Work-life imbalance: informal care and paid employment

In the United Kingdom informal carers are people who look after relatives or friends who need extra support because of age, physical or learning disability or illness. The majority of informal carers are women and female carers also care for longer hours and for longer durations than men. Thus women and older women in particular, shoulder the burden of informal care. We consider the costs of caring in terms of the impact that these kinds of caring responsibilities have on employment. The research is based on the responses of informal carers to a dedicated questionnaire and in-depth interviews with a smaller sub-sample of carers. Our results indicate that the duration of a caring episode as well as the hours carers commit to caring impact on their employment participation. In addition carers’ employment is affected by financial considerations, the needs of the person they care for, carers’ beliefs about the compatibility of informal care and paid work and employers’ willingness to accommodate carers’ needs. Overall, the research confirms that informal carers continue to face difficulties when they try to combine employment and care in spite of recent policy initiatives designed to help them

WGS for surveillance of antimicrobial resistance:A pilot study to detect the prevalence and mechanism of resistance to azithromycin in a UK population of non-typhoidal Salmonella

Objectives: WGS and phenotypic methods were used to determine the prevalence of azithromycin resistance in Salmonella enterica isolates from the UK and to identify the underlying mechanisms of resistance.  Methods: WGS by Illumina HiSeq was carried out on 683 Salmonella spp. isolates. Known genes associated with azithromycin resistance were detected by WGS using a mapping-based approach. Macrolide resistance determinants were identified and the genomic context of these elements was assessed by various bioinformatics tools. Susceptibility testing was in accordance with EUCAST methodology (MIC ≤16 mg/L).  Results: Fifteen isolates of non-typhoidal Salmonella enterica belonging to serovars Salmonella Blockley, Salmonella Typhimurium, Salmonella Thompson, Salmonella Ridge and Salmonella Kentucky showed resistance or decreased susceptibility to azithromycin (from 6 to >16 mg/L) due to the presence of macrolide resistance genes mphA, mphB or mefB. These genes were either plasmid or chromosomally mediated. Azithromycin-resistant Salmonella Blockley isolates harboured a macrolide inactivation gene cluster, mphA-mrx-mphr(A), within a novel Salmonella azithromycin resistance genomic island (SARGI) determined by MinION sequencing. This is the first known chromosomally mediated mphA gene cluster described in salmonellae. Phylogenetic analysis and epidemiological information showed that mphA Salmonella Blockley isolates were not derived from a single epidemiologically related event. The azithromycin MICs of the 15 Salmonella spp. isolates showed that the presence of the mphA gene was associated with MIC ≥16 mg/L, while the presence of mefB or mphB was not.  Conclusions: Azithromycin resistance due to acquisition of known macrolide resistance genes was seen in four different Salmonella serovars and can be either plasmid-encoded or chromosomally encoded

Risk factors for negative experiences during psychotherapy

Background: It is estimated that between 3% and 15% of patients have a negative experience of psychotherapy, but little is understood about this. Aims: The aim of this study was to investigate the factors associated with patients’ negative therapy experiences. Method: The data comprised 185 patient and 304 therapist questionnaires, 20 patient and 20 therapist interviews. Patients reported on an unhelpful or harmful experience of therapy, and therapists on a therapy where they thought the patient they were working with had a poor or harmful experience. These were transcribed and analysed using thematic analysis. Results: There was a Lack of fit between Patient needs, Therapist skills, and Service structures. This could result in Fault Lines, a tension between Safety and containment and Power and control. This tension led to Strain and Poor Engagement, which led to Consequences following the negative therapy experience. Conclusions: Patients require clear information, choice, involvement in decision-making, explicit contracting and clarity about sessions and progress. Opportunities for patient feedback should be the norm, where the therapist and service are vigilant for signs of deterioration and solutions considered.Clinical and methodological significance of this article: Estimates of “unwanted effects,” including long-lasting effects, of psychotherapy have ranged from 3% to 15%. Few empirical studies have been conducted in this area. This study aimed to address this gap and provide clinicians with a model of risk factors for negative therapy effects. The findings of this study indicate the importance of providing patients with a supportive service structure that offers clear information, choice and involvement in decision-making. Explicit contracting at the beginning of therapy and clarity about sessions and progress are also important in managing patient expectations throughout. Opportunities for patient feedback should be provided

What's in a Name? Species-Wide Whole-Genome Sequencing Resolves Invasive and Noninvasive Lineages of Salmonella enterica Serotype Paratyphi B

For 100 years, it has been obvious that Salmonella enterica strains sharing the serotype with the formula 1,4,[ 5], 12: b:1,2-now known as ParatyphiB-can cause diseases ranging from serious systemic infections to self-limiting gastroenteritis. Despite considerable predicted diversity between strains carrying the common Paratyphi B serotype, there remain few methods that subdivide the group into groups that are congruent with their disease phenotypes. Paratyphi B therefore represents one of the canonical examples in Salmonella where serotyping combined with classical microbiological tests fails to provide clinically informative information. Here, we use genomics to provide the first high-resolution view of this serotype, placing it into a wider genomic context of the Salmonella enterica species. These analyses reveal why it has been impossible to subdivide this serotype based upon phenotypic and limited molecular approaches. By examining the genomic data in detail, we are able to identify common features that correlate with strains of clinical importance. The results presented here provide new diagnostic targets, as well as posing important new questions about the basis for the invasive disease phenotype observed in a subset of strains. IMPORTANCE Salmonella enterica strains carrying the serotype Paratyphi B have long been known to possess Jekyll and Hyde characteristics; some cause gastroenteritis, while others cause serious invasive disease. Understanding what makes up the population of strains carrying this serotype, as well as the source of their invasive disease, is a 100-year-old puzzle that we address here using genomics. Our analysis provides the first high-resolution view of this serotype, placing strains carrying serotype Paratyphi B into the wider genomic context of the Salmonella enterica species. This work reveals a history of disease dating back to the middle ages, caused by a group of distinct lineages with various abilities to cause invasive disease. By quantifying the key genomic differences between the invasive and noninvasive populations, we are able to identify key virulence-related targets that can form the basis of simple, rapid, point-of-care tests.Peer reviewe

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19:a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

This study was funded by an investigator-initiated research grant from Insmed (Bridgewater, NJ, USA). The authors acknowledge the funding and logistical support from the UK National Institute for Health and Care Research.Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.Publisher PDFPeer reviewe

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19