells in an LP state increases over several weeks of LP-exposure. We also identify BMAL2 as a critical LP-activated photoperiodic regulator of EYA3, thus coupling the circadian clock to mammalian photoperiodism. Conclusions Our data confirm that individual PT thyrotroph cells operate as binary switches, driving dynamic changes in neuroendocrine responses over several weeks, and we identify BMAL2 as a key up-stream circadian switch. Long-term timing is thus driven in a gradual digital-like accumulation of individual cells that switch phenotype in a stochastic manner. Single cell analysis is thus an essential platform to define complex dynamic tissue responses, and we demonstrate that seasonal timing is driven by rhythmic re-capitulation of developmental pathways in PT thyrotroph endocrine cells