Surviving stomach bugs in UK ethnic groups: a qualitative study.

BACKGROUND: The exposure patterns across ethnic groups are unclear for stomach bugs that cause self-limiting symptoms, significantly burdening UK health-care services and the economy. This study seeks to fill this gap by exploring how inequalities arise in managing stomach bugs in UK ethnic groups. METHODS: A qualitative study using semi-structured interviews was undertaken. Ethics approval was given by the University of Liverpool, and data were collected by IZ over 11 months from July 26, 2022, and May 26, 2023. Purposive sampling was used to recruit a general UK population sample (excluding health-care professionals) who were adults, partners, and parents, from an ethnic minority group, with recent diarrhoea, vomiting, or a stomach bug over the past 6 months. Recruitment was conducted through community gatekeepers using flyers. Participants were interviewed in person or virtually and gave written informed consent. An incentive of an Amazon voucher of £10 was imbursed to participants for their time. Interviews were audio-recorded using a password-protected digital recorder, transcribed verbatim, and analysed using reflexive thematic analysis. FINDINGS: 36 interviews (median age 31·5 years) were conducted with 11 women of Pakistani (n=6), Bangladeshi (n=2), Indian (n=2) and Arab ethnicity (n=1), and 25 men of Black (n=22), Pakistani (n=2), and Indian (n=1) ethnicity. This sample enabled an exploration of within-ethnic group experiences of stomach bugs in participants who self-defined their age, sex, and ethnicity. Themes such as managing food preparation (n=16), travel abroad (n=17), and personal cleanliness (n=3) were consistently reported across transcripts. The findings corroborate existing literature that there are more similarities than divergences in the management of stomach bugs across ethnic groups, such as the burden of care disproportionately affecting women and using over-the-counter medication to manage symptoms. INTERPRETATION: We do not know if the impact of these experiences across ethnic groups is entirely representative of the broader ethnic categories (ie, Asian vs Indian, Pakistani, and Bangladeshi) they belong to or if there are inequalities in their impact on ethnic groups living in different circumstances (ie, UK born vs migrant). FUNDING: National Institute for Health and Care Research (NIHR).

'A system that is struggling': understanding health protection resilience in England during the COVID-19 pandemic through the experiences of local health protection responders.

BACKGROUND: Local health protection systems play a crucial role in infectious disease prevention and control and were critical to COVID-19 pandemic responses. Despite this vital function, few studies have explored the lived experience of health protection responders managing COVID-19. We provide new insights by examining how COVID-19 shaped infectious disease prevention and control in local health protection systems in England. METHODS: Semi-structured interviews were conducted with twenty local health protection responders from three contrasting local authority areas, and Public Health England (PHE) health protection teams, in England between June 2021 - March 2022. Participants were from: PHE health protection teams (n=6); local authority public health teams (n=5); local authority Public Protection Services (n=7); and local authority commissioned Infection Prevention and Control Teams (n=2). Data were analysed using reflexive thematic analysis. RESULTS: First, participants acknowledged the pandemic caused an unprecedented workload and disruption to local health protection service delivery. There was not enough capacity within existing local health protection systems to manage the increased workload. PHE health protection teams therefore transferred some COVID-19 related health protection tasks to other staff, mainly those employed by local authorities. Second, health protection responders highlighted how COVID-19 drew attention to the weaknesses in local health protection systems already stressed by reduced funding in the years leading up to the pandemic. Injecting money into the COVID-19 response did not completely overcome former losses in specialist health protection workforce. Third, health protection responders described how pandemic management raised the profile of public health, especially infectious disease prevention and control. Managing COVID-19 strengthened collaborative working, resulting in enhanced capacity of local health protection systems at the time. CONCLUSION: The COVID-19 pandemic challenged the public health preparedness of all countries. Health protection responders in this study also expressed many challenges. There was insufficient resilience in these local health protection systems and an inability to scale up the specialist health protection workforce, as required in a pandemic situation. The UK needs to learn from the pandemic experience by acknowledging and addressing the challenges faced by local health protection responders so that it can more effectively respond to future threats.

Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders.

PURPOSE: Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge. METHODS: We tested this hypothesis in the United Kingdom-wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes. RESULTS: We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication. CONCLUSION: This study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients.

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.

BACKGROUND: Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. METHODS: The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. FINDINGS: Around 80,000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. INTERPRETATION: Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. FUNDING: Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.

FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation.

The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chromosome X (i(Xq)), using whole-genome tiling path array comparative genomic hybridization (aCGH), ultra-high resolution targeted aCGH and sequencing, we provide evidence that the FoSTeS and MMBIR mechanisms can generate large-scale gross chromosomal rearrangements leading to the deletion and duplication of entire chromosome arms, thus suggesting an important role for DNA replication-based mechanisms in both the development of genomic disorders and cancer. Furthermore, we elucidate the mechanisms of dicentric i(Xq) (idic(Xq)) formation and show that most idic(Xq) chromosomes result from non-allelic homologous recombination between palindromic low copy repeats and highly homologous palindromic LINE elements. We also show that non-recurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.

Fear of crime and the environment: systematic review of UK qualitative evidence.

BACKGROUND: The fear of crime may have negative consequences for health and wellbeing. It is influenced by factors in the physical and social environment. This study aimed to review and synthesize qualitative evidence from the UK on fear of crime and the environment. METHODS: Eighteen databases were searched, including crime, health and social science databases. Qualitative studies conducted in the UK which presented data on fear of crime and the environment were included. Quality was assessed using Hawker et al.'s framework. Data were synthesized thematically. RESULTS: A total of 40 studies were included in the review. Several factors in the physical environment are perceived to impact on fear of crime, including visibility and signs of neglect. However, factors in the local social environment appear to be more important as drivers of fear of crime, including social networks and familiarity. Broader social factors appear to be of limited relevance. There is considerable evidence for limitations on physical activity as a result of fear of crime, but less for mental health impacts. CONCLUSIONS: Fear of crime represents a complex set of responses to the environment. It may play a role in mediating environmental impacts on health and wellbeing.

Genomic analyses of hair from Ludwig van Beethoven.

Ludwig van Beethoven (1770-1827) remains among the most influential and popular classical music composers. Health problems significantly impacted his career as a composer and pianist, including progressive hearing loss, recurring gastrointestinal complaints, and liver disease. In 1802, Beethoven requested that following his death, his disease be described and made public. Medical biographers have since proposed numerous hypotheses, including many substantially heritable conditions. Here we attempt a genomic analysis of Beethoven in order to elucidate potential underlying genetic and infectious causes of his illnesses. We incorporated improvements in ancient DNA methods into existing protocols for ancient hair samples, enabling the sequencing of high-coverage genomes from small quantities of historical hair. We analyzed eight independently sourced locks of hair attributed to Beethoven, five of which originated from a single European male. We deemed these matching samples to be almost certainly authentic and sequenced Beethoven's genome to 24-fold genomic coverage. Although we could not identify a genetic explanation for Beethoven's hearing disorder or gastrointestinal problems, we found that Beethoven had a genetic predisposition for liver disease. Metagenomic analyses revealed furthermore that Beethoven had a hepatitis B infection during at least the months prior to his death. Together with the genetic predisposition and his broadly accepted alcohol consumption, these present plausible explanations for Beethoven's severe liver disease, which culminated in his death. Unexpectedly, an analysis of Y chromosomes sequenced from five living members of the Van Beethoven patrilineage revealed the occurrence of an extra-pair paternity event in Ludwig van Beethoven's patrilineal ancestry.

DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources.

Many patients suffering from developmental disorders harbor submicroscopic deletions or duplications that, by affecting the copy number of dosage-sensitive genes or disrupting normal gene expression, lead to disease. However, many aberrations are novel or extremely rare, making clinical interpretation problematic and genotype-phenotype correlations uncertain. Identification of patients sharing a genomic rearrangement and having phenotypic features in common leads to greater certainty in the pathogenic nature of the rearrangement and enables new syndromes to be defined. To facilitate the analysis of these rare events, we have developed an interactive web-based database called DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources) which incorporates a suite of tools designed to aid the interpretation of submicroscopic chromosomal imbalance, inversions, and translocations. DECIPHER catalogs common copy-number changes in normal populations and thus, by exclusion, enables changes that are novel and potentially pathogenic to be identified. DECIPHER enhances genetic counseling by retrieving relevant information from a variety of bioinformatics resources. Known and predicted genes within an aberration are listed in the DECIPHER patient report, and genes of recognized clinical importance are highlighted and prioritized. DECIPHER enables clinical scientists worldwide to maintain records of phenotype and chromosome rearrangement for their patients and, with informed consent, share this information with the wider clinical research community through display in the genome browser Ensembl. By sharing cases worldwide, clusters of rare cases having phenotype and structural rearrangement in common can be identified, leading to the delineation of new syndromes and furthering understanding of gene function.

aCGH.Spline--an R package for aCGH dye bias normalization.

MOTIVATION: The careful normalization of array-based comparative genomic hybridization (aCGH) data is of critical importance for the accurate detection of copy number changes. The difference in labelling affinity between the two fluorophores used in aCGH-usually Cy5 and Cy3-can be observed as a bias within the intensity distributions. If left unchecked, this bias is likely to skew data interpretation during downstream analysis and lead to an increased number of false discoveries. RESULTS: In this study, we have developed aCGH.Spline, a natural cubic spline interpolation method followed by linear interpolation of outlier values, which is able to remove a large portion of the dye bias from large aCGH datasets in a quick and efficient manner. CONCLUSIONS: We have shown that removing this bias and reducing the experimental noise has a strong positive impact on the ability to detect accurately both copy number variation (CNV) and copy number alterations (CNA).

Effectiveness of return-to-work interventions for disabled people: a systematic review of government initiatives focused on changing the behaviour of employers.

BACKGROUND: OECD countries over the past two decades have implemented a range of labour market integration initiatives to improve the employment chances of disabled and chronically ill individuals. This article presents a systematic review and evidence synthesis on effectiveness of government interventions to influence employers' employment practices concerning disabled and chronically ill individuals in five OECD countries. A separate paper reports on interventions to influence the behaviour of employees. METHODS: Electronic and grey literature searches to identify all empirical studies reporting employment effects and/or process evaluations of government policies aimed at changing the behaviour of employers conducted between 1990 and 2008 from Canada, Denmark, Norway, Sweden and the UK. RESULTS: Few studies provided robust evaluations of the programmes or their differential effects and selection of participants into programmes may distort the findings of even controlled studies. A population-level effect of legislation to combat discrimination by employers could not be detected. Workplace adjustments had positive impacts on employment, but low uptake. Financial incentives such as wage subsidies can work if they are sufficiently generous. Involving employers in return-to-work planning can reduce subsequent sick leave and be appreciated by employees, but this policy has not been taken up with the level of intensity that is likely to make a difference. Some interventions favour the more advantaged disabled people and those closer to the labour market. CONCLUSIONS: Future evaluations need to pay more attention to differential impact of interventions, degree of take-up, non-stigmatizing implementation and wider policy context in each country.

Molar-incisor hypomineralisation combat: exploratory qualitative interviews with general dental practitioners in England regarding the management of children with molar-incisor hypomineralisation.

Introduction Molar-incisor hypomineralisation (MIH) presents as a spectrum, with severe cases becoming increasingly complex to manage. This study aimed to investigate the perceptions and experience of general dental practitioners (GDPs) in England when managing children with MIH.Method Semi-structured telephone interviews with GDPs who regularly treat children took place in May 2020. A sample of four male and six female GDPs with 1-15 years of experience was achieved through purposively sampling interested parties following advertisement via professional groups. Thematic analysis using a realist and inductive approach was used in analysis.Results The overarching theme was of managing uncertainty, with four subthemes: setting the scene; fighting the tooth; working within the system; and self and interpersonal insight. Despite being knowledgeable, participants expressed varying levels of confidence in many aspects while managing children with MIH. There was a great deal of uncertainty surrounding 'doing the right thing' across the themes. Systemic barriers to managing children with MIH within the general dental service were identified.Conclusion The challenges of managing children with MIH was experienced as 'uncertainty'. Barriers within the general dental service made managing children with MIH difficult and participants relied on colleagues in secondary care to manage severe cases.

Assembling the evidence jigsaw: insights from a systematic review of UK studies of individual-focused return to work initiatives for disabled and long-term ill people.

BACKGROUND: Employment rates of long-term ill and disabled people in the UK are low and 2.63 million are on disability-related state benefits. Since the mid-1990s, UK governments have experimented with a range of active labour market policies aimed to move disabled people off benefits and into work to reduce the risk of poverty and social exclusion. This systematic review asks what employment impact have these interventions had and how might they work better? METHODS: A systematic review of observational and qualitative empirical studies and systematic reviews published between 2002 and mid-2008 reporting employment effects and/or process evaluations of national UK government interventions focused on helping long-term sick or disabled people (aged 16-64) into the open labour market. This built on our previous systematic review which covered the years 1970 to 2001. RESULTS: Searches identified 42 studies, 31 of which evaluated initiatives with an individual focus (improving an individual's employability or providing financial support in returning to work) while 11 evaluated initiatives with an environmental focus (directed at the employment environment or changing the behaviour of employers). This paper synthesises evidence from the 31 studies with an individual focus. The use of personal advisors and individual case management in these schemes helped some participants back to work. Qualitative studies, however, revealed that time pressures and job outcome targets influenced advisors to select 'easier-to-place' claimants into programmes and also inhibited the development of mutual trust, which was needed for individual case management to work effectively. Financial incentives can help with lasting transitions into work, but the incentives were often set too low or were too short-term to have an effect. Many of the studies suffered from selection bias into these programmes of more work-ready claimants. Even though these were national programmes, they had very low awareness and take-up rates, making it unlikely that a population-level impact would be achieved even if effective for participants. CONCLUSIONS: The evidence reveals barriers and facilitators for the effective implementation of these types of interventions that could inform the continuing welfare reforms. The evidence points towards the need for more long-term, sustained and staged support for those furthest from the labour market.

How do macro-level contexts and policies affect the employment chances of chronically ill and disabled people? Part I: The impact of recession and deindustrialization.

Low employment rates of chronically ill and disabled people are of serious concern. Being out of work increases the risk of poverty and social exclusion, which may further damage the health of these groups, exacerbating health inequalities. Macro-level policies have a potentially tremendous impact on their employment chances, and these influences urgently need to be understood as the current economic crisis intensifies. In Part I of this two-part study, the authors examine employment trends for people who report a chronic illness or disability, by gender and educational level, in Canada, Denmark, Norway, Sweden, and the United Kingdom in the context of economic booms and busts and deindustrialization. People with the double burden of chronic illness and low education have become increasingly marginalized from the labor market. Deindustrialization may have played a part in this process. In addition, periods of high unemployment have sparked a downward trend in employment for already marginalized groups who did not feel the benefits when the economy improved. Norway and Sweden have been better able to protect the employment of these groups than the United Kingdom and Canada. These contextual differences suggest that other macro-level factors, such as active and passive labor market polices, may be important, as examined in part II.

How do macro-level contexts and policies affect the employment chances of chronically ill and disabled people? Part II: The impact of active and passive labor market policies.

The authors investigate three hypotheses on the influence of labor market deregulation, decommodification, and investment in active labor market policies on the employment of chronically ill and disabled people. The study explores the interaction between employment, chronic illness, and educational level for men and women in Canada, Denmark, Norway, Sweden, and the United Kingdom, countries with advanced social welfare systems and universal health care but with varying types of active and passive labor market policies. People with chronic illness were found to fare better in employment terms in the Nordic countries than in Canada or the United Kingdom. Their employment chances also varied by educational level and country. The employment impact of having both chronic illness and low education was not just additive but synergistic. This amplification was strongest for British men and women, Norwegian men, and Danish women. Hypotheses on the disincentive effects of tighter employment regulation or more generous welfare benefits were not supported. The hypothesis that greater investments in active labor market policies may improve the employment of chronically ill people was partially supported. Attention must be paid to the differential impact of macro-level policies on the labor market participation of chronically ill and disabled people with low education, a group facing multiple barriers to gaining employment.

21-(4-Methyl-phenyl-sulfon-yl)-4,7,13,16-tetra-oxa-1,10,21-triaza-bicyclo-[8.8.5]tricosane-19,23-dione: an N-tosyl-ated macrobicyclic dilactam.

The macrobicyclic title compound, C(23)H(35)N(3)O(8)S, contains two tertiary amide bridgehead N atoms and a toluene-sulfonamide N atom in the center of the five-atom bridging strand. The mol-ecule has a central cavity that is defined by the 18-membered ring identified by the N(2)O(4) donor atom set and two 15-membered rings with N(3)O(2) donor atom sets. The toluene-sulfonamide N atom adopts an exo orientation with respect to the central cavity, and the tosyl group is oriented on one side of the aza-bridging strand that connects the bridgehead N atoms.

Reproducible, portable, and efficient ancient genome reconstruction with nf-core/eager.

The broadening utilisation of ancient DNA to address archaeological, palaeontological, and biological questions is resulting in a rising diversity in the size of laboratories and scale of analyses being performed. In the context of this heterogeneous landscape, we present an advanced, and entirely redesigned and extended version of the EAGER pipeline for the analysis of ancient genomic data. This Nextflow pipeline aims to address three main themes: accessibility and adaptability to different computing configurations, reproducibility to ensure robust analytical standards, and updating the pipeline to the latest routine ancient genomic practices. The new version of EAGER has been developed within the nf-core initiative to ensure high-quality software development and maintenance support; contributing to a long-term life-cycle for the pipeline. nf-core/eager will assist in ensuring that a wider range of ancient DNA analyses can be applied by a diverse range of research groups and fields.

Navigating employment retention with a chronic health condition: a meta-ethnography of the employment experiences of people with musculoskeletal disorders in the UK.

Purpose: Musculoskeletal disorders (MSDs) are associated with high rates of work disability in the UK. This review synthesized qualitative evidence concerning the employment experiences of people with MSDs to explore the factors shaping their employment trajectories post-onset and the resources they draw on to remain in work.Material and methods: Systematic database searches identified 16 qualitative studies of the employment consequences of having a chronic MSD in the UK. Meta-ethnographic methods were utilized to synthesize this body of evidence. This included a translation of concepts across studies to produce a line of argument synthesis.Results: The lack of certainty associated with often fluctuating and invisible MSD symptoms leads to employees struggling to maintain a stable work identity. Work retention is aided by having: a clear diagnosis, occupational tasks commensurate with altered abilities, and employers and colleagues who understand the nature of the condition. The ability to negotiate and implement workplace adjustments aids work retention but is dependent upon having good quality employee-employer relationships and the degree of autonomy available to the employee.Conclusion: Individuals with MSDs must draw on a range of personal, social, organizational and institutional resources to remain in or return to work post-onset.Implications for rehabilitationThe fluctuating and invisible nature of chronic musculoskeletal disorders (MSDs) creates uncertainty for individuals about their ability to remain working or return-to-work.Individuals with MSDs must draw on a range of personal, social, organizational, and institutional resources to remain in work following onset.Work retention is aided by having a clear diagnosis; occupational tasks commensurate with altered abilities; and understanding employers and coworkers.Organizational flexibility and the ability to act autonomously by changing occupations or self-implementing or requesting work adjustments are particularly important for work retention.

Genetic diversity of HLA system in two populations from Puebla, Mexico: Puebla city and rural Puebla.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 2827 Mexicans from the state of Puebla living in the city of Puebla (N = 1994) and rural communities (N = 833), to obtain information regarding allelic and haplotypic frequencies. We found that the 16 most frequent haplotypes in Puebla are all of them Native American. Admixture estimates revealed that the main genetic components in the state of Puebla are Native American (72.21 ±â€¯1.25% by ML; 63.30% of Native American haplotypes) and European (21.05 ±â€¯1.92% by ML; 23.86% of European haplotypes), and a less prominent African genetic component (6.74 ±â€¯2.20% by ML; 6.20% of African haplotypes).

Genetic diversity of HLA system in two populations from Yucatán, Mexico: Mérida and rural Yucatán.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 324 Mexicans from the state of Yucatán living in the city of Mérida (N = 192) and rural communities (N = 132), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in the state of Yucatán include 16 Native American and one European haplotype. Admixture estimates revealed that the main genetic components in Yucatán are Native American (81.54 ±â€¯4.99% by ML; 62.92% of Native American haplotypes) and European (11.50 ±â€¯15.43% by ML; 23.26% of European haplotypes), and a less prominent African genetic component (6.96 ±â€¯10.47% by ML; 5.93% of African haplotypes).