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The impact of the electrolyte ion size on electrocatalytic reactions that occur within nanoconfined volumes is currently unknown. Herein, the effect of the size of solvated alkali metal ions on the oxygen reduction reaction (ORR) in acidic electrolytes was explored by using nanoparticles that contain isolated Pt nanochannels of 1–2 nm in diameter. The exterior surface of the nanoparticles was passivated to ensure that the ORR occurred only in the nanoconfined volume defined by the nanochannels. A number of alkali metal ions, with different hydrated sizes, were added into the acidic electrolyte, and different electrolyte ionic strengths were used to establish different levels of nanoconfinement. The results show that the ORR activity at comparatively positive applied potentials is not affected by the presence and nature of the alkali metal ions in the electrolyte. At less positive potentials, however, the activity is influenced by the presence of alkali metal ions in the electrolyte, and this is dependent on both the identity of the alkali metal ions and the electrolyte ionic strength. The differences in activities at less positive potentials are attributed to differences in the alkali metal ions’ accessibility to the nanoconfined space with Li+being accessible and decreasing the electrocatalytic activity relative to inaccessible K+ions that cannot enter the nanoconfined channels. This was corroborated by molecular dynamics modeling suggesting that the energy penalty for the alkali metal ions to enter the nanochannels is different for the different alkali metal ions and is affected by the surface charge of the nanochannel walls.

BackgroundTension pneumothorax following trauma is a life-threatening emergency and radiological investigation is normally discouraged prior to treatment in traditional trauma doctrines such as ATLS. Some trauma patients may be physiologically stable enough for diagnostic imaging and occult tension pneumothorax is discovered radiologically. We assessed the outcomes of these patients and compared them with those with clinical diagnosis of tension pneumothorax prior to imaging.MethodsA multicentre civilian–military collaborative network of six major trauma centres in the UK collected observational data from adult patients who had a diagnosis of traumatic tension pneumothorax during a 33-month period. Patients were divided into ‘radiological’(diagnosis following CT/CXR) or ‘clinical’(no prior CT/CXR) groups. The effect of radiological diagnosis on survival was analysed using multivariable logistic regression that included the covariates of age, gender, comorbidities and Injury Severity Score.ResultsThere were 133 patients, with a median age of 41 (IQR 24–61); 108 (81%) were male. Survivors included 49 of 59 (83%) in the radiological group and 59 of 74 (80%) in the clinical group (p=0.487). Multivariable logistic regression showed no significant association between radiological diagnosis and survival (OR 2.40, 95% CI 0.80 to 7.95; p=0.130). There was no significant difference in mortality between the groups.ConclusionRadiological imaging may be appropriate for selected trauma patients at risk of tension pneumothorax if they are considered haemodynamically stable. Trauma patients may be physiologically stable enough for radiological imaging but have occult tension pneumothorax because they did not have the typical clinical presentation. The historical dogma of the ‘forbidden scan’no longer applies to such patients.

Lung cancer is the second most common cancer in incidence and the leading cause of cancer deaths worldwide. Meanwhile, lung cancer screening with low-dose CT can reduce mortality. The UK National Screening Committee recommended targeted lung cancer screening on Sept 29, 2022, and asked for more modelling work to be done to help refine the recommendation. This study aims to develop and validate a risk prediction model—the CanPredict (lung) model—for lung cancer screening in the UK and compare the model performance against seven other risk prediction models.

Recent findings of NO near Gale Crater on Mars have been explained by two pathways: formation of nitric acid (HNO3) in a warm climate or formation of peroxynitric acid (HO2NO2) in a cool climate. Here, we put forth two hitherto unexplored pathways: (a) deposition of nitric/peroxynitric acid onto ice particles in a cold atmosphere, which settle quickly onto Mars' surface and (b) solar energetic particle‐induced production of nitric/peroxynitric acid. The deposition rates are enhanced and NO production is more efficient under the higher atmospheric pressures typical of Mars' ancient atmosphere. Depending on the unknown rate at which nitric/peroxynitric acid is lost from the surface, the new pathways could result in larger NO‐levels than those detected by the Mars Science Laboratory. We predict a 2:1 ratio of nitrite:nitrate would have deposited in cool surface climates with an icy atmosphere, whereas orders of magnitude more nitrate than nitrite is expected from warm surface climates. The nitrogen oxides discovered in present‐day soil on Mars likely formed in the atmosphere before being deposited on the ground. Two possible mechanisms are deposition of nitric acid (HNO3) when Mars had a warm climate and deposition of peroxynitric acid (HO2NO2) during cold climate. The latter scenario involves processes that have not been considered previously and leads to a much faster deposition rate for nitrogen oxides than was reported in previous studies: solar energetic particles splitting N2in the middle atmosphere, reactions of nitrogen oxides on the surfaces of ice particles in the atmosphere, and deposition of peroxynitric acid onto the Martian surface when surface pressure was higher. Depending on the unknown rate at which they are lost from the surface due to UV photolysis, the maximum accumulation rate for nitrogen oxides could be much larger than is required to explain the present day measurements. We predict that more nitrite would form than nitrate in a cool climate with an icy atmosphere, whereas in a warm climate much more nitrate than nitrite is expected. So, an investigation of the relative amounts of NO2:NO3in the soil in the present‐day measurements could reveal the climate state under which the salts formed. In a cold climate, heterogeneous reactions with atmospheric ice particles would cause faster deposition of HNOx than dry depositionFormation of HNOx species is faster for earlier Martian climates of larger surface pressureModeled NO accumulates to amounts greater than present‐day measurements, so we propose there may be a loss mechanism that is unidentified In a cold climate, heterogeneous reactions with atmospheric ice particles would cause faster deposition of HNOx than dry deposition Formation of HNOx species is faster for earlier Martian climates of larger surface pressure Modeled NO accumulates to amounts greater than present‐day measurements, so we propose there may be a loss mechanism that is unidentified

Polygenic risk influences susceptibility to cancer. We assessed whether polygenic risk scores could be used in conjunction with other predictors of future disease status in cost-effective risk-stratified screening for cancer.

The manufacturing route toward verinurad, an amphoteric, class II atropisomer that readily forms solvates, has proven to be highly complex. This previously required the isolation of intermediates with challenging physical properties and the application of cryogenic processes. New processes were designed and optimized, enabling the manufacture of 113 kg of verinurad in its desired polymorphic form. An interdisciplinary approach involving the synthesis, high-throughput experimentation, analytical chemistry, crystallization science, in silicomodeling, and engineering was employed. Kinetic measurement of enantiomerically enriched verinurad salts confirmed that racemization occurred within the clearance time frame, thus mitigating safety concerns associated with inherent axial chirality in verinurad.

Marfan syndrome (MFS) is one of the major heritable disorders of connective tissue with a prevalence of between 1 in 5-10 000. (1 2) It is characterised by features in [...]

We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes.

Evidence indicates that a melanoma prevention program using personalized genomic risk provision and genetic counseling can affect prevention behaviors, including reducing sunburns in adults with no melanoma history. This analysis evaluated its longer-term cost-effectiveness from an Australian health system perspective.

Earth’s distant past and potentially its future include extremely warm ‘hothouse’1climate states, but little is known about how the atmosphere behaves in such states. One distinguishing characteristic of hothouse climates is that they feature lower-tropospheric radiative heating, rather than cooling, due to the closing of the water vapour infrared window regions2. Previous work has suggested that this could lead to temperature inversions and substantial changes in cloud cover3–6, but no previous modelling of the hothouse regime has resolved convective-scale turbulent air motions and cloud cover directly, thus leaving many questions about hothouse radiative heating unanswered. Here we conduct simulations that explicitly resolve convection and find that lower-tropospheric radiative heating in hothouse climates causes the hydrologic cycle to shift from a quasi-steady regime to a ‘relaxation oscillator’ regime, in which precipitation occurs in short and intense outbursts separated by multi-day dry spells. The transition to the oscillatory regime is accompanied by strongly enhanced local precipitation fluxes, a substantial increase in cloud cover, and a transiently positive (unstable) climate feedback parameter. Our results indicate that hothouse climates may feature a novel form of ‘temporal’ convective self-organization, with implications for both cloud coverage and erosion processes.

The ‘Guinea Pig Club’ has been described as the most exclusive club in the world, but the entrance fee is something most men would care not to pay, and the conditions of membership are arduous in the extreme. The Guinea Pig Club was formed in July 1941 to support aircrew who were undergoing reconstructive plastic surgery after receiving burn injuries in the Second World War. This paper will explore the novel surgical techniques employed to treat the Guinea Pig Club members, their experiences at the hospital and their lives after the war and how Sir Archibald McIndoe and the Guinea Pig club members revolutionised burns plastic surgery as we know it today.

Here we present the results of the first paleoseismic study of the Kura fold‐thrust belt in Azerbaijan based on field mapping, fault trenching, and Quaternary dating. Convergence at rates of ∼10 mm/yr between the Arabian and Eurasian Plates is largely accommodated by the Kura fold‐thrust belt which stretches between central Azerbaijan and Georgia along the southern front of the Greater Caucasus (45–48°E). Although destructive historic earthquakes are known here, little is known about the active faults responsible for these earthquakes. A paleoseismic trench was excavated across a 2‐m‐high fault scarp near Agsu revealing evidence of two surface rupturing earthquakes. Radiocarbon dating of the faulted sediments limits the earthquake timing to AD 1713–1895 and AD 1872–2003. Allowing for uncertainties in dating, the two events likely correspond to historical destructive M∼ 7 earthquakes near Shamakhi, Azerbaijan in AD 1668 and 1902. A second trench 60 km west of Agsu was excavated near Goychay also revealing evidence of at least one event that occurred 334–118 BC. Holocene shortening and dip‐slip rates for the Kura fold‐thrust belt are ∼8.0 and 8.5 mm/yr, respectively, based on an uplifted strath terrace west of Agsu. The only known historical devastating (M> ∼7) earthquakes in the Kura region, west of Shamakhi, occurred in 1139 and possibly 1668. The lack of reported historical ruptures from the past 4–8 centuries in the Kura, in contrast with the numerous recorded destructive earthquakes in Shamakhi, suggests that the Kura fold‐thrust belt may have accumulated sufficient strain to produce a M> 7.7 earthquake. The Greater Caucasus Mountains stretching between the Black and Caspian Seas are a result of the northward subduction of the Arabian plate beneath Eurasia. For the last 1.5 million years, most of this plate motion has been accommodated by the Kura fold‐thrust belt in Azerbaijan & eastern Georgia. This plate motion produces infrequent but damaging large earthquakes. Here a geologic mapping and paleoseismic trenching investigation revealed evidence for large earthquakes in the eastern part of the Kura fold‐thrust belt of Azerbaijan. These earthquakes likely correspond to known historical earthquakes in 1668 and 1902, as well as one or more earlier, undocumented earthquakes. A lack of historical earthquakes to the west of this study area suggest that the rest of the Kura fold‐thrust belt may produce less frequent, but stronger earthquakes along this plate boundary. Two paleoseismic trenches near Goychay and Agsu, Azerbaijan provide evidence of at least three surface rupturing eventsEvents occurred 334–118 BC, AD 1713–1895, and AD 1872–2003. The latter two may correspond to historical earthquakes in 1668 and 1902Maximum Holocene shortening and dip‐slip rates of the frontal thrust sheet in the eastern Kura fold‐thrust belt are 8 and 8.5 mm/yr, respectively Two paleoseismic trenches near Goychay and Agsu, Azerbaijan provide evidence of at least three surface rupturing events Events occurred 334–118 BC, AD 1713–1895, and AD 1872–2003. The latter two may correspond to historical earthquakes in 1668 and 1902 Maximum Holocene shortening and dip‐slip rates of the frontal thrust sheet in the eastern Kura fold‐thrust belt are 8 and 8.5 mm/yr, respectively

Genetic polymorphism (rs1800693) of TNFRSF1A(type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy. In contrast to predictions, rs1800693GG homozygotes actually had significantly worse BASDAI (mean 4.2, 95% CI: 4–4.5) than AA homozygotes (mean 3.8, 95% CI: 3.7–4) in both the unadjusted (difference = 0.4, p= 0.006) and adjusted analyses (difference = 0.2–0.5, p= 0.002–0.04 depending on the adjustment model). We found no evidence that rs1900693predicted functional status (BASFI) or global disease scores (BAS-G), and it exerted no influence on either the intention to treat with or efficacy of anti-TNF treatment.

Reconciling the geology of Mars with models of atmospheric evolution remains a major challenge. Martian geology is characterized by past evidence for episodic surface liquid water, and geochemistry indicating a slow and intermittent transition from wetter to drier and more oxidizing surface conditions. Here we present a model that incorporates randomized injection of reducing greenhouse gases and oxidation due to hydrogen escape to investigate the conditions responsible for these diverse observations. We find that Mars could have transitioned repeatedly from reducing (hydrogen-rich) to oxidizing (oxygen-rich) atmospheric conditions in its early history. Our model predicts a generally cold early Mars, with mean annual temperatures below 240 K. If peak reducing-gas release rates and background carbon dioxide levels are high enough, it nonetheless exhibits episodic warm intervals sufficient to degrade crater walls, form valley networks and create other fluvial/lacustrine features. Our model also predicts transient build-up of atmospheric oxygen, which can help explain the occurrence of oxidized mineral species such as manganese oxides at Gale Crater. We suggest that the apparent Noachian–Hesperian transition from phyllosilicate deposition to sulfate deposition around 3.5 billion years ago can be explained as a combined outcome of increasing planetary oxidation, decreasing groundwater availability and a waning bolide impactor flux, which dramatically slowed the remobilization and thermochemical destruction of surface sulfates. Ultimately, rapid and repeated variations in Mars’s early climate and surface chemistry would have presented both challenges and opportunities for any emergent microbial life.

Genomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation. We examine whether the current evidence base reflects public tolerance for uncertainty for genomics to diagnose rare childhood genetic disease. We conducted focus groups with general population parents in Vancouver, Canada, and Oxford, United Kingdom, to discuss expectations and concerns related to genomic testing to diagnose rare childhood genetic disease. Applying a purposive sampling technique, recruitment continued until thematic saturation was reached. Transcripts were analysed using thematic analysis. Thirty-three parents participated across four focus groups. Participants valued causal diagnoses alongside management strategies to improve patient health and wellbeing. Further, participants valued expanding the evidence base to reduce evidentiary uncertainty while ensuring security of information. Willingness to pay out of pocket for testing reflected perceived familial health benefit. Diagnostic yield fails to fully capture valued outcomes, and efforts to resolve uncertainty better reflect public priorities. Evaluations of genomic testing that fully integrate valued endpoints are necessary to ensure consistency with best practices and public willingness to accept the uncertain familial benefit.

Waldenström macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88L265Pin more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity.

Abstract Objective -- To determine whether genetic factors associated with established rheumatiod arthritis could, in combination with rheumatiod factors, predict the development of radiological erosions in patient with early symmetrical [...]

Next generation sequencing (NGS) approaches are moving from research into clinical practice. However, the optimal NGS approach in well-defined adult-onset familial diseases, such as inherited cardiovascular disease, remains unclear. We aimed to determine which attributes encouraged or discouraged the uptake of genomic tests in this context, and whether this differed by test type. We conducted a web-based discrete choice experiment in health professionals in the UK who order NGS tests for inherited cardiovascular disease. Respondents completed 12 hypothetical choice tasks in which they selected a preferred test from four alternatives: whole genome sequencing, whole exome sequencing, panel testing and genetic testing not indicated. Tests were specified in terms of five attributes: diagnostic yield, detection rate for variants of unknown significance, cost, quantity of counselling received and disclosure of secondary findings. Mixed logit regression analysis was used to analyse the choice data. We found that uptake of NGS increases if tests identify more pathogenic mutations, identify fewer variants of unknown significance, or cost less. Respondents were willing to pay £117 for every 1% increase in diagnostic yield. Considerable heterogeneity was observed around preferences for several test attributes. Overall, panel testing had the highest predicted uptake rate. Our results indicate that NGS tests are valued by health professionals for well-defined adult-onset familial diseases, however, these professionals have strong preferences for panel testing rather than whole genome sequencing and whole exome sequencing. This finding suggests that different uptake rates should be explicitly modelled when designing and evaluating future genomic testing services.

Clopidogrel is an antiplatelet drug given to patients before and after having a percutaneous coronary intervention (PCI). Genomic variants in the CYP2C19gene are associated with variable enzyme activities affecting drug metabolism and hence, patients with reduced or increased enzymatic function have increased risk of bleeding. We conducted a cost-effectiveness analysis to compare a pharmacogenomics versus a non-pharmacogenomics-guided clopidogrel treatment for coronary artery syndrome patients undergoing PCI in the Spanish healthcare setting. A total of 549 patients diagnosed with coronary artery disease followed by PCI were recruited. Dual antiplatelet therapy was administrated to all patients from 1 to 12 months after PCI. Patients were classified into two groups: the Retrospective group was treated with clopidogrel based on the clinical routine practice and the Prospective group were initially genotyped for the presence of CYP2C19variant alleles before treatment with those carrying more than one CYP2C19variant alleles given prasugrel treatment. We collected data on established clinical and health outcome measures, including, per treatment arm: the percentage of patients that suffered from (a) myocardial infraction, (b) major bleeding and minor bleeding, (c) stroke, (d) the number of hospitalization days, and (e) the number of days patients spent in Intensive Care Unit. Our primary outcome measure for the cost-effectiveness analysis was Quality Adjusted Life Years (QALYs). To estimate the treatment cost for each patient, individual data on its resource used were combined with unit price data, obtained from Spanish national sources. The analysis predicts a survival of 0.9446 QALYs in the pharmacogenomics arm and 0.9379 QALYs in the non-pharmacogenomics arm within a 1-year horizon. The cumulative costs per patient were €2971 and €3205 for the Prospective and Retrospective groups, respectively. The main cost driver of total cost in both arms was hospitalization costs. The incremental cost-effectiveness ratio (ICER) was negative indicating that the PGx was a dominant option. Our data show that pharmacogenomics-guided clopidogrel treatment strategy may represent a cost-effective choice compared with non-pharmacogenomics-guided strategy for patients undergoing PCI.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Rheumatoid arthritis (RA) is a multisystem, autoimmune disorder and confers one of the strongest risks for cardiovascular disease (CVD) morbidity and mortality.

Enzymes are characterized by an active site that is typically embedded deeply within the protein shell thus creating a nanoconfined reaction volume in which high turnover rates occur. We propose nanoparticles with etched substrate channels as a simplified enzyme mimic, denominated nanozymes, for electrocatalysis. We demonstrate increased electrocatalytic activity for the oxygen reduction reaction using PtNi nanoparticles with isolated substrate channels. The PtNi nanoparticles comprise an oleylamine capping layer that blocks the external surface of the nanoparticles participating in the catalytic reaction. Oxygen reduction mainly occurs within the etched channels providing a nanoconfined reaction volume different from the bulk electrolyte conditions. The oxygen reduction reaction activity normalized by the electrochemically active surface area is enhanced by a factor of 3.3 for the nanozymes compared to the unetched nanoparticles and a factor of 2.1 compared to mesoporous PtNi nanoparticles that possess interconnecting pores.

This article seeks to evaluate the development of the Balkh Oasis in Northern Afghanistan, from the perspective of hydrological management. The concept of ‘oasis cities’ has been applied to several lowland settlement systems in Central Asia, characterised as fertile river deltas surrounded by deserts. Of these, the oasis surrounding the city of Balkh remains the least well archaeologically explored, in spite of the fact that it represents possibly the best preserved of similar hydrological systems. As new archaeological ground survey in the Balkh region remains challenging, the discussion here compares existing archaeological records and historical accounts of water management throughout the medieval and early modern period, combining them with evidence traced from high-resolution satellite imagery. The picture that emerges is a complex constellation of substantial settlements among agricultural lands beyond the core city, watered by tiers of divergent channels. Several key changes in the physical and political landscape necessitated the reorganisation of this hydrological network, and over time these shifts can be traced by contrasting the abandonment of some regions with the notable expansion of others.

To compare disease activity and disability over 2 years in early rheumatoid arthritis (RA) before and after implementation of treat‐to‐target therapy and identify predictors of adverse outcome. The Yorkshire Early Arthritis Register (YEAR) recruited 725 patients with early RAbetween 2002 and 2009, treated with a step‐up approach. The Inflammatory Arthritis Continuum study (IACON) recruited cases between 2010 and 2014 and treated to target. A total of 384 IACONcases met 2010 American College of Rheumatology/European League Against Rheumatism criteria. Latent growth curves of change in Disease Activity Score in 28 joints (DAS28) and the Health Assessment Questionnaire (HAQ) were compared between YEARand IACON. Latent class growth analysis identified trajectories of change. Baseline predictors of trajectories were identified using logistic regression. The mean DAS28 over 2 years was lower in IACONthan in YEAR. Latent trajectories of HAQchange in YEARwere high stable (21% of cohort), moderate reducing (35%), and low reducing (44%). Only moderate reducing (66%) and low reducing (34%) were seen in IACON. In both cohorts, female sex and fatigue predicted adverse HAQtrajectories (high stable and moderate reducing). Odds ratios (ORs) for moderate reducing compared to low reducing for women were 2.58 (95% confidence interval [95% CI] 1.69, 4.49) in YEARand 5.81 (95% CI2.44, 14.29) in IACON. ORs per centimeter fatigue visual analog score were 1.13 (95% CI1.07, 1.20) in YEARand 1.16 (95% CI1.12, 1.20) in IACON. Treat‐to‐target therapy gave more favorable trajectories of change in DAS28 and HAQ, but adverse HAQtrajectory was more likely in women with greater fatigue, suggesting such patients would benefit from interventions to improve function as well as reduce inflammation.

ABSTRACTThe dominant historical narrative for early Islamic frontier zones such as Arran, in the Caucasus, tends to focus on the administrative centres, the capital cities. As this story of development becomes synthesised and simplified, there has been a tendency to understand this process as the decline of one major centre and the rise of another, almost in the sense of city-states. This paper reconsiders the case of the changing capitals of Arran, to understand how urbanism developed in the Caucasus in the early Islamic period and how this gave rise to the situation as observed in the tenth–twelfth century when the region is essentially independent from the core Islamic lands, albeit regularly a vassal state. In doing so, new archaeological evidence is combined with that from existing historical sources, to propose a new model for the urban settlement patterns of the medieval period in the southeastern Caucasus.

Ankylosing spondylitis (AS) is the prototypic form of axial spondyloarthritis (axSpA). It is highly heritable, with studies conducted in twins and in unrelated cases and controls showing that the heritability for AS is much higher than those for inflammatory bowel disease or rheumatoid arthritis. To date, 116 loci have been identified, contributing to 28% of the genetic variation in the disease. These loci provide important clues into pathogenic pathways in the disease that have led to therapeutic advances such as the repositioning of IL-17 inhibitors in the disease. Much more research is currently required to determine the functional mechanisms by which the genetic associations operate, from which it is likely that novel therapeutic approaches will be developed.

This months' case study is from St. Margaret's Nursery, a maintained nursery school which is part of BEYA (Barnet Early Years Alliance.) It follows an example of how a group of children interact with an open-ended block play setup which is often seen in early years settings as part of their continuous provision.

The IL23R region on chromosome 1 exhibits complex associations with ankylosing spondylitis (AS). We used publicly available epigenomic information and historical genetic association data to identify a putative regulatory element (PRE) in the intergenic region between IL23R and IL12RB2, which includes two single-nucleotide polymorphisms (SNPs) independently associated with AS—rs924080 (P=2 × 10−3) and rs11578380 (P=2 × 10−4). In luciferase reporter assays, this PRE showed silencer activity (P<0.001). Haplotype and conditional analysis of 4230 historical AS cases and 9700 controls revealed a possible AS-associated extended haplotype, including the PRE and risk variants at three SNPs (rs11209026, rs11209032 and rs924080), but excluding the rs11578380 risk variant. However, the rs924080 association was absent after conditioning on the primary association with rs11209032, which, in contrast, was robust to conditioning on all other AS-associated SNPs in this region (P<2 × 10−8). The role of this putative silencer on some IL23R extended haplotypes therefore remains unclear.

We propose that the first Neoproterozoic Snowball Earth event, the Sturtian glaciation, was initiated by the injection of sulfate aerosols into the stratosphere. Geochronological data indicate that the Natkusiak magmatic assemblage of the Franklin large igneous province coincided with onset of the Sturtian glaciation. The Natkusiak was emplaced into an evaporite basin and entrained significant quantities of sulfur, which would have led to extensive SO2and H2S outgassing in hot convective plumes. The largest of these plumes could have penetrated the tropopause, leading to stratospheric sulfate aerosol formation and an albedo increase sufficient to force a Snowball. Radiative forcing was maximized by the equatorial location of the Franklin and the cool Neoproterozoic background climate, which would have lowered the tropopause height, increasing the rate of stratospheric aerosol injection. Our results have implications for understanding Phanerozoic mass extinction events, exoplanet habitability, and aerosol perturbations to the present‐day climate. The Franklin large igneous province was coincident with onset of the Sturtian Snowball Earth glaciationMultiyear to decadal fissure eruptions can inject enough sulfur aerosols to the stratosphere to initiate Snowball EarthCold background climate states are sensitive to ice‐albedo catastrophe because tropopause height is a function of surface temperature

The evidence for abundant liquid water on early Mars despite the faint young Sun is a long‐standing problem in planetary research. Here we present new ab initio spectroscopic and line‐by‐line climate calculations of the warming potential of reduced atmospheres on early Mars. We show that the strength of both CO2–H2and CO2–CH4collision‐induced absorption (CIA) has previously been significantly underestimated. Contrary to previous expectations, methane could have acted as a powerful greenhouse gas on early Mars due to CO2–CH4CIA in the critical 250–500 cm−1spectral window region. In atmospheres of 0.5 bar CO2or more, percent levels of H2or CH4raise annual mean surface temperatures by tens of degrees, with temperatures reaching 273 K for pressures of 1.25–2 bars and 2–10% of H2and CH4. Methane and hydrogen produced following aqueous alteration of Mars' crust could have combined with volcanically outgassed CO2to form transient atmospheres of this composition 4.5–3.5 Ga. Our results also suggest that inhabited exoplanets could retain surface liquid water at significant distances from their host stars. New ab initio and line‐by‐line calculations show that warming by H2in CO2atmospheres is far stronger than previously believedContrary to previous research, we show that methane could also have been an effective greenhouse gas on early MarsReducing atmospheres could have been produced transiently by a combination of aqueous alteration of Mars' crust and volcanic CO2outgassing

What allows a planet to be both within a potentially habitable zone and sustain habitability over long geologic time? With the advent of exoplanetary astronomy and the ongoing discovery of terrestrial‐type planets around other stars, our own solar system becomes a key testing ground for ideas about what factors control planetary evolution. Mars provides the solar system's longest record of the interplay of the physical and chemical processes relevant to habitability on an accessible rocky planet with an atmosphere and hydrosphere. Here we review current understanding and update the timeline of key processes in early Mars history. We then draw on knowledge of exoplanets and the other solar system terrestrial planets to identify six broad questions of high importance to the development and sustaining of habitability (unprioritized): (1) Is small planetary size fatal? (2) How do magnetic fields influence atmospheric evolution? (3) To what extent does starting composition dictate subsequent evolution, including redox processes and the availability of water and organics? (4) Does early impact bombardment have a net deleterious or beneficial influence? (5) How do planetary climates respond to stellar evolution, e.g., sustaining early liquid water in spite of a faint young Sun? (6) How important are the timescales of climate forcing and their dynamical drivers? Finally, we suggest crucial types of Mars measurements (unprioritized) to address these questions: (1) in situ petrology at multiple units/sites; (2) continued quantification of volatile reservoirs and new isotopic measurements of H, C, N, O, S, Cl, and noble gases in rocks that sample multiple stratigraphic sections; (3) radiometric age dating of units in stratigraphic sections and from key volcanic and impact units; (4) higher‐resolution measurements of heat flux, subsurface structure, and magnetic field anomalies coupled with absolute age dating. Understanding the evolution of early Mars will feed forward to understanding the factors driving the divergent evolutionary paths of the Earth, Venus, and thousands of small rocky extrasolar planets yet to be discovered. As more rocky planets are found around other stars, a key question is which factors are most important to understanding whether they are habitable? Within our solar system Mars preserves the longest record of the history of terrestrial planets, even longer than Earth. Exploration of Mars' rock record provides to the ability to understand why its environment ‐‐ its habitability ‐‐ changed so profoundly, going from a watery world, to the cold, dry world of today. In this paper, we review what is known of Mars history after several decades of exploration. We then list 6 key questions for understanding terrestrial planets generally and what makes them Earth‐like, Mars‐like, Venus‐like or otherwise have different fates. We then make recommendations of measurements needed in our own solar system, on Mars, to better understand how Earth‐like worlds change over time, keeping the ability to sustain life (or not) over time. Understanding the solar system terrestrial planets is crucial for interpretation of the history and habitability of rocky exoplanetsMars' accessible geologic record extends back past 4 Ga and possibly to as long ago as 5 Myr after solar system formationMars is key for testing theories of planetary evolution and processes that sustain habitability (or not) on rocky planets with atmospheres

AimsThe management of open lower limb fractures in the United Kingdom has evolved over the last ten years with the introduction of major trauma networks (MTNs), the publication of standards of care and the wide acceptance of a combined orthopaedic and plastic surgical approach to management. The aims of this study were to report recent changes in outcome of open tibial fractures following the implementation of these changes.Patients and MethodsData on all patients with an open tibial fracture presenting to a major trauma centre between 2011 and 2012 were collected prospectively. The treatment and outcomes of the 65 Gustilo Anderson Grade III B tibial fractures were compared with historical data from the same unit. ResultsThe volume of cases, the proportion of patients directly admitted and undergoing first debridement in a major trauma centre all increased. The rate of limb salvage was maintained at 94% and a successful limb reconstruction rate of 98.5% was achieved. The rate of deep bone infection improved to 1.6% (one patient) in the follow-up period. ConclusionThe reasons for these improvements are multifactorial, but the major trauma network facilitating early presentation to the major trauma centre, senior orthopaedic and plastic surgical involvement at every stage and proactive microbiological management, may be important factors. Take home message: This study demonstrates that a systemised trauma network combined with evidence based practice can lead to improvements in patient care.Cite this article: Bone Joint J2016;98-B:420–4.

This paper examines the effect of parish nursing as a faith community initiative to support the work of district and community nurses and improve health outcomes. It discusses the reasons why faith communities might embark upon health initiatives, and describes the practice of parish nursing and its history and development in the UK. With reference to both quantitative and qualitative outcomes, the relevance of the practice in the UK health scene is assessed. The paper suggests that connecting with the third sector through parish nursing could enhance the work of community and district nurses; this would present additional sources of holistic care and health promotion and can be offered in an optional but complementary manner to the care provided through the NHS.

Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B*27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B*27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B*27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.

IntroductionStandard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.MethodsThe Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant’s judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.DiscussionThis trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.

Slow and cumbersome laboratory diagnostics for Mycobacterium tuberculosiscomplex (MTBC) risk delayed treatment and poor patient outcomes. Whole-genome sequencing (WGS) could potentially provide a rapid and comprehensive diagnostic solution. In this prospective study, we compare real-time WGS with routine MTBC diagnostic workflows.

Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21?133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27and HLA-A*02:01were significantly associated with the presence of AAU (P<10-300and P=6 × 10-8, respectively). Secondary independent association with PSORS1C3(P=4.7 × 10-5) and TAP2(P=1.1 × 10-5) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 × 10-6). Heterogeneity testing showed that rs30187 in ERAP1has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS.