Climate change affects the distribution of diversity across marine food webs.

Many studies predict shifts in species distributions and community size composition in response to climate change, yet few have demonstrated how these changes will be distributed across marine food webs. We use Bayesian Additive Regression Trees to model how climate change will affect the habitat suitability of marine fish species across a range of body sizes and belonging to different feeding guilds, each with different habitat and feeding requirements in the northeast Atlantic shelf seas. Contrasting effects of climate change are predicted for feeding guilds, with spatially extensive decreases in the species richness of consumers lower in the food web (planktivores) but increases for those higher up (piscivores). Changing spatial patterns in predator-prey mass ratios and fish species size composition are also predicted for feeding guilds and across the fish assemblage. In combination, these changes could influence nutrient uptake and transformation, transfer efficiency and food web stability, and thus profoundly alter ecosystem structure and functioning.

Role of Half-of-Sites Reactivity and Inter-Subunit Communications in DAHP Synthase Catalysis and Regulation.

α-Carboxyketose synthases, including 3-deoxy-d-arabinoheptulosonate 7-phosphate synthase (DAHPS), are long-standing targets for inhibition. They are challenging targets to create tight-binding inhibitors against, and inhibitors often display half-of-sites binding and partial inhibition. Half-of-sites inhibition demonstrates the existence of inter-subunit communication in DAHPS. We used X-ray crystallography and spatially resolved hydrogen-deuterium exchange (HDX) to reveal the structural and dynamic bases for inter-subunit communication in Escherichia coli DAHPS(Phe), the isozyme that is feedback-inhibited by phenylalanine. Crystal structures of this homotetrameric (dimer-of-dimers) enzyme are invariant over 91% of its sequence. Three variable loops make up 8% of the sequence and are all involved in inter-subunit contacts across the tight-dimer interface. The structures have pseudo-twofold symmetry indicative of inter-subunit communication across the loose-dimer interface, with the diagonal subunits B and C always having the same conformation as each other, while subunits A and D are variable. Spatially resolved HDX reveals contrasting responses to ligand binding, which, in turn, affect binding of the second substrate, erythrose-4-phosphate (E4P). The N-terminal peptide, M1-E12, and the active site loop that binds E4P, F95-K105, are key parts of the communication network. Inter-subunit communication appears to have a catalytic role in all α-carboxyketose synthase families and a regulatory role in some members.

Assessment of Patient Satisfaction Among Cancer Patients Undergoing Radiotherapy.

The patient-provider relationship is a key driver of patient satisfaction as it relates to overall healthcare experience. We surveyed patients undergoing radiation therapy to determine what they consider to be the most valued qualities in their interactions with the healthcare team. An ethics-approved 35-item patient satisfaction survey was developed in-house to gain insights on patients' perception of their relationship with the healthcare team throughout their cancer journey. There were 199 completed survey, median age 68 years, 54% women and 45% men. Almost all (95%) "agreed" or "strongly agreed" that their physicians had been sensitive and compassionate. Over 90% felt that they received adequate explanations about their treatment, and had their questions answered. The vast majority (93%) felt included in the decision-making process. Patients reported the 5 most highly rated qualities among their healthcare providers (HCPs) as knowledge, kindness, honesty, good communication, and a cheerful attitude. Overall satisfaction was high but areas for improvement were identified including being offered future appointments for further discussion, more information about clinical trials, other treatments, and community resources. Patients noted their HCPs tended to focus on the physical and emotional needs of patients, but spiritual and cultural needs were rarely addressed. Patients receiving radiotherapy reported high rates of satisfaction across many aspects of their care. These findings also reinforce the different aspects of holistic care that can be improved, and serve as a reminder to clinicians that patients perceive their role as more than just that of a medical expert.

What's hot and what's not: Making sense of biodiversity 'hotspots'.

Conserving biogeographic regions with especially high biodiversity, known as biodiversity 'hotspots', is intuitive because finite resources can be focussed towards manageable units. Yet, biodiversity, environmental conditions and their relationship are more complex with multidimensional properties. Assessments which ignore this risk failing to detect change, identify its direction or gauge the scale of appropriate intervention. Conflicting concepts which assume assemblages as either sharply delineated communities or loosely collected species have also hampered progress in the way we assess and conserve biodiversity. We focus on the marine benthos where delineating manageable areas for conservation is an attractive prospect because it holds most marine species and constitutes the largest single ecosystem on earth by area. Using two large UK marine benthic faunal datasets, we present a spatially gridded data sampling design to account for survey effects which would otherwise be the principal drivers of diversity estimates. We then assess γ-diversity (regional richness) with diversity partitioned between α (local richness) and ß (dissimilarity), and their change in relation to covariates to test whether defining and conserving biodiversity hotspots is an effective conservation strategy in light of the prevailing forces structuring those assemblages. α-, ß- and γ-diversity hotspots were largely inconsistent with each metric relating uniquely to the covariates, and loosely collected species generally prevailed with relatively few distinct assemblages. Hotspots could therefore be an unreliable means to direct conservation efforts if based on only a component part of diversity. When assessed alongside environmental gradients, α-, ß- and γ-diversity provide a multidimensional but still intuitive perspective of biodiversity change that can direct conservation towards key drivers and the appropriate scale for intervention. Our study also highlights possible temporal declines in species richness over 30 years and thus the need for future integrated monitoring to reveal the causal drivers of biodiversity change.

Systematic variation in food web body-size structure linked to external subsidies.

The relationship between body mass (M) and size class abundance (N) depicts patterns of community structure and energy flow through food webs. While the general assumption is that M and N scale linearly (on log-log axes), nonlinearity is regularly observed in natural systems, and is theorized to be driven by nonlinear scaling of trophic level (TL) with M resulting in the rapid transfer of energy to consumers in certain size classes. We tested this hypothesis with data from 31 stream food webs. We predicted that allochthonous subsidies higher in the web results in nonlinear M-TL relationships and systematic abundance peaks in macroinvertebrate and fish size classes (latter containing salmonids), that exploit terrestrial plant material and terrestrial invertebrates, respectively. Indeed, both M-N and M-TL significantly deviated from linear relationships and the observed curvature in M-TL scaling was inversely related to that observed in M-N relationships. Systemic peaks in M-N, and troughs in M-TL occurred in size classes dominated by generalist invertebrates, and brown trout. Our study reveals how allochthonous resources entering high in the web systematically shape community size structure and demonstrates the relevance of a generalized metabolic scaling model for understanding patterns of energy transfer in energetically 'open' food webs.

Caesarean birth and risk of subsequent preterm birth: a retrospective cohort study.

OBJECTIVE: To determine the risk of spontaneous and medically indicated preterm birth associated with mode of birth in previous term-born pregnancy. DESIGN: Retrospective cohort study. SETTING: Two UK maternity units. POPULATION OR SAMPLE: A total of 16 340 women with first two consecutive singleton births and the first birth at term. METHODS: Retrospective cohort study using routinely collected clinical data. MAIN OUTCOME MEASURES: Incidence of spontaneous preterm birth and medically indicated preterm birth at less than 37 weeks of gestation after term birth, in relation to mode of birth in first pregnancy. Subgroup analysis on cervical dilatation at the time of first caesarean birth. RESULTS: Compared with vaginal birth, emergency caesarean birth at full dilatation was associated with an increase in spontaneous preterm birth (2.3% vaginal birth versus 4.5% full dilatation caesarean; adjusted odds ratio [aOR] 3.29, 95% CI 2.02-5.13, P < 0.001). Elective caesarean, emergency caesarean at <4 cm dilatation, and emergency caesarean at 4-9 cm dilatation were associated with increased medically indicated preterm birth (0.8% vaginal births versus 1.9% elective caesarean, 3.3% <4 cm caesarean, 1.3% 4-9 cm caesarean; aOR 2.30, 95% CI 1.19-4.15, P = 0.009; aOR 4.68, 95% CI 2.98-7.24, P < 0.001; and aOR 2.43, 95% CI 1.43-4.00, P = 0.001, respectively). CONCLUSIONS: Term caesarean in the first stage of labour or performed prelabour is associated with medically indicated preterm birth. Term caesarean in the second stage of labour is associated with spontaneous preterm birth. TWEETABLE ABSTRACT: Caesarean in the second stage of labour is associated with spontaneous preterm birth.

Modifying a covarying protein-DNA interaction changes substrate preference of a site-specific endonuclease.

Identifying and validating intermolecular covariation between proteins and their DNA-binding sites can provide insights into mechanisms that regulate selectivity and starting points for engineering new specificity. LAGLIDADG homing endonucleases (meganucleases) can be engineered to bind non-native target sites for gene-editing applications, but not all redesigns successfully reprogram specificity. To gain a global overview of residues that influence meganuclease specificity, we used information theory to identify protein-DNA covariation. Directed evolution experiments of one predicted pair, 227/+3, revealed variants with surprising shifts in I-OnuI substrate preference at the central 4 bases where cleavage occurs. Structural studies showed significant remodeling distant from the covarying position, including restructuring of an inter-hairpin loop, DNA distortions near the scissile phosphates, and new base-specific contacts. Our findings are consistent with a model whereby the functional impacts of covariation can be indirectly propagated to neighboring residues outside of direct contact range, allowing meganucleases to adapt to target site variation and indirectly expand the sequence space accessible for cleavage. We suggest that some engineered meganucleases may have unexpected cleavage profiles that were not rationally incorporated during the design process.

Structure-specific endonuclease activity of SNM1A enables processing of a DNA interstrand crosslink.

DNA interstrand crosslinks (ICLs) covalently join opposing strands, blocking both replication and transcription, therefore making ICL-inducing compounds highly toxic and ideal anti-cancer agents. While incisions surrounding the ICL are required to remove damaged DNA, it is currently unclear which endonucleases are needed for this key event. SNM1A has been shown to play an important function in human ICL repair, however its suggested role has been limited to exonuclease activity and not strand incision. Here we show that SNM1A has endonuclease activity, having the ability to cleave DNA structures that arise during the initiation of ICL repair. In particular, this endonuclease activity cleaves single-stranded DNA. Given that unpaired DNA regions occur 5' to an ICL, these findings suggest SNM1A may act as either an endonuclease and/or exonuclease during ICL repair. This finding is significant as it expands the potential role of SNM1A in ICL repair.

Active site residue identity regulates cleavage preference of LAGLIDADG homing endonucleases.

LAGLIDADG homing endonucleases (meganucleases) are site-specific mobile endonucleases that can be adapted for genome-editing applications. However, one problem when reprogramming meganucleases on non-native substrates is indirect readout of DNA shape and flexibility at the central 4 bases where cleavage occurs. To understand how the meganuclease active site regulates DNA cleavage, we used functional selections and deep sequencing to profile the fitness landscape of 1600 I-LtrI and I-OnuI active site variants individually challenged with 67 substrates with central 4 base substitutions. The wild-type active site was not optimal for cleavage on many substrates, including the native I-LtrI and I-OnuI targets. Novel combinations of active site residues not observed in known meganucleases supported activity on substrates poorly cleaved by the wild-type enzymes. Strikingly, combinations of E or D substitutions in the two metal-binding residues greatly influenced cleavage activity, and E184D variants had a broadened cleavage profile. Analyses of I-LtrI E184D and the wild-type proteins co-crystallized with the non-cognate AACC central 4 sequence revealed structural differences that correlated with kinetic constants for cleavage of individual DNA strands. Optimizing meganuclease active sites to enhance cleavage of non-native central 4 target sites is a straightforward addition to engineering workflows that will expand genome-editing applications.

Macrolide-susceptible probiotic Enterococcus faecium ST296 exhibits faecal-environmental-oral microbial community cycling among beef cattle in feedlots.

Enterococci are included in the United States National Antimicrobial Resistance Monitoring System to track antibiotic resistance among commensal Gram-positive enteric bacteria, largely due to their high abundance in food animals and in retail meat. In the U.S. cattle industry, macrolides are used to prevent and control liver abscesses, which cause significant economic losses. Previous studies have suggested that feeding tylosin and the intensity of the pen environment, both expand and sustain respectively the prevalence of multidrug resistance among enterococci in feedlot cattle. This has led to research into alternative feed supplements and improved stewardship practices. In a randomized controlled trial, we measured the impact of a probiotic and an altered pen environment on antimicrobial resistance among faecal Enterococcus spp. in cattle fed tylosin. Supplementing cattle with an Enterococcus faecium and Saccharomyces cerevisiae-based probiotic yielded the isolation of E. faecium of the probiotic sequence type (ST296) from faecal and environmental samples in treatment groups, as well as from cattle and the manure pack in nearby pens. Of importance, the probiotic strain also was found in a desiccated and milled manure pack sample taken 120 days after the initial trial ended. Phylogenetic and SNP analyses revealed clonal survival and spread compatible with faecal-environmental-oral recycling of the probiotic strain within and among cattle and pens. The increase in prevalence of the ST296 strain occurred concomitant with a decrease in ST240, the dominant sequence type associated with ermB and tet(M) resistance genes in this trial. SIGNIFICANCE AND IMPACT OF THE STUDY: We demonstrate that a macrolide-susceptible probiotic Enterococcus faecium ST296 strain fed to beef cattle becomes fully embedded in the microbial community cycling of bacteria via faecal-environmental-oral transmission within and among feedlot pens. An initial investment in feeding the probiotic is thereby leveraged into expanding numbers of susceptible bacteria in cattle and their environment, even among those cattle fed tylosin.

NeuNAc Oxime: A Slow-Binding and Effectively Irreversible Inhibitor of the Sialic Acid Synthase NeuB.

NeuB is a bacterial sialic acid synthase used by neuroinvasive bacteria to synthesize N-acetylneuraminate (NeuNAc), helping them to evade the host immune system. NeuNAc oxime is a potent slow-binding NeuB inhibitor. It dissociated too slowly to be detected experimentally, with initial estimates of its residence time in the active site being >47 days. This is longer than the lifetime of a typical bacterial cell, meaning that inhibition is effectively irreversible. Inhibition data fitted well to a model that included a pre-equilibration step with a Ki of 36 µM, followed by effectively irreversible conversion to an E*·I complex, with a k2 of 5.6 × 10-5 s-1. Thus, the inhibitor can subvert ligand release and achieve extraordinary residence times in spite of a relatively modest initial dissociation constant. The crystal structure showed the oxime functional group occupying the phosphate-binding site normally occupied by the substrate PEP and the tetrahedral intermediate. There was an ≈10% residual rate at high inhibitor concentrations regardless of how long NeuB and NeuNAc oxime were preincubated together. However, complete inhibition was achieved by incubating NeuNAc oxime with the actively catalyzing enzyme. This requirement for the enzyme to be actively turning over for the inhibitor to bind to the second subunit demonstrated an important role for intersubunit communication in the inhibitory mechanism.

Public attitudes towards novel reproductive technologies: a citizens' jury on mitochondrial donation.

STUDY QUESTION: Does an informed group of citizens endorse the clinical use of mitochondrial donation in a country where this is not currently permitted? SUMMARY ANSWER: After hearing balanced expert evidence and having opportunity for deliberation, a majority (11/14) of participants in a citizens' jury believed that children should be able to be born using mitochondrial donation. WHAT IS KNOWN ALREADY: Research suggests that patients, oocyte donors and health professionals support mitochondrial donation to prevent transmission of mitochondrial disease. Less is known about public acceptability of this novel reproductive technology, especially from evidence using deliberative methods. STUDY DESIGN, SIZE, DURATION: This study comprised a citizens' jury, an established method for determining the views of a well-informed group of community members. The jury had 14 participants, and ran over one and a half days in 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Jurors were members of the public with no experience of mitochondrial disease. They heard and engaged with relevant evidence and were asked to answer the question: 'Should Australia allow children to be born following mitochondrial donation?' MAIN RESULTS AND THE ROLE OF CHANCE: Eleven jurors decided that Australia should allow children to be born following mitochondrial donation; 7 of whom added conditions such as the need to limit who can access the intervention. Three jurors decided that children should not (or not yet) be born using this intervention. All jurors were particularly interested in the reliability of evidence, licensing/regulatory mechanisms and the rights of children to access information about their oocyte donors. LIMITATIONS, REASONS FOR CAUTION: Jurors' views were well informed and reflected critical deliberation and discussion, but are not intended to be representative of the whole population. WIDER IMPLICATIONS OF THE FINDINGS: When presented with high quality evidence, combined with opportunities to undertake structured deliberation of novel reproductive technologies, members of the public are able to engage in detailed discussions. This is the first study to use an established deliberative method to gauge public views towards mitochondrial donation. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a University of Sydney Industry and Community Collaboration Seed Award (2017), which was awarded contingent on additional funding from the Mito Foundation. Additional funding was provided by the Mito Foundation. The Foundation was not involved in jury facilitation or deliberation, nor analysis of research data. TRIAL REGISTRATION NUMBER: Not applicable.

Comparing biotic drivers of litter breakdown across stream compartments.

Litter breakdown in the streambed is an important pathway in organic carbon cycling and energy transfer in the biosphere that is mediated by a wide range of streambed organisms. However, most research on litter breakdown to date has focused on a small fraction of the taxa that drive it (e.g. microbial vs. macroinvertebrate-mediated breakdown) and has been limited to the benthic zone (BZ). Despite the importance of the hyporheic zone (HZ) as a bioreactor, little is known about what, or who, mediates litter breakdown in this compartment and whether breakdown rates differ between the BZ and HZ. Here, we explore the relationship between litter breakdown and the variation in community structure of benthic and hyporheic communities by deploying two standardized bioassays (cotton strips and two types of commercially available tea bags) in 30 UK streams that encompass a range of environmental conditions. Then, we modelled these assays as a response of the streambed compartment and the biological features of the streambed assemblage (Prokaryota, Protozoa and Eumetazoa invertebrates) to understand the generality and efficiency of litter processing across communities. Litter breakdown was much faster in the BZ compared with the HZ (around 5 times higher for cotton strips and 1.5 times faster for the tea leaves). However, differences in litter breakdown between the BZ and the HZ were mediated by the biological features of the benthos and the hyporheos. Biomass of all the studied biotic groups, α-diversity of Eumetazoa invertebrates and metabolic diversity of Prokaryota were important predictors that were positively related to breakdown coefficients demonstrating their importance in the functioning of the streambed ecosystem. Our study uses a novel multimetric bioassay that is able to disentangle the contribution by Prokaryota, Protozoa and Eumetazoa invertebrates to litter breakdown. In doing so, our study reveals new insights into how organic matter decomposition is partitioned across biota and streambed compartments.

Can mental health treatments help prevent or reduce intimate partner violence in low- and middle-income countries? A systematic review.

BACKGROUND: Epidemiological research suggests an interrelationship between mental health problems and the (re)occurrence of intimate partner violence (IPV). However, little is known about the impact of mental health treatments on IPV victimization or perpetration, especially in low- and middle-income countries (LMIC). METHODS: We conducted a systematic review to identify prospective, controlled studies of mental health treatments in LMIC. We defined 'mental health treatment' as an intervention for individuals experiencing mental ill health (including substance misuse) including a substantial psychosocial or pharmacological component. Studies had to measure a mental health and IPV outcome. We searched across multi-disciplinary databases using a structured search strategy. Screening of title/abstracts and full-text eligibility assessments were conducted by two researchers independently, data were extracted using a piloted spreadsheet, and a narrative synthesis was generated. RESULTS: We identified seven studies reported in 11 papers conducted in five middle-income countries. With the exception of blinding, studies overall showed acceptable levels of risk of bias. Four of the seven studies focused on dedicated mental health treatments in various populations, including: common mental disorders in earthquake survivors; depression in primary care; alcohol misuse in men; and alcohol misuse in female adult sex workers. The dedicated mental health treatments targeting depression or alcohol misuse consistently reduced levels of these outcomes. The two studies targeting depression also reduced short-term IPV, but no IPV benefits were identified in the two alcohol-focused studies. The other three studies evaluated integrated interventions, in which a focus on substance misuse was part of efforts to reduce HIV/AIDS and violence against particularly vulnerable women. In contrast to the dedicated mental health interventions, the integrated interventions did not consistently reduce mental ill health or alcohol misuse compared to control conditions. CONCLUSIONS: Too few studies have been conducted to judge whether mental health treatments may provide a beneficial strategy to prevent or reduce IPV in LMIC. Key future research questions include: whether promising initial evidence on the effects of depression interventions on reducing IPV hold more broadly, the required intensity of mental health components in integrated interventions, and the identification of mechanisms of IPV that are amenable to mental health intervention.

Mechanism for accurate, protein-assisted DNA annealing by Deinococcus radiodurans DdrB.

Accurate pairing of DNA strands is essential for repair of DNA double-strand breaks (DSBs). How cells achieve accurate annealing when large regions of single-strand DNA are unpaired has remained unclear despite many efforts focused on understanding proteins, which mediate this process. Here we report the crystal structure of a single-strand annealing protein [DdrB (DNA damage response B)] in complex with a partially annealed DNA intermediate to 2.2 Å. This structure and supporting biochemical data reveal a mechanism for accurate annealing involving DdrB-mediated proofreading of strand complementarity. DdrB promotes high-fidelity annealing by constraining specific bases from unauthorized association and only releases annealed duplex when bound strands are fully complementary. To our knowledge, this mechanism provides the first understanding for how cells achieve accurate, protein-assisted strand annealing under biological conditions that would otherwise favor misannealing.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

Bending the rules: exploitation of allochthonous resources by a top-predator modifies size-abundance scaling in stream food webs.

Body mass-abundance (M-N) allometries provide a key measure of community structure, and deviations from scaling predictions could reveal how cross-ecosystem subsidies alter food webs. For 31 streams across the UK, we tested the hypothesis that linear log-log M-N scaling is shallower than that predicted by allometric scaling theory when top predators have access to allochthonous prey. These streams all contained a common and widespread top predator (brown trout) that regularly feeds on terrestrial prey and, as hypothesised, deviations from predicted scaling increased with its dominance of the fish assemblage. Our study identifies a key beneficiary of cross-ecosystem subsidies at the top of stream food webs and elucidates how these inputs can reshape the size-structure of these 'open' systems.

Pretreatment chest x-ray severity and its relation to bacterial burden in smear positive pulmonary tuberculosis.

BACKGROUND: Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. METHODS: Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577-87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. RESULTS: For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16-30, p < 0.001) in patients without cavitation compared to those with cavitation. The median percentage of lung-field affected was 18.1% (IQR 11.3-28.8%). For every 10-fold increase in TTP, the area of lung field affected decreased by 11.4%. Multivariable models showed that serum albumin decreased significantly as the percentage of lung field area increased in both those with and without cavitation. In addition, BMI and logged TTP had a small but significant effect in those with cavitation and the number of severe TB symptoms in the non-cavitation group also had a small effect, whilst other factors found to be significant on univariable analysis lost this effect in the model. CONCLUSIONS: The radiological severity of disease on chest x-ray prior to treatment in smear positive pulmonary TB patients is weakly associated with the bacterial burden. When compared against other variables at diagnosis, this effect is lost in those without cavitation. Radiological severity does reflect the overall disease severity in smear positive pulmonary TB, but we suggest that clinicians should be cautious in over-interpreting the significance of radiological disease extent at diagnosis.

Alterations in circulating lymphoid cell populations in systemic small vessel vasculitis are non-specific manifestations of renal injury.

Innate lymphocyte populations, such as innate lymphoid cells (ILCs), γδ T cells, invariant natural killer T (iNK T) cells and mucosal-associated invariant T (MAIT) cells are emerging as important effectors of innate immunity and are involved in various inflammatory and autoimmune diseases. The aim of this study was to assess the frequencies and absolute numbers of innate lymphocytes as well as conventional lymphocytes and monocytes in peripheral blood from a cohort of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV) patients. Thirty-eight AAV patients and 24 healthy and disease controls were included in the study. Patients with AAV were sampled both with and without immunosuppressive treatment, and in the setting of both active disease and remission. The frequencies of MAIT and ILC2 cells were significantly lower in patients with AAV and in the disease control group compared to healthy controls. These reductions in the AAV patients remained during remission. B cell count and frequencies were significantly lower in AAV in remission compared to patients with active disease and disease controls. Despite the strong T helper type 2 (Th) preponderance of eosinophilic granulomatosis with polyangiitis, we did not observe increased ILC2 frequency in this cohort of patients. The frequencies of other cell types were similar in all groups studied. Reductions in circulating ILC2 and MAIT cells reported previously in patients with AAV are not specific for AAV, but are more likely to be due to non-specific manifestations of renal impairment and chronic illness. Reduction in B cell numbers in AAV patients experiencing remission is probably therapy-related.

Living and dying with metastatic bowel cancer: Serial in-depth interviews with patients.

Colorectal cancer is the second highest cause of cancer deaths. There are significant physical and psycho-social effects on quality of life with advanced disease. Despite this, there are few accounts of the patient experience from advanced illness through to dying. We elicited the longitudinal experiences of living and dying with incurable metastatic colorectal cancer by conducting serial interviews with patients for 12 months or until they died. The interviews were analysed, using a narrative approach, longitudinally as case studies and then together. Thirty-six interviews with 16 patients were conducted. Patients experience metastatic colorectal cancer in three phases; (1) Diagnosis and initial treatment; (2) Deterioration and social isolation and (3) Death and dying. Many patients initially said they hoped to survive, but, as "private" and in-depth accounts of the experience emerged in further interviews, so did the understanding that this hope co-existed with the knowledge that death was near. Palliative chemotherapy and the challenge of accessing private accounts of patient experience can inhibit care planning and prevent patients benefitting from an active holistic palliative care approach earlier in the disease trajectory. This study has immediate clinical relevance for health care professionals in oncology, palliative care and primary care.