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Naimish R Patel,1,2 Danen M Cunoosamy,1 Malin Fagerås,1 Ziad Taib,1 Sara Asimus,1 Tove Hegelund-Myrbäck,1 Sofia Lundin,1 Katerina Pardali,1 Nisha Kurian,1 Eva Ersdal,1 Cecilia Kristensson,1 Katarina Korsback,1 Robert Palmér,1 Mary N Brown,3 Steven Greenaway,4 Leonard Siew,4 Graham W Clarke,4,5 Stephen I Rennard,6,7 Barry J Make,8 Robert A Wise,9 Paul Jansson11Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Hospital, Boston, MA, 3Innovative Medicines and Early Development, AstraZeneca, Boston, MA, USA; 4Quintiles Drug Research Unit at Guy’s Hospital, London, 5Department of Cardiothoracic Pharmacology, NHLI, Imperial College London, London, UK; 6Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska, Omaha, NE, USA; 7Clinical Discovery Unit, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK; 8Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO, 9Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD, USABackground: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18–55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40–85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations.Results: The p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38β isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p

The role of anti-WNT ZNRF3 is central to determining gonadal fate: XY mice lacking functional ZNRF3 exhibit a highly variable gonadal sex reversal phenotype in the fetal period, characterised by appearance of ovarian tissue. To investigate this sex reversal further, we used single-cell RNA-seq to examine the transcriptomes of XY Znrf3-deficient gonads during the mouse sex-determining period. Analyses of cell trajectories in mutant gonads reveal the failure of pre-supporting cells to commit to the Sertoli cell fate, XY granulosa cell development, unstable commitment in those cells that reach the Sertoli path and enhanced contribution to a supporting-like cell fate. By developing a machine learning-based score for transcriptomic similarity to Sertoli and granulosa, we show pervasive disruption to acquisition of testicular cell fate in the mutant supporting cell lineage, with large numbers of cells co-expressing pro-Sertoli and pro-granulosa markers. These data reveal that loss of Znrf3 results in transcriptomic and cellular heterogeneity, with shifts in cellular sex identity that undermine a simple binary model in which mutant supporting cell precursors achieve either Sertoli or granulosa cell differentiation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Integration of symptom and palliative care for people with advanced cancer is established in many tumour types, but its role in people with hepatocellular carcinoma (HCC) has not been clearly defined. This study aims to evaluate the clinical and cost effectiveness of an intervention involving a suite of strategies designed to assess and treat palliative care symptoms and needs in adult outpatients with HCC attending four New South Wales (NSW) metropolitan tertiary hospitals., Methods: This trial will use a pragmatic cluster-based randomised-controlled design, with ambulatory HCC services as the clusters. HCC patients will be recruited if they have Barcelona Clinical Liver Cancer (BCLC) stage A disease with active tumour or a current or prior diagnosis of BCLC stage B or C disease regardless of tumour activity. Patients with BCLC stage D disease will be excluded as palliative care is the standard of care (SOC) in this group. Cluster sites will be randomised to the study intervention or control where patients are managed according to SOC. All participants will complete the liver-specific Edmonton Symptom Assessment Scale (ESAS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire at regular ambulatory clinic appointments. At intervention sites, patients scoring ≥ 5 on any liver-specific ESAS symptom will be referred to palliative care physicians for consultation. The primary clinical outcome will be improvement in all symptoms scored ≥ 5 on the liver-specific ESAS by 50% within 3 months and the primary implementation outcome will recording the liver-specific ESAS in ≥ 80% of all participants attending clinic appointments. Caregivers of patients enrolled in the trial will be invited to perform Carer Support Needs Assessment Tool at each appointment., Discussion: This trial will inform if earlier palliative care involvement significantly reduces the symptom burden associated with HCC. If found to be effective, earlier implementation of palliative care consultation should be included in HCC treatment guidelines., Trial Registration: ACTRN12623000010695. Registered on September 1, 2023., (© 2024. The Author(s).)

The UK Overseas Territories (UKOTs) are small, often remote territories with historical and territorial links to the UK. They range from densely populated areas (Cayman, Bermuda, Gibraltar) to land with no permanent inhabitants (British Antarctic Territory, South Georgia). However, they are linked by ecosystem instability (the permacrisis) including antimicrobial resistance (AMR), climate change and biodiversity disruption. The Chief Medical Officers of the UKOTs met in June 2024 and were unanimous in their concerns about the threat of global AMR. They have issued this statement on their hopes and expectations for the United Nations' General Assembly High-Level Meeting, in September 2024. These may be summarized by the hope of achieving united and sustained global political will to reduce the threat of AMR by equitable access to treatments, prevention of AMR by sanitation and accurate diagnostics, and education in health care and the public., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Introduction: Concerns have been raised internationally about the palliative care needs of migrants and First Nations people. This article presents insights from research investigating the end-of-life needs of Aboriginal and culturally and linguistically diverse people living in Western Sydney, Australia. This region has a large rapidly growing, and highly diverse population and on average low socioeconomic status. The research was guided by an advisory panel made up of representatives of supportive and palliative medicine, bereavement support, Aboriginal health, and multicultural health facilities. It aimed to generate findings to support the delivery of culturally sensitive services in the public health system., Method: The multi-method design and the conduct of the research were informed by the literature on researching with marginalized groups which highlights the ethical considerations needed to avoid replicating past injustices. Qualitative data was generated from key informants and community focus groups., Results: The analysis revealed seven themes and some suggested solutions which were relevant across several themes. The seven themes were: the Need for trusted relationships; Talking about death and dying; Knowledge of key services; Decision-making and obtaining consent from the patient; Appropriate physical spaces; Cultural practices around EOL; and Language barriers., Discussion: Within each theme a variety of cultural beliefs and practices were revealed that conflicted with mainstream medical systems, indicating the need for changes in such systems. 'Compassionate Communities' was identified as a model to support the necessary changes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Leonard, Paton, Hinton, Greenaway and Thomson.)

Background: Administrative data and clinician documentation have not been directly compared for reporting palliative care, despite concerns about under-reporting., Objective: The aim of this study was to verify the use of routinely collected administrative data for reporting in-hospital palliation and to examine factors associated with coded palliative care in hospital administrative data., Method: Hospital administrative data and inpatient palliative care activity documented in medical records were compared for patients dying in hospital between 1 July 2017 and 31 December 2017. Coding of palliative care in administrative data is based on hospital care type coded as "palliative care" and/or assignment of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD-10-AM) palliative care diagnosis code Z51.5. Medical records were searched for specified keywords, which, read in context, indicated a palliative approach to care. The list of keywords (palliative, end of life, comfort care, cease observations, crisis medications, comfort medications, syringe driver, pain or symptom management, no cardiopulmonary resuscitation, advance medical plan/resuscitation plan, deteriorating, agitation, restless and delirium) was developed in consultation with seven local clinicians specialising in palliative care or geriatric medicine., Results: Of the 576 patients who died in hospital, 246 were coded as having received palliative care, either solely by the ICD-10-AM diagnosis code Z51.5 (42%) or in combination with a "palliative care" care type (58%). Just over one-third of dying patients had a palliative care specialist involved in their hospital care. Involvement of a palliative care specialist and a cancer diagnosis substantially increased the odds of a Z51.5 code (odds ratio = 11 and 4, respectively). The majority of patients with a "syringe driver" or identified as being at the "end of life" were assigned a Z51.5 code (73.5% and 70.5%, respectively), compared to 53.8% and 54.7%, respectively, for "palliative" or "comfort care." For each keyword indicating a palliative approach to care, the Z51.5 code was more likely to be assigned if the patient had specialist palliative care input or if they had cancer., Conclusion: Our results suggest administrative data under-represented in-hospital palliative care, at least partly due to medical record documentation that failed to meet ICD-10-AM coding criteria. Collaboration between clinicians and coders can enhance the quality of records and, consequently, administrative data.

Gonadal sex determination represents a unique model for studying cell fate decisions. However, a complete understanding of the different cell lineages forming the developing testis and ovary remains elusive. Here, we investigated the origin, specification, and subsequent sex-specific differentiation of a previously uncharacterized population of supporting-like cells (SLCs) in the developing mouse gonads. The SLC lineage is closely related to the coelomic epithelium and specified as early as E10.5, making it the first somatic lineage to be specified in the bipotential gonad. SLC progenitors are localized within the genital ridge at the interface with the mesonephros and initially coexpress Wnt4 and Sox9 . SLCs become sexually dimorphic around E12.5, progressively acquire a more Sertoli- or pregranulosa-like identity and contribute to the formation of the rete testis and rete ovarii. Last, we found that WNT4 is a crucial regulator of the SLC lineage and is required for normal development of the rete testis.

Background: Topologically associating domains (TADs) are thought to act as functional units in the genome. TADs co-localise genes and their regulatory elements as well as forming the unit of genome switching between active and inactive compartments. This has led to the speculation that genes which are required for similar processes may fall within the same TADs, allowing them to share regulatory programs and efficiently switch between chromatin compartments. However, evidence to link genes within TADs to the same regulatory program is limited., Results: We investigated the functional similarity of genes which fall within the same TAD. To do this we developed a TAD randomisation algorithm to generate sets of "random TADs" to act as null distributions. We found that while pairs of paralogous genes are enriched in TADs overall, they are largely depleted in TADs with CCCTC-binding factor (CTCF) ChIP-seq peaks at both boundaries. By assessing gene constraint as a proxy for functional importance we found that genes which singly occupy a TAD have greater functional importance than genes which share a TAD, and these genes are enriched for developmental processes. We found little evidence that pairs of genes in CTCF bound TADs are more likely to be co-expressed or share functional annotations than can be explained by their linear proximity alone., Conclusions: These results suggest that algorithmically defined TADs consist of two functionally different groups, those which are bound by CTCF and those which are not. We detected no association between genes sharing the same CTCF TADs and increased co-expression or functional similarity, other than that explained by linear genome proximity. We do, however, find that functionally important genes are more likely to fall within a TAD on their own suggesting that TADs play an important role in the insulation of these genes., (© 2022. The Author(s).)

The concepts and elements determining quality of care at the End of Life may vary across professional groups but there is consensus that high-quality care at the End of Life is beneficial for the patient, families, health systems and society at large. This scoping review aimed to elucidate gaps in the delivery of this specific type of care in older people from the clinicians' perspective, and to identify potential solutions to both improve this care and promote work satisfaction by the involved clinicians. Twelve studies published since 2010 with data from 18 countries identified four major gaps: (1) Core clinical competencies; (2) Shared decision-making; (3) Health care system, environmental context, and resources; and (4) Organisational leadership, culture and legislation. Multiple suggestions for staff communications training, multidisciplinary mentoring, and advance care planning alignment with patient wishes were identified. However, a clear picture arose of consistently unmet needs that have been previously highlighted in research for more than a decade. This indicates poor uptake of previous recommendations and highlights the difficulties in changing the service culture to ensure provision of optimal services at the End of Life. Future investigations on the reasons for poor uptake and identification of effective approaches to execute the agreed recommendations are warranted., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

To get the best possible results from current quantum devices error mitigation is essential. In this work we present a simple but effective error mitigation technique based on the assumption that noise in a deep quantum circuit is well described by global depolarizing error channels. By measuring the errors directly on the device, we use an error model ansatz to infer error-free results from noisy data. We highlight the effectiveness of our mitigation via two examples of recent interest in quantum many-body physics: entanglement measurements and real-time dynamics of confinement in quantum spin chains. Our technique enables us to get quantitative results from the IBM quantum computers showing signatures of confinement, i.e., we are able to extract the meson masses of the confined excitations which were previously out of reach. Additionally, we show the applicability of this mitigation protocol in a wider setting with numerical simulations of more general tasks using a realistic error model. Our protocol is device-independent, simply implementable, and leads to large improvements in results if the global errors are well described by depolarization.

We aimed to identify the level of prognostic disclosure, type of prognostic information and delivery format of prognostic communication that older adults diagnosed with a life-limiting illness or caregivers prefer to receive. We developed and pilot tested an open-ended survey to 15 older patients and caregivers who had experience in health services for life-limiting illness either for a relative, friend or themselves. Five hypothetical clinical scenarios of prognostic options were presented to ascertain preferences. The preferred format to receive prognostic information was verbal delivery by the clinician with a written summary. Photos and videos were less favoured, and a table with numbers/percentages was least preferred. Distress levels to the prognostic scenarios were low, with the exception of a photo. We conclude that older patients/caregivers want end-of-life prognostic information delivered the traditional way, verbally by clinicians. Options to deliver prognostic information may vary across patient groups but empower clinicians in introducing end-of-life discussions with patients/caregivers. Our study illustrates the feasibility of involving terminal patients and caregivers in research that contributes to eliciting prognostic preferences. Further research is needed to understand whether the prognostic preferences of hospitalized patients with life-limiting illness differ.

Objective: To quantify and examine specialist palliative care (SPC) in-hospital activity and compare it to routinely collected administrative data on palliative care (PC)., Methods: All patients discharged from a large acute care tertiary hospital in New South Wales, Australia, between July 1 and December 31, 2017, were identified from the hospital's data warehouse. Administrative data were supplemented with information from the electronic medical record for hospital stays which were assigned the PC additional diagnosis code (Z51.5); had a "palliative care" care type; or included SPC consultation., Results: Of 34 653 hospital stays, 524 were coded as receiving PC-based on care type (43%) and/or diagnosis code Z51.5 (100%). Specialist palliative care provided 1717 consultations over 507 hospital stays. Patients had 2 (median; interquartile range: 1-4) consultations during an average stay of 15.3 days (SD 15.78; median 10); the first occurred 7.0 days (SD 12.13; median 3) after admission. Of patient stays with an SPC consultation, 70% were assigned the PC Z51.5 code; 60% were referred for symptom management; 68% had cancer. One hundred forty-one patients were under a palliative specialist-either from initial hospital admission (49.6%) or later in their stay., Conclusions: Palliative care specialists provide expert input into patient management, benefitting patients and other clinicians. Administrative data inadequately capture their involvement in patient care, especially consultations, and are therefore inappropriate for reporting SPC activity. Exclusion of information related to SPC activity results in an incomplete and distorted representation of PC services and fails to acknowledge the valuable contribution made by SPC.

Background: Efforts to elucidate the function of enhancers in vivo are underway but their vast numbers alongside differing enhancer architectures make it difficult to determine their impact on gene activity. By systematically annotating multiple mouse tissues with super- and typical-enhancers, we have explored their relationship with gene function and phenotype., Results: Though super-enhancers drive high total- and tissue-specific expression of their associated genes, we find that typical-enhancers also contribute heavily to the tissue-specific expression landscape on account of their large numbers in the genome. Unexpectedly, we demonstrate that both enhancer types are preferentially associated with relevant 'tissue-type' phenotypes and exhibit no difference in phenotype effect size or pleiotropy. Modelling regulatory data alongside molecular data, we built a predictive model to infer gene-phenotype associations and use this model to predict potentially novel disease-associated genes., Conclusion: Overall our findings reveal that differing enhancer architectures have a similar impact on mammalian phenotypes whilst harbouring differing cellular and expression effects. Together, our results systematically characterise enhancers with predicted phenotypic traits endorsing the role for both types of enhancers in human disease and disorders.

Objective: Use of palliative care in hospitals for people at end of life varies. We examined rate and time of in-hospital palliative care use and associated interhospital variations., Methods: We used admissions from all hospitals in New South Wales, Australia, within a 12-month period, for a cohort of adults who died in 73 public acute care hospitals between July 2010 and June 2014. Receiving palliative care and its timing were based on recorded use., Results: Among 90 696 adults who died, 27% received palliative care, and the care was initiated 7.6 days (mean; SD: 3.3 days) before death. Over the 5-year period, the palliative care rate rose by 58%, varying extent across chronic conditions. The duration of palliative care before death declined by 7%. Patient (demographics, morbidities and service use) and hospital factors (size, location and availability of palliative care unit) explained half of the interhospital variation in outcomes: adjusted IQR in rate and duration of palliative care among hospitals were 23%-39% and 5.2-8.7 days, respectively. Hospitals with higher rates often initiated palliative care earlier (correlation: 0.39; p<0.01)., Conclusion: Despite an increase over time in the palliative care rate, its initiation was late and of brief duration. Palliative care use was associated with patient and hospital characteristics; however, half of the between hospital variation remained unexplained. The observed suboptimal practices and variability indicate the need for expanded and standardised use of palliative care supported by assessment tools, service enhancement and protocols., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Over the last century, the study of mouse behavior has uncovered insights into brain molecular mechanisms while revealing potential causes of many neurological disorders. To this end, researchers have widely exploited the use of mutant strains, including those generated in mutagenesis screens and those produced using increasingly sophisticated genome engineering technologies. It is now relatively easy to access mouse models carrying alleles that faithfully recapitulate changes found in human patients or bearing variants of genes that provide data on those genes' functions. Concurrent with these developments has been an appreciation of the limitations of some current testing platforms, especially those monitoring complex behaviors. Out-of-cage observational testing is useful in describing overt persistent phenotypes but risks missing sporadic or intermittent events. Furthermore, measuring the progression of a phenotype, potentially over many months, can be difficult while relying on assays that may be susceptible to changes in the testing environment. In recent years, there has also been increasing awareness that measurement of behaviors in isolation can be limiting, given that mice attempt to hide behavioral cues of vulnerability. To overcome these limitations, laboratory animal science is capitalizing on progress in data capture and processing expertise. Moreover, as additional recording modes become commonplace, ultrasonic vocalization recording is an appealing focus, as mice use vocalizations in various social contexts. Using video and audio technologies, we record the voluntary, unprovoked behaviors and vocalizations of mice in social groups. Adoption of these approaches is undoubtedly set to increase, as they capture the round-the-clock behavior of mouse strains. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Continuous recording of home cage activity using the Home Cage Analyzer (HCA) system Support Protocol: Subcutaneous insertion of a radio frequency identification microchip in the inguinal area Basic Protocol 2: Continuous recording of mouse ultrasonic vocalizations in the home cage., (© 2020 Wiley Periodicals LLC.)

Aging is inevitable, and our society must deal with the consequences: namely, an increased incidence of disease and ill health. Many mouse models of disease are acute or early onset or are induced in young mice, despite the fact that aging is a significant risk factor for a range of significant diseases. To improve modeling of such diseases, we should incorporate aging into our models. Many systems are affected by aging, with a decline in mitochondrial function, an increase in senescence, a loss of resilience, telomere shortening, and a decline in immune function being key factors in the increased susceptibility to disease that is associated with aging. To develop novel models of age-related disease, we undertook a phenotype-driven screen of a pipeline of mutagenized mice. Here, we describe some of the underlying protocols and outline important aspects to consider when studying aged mice. © 2018 by John Wiley & Sons, Inc., (© 2018 John Wiley & Sons, Inc.)

High-throughput phenotyping is a cornerstone of numerous functional genomics projects. In recent years, imaging screens have become increasingly important in understanding gene-phenotype relationships in studies of cells, tissues and whole organisms. Three-dimensional (3D) imaging has risen to prominence in the field of developmental biology for its ability to capture whole embryo morphology and gene expression, as exemplified by the International Mouse Phenotyping Consortium (IMPC). Large volumes of image data are being acquired by multiple institutions around the world that encompass a range of modalities, proprietary software and metadata. To facilitate robust downstream analysis, images and metadata must be standardized to account for these differences. As an open scientific enterprise, making the data readily accessible is essential so that members of biomedical and clinical research communities can study the images for themselves without the need for highly specialized software or technical expertise. In this article, we present a platform of software tools that facilitate the upload, analysis and dissemination of 3D images for the IMPC. Over 750 reconstructions from 80 embryonic lethal and subviable lines have been captured to date, all of which are openly accessible at mousephenotype.org. Although designed for the IMPC, all software is available under an open-source licence for others to use and develop further. Ongoing developments aim to increase throughput and improve the analysis and dissemination of image data. Furthermore, we aim to ensure that images are searchable so that users can locate relevant images associated with genes, phenotypes or human diseases of interest., (© The Author 2016. Published by Oxford University Press.)

Frailty is a state of vulnerability resulting from cumulative decline in many physiological systems during a lifetime. It is progressive and considered largely irreversible, but its progression may be controlled and can be slowed down and its precursor -pre-frailty- can be treated with multidisciplinary intervention. The aim of this narrative review is to provide an overview of the different ways of measuring frailty in community settings, hospital, emergency, general practice and residential aged care; suggest occupational groups who can assess frailty in various services; discuss the feasibility of comprehensive geriatric assessments; and summarise current evidence of its management guidelines. We also suggest practical recommendations to recognise frail patients near the end of life, so discussions on goals of care, advance care directives, and shared decision-making including early referrals to palliative and supportive care can take place before an emergency arises. We acknowledge the barriers to systematically assess frailty and the absence of consensus on best instruments for different settings. Nevertheless, given its potential consequences including prolonged suffering, disability and death, we recommend identification of frailty levels should be universally attempted in older people at any health service, to facilitate care coordination, and honest discussions on preferences for advance care with patients and their caregivers., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans.

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

Background: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response., Methods: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage., Results: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3% reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0% reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers., Conclusions: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.

Understanding phenotype-genotype correlations in retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Müller and microglia activation and telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers., (© The Author 2014. Published by Oxford University Press.)

Background: The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms., Results: We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems., Conclusions: Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.

Two large-scale phenotyping efforts, the European Mouse Disease Clinic (EUMODIC) and the Wellcome Trust Sanger Institute Mouse Genetics Project (SANGER-MGP), started during the late 2000s with the aim to deliver a comprehensive assessment of phenotypes or to screen for robust indicators of diseases in mouse mutants. They both took advantage of available mouse mutant lines but predominantly of the embryonic stem (ES) cells resources derived from the European Conditional Mouse Mutagenesis programme (EUCOMM) and the Knockout Mouse Project (KOMP) to produce and study 799 mouse models that were systematically analysed with a comprehensive set of physiological and behavioural paradigms. They captured more than 400 variables and an additional panel of metadata describing the conditions of the tests. All the data are now available through EuroPhenome database (www.europhenome.org) and the WTSI mouse portal (http://www.sanger.ac.uk/mouseportal/), and the corresponding mouse lines are available through the European Mouse Mutant Archive (EMMA), the International Knockout Mouse Consortium (IKMC), or the Knockout Mouse Project (KOMP) Repository. Overall conclusions from both studies converged, with at least one phenotype scored in at least 80% of the mutant lines. In addition, 57% of the lines were viable, 13% subviable, 30% embryonic lethal, and 7% displayed fertility impairments. These efforts provide an important underpinning for a future global programme that will undertake the complete functional annotation of the mammalian genome in the mouse model.

The MouseBook (http://www.mousebook.org) databases and web portal provide access to information about mutant mouse lines held as live or cryopreserved stocks at MRC Harwell. The MouseBook portal integrates curated information from the MRC Harwell stock resource, and other Harwell databases, with information from external data resources to provide value-added information above and beyond what is available through other routes such as International Mouse Stain Resource (IMSR). MouseBook can be searched either using an intuitive Google style free text search or using the Mammalian Phenotype (MP) ontology tree structure. Text searches can be on gene, allele, strain identifier (e.g. MGI ID) or phenotype term and are assisted by automatic recognition of term types and autocompletion of gene and allele names covered by the database. Results are returned in a tabbed format providing categorized results identified from each of the catalogs in MouseBook. Individual result lines from each catalog include information on gene, allele, chromosomal location and phenotype, and provide a simple click-through link to further information as well as ordering the strain. The infrastructure underlying MouseBook has been designed to be extensible, allowing additional data sources to be added and enabling other sites to make their data directly available through MouseBook.

The importance and meaning of social and recreational travel for a diverse group of Auckland residents is explored in this article. Study participants identified a range of social and health benefits, including maintaining social connections with family and friends, opportunities to participate in physical activity, and reducing stress. However, many of these trips are by car. New Zealand has one of the highest rates of private car ownership internationally, low-density urban development, and a poor public transport infrastructure. Social and recreational trips make up a sizeable proportion of domestic travel and are contributing to New Zealand's increasing rate of CO2 emissions. There is an obvious need to address the negative ecological impacts of human activity. Our findings suggest that alongside strategies to reduce CO2 emissions, it also is important to introduce measures to maintain the benefits from social and recreational travel. Suggestions are made for further areas of research.