Neuromechanical adaptations of foot function to changes in surface stiffness during hopping

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this recordHumans choose work-minimizing movement strategies when interacting with compliant surfaces. Our ankles are credited with stiffening our lower limbs and maintaining the excursion of our body's center of mass on a range of surface stiffnesses. We may also be able to stiffen our feet through an active contribution from our plantar intrinsic muscles (PIMs) on such surfaces. However, traditional modelling of the ankle joint has masked this contribution. We compared foot and ankle mechanics and muscle activation on Low, Medium and High stiffness surfaces during bilateral hopping using a traditional and anatomical ankle model. The traditional ankle model overestimated work and underestimated quasi-stiffness compared to the anatomical model. Hopping on a low stiffness surface resulted in less longitudinal arch compression with respect to the high stiffness surface. However, because midfoot torque was also reduced, midfoot quasi-stiffness remained unchanged. We observed lower activation of the PIMs, soleus and tibialis anterior on the low and medium stiffness conditions, which paralleled the pattern we saw in the work performed by the foot and ankle. Rather than performing unnecessary work, participants altered their landing posture to harness the energy stored by the sprung surface in the low and medium conditions. These findings highlight our preference to minimize mechanical work when transitioning to compliant surfaces and highlight the importance of considering the foot as an active, multi-articular, part of the human leg

The impact and cost-effectiveness of combined HIV prevention scenarios among transgender women sex-workers in Lima, Peru: A mathematical modelling study

Background HIV incidence remains high among transgender women in Lima, Peru, most of whom report sex work. On the basis of a stakeholder analysis and health system capacity assessment, we designed a mathematical model to guide HIV programmatic planning among transgender women sex workers (TWSW) in Lima. Methods Using a deterministic compartmental model, we modelled HIV transmission among TWSW, their stable partners, and their clients to estimate the impact and cost-effectiveness of combinations of interventions compared with the standard of care on reducing HIV incidence over a 10-year period. We simulated HIV transmission accounting for differences in sexual positioning in anal intercourse and condom use by partner type and fitted the model to HIV surveillance data using Latin hypercube sampling. The interventions we considered were 15% relative increase in condom use with clients and 10% relative increase with stable partners; increase in antiretroviral treatment (ART) coverage at CD4 count lower than 500 cells per mm3 and greater than or equal to 500 cells per mm3; and 15% pre-exposure prophylaxis (PrEP) coverage using generic and branded formulations. We considered a basic scenario accounting for current limitations in the Peruvian HIV services and an enhanced scenario assuming achievement of the UNAIDS 90-90-90 targets and general improvements in HIV services. The 50 best fits according to log-likelihood were used to give the minimum and maximum values of intervention effect for each combination. We used disability-adjusted life-years (DALYs) to measure the negative health outcomes associated with HIV infection that could be averted through the interventions investigated and calculated incremental cost-effectiveness ratios to compare their cost-effectiveness. Findings Under the basic scenario, combining the four interventions of increasing condom use with clients and stable partners, extending ART to people with CD4 count greater than or equal to 500 cells per mm3, and 15% PrEP coverage with generic drugs would avert 47% (range 27–51) of new infections in TWSW, their clients, and their stable partners over 10 years, with an incremental cost-effectiveness ratio of US$509 per DALY averted. Under the enhanced scenario, this strategy would avert 61$1003 per DALY averted. Under both scenarios, implementation of this strategy approaches or surpasses the 50% incidence reduction goal and would represent a cost-effective use of country resources if generic PrEP drugs are used. The total cost of implementing this strategy under the enhanced scenario would be approximately $1·2 million per year over 10 years, corresponding to 10% of the current Global Fund's yearly contribution in Peru. Interpretation Investments in HIV services among TWSW in Lima would be cost-effective, even under stringent cost-effectiveness criteria when accounting for setting-specific resource constraints. Notable improvements in HIV testing rates, innovative interventions to increase condom use, and reduced PrEP costs will be key to achieving the 50% incidence reduction goal. Modelling studies incorporating stakeholders' perspectives and health system assessments can bring added value to HIV policy making

Neuromechanical adaptations of foot function when hopping on a damped surface

This is the author accepted manuscript. The final version is available on open access from the American Physiological Society via the DOI in this recordTo preserve motion, humans must adopt actuator-like dynamics to replace energy that is dissipated during contact with damped surfaces. Our ankle plantar flexors are credited as the primary source of work generation. Our feet and their intrinsic foot muscles also appear to be an important source of generative work, but their contributions to restoring energy to the body remain unclear. Here, we test the hypothesis that our feet help to replace work dissipated by a damped surface through controlled activation of the intrinsic foot muscles. We used custom-built platforms to provide both elastic and damped surfaces and asked participants to perform a bilateral hopping protocol on each. We recorded foot motion and ground reaction forces, alongside muscle activation, using intramuscular electromyography from flexor digitorum brevis, abductor hallucis, soleus and tibialis anterior. Hopping in the Damped condition resulted in significantly greater positive work and contact-phase muscle activation compared to the Elastic condition. The foot contributed 25% of the positive work performed about the ankle, highlighting the importance of the foot when humans adapt to different surfaces.Australian Research Council (ARC)QUEX Institut

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

Background Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Associations between cardiorespiratory fitness, physical activity and clustered cardiometabolic risk in children and adolescents: the HAPPY study

Clustering of cardiometabolic risk factors can occur during childhood and predisposes individuals to cardiometabolic disease. This study calculated clustered cardiometabolic risk in 100 children and adolescents aged 10-14 years (59 girls) and explored differences according to cardiorespiratory fitness (CRF) levels and time spent at different physical activity (PA) intensities. CRF was determined using a maximal cycle ergometer test, and PA was assessed using accelerometry. A cardiometabolic risk score was computed as the sum of the standardised scores for waist circumference, blood pressure, total cholesterol/high-density lipoprotein ratio, triglycerides and glucose. Differences in clustered cardiometabolic risk between fit and unfit participants, according to previously proposed health-related threshold values, and between tertiles for PA subcomponents were assessed using ANCOVA. Clustered risk was significantly lower (p < 0.001) in the fit group (mean 1.21 ± 3.42) compared to the unfit group (mean -0.74 ± 2.22), while no differences existed between tertiles for any subcomponent of PA. Conclusion These findings suggest that CRF may have an important cardioprotective role in children and adolescents and highlights the importance of promoting CRF in youth

Impaired development of the cerebral cortex in infants with congenital heart disease is correlated to reduced cerebral oxygen delivery

Neurodevelopmental impairment is the most common comorbidity associated with complex congenital heart disease (CHD), while the underlying biological mechanism remains unclear. We hypothesised that impaired cerebral oxygen delivery in infants with CHD is a cause of impaired cortical development, and predicted that cardiac lesions most associated with reduced cerebral oxygen delivery would demonstrate the greatest impairment of cortical development. We compared 30 newborns with complex CHD prior to surgery and 30 age-matched healthy controls using brain MRI. The cortex was assessed using high resolution, motion-corrected T2-weighted images in natural sleep, analysed using an automated pipeline. Cerebral oxygen delivery was calculated using phase contrast angiography and pre-ductal pulse oximetry, while regional cerebral oxygen saturation was estimated using near-infrared spectroscopy. We found that impaired cortical grey matter volume and gyrification index in newborns with complex CHD was linearly related to reduced cerebral oxygen delivery, and that cardiac lesions associated with the lowest cerebral oxygen delivery were associated with the greatest impairment of cortical development. These findings suggest that strategies to improve cerebral oxygen delivery may help reduce brain dysmaturation in newborns with CHD, and may be most relevant for children with CHD whose cardiac defects remain unrepaired for prolonged periods after birth

Diagnostic and treatment characteristics of polycystic ovary syndrome: descriptive measurements of patient perception and awareness from 657 confidential self-reports

BACKGROUND: This investigation was undertaken to describe patient perception and awareness of the polycystic ovary syndrome (PCOS), the most common cause of anovulation/oligoovulation among women of reproductive age. METHODS: Fifteen parameters were evaluated by a computer-based research instrument accessed by a large, unscreened population. Incomplete questionnaires were not entered, and responses were electronically tabulated to block duplicate submissions. RESULTS: From 657 participants, the majority (63%) were between 26–34 years old; mean BMI was 30.4 kg/m(2). 343 of 657 had at least one pregnancy and 61% of the study group had taken fertility medicine (any type) at least once. Physicians were the most common provider of PCOS information for all study participants, irrespective of age. Patient emotions associated with the diagnosis of PCOS included "frustration" (67%), "anxiety" (16%), "sadness" (10%), and "indifference" (2%). Self-reported patient aptitude regarding PCOS was scored as high or "very aware" in >60% of women. Respondents were also asked: "If your PCOS could be safely and effectively helped by something else besides fertility drugs or birth control pills, would that interest you?" Interest in alternative PCOS treatments was expressed by 99% of the sample (n = 648). CONCLUSIONS: In our study population, most women associated negative emotions with PCOS although the self-reported knowledge level for the disorder was high. While these women regarded their obstetrician-gynecologist as integral to their PCOS education, traditional PCOS therapies based on oral contraceptives or ovulation induction agents were regarded as unsatisfactory by most women

The SNAPSHOT study protocol : SNAcking, Physical activity, Self-regulation, and Heart rate Over Time

Peer reviewedPublisher PD

An autonomous chemically fuelled small-molecule motor

Molecular machines are among the most complex of all functional molecules and lie at the heart of nearly every biological process. A number of synthetic small-molecule machines have been developed, including molecular muscles, synthesizers, pumps, walkers, transporters and light-driven and electrically driven rotary motors. However, although biological molecular motors are powered by chemical gradients or the hydrolysis of adenosine triphosphate (ATP), so far there are no synthetic small-molecule motors that can operate autonomously using chemical energy (that is, the components move with net directionality as long as a chemical fuel is present). Here we describe a system in which a small molecular ring (macrocycle) is continuously transported directionally around a cyclic molecular track when powered by irreversible reactions of a chemical fuel, 9-fluorenylmethoxycarbonyl chloride. Key to the design is that the rate of reaction of this fuel with reactive sites on the cyclic track is faster when the macrocycle is far from the reactive site than when it is near to it. We find that a bulky pyridine-based catalyst promotes carbonate-forming reactions that ratchet the displacement of the macrocycle away from the reactive sites on the track. Under reaction conditions where both attachment and cleavage of the 9-fluorenylmethoxycarbonyl groups occur through different processes, and the cleavage reaction occurs at a rate independent of macrocycle location, net directional rotation of the molecular motor continues for as long as unreacted fuel remains. We anticipate that autonomous chemically fuelled molecular motors will find application as engines in molecular nanotechnology.</p