iDeLUCS: a deep learning interactive tool for alignment-free clustering of DNA sequences.

SUMMARY: We present an interactive Deep Learning-based software tool for Unsupervised Clustering of DNA Sequences (iDeLUCS), that detects genomic signatures and uses them to cluster DNA sequences, without the need for sequence alignment or taxonomic identifiers. iDeLUCS is scalable and user-friendly: its graphical user interface, with support for hardware acceleration, allows the practitioner to fine-tune the different hyper-parameters involved in the training process without requiring extensive knowledge of deep learning. The performance of iDeLUCS was evaluated on a diverse set of datasets: several real genomic datasets from organisms in kingdoms Animalia, Protista, Fungi, Bacteria, and Archaea, three datasets of viral genomes, a dataset of simulated metagenomic reads from microbial genomes, and multiple datasets of synthetic DNA sequences. The performance of iDeLUCS was compared to that of two classical clustering algorithms (k-means++ and GMM) and two clustering algorithms specialized in DNA sequences (MeShClust v3.0 and DeLUCS), using both intrinsic cluster evaluation metrics and external evaluation metrics. In terms of unsupervised clustering accuracy, iDeLUCS outperforms the two classical algorithms by an average of ∼20%, and the two specialized algorithms by an average of ∼12%, on the datasets of real DNA sequences analyzed. Overall, our results indicate that iDeLUCS is a robust clustering method suitable for the clustering of large and diverse datasets of unlabeled DNA sequences. AVAILABILITY AND IMPLEMENTATION: iDeLUCS is available at https://github.com/Kari-Genomics-Lab/iDeLUCS under the terms of the MIT licence.

RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon/STAT1 pro-apoptosis signaling.

BACKGROUND: RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM+ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. METHODS: We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm-/- mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm-loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. RESULTS: Rhamm-loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm-loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm-/- primary tumor clones that are enriched in lung metastases. Rhamm-/- tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM+ve tumor cells to a significantly greater extent than RHAMM-ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. CONCLUSION: RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

SomaticSiMu: a mutational signature simulator.

SUMMARY: SomaticSiMu is an in silico simulator of single and double base substitutions, and single base insertions and deletions in an input genomic sequence to mimic mutational signatures. SomaticSiMu outputs simulated DNA sequences and mutational catalogues with imposed mutational signatures. The tool is the first mutational signature simulator featuring a graphical user interface, control of mutation rates and built-in visualization tools of the simulated mutations. Simulated datasets are useful as a ground truth to test the accuracy and sensitivity of DNA sequence classification tools and mutational signature extraction tools under different experimental scenarios. The reliability of SomaticSiMu was affirmed by (i) supervised machine learning classification of simulated sequences with different mutation types and burdens, and (ii) mutational signature extraction from simulated mutational catalogues. AVAILABILITY AND IMPLEMENTATION: SomaticSiMu is written in Python 3.8.3. The open-source code, documentation and tutorials are available at https://github.com/HillLab/SomaticSiMu under the terms of the CreativeCommonsAttribution4.0InternationalLicense. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Barriers to health in women of reproductive age living with or at risk of non-communicable diseases in Nigeria: a Photovoice study.

BACKGROUND: Nigeria has one of the highest maternal mortality ratios (MMR) globally with an MMR of 512 (per 100,000 live births) and the proportion of maternal deaths due to non-communicable diseases (NCDs) is increasing. While evidence shows that many of these deaths are preventable, limited attention is being paid to the unique vulnerabilities and experiences of women of reproductive age (WRA) with NCDs and their risk factors, as well as the barriers to the screening, diagnosis, and management of these diseases in Nigeria. METHODS: This study explored the lives of WRA in Lagos and Federal Capital Territory in Nigeria from May to June 2019 using a community-based participatory research (CBPR) methodology called Photovoice which is aligned with CBPR as it includes procedures such as the identification of important community issues, discussion of photo assignments and data analysis. Twenty-four women of reproductive age were provided with digital cameras and trained on how to capture photos that conveyed their current health, healthcare utilization and engagement, and experience journeys. Individual interviews with the women were held for an in-depth exploration of the photographs. The data was then analysed thematically. RESULTS: Six distinct themes were identified across the barriers highlighted by the women: food and nutrition, home and family, neighborhood-built environment, economic instability, religion and spirituality and low prioritization of self-care. These themes captured the challenge of reduced agency, limited contribution and participation, and a complex relationship between visible and invisible illness. CONCLUSION: The perspectives of WRA in Nigeria obtained through this qualitative research provided a strong substratum for understanding the environmental barriers that predispose WRA to NCDs in Nigeria. The results of the study are useful for the improvement of woman-centred services of prevention, diagnosis, and management of NCD risk factors across the maternal and reproductive health care continuum in Nigeria.

Effect of police enforcement and extreme social inequalities on violence and mental health among women who sell sex: findings from a cohort study in London, UK.

OBJECTIVES: To examine legal and social determinants of violence, anxiety/depression among sex workers. METHODS: A participatory prospective cohort study among women (inclusive of transgender) ≥18 years, selling sex in the last 3 months in London between 2018 and 2019. We used logistic generalised estimating equation models to measure associations between structural factors on recent (6 months) violence from clients or others (local residents, strangers), depression/anxiety (Patient Health Questionnaire-4). RESULTS: 197 sex workers were recruited (96% cisgender-women; 46% street-based; 54% off-street) and 60% completed a follow-up questionnaire. Street-based sex workers experienced greater inequalities compared with off-street in relation to recent violence from clients (73% vs 36%); police (42% vs 7%); intimate partner violence (IPV) (56% vs 18%) and others (67% vs 17%), as well as homelessness (65% vs 7%) and recent law enforcement (87% vs 9%). Prevalence of any STI was 17.5% (17/97). For street-based sex workers, recent arrest was associated with violence from others (adjusted OR (aOR) 2.77; 95% CI 1.11 to 6.94) and displacement by police was associated with client violence (aOR 4.35; 95% CI 1.36 to 13.90). Financial difficulties were also associated with client violence (aOR 4.66; 95% CI 1.64 to 13.24). Disability (aOR 3.85; 95% CI 1.49 to 9.95) and client violence (aOR 2.55; 95% CI 1.10 to 5.91) were associated with anxiety/depression. For off-street sex workers, financial difficulties (aOR 3.66; 95% CI 1.64 to 8.18), unstable residency (aOR 3.19; 95% CI 1.36 to 7.49), IPV (aOR 3.77; 95% CI 1.30 to 11.00) and alcohol/drug use were associated with client violence (aOR 3.16; 95% CI 1.26 to 7.92), while always screening and refusing clients was protective (aOR 0.36; 95% CI 0.15 to 0.87). Disability (aOR 5.83; 95% CI 2.34 to 14.51), unmet mental health needs (aOR 3.08; 95% CI 1.15 to 8.23) and past eviction (aOR 3.99; 95% CI 1.23 to 12.92) were associated with anxiety/depression. CONCLUSIONS: Violence, anxiety/depression are linked to poverty, unstable housing and police enforcement. We need to modify laws to allow sex workers to work safely and increase availability of housing and mental health services.

The Effect of Systemic Racism and Homophobia on Police Enforcement and Sexual and Emotional Violence among Sex Workers in East London: Findings from a Cohort Study.

There is extensive qualitative evidence of violence and enforcement impacting sex workers who are ethnically or racially minoritized, and gender or sexual minority sex workers, but there is little quantitative evidence. Baseline and follow-up data were collected among 288 sex workers of diverse genders (cis/transgender women and men and non-binary people) in London (2018-2019). Interviewer-administered and self-completed questionnaires included reports of rape, emotional violence, and (un)lawful police encounters. We used generalized estimating equation models (Stata vs 16.1) to measure associations between (i) ethnic/racial identity (Black, Asian, mixed or multiple vs White) and recent (6 months) or past police enforcement and (ii) ethnic/racial and sexual identity (lesbian, gay or bisexual (LGB) vs. heterosexual) with recent rape and emotional violence (there was insufficient data to examine the association with transgender/non-binary identities). Ethnically/racially minoritized sex workers (26.4%) reported more police encounters partly due to increased representation in street settings (51.4% vs 30.7% off-street, p = 0.002). After accounting for street setting, ethnically/racially minoritized sex workers had higher odds of recent arrest (adjusted odds ratio 2.8, 95% CI 1.3-5.8), past imprisonment (aOR 2.3, 95% CI 1.1-5.0), police extortion (aOR 3.3, 95% CI 1.4-7.8), and rape (aOR 3.6, 95% CI 1.1-11.5). LGB-identifying sex workers (55.4%) were more vulnerable to rape (aOR 2.4, 95% CI 1.1-5.2) and emotional violence. Sex workers identifying as ethnically/racially minoritized (aOR 2.1, 95% CI 1.0-4.5), LGB (aOR 2.0, 95% CI 1.0-4.0), or who use drugs (aOR 2.0, 95% CI 1.1-3.8) were more likely to have experienced emotional violence than white-identifying, heterosexual or those who did not use drugs. Experience of any recent police enforcement was associated with increased odds of rape (aOR 3.6, 95% CI 1.3-8.4) and emotional violence (aOR 4.9, 95% CI 1.8-13.0). Findings show how police enforcement disproportionately targets ethnically/racially minoritized sex workers and contributes to increased risk of rape and emotional violence, which is elevated among sexual and ethnically/racially minoritized workers.

An exploratory study of client and provider experience and perceptions of facility-based childbirth care in Quiché, Guatemala.

INTRODUCTION: Respectful maternity care (RMC) is fundamental to women's and families' experience of care and their decision about where to give birth. Studies from multiple countries describe the mistreatment of women during facility-based childbirth, though only a small number of studies from Guatemala have been published. Less information is available on women's negative and positive experiences of childbirth care and health workers' perceptions and experiences of providing maternity care. METHODS: As part of a program implemented in the Western Highlands of Guatemala to improve quality of reproductive maternal newborn and child health care, a mixed methods assessment was conducted in three hospitals and surrounding areas to understand women's and health workers' experience and perceptions of maternity care. The quantitative component included a survey of 31 maternity health workers and 140 women who had recently given birth in these hospitals. The qualitative component included in-depth interviews (IDIs) and focus group discussions (FGDs) with women and maternity health workers and managers. RESULTS: Women reported a mix of positive and negative experiences of childbirth care related to interpersonal and health system factors. 81% of surveyed women reported that health workers had treated them with respect while 21.4% of women reported verbal abuse. Fifty-five percent and 12% of women, respectively, reported not having access to a private toilet and bath or shower. During IDIs and FGDs, many women described higher rates of verbal abuse directed at women who do not speak Spanish. A regression analysis of survey results indicated that speaking Ixil or K'iche at home was associated with a higher likelihood of women being treated negatively during childbirth in a facility. Health worker survey results corroborated negative aspects of care described by women and also reported mistreatment of health workers by clients and families (70.9%) and colleagues (48.2%). CONCLUSIONS: This study adds to the literature on women's experience of institutional childbirth and factors that influence this experience by triangulating experience and perceptions of both women and health workers. This assessment highlights opportunities to address mistreatment of both women and health workers and to build on positive care attributes to strengthen RMC for all women.

Differential Gene Expression of Brachypodium distachyon Roots Colonized by Gluconacetobacter diazotrophicus and the Role of BdCESA8 in the Colonization.

Alternatives to synthetic nitrogen fertilizer are needed to reduce the costs of crop production and offset environmental damage. Nitrogen-fixing bacterium Gluconacetobacter diazotrophicus has been proposed as a possible biofertilizer for monocot crop production. However, the colonization of G. diazotrophicus in most monocot crops is limited and deep understanding of the response of host plants to G. diazotrophicus colonization is still lacking. In this study, the molecular response of the monocot plant model Brachypodium distachyon was studied during G. diazotrophicus root colonization. The gene expression profiles of B. distachyon root tissues colonized by G. diazotrophicus were generated via next-generation RNA sequencing, and investigated through gene ontology and metabolic pathway analysis. The RNA sequencing results indicated that Brachypodium is actively involved in G. diazotrophicus colonization via cell wall synthesis. Jasmonic acid, ethylene, gibberellin biosynthesis. nitrogen assimilation, and primary and secondary metabolite pathways are also modulated to accommodate and control the extent of G. diazotrophicus colonization. Cellulose synthesis is significantly downregulated during colonization. The loss of function mutant for Brachypodium cellulose synthase 8 (BdCESA8) showed decreased cellulose content in xylem and increased resistance to G. diazotrophicus colonization. This result suggested that the cellulose synthesis of the secondary cell wall is involved in G. diazotrophicus colonization. The results of this study provide insights for future research in regard to gene manipulation for efficient colonization of nitrogen-fixing bacteria in Brachypodium and monocot crops.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

MLDSP-GUI: an alignment-free standalone tool with an interactive graphical user interface for DNA sequence comparison and analysis.

SUMMARY: Machine Learning with Digital Signal Processing and Graphical User Interface (MLDSP-GUI) is an open-source, alignment-free, ultrafast, computationally lightweight, and standalone software tool with an interactive GUI for comparison and analysis of DNA sequences. MLDSP-GUI is a general-purpose tool that can be used for a variety of applications such as taxonomic classification, disease classification, virus subtype classification, evolutionary analyses, among others. AVAILABILITY AND IMPLEMENTATION: MLDSP-GUI is open-source, cross-platform compatible, and is available under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/). The executable and dataset files are available at https://sourceforge.net/projects/mldsp-gui/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

ML-DSP: Machine Learning with Digital Signal Processing for ultrafast, accurate, and scalable genome classification at all taxonomic levels.

BACKGROUND: Although software tools abound for the comparison, analysis, identification, and classification of genomic sequences, taxonomic classification remains challenging due to the magnitude of the datasets and the intrinsic problems associated with classification. The need exists for an approach and software tool that addresses the limitations of existing alignment-based methods, as well as the challenges of recently proposed alignment-free methods. RESULTS: We propose a novel combination of supervised Machine Learning with Digital Signal Processing, resulting in ML-DSP: an alignment-free software tool for ultrafast, accurate, and scalable genome classification at all taxonomic levels. We test ML-DSP by classifying 7396 full mitochondrial genomes at various taxonomic levels, from kingdom to genus, with an average classification accuracy of >97%. A quantitative comparison with state-of-the-art classification software tools is performed, on two small benchmark datasets and one large 4322 vertebrate mtDNA genomes dataset. Our results show that ML-DSP overwhelmingly outperforms the alignment-based software MEGA7 (alignment with MUSCLE or CLUSTALW) in terms of processing time, while having comparable classification accuracies for small datasets and superior accuracies for the large dataset. Compared with the alignment-free software FFP (Feature Frequency Profile), ML-DSP has significantly better classification accuracy, and is overall faster. We also provide preliminary experiments indicating the potential of ML-DSP to be used for other datasets, by classifying 4271 complete dengue virus genomes into subtypes with 100% accuracy, and 4,710 bacterial genomes into phyla with 95.5% accuracy. Lastly, our analysis shows that the "Purine/Pyrimidine", "Just-A" and "Real" numerical representations of DNA sequences outperform ten other such numerical representations used in the Digital Signal Processing literature for DNA classification purposes. CONCLUSIONS: Due to its superior classification accuracy, speed, and scalability to large datasets, ML-DSP is highly relevant in the classification of newly discovered organisms, in distinguishing genomic signatures and identifying their mechanistic determinants, and in evaluating genome integrity.

"I kind of gave up on it after a while, became too hard, closed my eyes, didn't want to know about it"-adults with type 1 diabetes mellitus describe defeat in the context of low social support.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a lifelong condition that requires diligent self-management to avoid complications. Living with T1DM is a considerable challenge and the inability to follow a prescribed regimen is often termed non-compliance. However, this fails to acknowledge that for some people the barriers to glycaemic control may be insurmountable. OBJECTIVE: This qualitative study explores the structural determinants, social context and lived experience of T1DM with 17 adults to understand influences on patterns of self-care, engagement with and trust in health-care services, and health outcomes. RESULTS: Their stories tell us that strong social support is vital to disease adaptation and ongoing management. When social support is absent, the story is one of struggling with intensive diabetes management alone and difficulty controlling blood glucose levels. When confronted with suboptimal glycaemic control, participants isolated from social support developed combative relationships with health-care providers and disengaged from health care. Their subsequent slide to chronic comorbid illness is steep and this study reveals the heartache and loss experienced when difficult life circumstances and low levels of social support have led to irreparable kidney damage. CONCLUSION: Patterns of poor glycaemic control viewed in the health-care encounter without an understanding of the context or life circumstances in which they are occurring can lead to an inability to engage with health-care services. Disengagement from services and the absence of specialist care further isolates people, leaving them managing their diabetes alone with limited success.

A comparison of self-reported quality of life for an Australian haemodialysis and haemodiafiltration cohort.

AIMS: Haemodiafiltration (HDF) has been widely studied for evidence of superior outcomes in comparison with conventional haemodialysis (HD), and there is increasing interest in determining if HDF confers any benefit in relation to quality of life. Studies have been conducted with randomized incident patients; however, little is known regarding HDF and quality of life for prevalent patients. This study examined and compared self-reported quality of life at two time points, 12 months apart in a cohort of satellite HD and HDF patients, using a disease specific questionnaire to determine if HDF conferred an advantage. METHODS: A longitudinal study with a linear mixed-effect model measuring quality of life in a cohort of 171 patients (HD, n = 85, HDF, n = 86) in seven South Australian satellite dialysis centres. RESULTS: Factors associated with significant reduction across the Kidney Disease Quality Of Life™ domains measured were younger age (- 20 to - 29) and comorbid diabetes (- 4.8 to - 11.1). HDF was not associated with moderation of this reduction at either time point (P > 0.05). Baseline physical functioning was reported as very low (median 33.9) and further reduced at time point two. In addition, dialysing for more than 12 h per week in a satellite dialysis unit was associated with reduced quality of life in relation to the burden of kidney disease (- 13.69). CONCLUSION: This study has demonstrated that younger age and comorbid diabetes were responsible for a statistically significant reduction in quality of life, and HDF did not confer any advantage.

Social disparities in the prevalence of diabetes in Australia and in the development of end stage renal disease due to diabetes for Aboriginal and Torres Strait Islanders in Australia and Maori and Pacific Islanders in New Zealand.

BACKGROUND: Disparities in health status occur between people with differing socioeconomic status and disadvantaged groups usually have the highest risk exposure and the worst health outcome. We sought to examine the social disparities in the population prevalence of diabetes and in the development of treated end stage renal disease due to type 1 diabetes which has not previously been studied in Australia and New Zealand in isolation from type 2 diabetes. METHODS: This observational study examined the population prevalence of diabetes in a sample of the Australian population (7,434,492) using data from the National Diabetes Services Scheme and of treated end stage renal disease due to diabetes using data from the Australian and New Zealand Dialysis and Transplant Registry. The data were then correlated with the Australian Bureau of Statistics Socioeconomic Indexes for Areas for an examination of socioeconomic disparities. RESULTS: There is a social gradient in the prevalence of diabetes in Australia with disease incidence decreasing incrementally with increasing affluence (Spearman's rho = .765 p < 0.001). There is a higher risk of developing end stage renal disease due to type 1 diabetes for males with low socioeconomic status (RR 1.20; CI 1.002-1.459) in comparison to females with low socioeconomic status. In Australia and New Zealand Aboriginal and Torres Strait Islanders, Maori and Pacific Islanders appear to have a low risk of end stage renal disease due to type 1 diabetes but continue to carry a vastly disproportionate burden of end stage renal disease due to type 2 diabetes (RR 6.57 CI 6.04-7.14 & 6.48 CI 6.02-6.97 respectively p < 0.001) in comparison to other Australian and New Zealanders. CONCLUSION: Whilst low socioeconomic status is associated with a higher prevalence of diabetes the inverse social gradient seen in this study has not previously been reported. The social disparity seen in relation to treated end stage renal disease due to type 2 diabetes for Aboriginal and Torres Strait Islanders, Maori and Pacific Islanders has changed very little in the past 20 years. Addressing the increasing incidence of diabetes in Australia requires consideration of the underlying social determinants of health.

A common monitoring framework for ending preventable maternal mortality, 2015-2030: phase I of a multi-step process.

BACKGROUND: While global maternal mortality declined 44 % between 1990 and 2015, the majority of countries fell short of attaining Millennium Development Goal targets. The Sustainable Development Goals (SDGs), adopted in late 2015, include a target to reduce national maternal mortality ratios (MMR) to achieve a global average of 70 per 100,000 live births by 2030. A comprehensive paper outlining Strategies toward Ending Preventable Maternal Mortality (EPMM) was launched in February 2015 to support achievement of the SDG global targets. To date, there has not been consensus on a set of core metrics to track progress toward the overall global maternal mortality target, which has made it difficult to systematically monitor maternal health status and programs over time. FINDINGS: The World Health Organization (WHO), Maternal Health Taskforce (MHTF), and the US Agency for International Development (USAID) along with its flagship Maternal and Child Survival Program (MCSP), facilitated a consultative process to seek consensus on maternal health indicators for global monitoring and reporting by all countries. Consensus was reached on 12 indicators and four priority areas for further indicator development and testing. These indicators are being harmonized with the Every Newborn Action Plan core metrics for a joint global maternal newborn monitoring framework. Next steps include a similar process to agree upon indicators to monitor social, political and economic determinants of maternal health and survival highlighted in the EPMM strategies. CONCLUSION: This process provides a foundation for the maternal health community to work collaboratively to track progress on core global indicators. It is important that actors continue to work together through transparent and participatory processes to track progress to end preventable maternal mortality and achieve the SDG maternal mortality targets.

Genomic copy number variation in Mus musculus.

BACKGROUND: Copy number variation is an important dimension of genetic diversity and has implications in development and disease. As an important model organism, the mouse is a prime candidate for copy number variant (CNV) characterization, but this has yet to be completed for a large sample size. Here we report CNV analysis of publicly available, high-density microarray data files for 351 mouse tail samples, including 290 mice that had not been characterized for CNVs previously. RESULTS: We found 9634 putative autosomal CNVs across the samples affecting 6.87% of the mouse reference genome. We find significant differences in the degree of CNV uniqueness (single sample occurrence) and the nature of CNV-gene overlap between wild-caught mice and classical laboratory strains. CNV-gene overlap was associated with lipid metabolism, pheromone response and olfaction compared to immunity, carbohydrate metabolism and amino-acid metabolism for wild-caught mice and classical laboratory strains, respectively. Using two subspecies of wild-caught Mus musculus, we identified putative CNVs unique to those subspecies and show this diversity is better captured by wild-derived laboratory strains than by the classical laboratory strains. A total of 9 genic copy number variable regions (CNVRs) were selected for experimental confirmation by droplet digital PCR (ddPCR). CONCLUSION: The analysis we present is a comprehensive, genome-wide analysis of CNVs in Mus musculus, which increases the number of known variants in the species and will accelerate the identification of novel variants in future studies.

Count every newborn; a measurement improvement roadmap for coverage data.

BACKGROUND: The Every Newborn Action Plan (ENAP), launched in 2014, aims to end preventable newborn deaths and stillbirths, with national targets of ≤12 neonatal deaths per 1000 live births and ≤12 stillbirths per 1000 total births by 2030. This requires ambitious improvement of the data on care at birth and of small and sick newborns, particularly to track coverage, quality and equity. METHODS: In a multistage process, a matrix of 70 indicators were assessed by the Every Newborn steering group. Indicators were graded based on their availability and importance to ENAP, resulting in 10 core and 10 additional indicators. A consultation process was undertaken to assess the status of each ENAP core indicator definition, data availability and measurement feasibility. Coverage indicators for the specific ENAP treatment interventions were assigned task teams and given priority as they were identified as requiring the most technical work. Consultations were held throughout. RESULTS: ENAP published 10 core indicators plus 10 additional indicators. Three core impact indicators (neonatal mortality rate, maternal mortality ratio, stillbirth rate) are well defined, with future efforts needed to focus on improving data quantity and quality. Three core indicators on coverage of care for all mothers and newborns (intrapartum/skilled birth attendance, early postnatal care, essential newborn care) have defined contact points, but gaps exist in measuring content and quality of the interventions. Four core (antenatal corticosteroids, neonatal resuscitation, treatment of serious neonatal infections, kangaroo mother care) and one additional coverage indicator for newborns at risk or with complications (chlorhexidine cord cleansing) lack indicator definitions or data, especially for denominators (population in need). To address these gaps, feasible coverage indicator definitions are presented for validity testing. Measurable process indicators to help monitor health service readiness are also presented. A major measurement gap exists to monitor care of small and sick babies, yet signal functions could be tracked similarly to emergency obstetric care. CONCLUSIONS: The ENAP Measurement Improvement Roadmap (2015-2020) outlines tools to be developed (e.g., improved birth and death registration, audit, and minimum perinatal dataset) and actions to test, validate and institutionalise proposed coverage indicators. The roadmap presents a unique opportunity to strengthen routine health information systems, crosslinking these data with civil registration and vital statistics and population-based surveys. Real measurement change requires intentional transfer of leadership to countries with the greatest disease burden and will be achieved by working with centres of excellence and existing networks.

The social determinants of health for people with type 1 diabetes that progress to end-stage renal disease.

OBJECTIVE: Self-management of type 1 diabetes over a lifetime is complex and challenging even in the best of circumstances, and the social environment can be a powerful determinant of health behaviours and outcomes. The aim of this study was to identify how social determinants of health can impact on the capacity of young people to manage their glycaemic control. METHODS: The findings emerged from a constructivist grounded theory approach through an in-depth examination of life course events that were recounted through qualitative interviews. The rich descriptive detail obtained from this enquiry locates common experiences and the context in which concordance with therapies occurs and health behaviours develop. RESULTS: This qualitative study of young people with type 1 diabetes who have developed end-stage renal disease demonstrates that there are many factors beyond individual control that can contribute to health outcomes. The social determinants of childhood environment, education, socio-economic status, gender and the culture of public health can contribute to disengagement from treatment regimens and the health-care system and to the development of microvascular complications at a comparatively young age. CONCLUSION: These findings challenge the assumptions of health-care practitioners about individual responsibility and highlight the importance of considering how social determinants can shape lives, behaviours and health.

HD-CNV: hotspot detector for copy number variants.

SUMMARY: Copy number variants (CNVs) are a major source of genetic variation. Comparing CNVs between samples is important in elucidating their potential effects in a wide variety of biological contexts. HD-CNV (hotspot detector for copy number variants) is a tool for downstream analysis of previously identified CNV regions from multiple samples, and it detects recurrent regions by finding cliques in an interval graph generated from the input. It creates a unique graphical representation of the data, as well as summary spreadsheets and UCSC (University of California, Santa Cruz) Genome Browser track files. The interval graph, when viewed with other software or by automated graph analysis, is useful in identifying genomic regions of interest for further study. AVAILABILITY AND IMPLEMENTATION: HD-CNV is an open source Java code and is freely available, with tutorials and sample data from http://daleylab.org. CONTACT: jcamer7@uwo.ca

CD44 and RHAMM Are Microenvironmental Sensors with Dual Metastasis Promoter and Suppressor Functions.

The progression of primary tumors to metastases remains a significant roadblock to the treatment of most cancers. Emerging evidence has identified genes that specifically affect metastasis and are potential therapeutic targets for managing tumor progression. However, these genes can have dual tumor promoter and suppressor functions that are contextual in manifestation, and that complicate their development as targeted therapies. CD44 and RHAMM/HMMR are examples of multifunctional proteins that can either promote or suppress metastases, as demonstrated in experimental models. These two proteins can be viewed as microenvironmental sensors and this minireview addresses the known mechanistic underpinnings that may determine their metastasis suppressor versus promoter functions. Leveraging this mechanistic knowledge for CD44, RHAMM, and other multifunctional proteins is predicted to improve the precision of therapeutic targeting to achieve more effective management of metastasis.

The impact of policing and homelessness on violence experienced by women who sell sex in London: a modelling study.

Street-based sex workers experience considerable homelessness, drug use and police enforcement, making them vulnerable to violence from clients and other perpetrators. We used a deterministic compartmental model of street-based sex workers in London to estimate whether displacement by police and unstable housing/homelessness increases client violence. The model was parameterized and calibrated using data from a cohort study of sex workers, to the baseline percentage homeless (64%), experiencing recent client violence (72%), or recent displacement (78%), and the odds ratios of experiencing violence if homeless (1.97, 95% confidence interval 0.88-4.43) or displaced (4.79, 1.99-12.11), or of experiencing displacement if homeless (3.60, 1.59-8.17). Ending homelessness and police displacement reduces violence by 67% (95% credible interval 53-81%). The effects are non-linear; halving the rate of policing or becoming homeless reduces violence by 5.7% (3.5-10.3%) or 6.7% (3.7-10.2%), respectively. Modelled interventions have small impact with violence reducing by: 5.1% (2.1-11.4%) if the rate of becoming housed increases from 1.4 to 3.2 per person-year (Housing First initiative); 3.9% (2.4-6.9%) if the rate of policing reduces by 39% (level if recent increases had not occurred); and 10.2% (5.9-19.6%) in combination. Violence reduces by 26.5% (22.6-28.2%) if half of housed sex workers transition to indoor sex work. If homelessness decreased and policing increased as occurred during the COVID-19 pandemic in 2020, the impact on violence is negligible, decreasing by 0.7% (8.7% decrease-4.1% increase). Increasing housing and reducing policing among street-based sex workers could substantially reduce violence, but large changes are needed.