Hanging in there: Prenatal origins of antigravity homeostasis in humans

All life on Earth must find a way to manage the continuous perturbation of gravity. From birth, and even before, humans exhibit effortful antigravity work to enact bodily, postural and behavioural form despite gravity. Indeed, observable antigravity behaviour is a standard diagnostic indicator of neonatal sensorimotor health. Antigravity behaviour has been investigated extensively in its biomechanical details. Yet its motivational structure has not been a focus of research. What drives the human body to expend energy on this effortful behaviour? It is widely understood that thermic homeostasis in humans is organised around conserving core body temperature at a set-point of 36.5-37.5oC. There is currently no equivalent concept of a general homeostatic set-point driving antigravity effort. In this theoretical paper, we aim to establish such a concept. We make the case that the core developmental set-point for human antigravity homeostasis is neutral buoyancy (gravity and buoyant force are balanced), which is afforded to the foetus by its approximately equi-dense amniotic fluid medium in utero. We argue that postnatally, the general task of human antigravity balance is to emulate the conditions of neutral buoyancy, based upon prenatal experience thereof. Our aim in this paper is to sketch a high-level outline of a novel characterisation of antigravity balance as conservative homeostasis, and lay out some implications and predictions of this model, with the intention of spurring wider research and discussion on this hitherto little explored topic. Keywords: antigravity, posture, homeostasis, prenatal, buoyancy, density, fetus, foetusComment: 19 pages (including references) Zero figure

Tetrahydrobiopterin Supplementation Improves Endothelial Function But Does Not Alter Aortic Stiffness in Patients With Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness. METHODS AND RESULTS: We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH4 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH4 improved endothelial function, but there was no change with placebo (mean±SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH4 supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, P=0.6; short-term 0.03±1.46 m/s, P=0.9). CONCLUSION: Both acute and short-term supplementation with oral BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.KMMP and IBW were funded by British Heart Foundation. IBW, JC and NS received funding from the Comprehensive Local Research Network and IBW and JC from the National Institute for Health Research: Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley Blackwell via http://dx.doi.org/10.1161/JAHA.115.00276

Mood and neural responses to social rejection do not seem to be altered in resilient adolescents with a history of adversity.

Childhood adversity (CA) increases the risk of subsequent mental health problems. Adolescent social support (from family and/or friends) reduces the risk of mental health problems after CA. However, the mechanisms of this effect remain unclear, and we speculate that they are manifested on neurodevelopmental levels. Therefore, we investigated whether family and/or friendship support at ages 14 and 17 function as intermediate variables for the relationship between CA before age 11 and affective or neural responses to social rejection feedback at age 18. We studied 55 adolescents with normative mental health at age 18 (26 with CA and therefore considered "resilient"), from a longitudinal cohort. Participants underwent a Social Feedback Task in the magnetic resonance imaging scanner. Social rejection feedback activated the dorsal anterior cingulate cortex and the left anterior insula. CA did not predict affective or neural responses to social rejection at age 18. Yet, CA predicted better friendships at age 14 and age 18, when adolescents with and without CA had comparable mood levels. Thus, adolescents with CA and normative mood levels have more adolescent friendship support and seem to have normal mood and neural responses to social rejection.This work was supported by grants from Friends of Peterhouse Medical Fund Cambridge (RG 51114), the Wellcome Trust (RG 074296), and the UK Medical Research Council (MC US A060 0019). JF is supported by the Medical Research Council Doctoral Training/Sackler Fund and the Pinsent Darwin Fund. JS is supported by the UK Medical Research Council (MC US A060 0019). ADA is supported by the Aker Scholarship. SS is supported by the Wellcome Trust (209127/Z/17/Z). IMG is funded by a Wellcome Trust Strategic Award and declares consulting to Lundbeck. ALvH is supported by the Royal Society (DH15017 & RGF\EA\180029 & RGF\RI\180064), and MQ (MQBFC/2). Funders of the authors played no role in the study conduction, analysis performance, or the reporting of the study

Seasonality, risk-factors and burden of community-acquired pneumonia in COPD patients: A population database study using linked healthcare records

Community acquired pneumonia (CAP) is more common in patients with chronic obstructive pulmonary disease (COPD) than in the adult general population, with studies of hospitalised CAP consistently reporting COPD as a frequent comorbidity. However, despite an increasing recognition of its importance, large studies evaluating the incidence patterns over time, risk-factors and burden of CAP in COPD are currently lacking.A retrospective observational study using a large UK-based database of linked primary and secondary care records was conducted. Patients with a diagnosis of COPD aged ?40 years were followed for 5 years from the 1st January 2010. CAP and exacerbation episodes were identified from hospital discharge data and primary care coding records, and rates were calculated per month, adjusting for mortality, and displayed over time. In addition, baseline factors predicting future risk of CAP and hospital admission at CAP, were identified. 14513 COPD patients were identified: 13.4% (n=1938) had ?1 CAP episode, of whom 18.8% suffered from recurrent (?2) CAP. Highest rates of both CAP and exacerbations were seen in winter. A greater proportion of frequent, compared to infrequent exacerbators experienced recurrent CAP (5.1% versus 2.0% respectively, p&lt;0.001) 75.6% of CAP episodes were associated with hospital admission compared to 22.1% of exacerbations. Older age and increasing grade of airflow limitation were independently associated with increased odds of CAP and hospital admission at CAP. Other independent predictors of future CAP included lower body mass index, inhaled-corticosteroid use, prior frequent exacerbations and comorbidities including ischaemic heart disease and diabetes. CAP in COPD demonstrates clear seasonal patterns, with patient characteristics predictive of the odds of future CAP and hospital admission at CAP. Highlighting this burden of COPD-associated CAP during the winter period, informs us of the likely triggers and the need for more effective preventive strategies.<br/

A Uniform Approximation for the Fidelity in Chaotic Systems

In quantum/wave systems with chaotic classical analogs, wavefunctions evolve in highly complex, yet deterministic ways. A slight perturbation of the system, though, will cause the evolution to diverge from its original behavior increasingly with time. This divergence can be measured by the fidelity, which is defined as the squared overlap of the two time evolved states. For chaotic systems, two main decay regimes of either Gaussian or exponential behavior have been identified depending on the strength of the perturbation. For perturbation strengths intermediate between the two regimes, the fidelity displays both forms of decay. By applying a complementary combination of random matrix and semiclassical theory, a uniform approximation can be derived that covers the full range of perturbation strengths. The time dependence is entirely fixed by the density of states and the so-called transition parameter, which can be related to the phase space volume of the system and the classical action diffusion constant, respectively. The accuracy of the approximations are illustrated with the standard map.Comment: 16 pages, 4 figures, accepted in J. Phys. A, special edition on Random Matrix Theor

Breast milk and in utero transmission of HIV-1 select for envelope variants with unique molecular signatures

Additional file 5: Figure S5. Representative CD4 infectivity curves using Affinofile cells for IUT (top) and BMT (bottom) maternal–infant pairs. Affinofile cells were induced to generate a 100-fold range of CD4 surface density (ABS/cell) and infected with 2000 IU pseudotyped virus. Percent infection was measured as the percent luciferase relative to infected and maximally induced Affinofile cells. Data shown are representative curves among 3–4 experimental replicates

A systematic review of strategies to recruit and retain primary care doctors

Background There is a workforce crisis in primary care. Previous research has looked at the reasons underlying recruitment and retention problems, but little research has looked at what works to improve recruitment and retention. The aim of this systematic review is to evaluate interventions and strategies used to recruit and retain primary care doctors internationally. Methods A systematic review was undertaken. MEDLINE, EMBASE, CENTRAL and grey literature were searched from inception to January 2015.Articles assessing interventions aimed at recruiting or retaining doctors in high income countries, applicable to primary care doctors were included. No restrictions on language or year of publication. The first author screened all titles and abstracts and a second author screened 20%. Data extraction was carried out by one author and checked by a second. Meta-analysis was not possible due to heterogeneity. Results 51 studies assessing 42 interventions were retrieved. Interventions were categorised into thirteen groups: financial incentives (n=11), recruiting rural students (n=6), international recruitment (n=4), rural or primary care focused undergraduate placements (n=3), rural or underserved postgraduate training (n=3), well-being or peer support initiatives (n=3), marketing (n=2), mixed interventions (n=5), support for professional development or research (n=5), retainer schemes (n=4), re-entry schemes (n=1), specialised recruiters or case managers (n=2) and delayed partnerships (n=2). Studies were of low methodological quality with no RCTs and only 15 studies with a comparison group. Weak evidence supported the use of postgraduate placements in underserved areas, undergraduate rural placements and recruiting students to medical school from rural areas. There was mixed evidence about financial incentives. A marketing campaign was associated with lower recruitment. Conclusions This is the first systematic review of interventions to improve recruitment and retention of primary care doctors. Although the evidence base for recruiting and care doctors is weak and more high quality research is needed, this review found evidence to support undergraduate and postgraduate placements in underserved areas, and selective recruitment of medical students. Other initiatives covered may have potential to improve recruitment and retention of primary care practitioners, but their effectiveness has not been established

Diversity, fragmentation, and connectivity across the UK amphibian and reptile data management landscape

Large-scale biodiversity monitoring remains a challenge in science and policy. ‘Biodiversity Observation Networks’ provide an integrated infrastructure for monitoring biodiversity through timely discovery, access, and re-use of data, but their establishment relies on an in-depth understanding of existing monitoring effort. We performed a scoping review and network analysis to assess the scope of available data on amphibians and reptiles in the UK and catalogue the mobilisation of information across the data landscape, thereby highlighting existing gaps. The monitoring portfolio has grown rapidly in recent decades, with over three times as many data sources than there are amphibian and reptile species in the UK now available. We identified 45 active sources of ‘FAIR’ (‘Findable’, ‘Accessible’, ‘Interoperable’ and ‘Reusable’) data. The taxonomic, geographic and temporal coverage of datasets appears largely uneven and no single source is currently suitable for producing robust multispecies assessments on large scales. A dynamic and patchy exchange of data occurs between different recording projects, recording communities and digital data platforms. The National Biodiversity Network Atlas is a highly connected source but the scope of its data (re-)use is potentially limited by insufficient accompanying metadata. The emerging complexity and fragmented nature of this dynamic data landscape is likely to grow without a concerted effort to integrate existing activities. The factors driving this complexity extend beyond the UK and to other facets of biodiversity. We recommend integration and greater stakeholder collaboration behind a coordinated infrastructure for data collection, storage and analysis, capable of delivering comprehensive assessments for large-scalecbiodiversity monitorin

Climate warming, marine protected areas and the ocean-scale integrity of coral reef ecosystems

Coral reefs have emerged as one of the ecosystems most vulnerable to climate variation and change. While the contribution of a warming climate to the loss of live coral cover has been well documented across large spatial and temporal scales, the associated effects on fish have not. Here, we respond to recent and repeated calls to assess the importance of local management in conserving coral reefs in the context of global climate change. Such information is important, as coral reef fish assemblages are the most species dense vertebrate communities on earth, contributing critical ecosystem functions and providing crucial ecosystem services to human societies in tropical countries. Our assessment of the impacts of the 1998 mass bleaching event on coral cover, reef structural complexity, and reef associated fishes spans 7 countries, 66 sites and 26 degrees of latitude in the Indian Ocean. Using Bayesian meta-analysis we show that changes in the size structure, diversity and trophic composition of the reef fish community have followed coral declines. Although the ocean scale integrity of these coral reef ecosystems has been lost, it is positive to see the effects are spatially variable at multiple scales, with impacts and vulnerability affected by geography but not management regime. Existing no-take marine protected areas still support high biomass of fish, however they had no positive affect on the ecosystem response to large-scale disturbance. This suggests a need for future conservation and management efforts to identify and protect regional refugia, which should be integrated into existing management frameworks and combined with policies to improve system-wide resilience to climate variation and change

Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib

Bites from elapid snakes typically result in neurotoxic symptoms in snakebite victims. Neurotoxins are, therefore, often the focus of research relating to understanding the pathogenesis of elapid bites. However, recent evidence suggests that some elapid snake venoms contain anticoagulant toxins which may help neurotoxic components spread more rapidly. This study examines the effects of venom from the West African black-necked spitting cobra (Naja nigricollis) on blood coagulation and identifies potential coagulopathic toxins. An integrated RPLC-MS methodology, coupled with nanofractionation, was first used to separate venom components, followed by MS, proteomics and coagulopathic bioassays. Coagulation assays were performed on both crude and nanofractionated N. nigricollis venom toxins as well as PLA2s and 3FTx purified from the venom. Assays were then repeated with the addition of either the phospholipase A2 inhibitor varespladib or the snake venom metalloproteinase inhibitor marimastat to assess whether either toxin inhibitor is capable of neutralizing coagulopathic venom activity. Subsequent proteomic analysis was performed on nanofractionated bioactive venom toxins using tryptic digestion followed by nanoLC-MS/MS measurements, which were then identified using Swiss-Prot and species-specific database searches. Varespladib, but not marimastat, was found to significantly reduce the anticoagulant activity of N. nigricollis venom and MS and proteomics analyses confirmed that the anticoagulant venom components mostly consisted of PLA2 proteins. We, therefore, conclude that PLA2s are the most likely candidates responsible for anticoagulant effects stimulated by N. nigricollis venom