Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum.

OBJECTIVE: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes. METHODS: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS. RESULTS: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31 of 114 GDRs curated (27%), moderate for 38 (33%), limited for 43 (38%), and disputed for 2 (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 were autosomal dominant, and 3 were X-linked. INTERPRETATION: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multisystem organ surveillance, recurrence risk counseling, reproductive choice, natural history studies, and determination of eligibility for interventional clinical trials. ANN NEUROL 2023;94:696-712.

External electrical and pharmacological cardioversion for atrial fibrillation, atrial flutter or atrial tachycardias: a network meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is the most frequent sustained arrhythmia. Cardioversion is a rhythm control strategy to restore normal/sinus rhythm, and can be achieved through drugs (pharmacological) or a synchronised electric shock (electrical cardioversion). OBJECTIVES: To assess the efficacy and safety of pharmacological and electrical cardioversion for atrial fibrillation (AF), atrial flutter and atrial tachycardias. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Conference Proceedings Citation Index-Science (CPCI-S) and three trials registers (ClinicalTrials.gov, WHO ICTRP and ISRCTN) on 14 February 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) at the individual patient level. Patient populations were aged ≥ 18 years with AF of any type and duration, atrial flutter or other sustained related atrial arrhythmias, not occurring as a result of reversible causes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology to collect data and performed a network meta-analysis using the standard frequentist graph-theoretical approach using the netmeta package in R. We used GRADE to assess the quality of the evidence which we presented in our summary of findings with a judgement on certainty. We calculated differences using risk ratios (RR) and 95% confidence intervals (CI) as well as ranking treatments using a P value. We assessed clinical and statistical heterogeneity and split the networks for the primary outcome and acute procedural success, due to concerns about violating the transitivity assumption. MAIN RESULTS: We included 112 RCTs (139 records), from which we pooled data from 15,968 patients. The average age ranged from 47 to 72 years and the proportion of male patients ranged from 38% to 92%. Seventy-nine trials were considered to be at high risk of bias for at least one domain, 32 had no high risk of bias domains, but had at least one domain classified as uncertain risk, and one study was considered at low risk for all domains. For paroxysmal AF (35 trials), when compared to placebo, anteroapical (AA)/anteroposterior (AP) biphasic truncated exponential waveform (BTE) cardioversion (RR: 2.42; 95% CI 1.65 to 3.56), quinidine (RR: 2.23; 95% CI 1.49 to 3.34), ibutilide (RR: 2.00; 95% CI 1.28 to 3.12), propafenone (RR: 1.98; 95% CI 1.67 to 2.34), amiodarone (RR: 1.69; 95% CI 1.42 to 2.02), sotalol (RR: 1.58; 95% CI 1.08 to 2.31) and procainamide (RR: 1.49; 95% CI 1.13 to 1.97) likely result in a large increase in maintenance of sinus rhythm until hospital discharge or end of study follow-up (certainty of evidence: moderate). The effect size was larger for AA/AP incremental and was progressively smaller for the subsequent interventions. Despite low certainty of evidence, antazoline may result in a large increase (RR: 28.60; 95% CI 1.77 to 461.30) in this outcome. Similarly, low-certainty evidence suggests a large increase in this outcome for flecainide (RR: 2.17; 95% CI 1.68 to 2.79), vernakalant (RR: 2.13; 95% CI 1.52 to 2.99), and magnesium (RR: 1.73; 95% CI 0.79 to 3.79). For persistent AF (26 trials), one network was created for electrical cardioversion and showed that, when compared to AP BTE incremental energy with patches, AP BTE maximum energy with patches (RR 1.35, 95% CI 1.17 to 1.55) likely results in a large increase, and active compression AP BTE incremental energy with patches (RR: 1.14, 95% CI 1.00 to 1.131) likely results in an increase in maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence: high). Use of AP BTE incremental with paddles (RR: 1.03, 95% CI 0.98 to 1.09; certainty of evidence: low) may lead to a slight increase, and AP MDS Incremental paddles (RR: 0.95, 95% CI 0.86 to 1.05; certainty of evidence: low) may lead to a slight decrease in efficacy. On the other hand, AP MDS incremental energy using patches (RR: 0.78, 95% CI 0.70 to 0.87), AA RBW incremental energy with patches (RR: 0.76, 95% CI 0.66 to 0.88), AP RBW incremental energy with patches (RR: 0.76, 95% CI 0.68 to 0.86), AA MDS incremental energy with patches (RR: 0.76, 95% CI 0.67 to 0.86) and AA MDS incremental energy with paddles (RR: 0.68, 95% CI 0.53 to 0.83) probably result in a decrease in this outcome when compared to AP BTE incremental energy with patches (certainty of evidence: moderate). The network for pharmacological cardioversion showed that bepridil (RR: 2.29, 95% CI 1.26 to 4.17) and quindine (RR: 1.53, (95% CI 1.01 to 2.32) probably result in a large increase in maintenance of sinus rhythm at hospital discharge or end of study follow-up when compared to amiodarone (certainty of evidence: moderate). Dofetilide (RR: 0.79, 95% CI 0.56 to 1.44), sotalol (RR: 0.89, 95% CI 0.67 to 1.18), propafenone (RR: 0.79, 95% CI 0.50 to 1.25) and pilsicainide (RR: 0.39, 95% CI 0.02 to 7.01) may result in a reduction in this outcome when compared to amiodarone, but the certainty of evidence is low. For atrial flutter (14 trials), a network could be created only for antiarrhythmic drugs. Using placebo as the common comparator, ibutilide (RR: 21.45, 95% CI 4.41 to 104.37), propafenone (RR: 7.15, 95% CI 1.27 to 40.10), dofetilide (RR: 6.43, 95% CI 1.38 to 29.91), and sotalol (RR: 6.39, 95% CI 1.03 to 39.78) probably result in a large increase in the maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence: moderate), and procainamide (RR: 4.29, 95% CI 0.63 to 29.03), flecainide (RR 3.57, 95% CI 0.24 to 52.30) and vernakalant (RR: 1.18, 95% CI 0.05 to 27.37) may result in a large increase in maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence: low). All tested electrical cardioversion strategies for atrial flutter had very high efficacy (97.9% to 100%). The rate of mortality (14 deaths) and stroke or systemic embolism (3 events) at 30 days was extremely low. Data on quality of life were scarce and of uncertain clinical significance. No information was available regarding heart failure readmissions. Data on duration of hospitalisation was scarce, of low quality, and could not be pooled. AUTHORS' CONCLUSIONS: Despite the low quality of evidence, this systematic review provides important information on electrical and pharmacological strategies to help patients and physicians deal with AF and atrial flutter. In the assessment of the patient comorbidity profile, antiarrhythmic drug onset of action and side effect profile versus the need for a physician with experience in sedation, or anaesthetics support for electrical cardioversion are key aspects when choosing the cardioversion method.

Preferences for deinfibulation (opening) surgery and female genital mutilation service provision: A qualitative study.

OBJECTIVE: To explore the views of female genital mutilation (FGM) survivors, men and healthcare professionals (HCPs) on the timing of deinfibulation surgery and NHS service provision. DESIGN: Qualitative study informed by the sound of silence framework. SETTING: Survivors and men were recruited from three FGM prevalent areas of England. HCPs and stakeholders were from across the UK. SAMPLE: Forty-four survivors, 13 men and 44 HCPs. Ten participants at two community workshops and 30 stakeholders at a national workshop. METHODS: Hybrid framework analysis of 101 interviews and three workshops. RESULTS: There was no consensus across groups on the optimal timing of deinfibulation for survivors who wished to be deinfibulated. Within group, survivors expressed a preference for deinfibulation pre-pregnancy and HCPs antenatal deinfibulation. There was no consensus for men. Participants reported that deinfibulation should take place in a hospital setting and be undertaken by a suitable HCP. Decision making around deinfibulation was complex but for those who underwent surgery it helped to mitigate FGM impacts. Although there were examples of good practice, in general, FGM service provision was suboptimal. CONCLUSION: Deinfibulation services need to be widely advertised. Information should highlight that the procedure can be carried out at different time points, according to preference, and in a hospital by suitable HCPs. Future services should ideally be developed with survivors, to ensure that they are clinically and culturally appropriate. Guidelines would benefit from being updated to reflect the needs of survivors and to ensure consistency in provision.

A study of prisms and therapy in attention loss after stroke (SPATIAL): A feasibility randomised controlled trial.

OBJECTIVE: Investigate feasibility and acceptability of prism adaptation training for people with inattention (spatial neglect), early after stroke, during usual care. DESIGN: Phase II feasibility randomised controlled trial with 3:1 stratified allocation to standard occupational therapy with or without intervention, and nested process evaluation. SETTING: Ten hospital sites providing in-patient stroke services. PARTICIPANTS: Screened positive for inattention more than one-week post-stroke; informal carers. Occupational therapists participated in qualitative interviews. INTERVENTION: Adjunctive prism adaptation training at the start of standard occupational therapy sessions for three weeks. MAIN MEASURES: Feasibility measures included recruitment and retention rates, intervention fidelity and attrition. Outcomes collected at baseline, 3 weeks and 12 weeks tested measures including Nottingham Extended Activities of Daily Living Scale. Acceptability was explored through qualitative interviews and structured questions. RESULTS: Eighty (31%) patients were eligible, 57 (71%) consented, 54 randomised (40:13, +1 exclusion) and 39 (74%) completed 12-week outcomes. Treatment fidelity was good: participants received median eight intervention sessions (IQR: 5, 12) lasting 4.7 min (IQR: 4.1, 5.0). All six serious adverse events were unrelated. There was no signal that patients allocated to intervention did better than controls. Twenty five of 35 recruited carers provided outcomes with excellent data completeness. Therapists, patients and carers found prism adaptation training acceptable. CONCLUSIONS: It is feasible and acceptable to conduct a high-quality definitive trial of prism adaptation training within occupational therapy early after stroke in usual care setting, but difficult to justify given no sign of benefit over standard occupational therapy. CLINICAL TRIAL REGISTRATION: https://www.isrctn.com/ Ref ISRCTN88395268.

School nursing: New ways of working with children and young people during the Covid-19 pandemic: A scoping review.

AIM: To examine how school nurse practice evolved as a result of the Covid-19 pandemic. DESIGN: A scoping review of international literature, conducted and reported in line with Arksey and O'Malley's (2005) framework. DATA SOURCES: Searches were conducted in September 2021. Ten databases were searched: The British Nursing Database, CINAHL, Cochrane Library, Consumer Health Database, Health and Medicine, Nursing and Allied Health, Public Health, PsycINFO, PubMed and Web of Science. Relevant grey literature was identified through hand searching. REVIEW METHODS: A minimum of three reviewers independently screened articles and two reviewers independently undertook data extraction, with any decisions made collaboratively with the wider team. Much of the literature was not empirical work and so it was not possible to apply a traditional quality appraisal framework. RESULTS: Searches identified 554 papers (after deduplication) which were screened against title and abstract. Following the full-text review, 38 articles underwent data extraction and analysis. The review findings highlighted that school nurses adapted their practice to ensure they were able to continue providing their formal and informal school health offer to children, young people and their families and continued working closely with the multidisciplinary team. In addition, the expanded public health role generated by Covid-19 for school nurses' work was considerable, multi-layered and added to their routine workload. School nurses displayed resilience, adaptability and creativity in their response to delivering services during Covid-19. CONCLUSION: School nurses took on a leading public health role during the Covid-19 pandemic. Some developments and practices were highlighted as beneficial to continue beyond the pandemic. However, formal evaluation is needed to identify which practices may merit integration into routine practice. Continued investment in staff and infrastructure will be essential to ensuring school nurses continue to expand their practice and influence as public health experts.

Incidence, morbidity, mortality and disparities in dementia: A population linked electronic health records study of 4.3 million individuals.

INTRODUCTION: We report dementia incidence, comorbidities, reasons for health-care visits, mortality, causes of death, and examined dementia patterns by relative deprivation in the UK. METHOD: A longitudinal cohort analysis of linked electronic health records from 4.3 million people in the UK was conducted to investigate dementia incidence and mortality. Reasons for hospitalization and causes of death were compared in individuals with and without dementia. RESULTS: From 1998 to 2016 we observed 145,319 (3.1%) individuals with incident dementia. Repeated hospitalizations among senior adults for infection, unknown morbidity, and multiple primary care visits for chronic pain were observed prior to dementia diagnosis. Multiple long-term conditions are present in half of the individuals at the time of diagnosis. Individuals living in high deprivation areas had higher dementia incidence and high fatality. DISCUSSION: There is a considerable disparity of dementia that informs priorities of prevention and provision of patient care.

Maladaptive therapist schemas in CBT practice, training and supervision: A scoping review.

BACKGROUND: Maladaptive therapist schemas are hypothesized to generate difficulties within cognitive behavioural therapy (CBT) practice, training and supervision. Without adequate identification and management, they negatively affect the cognitions and emotions of the therapist, leading them to behave in ways that risk ruptures or therapy and supervision being delivered in a suboptimal fashion. Consequently, there is a need to synthesize the research that has been undertaken to date on the content, prevalence, identification and management of maladaptive therapist schemas. METHOD: A scoping review was undertaken of studies that have been published since 2001 on the impact of maladaptive therapist schemas (also referred to interchangeably as beliefs or cognitions) in CBT practice, training and supervision. Thirteen studies were identified in a literature search from four electronic databases, a reference list search of identified articles and hand searches. RESULTS: Three overall themes were identified in the research: (1) prevalence of therapist schemas, (2) specific therapist beliefs and (3) therapist characteristics associated with the delivery of suboptimal CBT or supervision. While there is little empirical support for therapist schemas, therapist resistance and beliefs relating to the fear of using exposure therapy were identified. Therapist intolerance of uncertainty and self-esteem were recurrent factors. CONCLUSION: There is no consensus on how to define, identify, formulate or respond to maladaptive therapist beliefs or schemas in clinical practice, training or supervision. Further research is needed to better understand their origins, maintaining factors and appropriate management of their impact.

A clinical laboratory's experience using GeneMatcher-Building stronger gene-disease relationships.

The use of whole-genome sequencing (WGS) has accelerated the pace of gene discovery and highlighted the need for open and collaborative data sharing in the search for novel disease genes and variants. GeneMatcher (GM) is designed to facilitate connections between researchers, clinicians, health-care providers, and others to help in the identification of additional patients with variants in the same candidate disease genes. The Illumina Clinical Services Laboratory offers a WGS test for patients with suspected rare and undiagnosed genetic disease  and regularly submits potential candidate genes to GM to strengthen gene-disease relationships. We describe our experience with GM, including criteria for evaluation of candidate genes, and our workflow for the submission and review process. We have made 69 submissions, 36 of which are currently active. Ten percent of submissions have resulted in publications, with an additional 14 submissions part of ongoing collaborations and expected to result in a publication.

Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

BACKGROUND: Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS. METHODS: In this randomised controlled trial, postmenopausal women aged 50-74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1-17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (-41·8 to -2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (-21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group. INTERPRETATION: The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended. FUNDING: National Institute for Health Research, Cancer Research UK, and The Eve Appeal.

Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of ß-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). ß-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human ß-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455.

Barriers and enablers to participating in regular screening programmes for women with cerebral palsy: A qualitative life course study.

AIMS: To determine the barriers and enablers to regular, women-oriented screening programmes for women with cerebral palsy (CP); and to discuss the participants' suggestions for change. DESIGN: Qualitative life course approach. METHODS: Twenty-five life course interviews were conducted with women in 2020 who identified as having a diagnosis of CP. Interviews were conducted in person or using electronic platforms. Framework analysis was used to interpret the data. FINDINGS: Access and utilization of regular screening programmes for women with CP across the life course are determined by multiple socioecological factors. Three themes are discussed focusing particularly on cervical and breast screening: 1. barriers, 2. enablers and 3. women's suggestions for change. Some women chose to opt out of sexual health checks for fear they would be too uncomfortable or the procedure would be too difficult. Practitioner attitudes towards disability in general, as well as the extent to which they understood the effects of CP for women, was highlighted as a barrier. Accessibility and adaptability of the environment also influenced women's uptake of screening. CONCLUSION: Women with CP face many challenges to their sexual and reproductive healthcare. These can deter them from participating in regular women-oriented screening programmes, which puts them at higher risk of preventable diseases. Understanding the lifelong effects of CP for women, and the interaction with their reproductive health could help to reduce unmet needs and increase participation in relevant screening across the life course. IMPACT: Knowledge of the challenges to regular screening programmes experienced by women with CP across the life course is crucial to provide appropriate preventative healthcare for women with CP across different stages of life. Elements of this knowledge could have benefits for the care of all disabled women.

The risk of COVID-19 in survivors of domestic violence and abuse.

A 'shadow pandemic' of domestic violence and abuse (DVA) has emerged secondary to strict public health measures containing the spread of SARS-CoV-2. Many countries have implemented policies to allow the free movement of DVA survivors in attempts to minimise their exposure to abusive environments. Although these policies are well received, as a result there is a possibility of increased COVID-19 transmission within this vulnerable group who are not currently prioritised for vaccination. Therefore, we aimed to compare the risk of developing suspected or confirmed COVID-19 in women (aged over 16 years) exposed to DVA against age-sex-matched unexposed controls, following adjustment for known COVID-19 risk factors. A population-based retrospective open cohort study was undertaken between the 31 January 2020 and 28 February 2021 using 'The Health Improvement Network' database. We identified 10,462 eligible women exposed to DVA who were matched to 41,467 similarly aged unexposed women. Following adjustment for key covariates, women exposed to DVA were at an increased risk (aHR 1.57; 95% CI 1.29-1.90) of suspected/confirmed COVID-19 compared to unexposed women. These findings support previous calls for positive policy action improving DVA surveillance and prioritising survivors for COVID-19 vaccination.

Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds.

Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150-500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.

Feasibility and acceptability of the "Never Events" method in the context of multi-agency child protection: findings from an exploratory study.

This report outlines an exploratory study that investigated whether the "Never Events" system - first used in healthcare contexts to identify and investigate preventable incidents that cause serious harm or death as a result of human error - could be adapted in the context of UK multi-agency child protection. Using a sequential design, two online surveys were carried out that explored practitioners' (n = 46) views about the feasibility of adopting the Never Events model and what, if any, incidents or events could be investigated plausibly using such a model. Practitioners were drawn from a purposive sample. An inter-disciplinary panel of senior practitioners - drawn from nursing, public health, social work and child mental health services- discussed the surveys' findings and the list of proposed child protection Never Events. The findings indicate that the complex, judgment-based nature of child protection contributes to difficulties creating shared understandings about what constitutes harm and the extent to which multi-agency systems can share decision-making and responsibility for the way they identify and support families. Thinking through and discussing the relative strengths and limitations of the Never Events model may nevertheless be a valuable exercise in interprofessional training and the design of highly localized review and reporting systems.

Mixed methods study of clinicians' perspectives on barriers to implementation of treat to target in psoriatic arthritis.

OBJECTIVES: In treat to target (T2T), the patient is treated to reach and maintain specified and sequentially measured goals, such as remission or low disease activity. T2T in psoriatic arthritis (PsA) has demonstrated improved clinical and patient-reported outcomes and is recommended in European guidelines. However, most clinicians do not use T2T in PsA. This study examined the barriers and enablers to implementation in practice. METHODS: Sequential mixed methods comprising a qualitative design (interviews and focus group) to inform a quantitative design (survey). Qualitative data were analysed thematically, and quantitative statistics were analysed descriptively. RESULTS: Nineteen rheumatology clinicians participated in telephone interviews or a face-to-face focus group. An overarching theme 'Complexity' (including 'PsA vs Rheumatoid Arthritis', 'Measurement' and 'Resources') and an underpinning theme 'Changes to current practice' (including 'Reluctance due to organisational factors' and 'Individual determination to make changes') were identified. 153 rheumatology clinicians responded to an online survey. Barriers included limited clinical appointment time to collect outcome data (54.5%) and lack of training in assessing skin disease (35%). Enablers included provision of a protocol (86.4%), a local implementation lead (80.9%), support in clinic to measure outcomes (83.3%) and training in T2T (69.8%). The importance of regular audit with feedback, specialist PsA clinics and a web-based electronic database linked to hospital/national information technology (IT) systems were also identified as enablers. CONCLUSIONS: Implementation of T2T in PsA requires an integrated approach to address the support, training and resource needs of individual clinicians, rheumatology teams, local IT systems and service providers to maximise success.

Female survivors of intimate partner violence and risk of depression, anxiety and serious mental illness.

BACKGROUND: Internationally, intimate partner violence (IPV) cohorts have demonstrated associations with depression and anxiety. However, this association has not yet been described in a UK population, nor has the association with serious mental illness (SMI). AIMS: To explore the relationship between IPV exposure and mental illness in a UK population. METHOD: We designed a retrospective cohort study whereby we matched 18 547 women exposed to IPV to 74 188 unexposed women. Outcomes of interest (anxiety, depression and SMI) were identified through clinical codes. RESULTS: At baseline, 9174 (49.5%) women in the exposed group had some form of mental illness compared with 17 768 (24.0%) in the unexposed group, described as an adjusted odds ratio of 2.62 (95% CI 2.52-2.72). Excluding those with mental illness at baseline, 1254 exposed women (incidence rate 46.62 per 1000 person-years) went on to present with any type of mental illness compared with 3119 unexposed women (incidence rate 14.93 per 1000 person-years), with an aIRR of 2.77 (95% CI 2.58-2.97). Anxiety (aIRR 1.99, 95% CI 1.80-2.20), depression (aIRR 3.05, 95% CI 2.81-3.31) and SMI (aIRR 3.08, 95% CI 2.19-4.32) were all associated with exposure to IPV. CONCLUSIONS: IPV remains a significant public health issue in the UK. We have demonstrated the significant recorded mental health burden associated with IPV in primary care, at both baseline and following exposure. Clinicians must be aware of this association to reduce mental illness diagnostic delay and improve management of psychological outcomes in this group of patients.

What feedback do reviewers give when reviewing qualitative manuscripts? A focused mapping review and synthesis.

BACKGROUND: Peer review is at the heart of the scientific process. With the advent of digitisation, journals started to offer electronic articles or publishing online only. A new philosophy regarding the peer review process found its way into academia: the open peer review. Open peer review as practiced by BioMed Central (BMC) is a type of peer review where the names of authors and reviewers are disclosed and reviewer comments are published alongside the article. A number of articles have been published to assess peer reviews using quantitative research. However, no studies exist that used qualitative methods to analyse the content of reviewers' comments. METHODS: A focused mapping review and synthesis (FMRS) was undertaken of manuscripts reporting qualitative research submitted to BMC open access journals from 1 January - 31 March 2018. Free-text reviewer comments were extracted from peer review reports using a 77-item classification system organised according to three key dimensions that represented common themes and sub-themes. A two stage analysis process was employed. First, frequency counts were undertaken that allowed revealing patterns across themes/sub-themes. Second, thematic analysis was conducted on selected themes of the narrative portion of reviewer reports. RESULTS: A total of 107 manuscripts submitted to nine open-access journals were included in the FMRS. The frequency analysis revealed that among the 30 most frequently employed themes "writing criteria" (dimension II) is the top ranking theme, followed by comments in relation to the "methods" (dimension I). Besides that, some results suggest an underlying quantitative mindset of reviewers. Results are compared and contrasted in relation to established reporting guidelines for qualitative research to inform reviewers and authors of frequent feedback offered to enhance the quality of manuscripts. CONCLUSIONS: This FMRS has highlighted some important issues that hold lessons for authors, reviewers and editors. We suggest modifying the current reporting guidelines by including a further item called "Degree of data transformation" to prompt authors and reviewers to make a judgment about the appropriateness of the degree of data transformation in relation to the chosen analysis method. Besides, we suggest that completion of a reporting checklist on submission becomes a requirement.

A systematic review exploring palliative care for families who are forced migrants.

AIMS: To explore the palliative care experiences of forced migrant children, families, and healthcare professionals (HCPs) highlighting successes, challenges, and associated practice implications. DESIGN: Systematic literature review. DATA SOURCES: The following search engines were searched from 2008 - 2018: Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health, MEDLINE, Embase, ProQuest, Scopus, Psycinfo, and Web of Science. Extensive reference and citation checking were also conducted. REVIEW METHODS: Systematic review followed PRISMA guidelines with prepared PROSPERO registered protocol #CRD42019129200. English language qualitative, quantitative, or mixed methods studies were eligible for inclusion. Study quality was appraised using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Eighteen studies (reported in 20 articles) met the final inclusion criteria. Most focused on challenges to care provision. Thematic analysis following methods proposed by Braun and Clarke was undertaken. Five themes were identified: (a) divergence of beliefs and expectations; (b) communication; (c) navigating healthcare systems; (d) burdens and coping strategies; and (e) training and knowledge. A compassionate, collaborative approach with mutual respect crossed themes and was linked to high-quality care. CONCLUSION: Forced migrant families have multiple needs including physical and emotional support and help in navigating complex systems. Professional interpreters can ease communication barriers when resourced appropriately. Individualized care is crucial to addressing the intricate mosaic of culture such families present. A cultural sensitivity/insensitivity framework is presented that may help guide future interactions and priorities for those working in children's palliative care. IMPACT: This systematic review explored the international experiences of palliative care for forced migrant families. The findings highlight the plight of families who experience multiple traumas and increased levels of grief and loss through their migration experiences and when caring for a child with a life-limiting condition. This research has potential to have an impact on professionals working with culturally diverse families in all palliative care settings.

The state of mixed methods research in nursing: A focused mapping review and synthesis.

AIMS: To consider the scope and quality of mixed methods research in nursing. DESIGN: Focused mapping review and synthesis (FMRS). DATA SOURCES: Five purposively selected journals: International Journal of Nursing Studies, Journal of Nursing Scholarship, Journal of Advanced Nursing, Worldviews on Evidence-Based Nursing, and Journal of Mixed Methods Research. REVIEW METHODS: In the target journals, titles and abstracts from papers published between 2015-2018 were searched for the words or derivative words 'mixed methods'. Additional keyword searches were undertaken using each journal's search tool. We included studies that investigated nursing and reported to use a mixed methods approach. Articles that met the inclusion criteria were read in full and information was extracted onto a predetermined pro forma. Findings across journals were then synthesized to illustrate the current state of mixed methods research in nursing. RESULTS: We located 34 articles that reported on mixed methods research, conducted across 18 countries. Articles differed significantly both within and across journals in terms of conformity to a mixed methods approach. We assessed the studies for the quality of their reporting as regard the use of mixed methods. Nineteen studies were rated as satisfactory or good, with 15 rated as poorly described. Primarily, a poor rating was due to the absence of stating an underpinning methodological approach to the study and/or limited detail of a crucial integration phase. CONCLUSIONS: Our FMRS revealed a paucity of published mixed methods research in the journals selected. When they are published, there are limitations in the detail given to the underpinning methodological approach and theoretical explanation.