Infection induces tissue-resident memory NK cells that safeguard tissue health.

Tissue health is dictated by the capacity to respond to perturbations and then return to homeostasis. Mechanisms that initiate, maintain, and regulate immune responses in tissues are therefore essential. Adaptive immunity plays a key role in these responses, with memory and tissue residency being cardinal features. A corresponding role for innate cells is unknown. Here, we have identified a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells were recruited in a CX3CR1-dependent manner to the salivary glands where they formed NKRM cells, a long-lived, tissue-resident population that prevented autoimmunity via TRAIL-dependent elimination of CD4+ T cells. Thus, NK cells develop adaptive-like features, including long-term residency in non-lymphoid tissues, to modulate inflammation, restore immune equilibrium, and preserve tissue health. Modulating the functions of NKRM cells may provide additional strategies to treat inflammatory and autoimmune diseases.

FOXG1 targets BMP repressors and cell cycle inhibitors in human neural progenitor cells.

FOXG1 is a critical transcription factor in human brain where loss-of-function mutations cause a severe neurodevelopmental disorder, while increased FOXG1 expression is frequently observed in glioblastoma. FOXG1 is an inhibitor of cell patterning and an activator of cell proliferation in chordate model organisms but different mechanisms have been proposed as to how this occurs. To identify genomic targets of FOXG1 in human neural progenitor cells (NPCs), we engineered a cleavable reporter construct in endogenous FOXG1 and performed chromatin immunoprecipitation (ChIP) sequencing. We also performed deep RNA sequencing of NPCs from two females with loss-of-function mutations in FOXG1 and their healthy biological mothers. Integrative analyses of RNA and ChIP sequencing data showed that cell cycle regulation and Bone Morphogenic Protein (BMP) repression gene ontology categories were over-represented as FOXG1 targets. Using engineered brain cell lines, we show that FOXG1 specifically activates SMAD7 and represses CDKN1B. Activation of SMAD7 which inhibits BMP signaling may be one way that FOXG1 patterns the forebrain, while repression of cell cycle regulators such as CDKN1B may be one way that FOXG1 expands the NPC pool to ensure proper brain size. Our data reveal novel mechanisms on how FOXG1 may control forebrain patterning and cell proliferation in human brain development.

Infant Sleep Hazards and the Risk of Sudden Unexpected Death in Infancy.

OBJECTIVE: To examine the effects of infant sofa-sleeping, recent use by caregivers of alcohol, cannabis, and/or other drugs, and bed type and pillows, on the risk of sudden unexpected death in infancy (SUDI) in New Zealand. STUDY DESIGN: A nationwide prospective case-control study was implemented between March 2012 and February 2015. Data were collected during interviews with parents/caregivers. "Hazards" were defined as infant exposure to 1 or more of sofa-sleeping and recent use by caregivers of alcohol, cannabis, and other drugs. The interaction of hazards with tobacco smoking in pregnancy and bed sharing, including for very young infants, and the difference in risk for Maori and non-Maori infants, also were assessed. RESULTS: The study enrolled 132 cases and 258 controls. SUDI risk increased with infant sofa-sleeping (imputed aOR [IaOR] 24.22, 95% CI 1.65-356.40) and with hazards (IaOR 3.35, 95% CI 1.40-8.01). The SUDI risk from the combination of tobacco smoking in pregnancy and bed sharing (IaOR 29.0, 95% CI 10.10-83.33) increased with the addition of 1 or more hazards (IaOR 148.24, 95% CI 15.72-1398), and infants younger than 3 months appeared to be at greater risk (IaOR 450.61, 95% CI 26.84-7593.14). CONCLUSIONS: Tobacco smoking in pregnancy and bed sharing remain the greatest SUDI risks for infants and risk increases further in the presence of sofa-sleeping or recent caregiver use of alcohol and/or cannabis and other drugs. Continued implementation of effective, appropriate programs for smoking cessation, safe sleep, and supplying safe sleep beds is required to reduce New Zealand SUDI rates and SUDI disparity among Maori.

The cost-effectiveness of antenatal and postnatal education and support interventions for women aimed at promoting breastfeeding in the UK.

BACKGROUND: Breastfeeding is associated with health benefits to mothers and babies and cost-savings to the health service. Breastfeeding rates in the UK are low for various reasons including cultural barriers, inadequate support to initiate and sustain breastfeeding, lack of information, or choice not to breastfeed. Education and support interventions have been developed aiming at promoting breastfeeding rates. The objective of this study was to assess the cost-effectiveness of such interventions for women, initiated antenatally or in the first 8 weeks postnatally, aiming at improving breastfeeding rates, in the UK. METHODS: A decision-analytic model was constructed to compare costs and quality-adjusted life-years (QALYs) of a breastfeeding intervention from the perspective of health and personal social services in England. Data on intervention effectiveness and the benefits of breastfeeding were derived from systematic reviews. Other model input parameters were obtained from published sources, supplemented by expert opinion. RESULTS: The incremental cost-effectiveness ratio (ICER) of the modelled intervention added on standard care versus standard care was £51,946/QALY, suggesting that the intervention is not cost-effective under National Institute for Health and Care Excellence (NICE) criteria in England. Sensitivity analysis suggested that the cost-effectiveness of the intervention improved as its effectiveness increased and intervention cost decreased. At the base-case effect (increase in breastfeeding rates 16-26 weeks after birth by 19%), the intervention was cost-effective (<£20,000/QALY) if its cost per woman receiving the intervention became ≈£40-£45. At the base-case cost (£84), the intervention was cost-effective if it increased breastfeeding rates by at least 35-40%. CONCLUSIONS: Available breastfeeding interventions do not appear to be cost-effective under NICE criteria in England. Future breastfeeding interventions need to have higher effectiveness or lower cost compared with currently available interventions in order to become cost-effective. Public health and other societal interventions that protect, promote and support breastfeeding may be key in improving breastfeeding rates in the UK.

Improving engagement with services to prevent Sudden Unexpected Death in Infancy (SUDI) in families with children at risk of significant harm: A systematic review of evidence.

This paper reports part of a wider systematic review commissioned by the English National Safeguarding Panel on Sudden Unexpected Death in Infancy (SUDI). The wider review covered three areas: interventions to improve safer sleep practices in high-risk families, interventions to improve engagement with services and decision making by parents at high risk of SUDI about infant sleep environments. Here, we report the qualitative and quantitative studies reviewed under the engagement strand. Parental engagement is understood to be a multidimensional task for health and social care professionals comprising attitudinal, relational and behavioural components. Following a PROSPERO registered systematic review synthesizing the three strands outlined, 28 papers were found to be relevant in the review of interventions to improve engagement with services in families with children at risk of significant harm through abuse or neglect. No studies were found that specifically focused on engagement of families at high risk for SUDI, so these wider engagement studies were included. The different types of intervention reported in the included studies are described under two broad themes: Enablers (including parental motivation and working with families) and Barriers. Given the focus in the studies on interventions that support parental engagement, the Enablers theme is more extensive than the Barriers reported although all studies noted well-understood barriers. The evidence underpinning these interventions and approaches are reviewed in this paper. We conclude that effective engagement is facilitated by experienced professionals given time to develop supportive non-judgemental relationships with families in their homes, working long-term, linking with communities and other services. While these conclusions have been drawn from wider studies aimed at reducing child maltreatment, we emphasize lessons to be drawn for SUDI prevention work with families with children at risk of significant harm.

Cytomegalovirus establishes a latent reservoir and triggers long-lasting inflammation in the eye.

Recent outbreaks of Ebola and Zika have highlighted the possibility that viruses may cause enduring infections in tissues like the eye, including the neural retina, which have been considered immune privileged. Whether this is a peculiarity of exotic viruses remains unclear, since the impact of more common viral infections on neural compartments has not been examined, especially in immunocompetent hosts. Cytomegalovirus is a common, universally distributed pathogen, generally innocuous in healthy individuals. Whether in immunocompetent hosts cytomegalovirus can access the eye, and reside there indefinitely, was unknown. Using the well-established murine cytomegalovirus infection model, we show that systemic infection of immunocompetent hosts results in broad ocular infection, chronic inflammation and establishment of a latent viral pool in the eye. Infection leads to infiltration and accumulation of anti-viral CD8+ T cells in the eye, and to the development of tissue resident memory T cells that localize to the eye, including the retina. These findings identify the eye as an unexpected reservoir for cytomegalovirus, and suggest that common viruses may target this organ more frequently than appreciated. Notably, they also highlight that infection triggers sustained inflammatory responses in the eye, including the neural retina.

The influence of self-compassion on perceived responsibility and shame following acquired brain injury.

PRIMARY OBJECTIVE: The purpose of this study was to investigate the influence of perceived personal responsibility for an acquired ABI (ABI) on shame, and whether self-compassion moderates this relationship. We hypothesized that people who perceived themselves to be responsible for their injury would have high levels of shame and poorer recovery outcomes. RESEARCH DESIGN: A mixed-methods design was employed using both standardized measures and a series of open questions. METHODS AND PROCEDURES: 66 participants with ABI were included in the analysis. Data were analyzed using descriptive statistics, correlations, multiple regression, and thematic analysis. MAIN OUTCOMES AND RESULTS: Significant relationships were found between self-compassion, shame, anxiety, and depression, but perceived responsibility for ABI was not correlated with any examined variables. Due to issues with the measurement of responsibility, it was not possible to complete all proposed forms of analysis. The thematic analysis revealed the ways participants' injuries affected their perceived level of functioning, its consequences for sense of self, shame, and self-compassion. CONCLUSIONS: This study concluded that people with ABI might experience shame with respect to the injury's impact on functioning. Study limitations and implications for providing therapeutic interventions such as Compassion Focused Therapy and Acceptance and Commitment Therapy are discussed.

Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS. METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. FINDINGS: Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057). INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

Noncardiac genetic predisposition in sudden infant death syndrome.

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls. METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis. RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS. CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity.

Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.

Deconstructing compassionate conservation.

Compassionate conservation focuses on 4 tenets: first, do no harm; individuals matter; inclusivity of individual animals; and peaceful coexistence between humans and animals. Recently, compassionate conservation has been promoted as an alternative to conventional conservation philosophy. We believe examples presented by compassionate conservationists are deliberately or arbitrarily chosen to focus on mammals; inherently not compassionate; and offer ineffective conservation solutions. Compassionate conservation arbitrarily focuses on charismatic species, notably large predators and megaherbivores. The philosophy is not compassionate when it leaves invasive predators in the environment to cause harm to vastly more individuals of native species or uses the fear of harm by apex predators to terrorize mesopredators. Hindering the control of exotic species (megafauna, predators) in situ will not improve the conservation condition of the majority of biodiversity. The positions taken by so-called compassionate conservationists on particular species and on conservation actions could be extended to hinder other forms of conservation, including translocations, conservation fencing, and fertility control. Animal welfare is incredibly important to conservation, but ironically compassionate conservation does not offer the best welfare outcomes to animals and is often ineffective in achieving conservation goals. Consequently, compassionate conservation may threaten public and governmental support for conservation because of the limited understanding of conservation problems by the general public.

Deconstrucción de la Conservación Compasiva Resumen La conservación compasiva se enfoca en cuatro principios: no causar daño; los individuos importan; la integración de los animales individualmente; y la coexistencia pacífica entre los humanos u los animales. Recientemente, la conservación compasiva ha sido promovida como una alternativa a la filosofía convencional de la conservación. Creemos que los ejemplos presentados por los conservacionistas compasivos han sido elegidos arbitraria o deliberadamente por estar enfocados en los mamíferos; por ser inherentes y no compasivos; y por ofrecer soluciones de conservación poco efectivas. La conservación compasiva se enfoca arbitrariamente en las especies carismáticas, principalmente los grandes depredadores y los megaherbívoros. La filosofía no es compasiva cuando deja que los depredadores invasores dentro del ambiente causen daño a un vasto número de individuos nativos o usa el miedo al daño por superdepredadores para aterrorizar a los mesodepredadores. El entorpecimiento del control de especies exóticas (megafauna, depredadores) in situ no mejorará las condiciones de conservación de la mayoría de la biodiversidad, incluso si los conservacionistas compasivos no dañan a los individuos exóticos. Las posiciones que toman los llamados conservacionistas compasivos sobre especies particulares y sobre las acciones de conservación podrían extenderse para entorpecer otros tipos de conservación, incluyendo las reubicaciones, el encercado para la conservación y el control de la fertilidad. El bienestar animal es increíblemente importante para la conservación e irónicamente, la conservación compasiva no ofrece los mejores resultados de bienestar para los animales y comúnmente es poco efectiva en el logro de los objetivos de conservación. Como consecuencia, la conservación compasiva puede poner en peligro el apoyo público y del gobierno que tiene la conservación debido al entendimiento poco limitado que tiene el público general sobre los problemas de conservación.

Peripheral natural killer cell maturation depends on the transcription factor Aiolos.

Natural killer (NK) cells are an innate lymphoid cell lineage characterized by their capacity to provide rapid effector functions, including cytokine production and cytotoxicity. Here, we identify the Ikaros family member, Aiolos, as a regulator of NK-cell maturation. Aiolos expression is initiated at the point of lineage commitment and maintained throughout NK-cell ontogeny. Analysis of cell surface markers representative of distinct stages of peripheral NK-cell maturation revealed that Aiolos was required for the maturation in the spleen of CD11b(high)CD27(-) NK cells. The differentiation block was intrinsic to the NK-cell lineage and resembled that found in mice lacking either T-bet or Blimp1; however, genetic analysis revealed that Aiolos acted independently of all other known regulators of NK-cell differentiation. NK cells lacking Aiolos were strongly hyper-reactive to a variety of NK-cell-mediated tumor models, yet impaired in controlling viral infection, suggesting a regulatory function for CD27(-) NK cells in balancing these two arms of the immune response. These data place Aiolos in the emerging gene regulatory network controlling NK-cell maturation and function.

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome.

OBJECTIVE: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. STUDY DESIGN: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. RESULTS: Although no exome-wide significant (P < 2.5 × 10-6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). CONCLUSIONS: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.

Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice.

Viral infection is a common, life-threatening complication after allogeneic bone marrow transplantation (BMT), particularly in the presence of graft-versus-host disease (GVHD). Using cytomegalovirus (CMV) as the prototypic pathogen, we have delineated the mechanisms responsible for the inability to mount protective antiviral responses in this setting. Although CMV infection was self-limiting after syngeneic BMT, in the presence of GVHD after allogeneic BMT, CMV induced a striking cytopathy resulting in universal mortality in conjunction with a fulminant necrotizing hepatitis. Critically, GVHD induced a profound dendritic cell (DC) defect that led to a failure in the generation of CMV-specific CD8(+) T-cell responses. This was accompanied by a defect in antiviral CD8(+) T cells. In combination, these defects dramatically limited antiviral T-cell responses. The transfer of virus-specific cells circumvented the DC defects and provided protective immunity, despite concurrent GVHD. These data demonstrate the importance of avoiding GVHD when reconstructing antiviral immunity after BMT, and highlight the mechanisms by which the adoptive transfer of virus-specific T cells overcome the endogenous defects in priming invoked by GVHD.

"Giving us hope": Parent and neonatal staff views and expectations of a planned family-centred discharge process (Train-to-Home).

BACKGROUND: Preparing families and preterm infants for discharge is relatively unstructured in many UK neonatal units (NNUs). Family-centred neonatal care and discharge planning are recommended but variable. DESIGN AND PARTICIPANTS: Qualitative interviews with 37 parents of infants in NNUs, and 18 nursing staff and 5 neonatal consultants explored their views of discharge planning and perceptions of a planned family-centred discharge process (Train-to-Home). Train-to-Home facilitates communication between staff and parents throughout the neonatal stay, using a laminated train and parent booklets. RESULTS: Parents were overwhelmingly positive about Train-to-Home. They described being given hope, feeling in control and having something visual to show their baby's progress. They reported positive involvement of fathers and families, how predicted discharge dates helped them prepare for home and ways staff engaged with Train-to-Home when communicating with them. Nursing staff reactions were mixed-some were uncertain about when to use it, but found the visual images powerful. Medical staff in all NNUs were positive about the intervention recognizing that it helped in communicating better with parents. CONCLUSIONS: Using a parent-centred approach to communication and informing parents about the needs and progress of their preterm infant in hospital is welcomed by parents and many staff. This approach meets the recommended prioritization of family-centred care for such families. Predicted discharge dates helped parents prepare for home, and the ways staff engaged with Train-to-Home when communicating with them helped them feel more confident as well as having something visual to show their baby's progress.

A natural genetic variant of granzyme B confers lethality to a common viral infection.

Many immune response genes are highly polymorphic, consistent with the selective pressure imposed by pathogens over evolutionary time, and the need to balance infection control with the risk of auto-immunity. Epidemiological and genomic studies have identified many genetic variants that confer susceptibility or resistance to pathogenic micro-organisms. While extensive polymorphism has been reported for the granzyme B (GzmB) gene, its relevance to pathogen immunity is unexplored. Here, we describe the biochemical and cytotoxic functions of a common allele of GzmB (GzmBW) common in wild mouse. While retaining 'Asp-ase' activity, GzmBW has substrate preferences that differ considerably from GzmBP, which is common to all inbred strains. In vitro, GzmBW preferentially cleaves recombinant Bid, whereas GzmBP activates pro-caspases directly. Recombinant GzmBW and GzmBP induced equivalent apoptosis of uninfected targets cells when delivered with perforin in vitro. Nonetheless, mice homozygous for GzmBW were unable to control murine cytomegalovirus (MCMV) infection, and succumbed as a result of excessive liver damage. Although similar numbers of anti-viral CD8 T cells were generated in both mouse strains, GzmBW-expressing CD8 T cells isolated from infected mice were unable to kill MCMV-infected targets in vitro. Our results suggest that known virally-encoded inhibitors of the intrinsic (mitochondrial) apoptotic pathway account for the increased susceptibility of GzmBW mice to MCMV. We conclude that different natural variants of GzmB have a profound impact on the immune response to a common and authentic viral pathogen.

Contact rates of wild-living and domestic dog populations in Australia: a new approach.

Dogs (Canis familiaris) can transmit pathogens to other domestic animals, humans and wildlife. Both domestic and wild-living dogs are ubiquitous within mainland Australian landscapes, but their interactions are mostly unquantified. Consequently, the probability of pathogen transfer among wild-living and domestic dogs is unknown. To address this knowledge deficit, we established 65 camera trap stations, deployed for 26,151 camera trap nights, to quantify domestic and wild-living dog activity during 2 years across eight sites in north-east New South Wales, Australia. Wild-living dogs were detected on camera traps at all sites, and domestic dogs recorded at all but one. No contacts between domestic and wild-living dogs were recorded, and limited temporal overlap in activity was observed (32 %); domestic dogs were predominantly active during the day and wild-living dogs mainly during the night. Contact rates between wild-living and between domestic dogs, respectively, varied between sites and over time (range 0.003-0.56 contacts per camera trap night). Contact among wild-living dogs occurred mainly within social groupings, and peaked when young were present. However, pup emergence occurred throughout the year within and between sites and consequently, no overall annual cycle in contact rates could be established. Due to infrequent interactions between domestic and wild-living dogs, there are likely limited opportunities for pathogen transmission that require direct contact. In contrast, extensive spatial overlap of wild and domestic dogs could facilitate the spread of pathogens that do not require direct contact, some of which may be important zoonoses.

The Confidential Inquiry into premature deaths of people with intellectual disabilities in the UK: a population-based study.

BACKGROUND: The Confidential Inquiry into premature deaths of people with intellectual disabilities in England was commissioned to provide evidence about contributory factors to avoidable and premature deaths in this population. METHODS: The population-based Confidential Inquiry reviewed the deaths of people with intellectual disabilities aged 4 years and older who had been registered with a general practitioner in one of five Primary Care Trust areas of southwest England, who died between June 1, 2010, and May 31, 2012. A network of health, social-care, and voluntary-sector services; community contacts; and statutory agencies notified the Confidential Inquiry of all deaths of people with intellectual disabilities and provided core data. The Office for National Statistics provided data about the coding of individual cause of death certificates. Deaths were described as avoidable (preventable or amenable), according to Office for National Statistics definitions. Contributory factors to deaths were identified and quantified by the case investigator, verified by a local review panel meeting, and agreed by the Confidential Inquiry overview panel. Contributory factors were grouped into four domains: intrinsic to the individual, within the family and environment, care provision, and service provision. The deaths of a comparator group of people without intellectual disabilities but much the same in age, sex, and cause of death and registered at the same general practices as those with intellectual disabilities were also investigated. FINDINGS: The Confidential Inquiry reviewed the deaths of 247 people with intellectual disabilities. Nearly a quarter (22%, 54) of people with intellectual disabilities were younger than 50 years when they died, and the median age at death was 64 years (IQR 52-75). The median age at death of male individuals with intellectual disabilities was 65 years (IQR 54-76), 13 years younger than the median age at death of male individuals in the general population of England and Wales (78 years). The median age at death of female individuals with intellectual disabilities was 63 years (IQR 54-75), 20 years younger than the median age at death for female individuals in the general population (83 years). Avoidable deaths from causes amenable to change by good quality health care were more common in people with intellectual disabilities (37%, 90 of 244) than in the general population of England and Wales (13%). Contributory factors to premature deaths in a subset of people with intellectual disabilities compared with a comparator group of people without intellectual disabilities included problems in advanced care planning (p=0·0003), adherence to the Mental Capacity Act (p=0·0008), living in inappropriate accommodation (p<0·0001), adjusting care as needs changed (p=0·009), and carers not feeling listened to (p=0·006). INTERPRETATION: The Confidential Inquiry provides evidence of the substantial contribution of factors relating to the provision of care and health services to the health disparities between people with and without intellectual disabilities. It is imperative to examine care and service provision for this population as potentially contributory factors to their deaths--factors that can largely be ameliorated. FUNDING: Department of Health for England.

Patterns of child death in England and Wales.

In the past century, child mortality has fallen to very low rates in all developed countries. However, rates between and within countries vary widely, and factors can be identified that could be modified to reduce the risk of future deaths. An understanding of the nature and patterns of child death and of the factors contributing to child deaths is essential to drive preventive initiatives. We discuss the epidemiology of child deaths in England and Wales. We use available data, particularly that of death registration and other available datasets, and published literature to emphasise issues relevant to reduction of child deaths in developed countries. We examine the different patterns of mortality at different ages in five broad categories of death: perinatal causes, congenital abnormalities, acquired natural causes, external causes, and unexplained deaths. For each category, we explore what is known about the main causes of death and some of the contributory factors. We then explain how this knowledge might be used to help to drive prevention initiatives.