Aerosol and physical atmosphere model parameters are both important sources of uncertainty in aerosol ERF

Changes in aerosols cause a change in net top-of-the-atmosphere (ToA) short-wave and long-wave radiative fluxes, rapid adjustments in clouds, water vapour and temperature, and cause an effective radiative forcing (ERF) of the planetary energy budget. The diverse sources of model uncertainty and the computational cost of running climate models make it difficult to isolate the main causes of aerosol ERF uncertainty and to understand how observations can be used to constrain it. We explore the aerosol ERF uncertainty by using fast model emulators to generate a very large set of aerosol-climate model variants that span the model uncertainty due to twenty-seven parameters related to atmospheric and aerosol processes. Sensitivity analyses shows that the uncertainty in the ToA flux is dominated (around 80 %) by uncertainties in the physical atmosphere model, particularly parameters that affect cloud reflectivity. However, uncertainty in the change in ToA flux caused by aerosol emissions over the industrial period (the aerosol ERF) is controlled by a combination of uncertainties in aerosol (around 60 %) and physical atmosphere (around 40 %) parameters. Four of the atmospheric and aerosol parameters that cause uncertainty in short-wave ToA flux (mostly parameters that directly scale cloud reflectivity, cloud water content or cloud droplet concentrations) also account for around 60% of the aerosol ERF uncertainty. The common causes of uncertainty mean that constraining the modelled planetary brightness to tightly match satellite observations changes the lower 95 % credible aerosol ERF value from −2.65 Wm−2 to −2.37 Wm−2. This suggests the strongest forcings (below around −2.4 Wm−2) are inconsistent with observations. These results show that, regardless of the fact that the ToA flux is an order of magnitude larger than the aerosol ERF, the observed flux can constrain the uncertainty in ERF because their values are connected by constrainable process parameters. The key to reducing the aerosol ERF uncertainty further will be to identify observations that can additionally constrain individual parameter ranges and/or combined parameter effects, which can be achieved through sensitivity analysis of perturbed parameter ensembles

Hypogravity reduces trunk admittance and lumbar muscle activation in response to external perturbations

Reduced paraspinal muscle size and flattening of spinal curvatures have been documented after spaceflight. Assessment of trunk adaptations to hypogravity can contribute to develop specific countermeasures. In this study, parabolic flights were used to investigate spinal curvature and muscle responses to hypogravity. Data from five trials at 0.25g, 0.50g and 0.75g were recorded from six participants, positioned in a kneeling-seated position. During the first two trials, participants maintained a normal, upright posture. In the last three trials, small-amplitude perturbations were delivered in the anterior direction at the T10 level. Spinal curvature was estimated using motion capture cameras. Trunk displacement and contact force between the actuator and participant were recorded. Muscle activity responses were collected using intramuscular electromyography (iEMG) of the deep and superficial lumbar multifidus, iliocostalis lumborum, longissimus thoracis, quadratus lumborum, transversus abdominis, obliquus internus and obliquus externus muscles. The root mean square iEMG and the average spinal angles were calculated. Trunk admittance and muscle responses to perturbations were calculated as closed-loop frequency response functions. Compared with 0.75g, 0.25g resulted in: lower activation of the longissimus thoracis (P=0.002); lower responses of the superficial multifidus at low frequencies (P=0.043); lower responses of the superficial multifidus (P=0.029) and iliocostalis lumborum (P=0.043); lower trunk admittance (P=0.037) at intermediate frequencies; and stronger responses of the transversus abdominis at higher frequencies (p=0.032). These findings indicate that exposure to hypogravity reduces trunk admittance, partially compensated by weaker stabilizing contributions of the paraspinal muscles and coinciding with an apparent increase of the deep abdominal muscle activity

Non-linear hierarchy of the quorum sensing signalling pathway in bloodstream form African trypanosomes.

Trypanosoma brucei, the agents of African trypanosomiasis, undergo density-dependent differentiation in the mammalian bloodstream to prepare for transmission by tsetse flies. This involves the generation of cell-cycle arrested, quiescent, stumpy forms from proliferative slender forms. The signalling pathway responsible for the quorum sensing response has been catalogued using a genome-wide selective screen, providing a compendium of signalling protein kinases phosphatases, RNA binding proteins and hypothetical proteins. However, the ordering of these components is unknown. To piece together these components to provide a description of how stumpy formation arises we have used an extragenic suppression approach. This exploited a combinatorial gene knockout and overexpression strategy to assess whether the loss of developmental competence in null mutants of pathway components could be compensated by ectopic expression of other components. We have created null mutants for three genes in the stumpy induction factor signalling pathway (RBP7, YAK, MEKK1) and evaluated complementation by expression of RBP7, NEK17, PP1-6, or inducible gene silencing of the proposed differentiation inhibitor TbTOR4. This indicated that the signalling pathway is non-linear. Phosphoproteomic analysis focused on one pathway component, a putative MEKK, identified molecules with altered expression and phosphorylation profiles in MEKK1 null mutants, including another component in the pathway, NEK17. Our data provide a first molecular dissection of multiple components in a signal transduction cascade in trypanosomes

New horizons in iron deficiency anaemia in older adults

Iron deficiency anaemia (IDA) is common in older adults and associated with a range of adverse outcomes. Differentiating iron deficiency from other causes of anaemia is important to ensure appropriate investigations and treatment. It is possible to make the diagnosis reliably using simple blood tests. Clinical evaluation and assessment are required to help determine the underlying cause and to initiate appropriate investigations. IDA in men and post-menopausal females is most commonly due to occult gastrointestinal blood loss until proven otherwise, although there is a spectrum of underlying causative pathologies. Investigation decisions should take account of the wishes of the patient and their competing comorbidities, individualising the approach. Management involves supplementation using oral or intravenous (IV) iron then consideration of treatment of the underlying cause of deficiency. Future research areas are outlined including the role of Hepcidin and serum soluble transferrin receptor measurement, quantitative faecal immunochemical testing, alternative dosing regimens and the potential role of IV iron preparations

Choice of Moisturiser for Eczema Treatment (COMET):feasibility study of a randomised controlled parallel group trial in children recruited from primary care

OBJECTIVES: To determine the feasibility of a randomised controlled trial of ‘leave on’ emollients for children with eczema. DESIGN: Single-centre, pragmatic, 4-arm, observer-blinded, parallel, randomised feasibility trial. SETTING: General practices in the UK. PARTICIPANTS: Children with eczema aged 1 month to <5 years. OUTCOME MEASURES: Primary outcome—proportion of parents who reported use of the allocated study emollient every day for the duration of follow-up (12 weeks). Other feasibility outcomes—participant recruitment and retention, data collection and completeness and blinding of observers to allocation. INTERVENTIONS: Aveeno lotion, Diprobase cream, Doublebase gel, Hydromol ointment. RESULTS: 197 children were recruited—107 by self-referral (mainly via practice mail-outs) and 90 by inconsultation (clinician consenting and randomising) pathways. Participants recruited inconsultation were younger, had more severe Patient-Oriented Eczema Measure scores and were more likely to withdraw than self-referrals. Parents of 20 (10%) of all the randomised participants reported using the allocated emollient daily for 84 days. The use of other non-study emollients was common. Completeness of data collected by parent-held daily diaries and at monthly study visits was good. Daily diaries were liked (81%) but mainly completed on paper rather than via electronic (‘app’) form. Major costs drivers were general practitioner consultations and eczema-related prescriptions. Observer unblinding was infrequent, and occurred at the baseline or first follow-up visit through accidental disclosure. CONCLUSIONS: It is feasible in a primary care setting to recruit and randomise young children with eczema to emollients, follow them up and collect relevant trial data, while keeping observers blinded to their allocation. However, reported use of emollients (study and others) has design implications for future trials. TRIAL REGISTRATION NUMBER: ISRCTN21828118/EudraCT2013-003001-26

Evaluation of SARS-CoV-2 antibody point of care devices in the laboratory and clinical setting

SARS-CoV-2 antibody tests have been marketed to diagnose previous SARS-CoV-2 infection and as a test of immune status. There is a lack of evidence on the performance and clinical utility of these tests. We aimed to carry out an evaluation of 14 point of care (POC) SARS-CoV-2 antibody tests. Serum from participants with previous RT-PCR (real-time polymerase chain reaction) confirmed SARS-CoV-2 infection and pre-pandemic serum controls were used to determine specificity and sensitivity of each POC device. Changes in sensitivity with increasing time from infection were determined on a cohort of study participants. Corresponding neutralising antibody status was measured to establish whether the detection of antibodies by the POC device correlated with immune status. Paired capillary and serum samples were collected to ascertain whether POC devices performed comparably on capillary samples. Sensitivity and specificity varied between the POC devices and in general did not meet the manufacturers’ reported performance characteristics, which signifies the importance of independent evaluation of these tests. The sensitivity peaked at ≥20 days following onset of symptoms, however sensitivity of 3 of the POC devices evaluated at extended time points showed that sensitivity declined with time. This was particularly marked at >140 days post infection. This is relevant if the tests are to be used for sero-prevalence studies. Neutralising antibody data showed that positive antibody results on POC devices did not necessarily confer high neutralising antibody titres, and that these POC devices cannot be used to determine immune status to the SARS-CoV-2 virus. Comparison of paired serum and capillary results showed that there was a decline in sensitivity using capillary blood. This has implications in the utility of the tests as they are designed to be used on capillary blood by the general population

Systematic review of the technical and physiological constraints of the Orion Multi-Purpose Crew Vehicle that affect the capability of astronauts to exercise effectively during spaceflight

Background The constraints of the Orion Multi-Purpose Crew Vehicle present challenges to the use of current exercise countermeasures necessary to prevent severe deconditioning of physiological systems during microgravity exposure beyond Low Earth Orbit. The purpose of this qualitative systematic review was to determine the technical constraints of the Orion Multi-Purpose Crew Vehicle which may hinder astronauts’ capabilities to effectively exercise during long distance spaceflight. Methods Databases were searched from the start of their records to December 2018. Included documents were quality assessed with the AMSRG quality scoring tool and Thematic Analysis was used to analyse the included documents to assess technical constraints of the Orion Multi-Purpose Crew Vehicle. Results 19 studies were included in the final review. All identified constraints, other than data transmission limitations, were found to ultimately be a result of the volume and upload mass constraints of the Orion Multi-Purpose Crew Vehicle. There was a lack of detailed studies and lack of consistency in specifying spacecraft in the literature that limit the conclusions of this review. Conclusion Space agencies are advised to ensure that information on relevant spacecraft constraints is readily available to researchers. This information should be made accessible in an official published document as opposed to disparate and grey literature, and include quantitative information rather than qualitative summaries

Effects of a six-week exercise intervention on function, pain and lumbar multifidus muscle cross-sectional area in chronic low back pain: A proof-of-concept study

Introduction Exercise with the Functional Re-adaptive Exercise Device (FRED) has previously been shown to activate the lumbar multifidus (LM) and transversus abdominis (TrA) muscles in non-symptomatic volunteers. This study aimed to determine the effects of a six-week FRED exercise intervention on pain intensity, patient-reported function and LM cross sectional area (CSA) in people with chronic non-specific low back pain (LBP). Methods Thirteen participants undertook six weeks of FRED exercise for up to 15 min, three times per week. At six weeks pre-, immediately pre-, immediately post-, and six and 15 weeks post-intervention, participants completed the Numeric Pain Rating Scale, Patient-Specific Functional Scale, and ultrasound imaging was used to assess the size of the LM muscles at L5 level. Changes in outcomes were assessed using effect size, confidence intervals and minimum clinically important difference (MCID). Results There was no improvement in pain intensity following the intervention. Patient-reported function improved by at least twice the MCID for all follow-up assessments compared to immediately pre-intervention (d = 4.20–6.58). Lumbar multifidus CSA showed a large effect size increase from immediately pre-intervention to immediately post-intervention (d = 0.8–1.1); this was maintained at six weeks post-intervention (not measured at 15 weeks post-intervention). Conclusion Six weeks of FRED exercise improved physical function in all 13 participants with chronic non-specific LBP who took part in this study and most participants' lumbar multifidus muscle CSA. On this basis, it may be an effective intervention for people with chronic LBP and should now be tested in a randomised controlled trial

Hypertension, Microvascular Pathology, and Prognosis After an Acute Myocardial Infarction

The rationale for our study was to investigate the pathophysiology of microvascular injury in patients with acute ST-segment–elevation myocardial infarction in relation to a history of hypertension. We undertook a cohort study using invasive and noninvasive measures of microvascular injury, cardiac magnetic resonance imaging at 2 days and 6 months, and assessed health outcomes in the longer term (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850). Three hundred twenty-four patients with acute myocardial infarction (mean age, 59 [12] years; blood pressure, 135 [25] / 79 [14] mm Hg; 237 [73%] male, 105 [32%] with antecedent hypertension) were prospectively enrolled during emergency percutaneous coronary intervention. Compared with patients without antecedent hypertension, patients with hypertension were older (63 [12] years versus 57 [11] years; P&lt;0.001) and a lower proportion were cigarette smokers (52 [50%] versus 144 [66%]; P=0.007). Coronary blood flow, microvascular resistance within the culprit artery, infarct pathologies, inflammation (C-reactive protein and interleukin-6) were not associated with hypertension. Compared with patients without antecedent hypertension, patients with hypertension had less improvement in left ventricular ejection fraction at 6 months from baseline (5.3 [8.2]% versus 7.4 [7.6]%; P=0.040). Antecedent hypertension was a multivariable associate of incident myocardial hemorrhage 2-day post-MI (1.81 [0.98–3.34]; P=0.059) and all-cause death or heart failure (n=47 events, n=24 with hypertension; 2.53 [1.28–4.98]; P=0.007) postdischarge (median follow-up 4 years). Severe progressive microvascular injury is implicated in the pathophysiology and prognosis of patients with a history of hypertension and acute myocardial infarction