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Objective: To compare pregnancy rates and outcomes for women with cystic fibrosis in the UK with those of the general population and assess the effect of the introduction of disease‐modifying treatment. Design: A population‐based longitudinal study, 2003–17. Setting: United Kingdom. Population: Women aged 15–44 years in the UK cystic fibrosis (CF) Registry compared with women in England and Wales. Methods: We calculated pregnancy and live‐birth rates for the CF population and the general population of England and Wales. For women with CF we compared pregnancy rates before and after ivacaftor was introduced in 2013. We further used CF registry data to assess pregnancy outcomes for mothers with CF, and to assess the relationship between maternal pre‐pregnancy lung function and nutritional status and child gestational age. Main outcome measures: Pregnancy and live‐birth rates and child gestational age. Results: Of 3831 women with CF, 661 reported 818 pregnancies. Compared with the general population, the pregnancy rate was 3.3 times lower in the CF population (23.5 versus 77.7 per 1000 woman‐years); the live‐birth rate was 3.5 times lower (17.4 versus 61.4 per 1000 woman‐years) with 70% of pregnancies in CF women resulting in live births; termination of pregnancy rates were also lower (9% versus 22%). Pregnancy rates increased post‐ivacaftor for eligible women with CF, from 29.7 to 45.7 per 1000 woman‐years. There was no association between pre‐pregnancy lung function/nutrition status and gestational age. Conclusions: Pregnancy rates in women with CF are about one‐third of the rates in the general population with favourable outcomes, and increased for eligible women post‐ivacaftor. Pregnancy rates in women with CF are about a third of the rate in England and Wales with 70% live births. Ivacaftor increases the rate. [ABSTRACT FROM AUTHOR]

Recent reports suggest that the use of an outpatient-based procedure (pneumatic retinopexy, PR) for retinal detachment repair should be encouraged within the UK, especially in light of Covid-19 and possible restrictions/competing demands on access to operating theatres. It is therefore essential that patients receive comprehensive information about the risks and benefits of this approach compared with a formal surgical repair either by pars plana vitrectomy (PPV) and/or scleral buckling (SB). We report a retrospective case series of retinal detachments (RD) satisfying the strict selection criteria for PR but who were managed with formal surgery. Single-operation success rate for PPV/SB at six months follow-up was 93.8% in our study, higher than published primary success rates for PR (60–80%). When counselling patients for possible PR, the ease, speed and potentially reduced co-morbidity of an outpatient-based procedure needs to be balanced against its significantly higher failure rate in comparison with primary PPV/SB. [ABSTRACT FROM AUTHOR]

A series of five trials was established in Great Britain to test the effectiveness of fourteen treatments and a control on reducing mortality and damage by pine weevil (Hylobius abietis) on recently replanted Sitka spruce (Picea sitchensis). Overall percentage mortality and damage was significantly different between trials, varying from a median of 24%–100%. The most effective treatments in reducing mortality were insecticides and physical barriers, with insecticides being most cost effective. Low volume applications of insecticides were found to be as effective as higher doses. Using larger trees did not reduce mortality compared to the control, nor did application of a controlled release fertiliser. At Auchencairn, the trial where mortality was highest no treatment provided protection and so there is a need to develop an effective and integrated approach to reducing damage by pine weevil. • There were significant differences between treatments in damage and mortality. • Insecticides and physical barriers provided most effective protection. • Larger trees did not affect mortality and damage. • Applying fertiliser did not affect level of damage and mortality. [ABSTRACT FROM AUTHOR]

Background: Mental health symptoms are common in people with epilepsy, impacting medication adherence, quality of life, and mortality. Early detection and timely interventions for mental health symptoms will be crucial for improved outcomes but the absence of standardized screening procedures and time constraints hinder regular assessment and management., Purpose: To evaluate feasibility, acceptability and, value of a digital tool for identifying mental health symptoms in adult and paediatric epilepsy outpatients using electronic Patient-Reported Outcome Measures (ePROMs)., Methods and Materials: The study used an established local platform (IMPARTS - Integrating Mental and Physical Healthcare: Research Training and Services) to develop an online tool using e-PROMS for a comprehensive mental health screen (psychiatric symptoms, neurodevelopmental traits, and psychosocial/behavioural risk factors) of people with epilepsy. Prior to attending the outpatient clinical epilepsy services at King's College Hospital, participants were invited to complete the online screening tool through an SMS appointment link., Results: Out of 1081 epilepsy patients (955 adults, 126 paediatric), 38.2% of adults and 51.6% of carers of paediatric patients accessed the ePROMs, with modest completion rates of 15% and 14%, respectively. Adults reported mild to significant anxiety (37.4%), minor to major depression symptoms (29.2%), and occasionally psychotic symptoms (11.1%). Adults with self-reported psychiatric symptoms reported significantly higher number of seizures, seizure burden, insomnia, autistic and ADHD traits and lower quality of life and perceived social support. Only 21% of those reporting psychiatric symptoms were receiving any form of mental health support. A large proportion of paediatric patients presented emotional/behavioural difficulties (32%), high impulsivity (38.8%), low self-esteem (27.7%), sleep difficulties (50%), comorbid neurodevelopmental syndromes (27.7%). Both groups reported good level of perceived social support., Conclusion: Our epilepsy adapted IMPARTS e-PROMS allowed remote screening for mental health symptoms, neurodevelopmental and resilience factors. Integrating these tools into electronic patient records might enhance early identification and facilitate referral to appropriate care pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aims: Considering emerging evidence on long COVID, comprehensive analyses of the post-acute complications of SARS-CoV-2 infection in the gastrointestinal and hepatobiliary systems are needed. We aimed to investigate the impact of COVID-19 on the long-term risk of gastrointestinal and hepatobiliary diseases and other digestive abnormalities., Methods: We used three large-scale population-based cohorts: the Korean cohort (discovery cohort), the Japanese cohort (validation cohort-A), and the UK Biobank (validation cohort-B). A total of 10,027,506 Korean, 12,218,680 Japanese, and 468,617 UK patients aged ≥20 years who had SARS-CoV-2 infection between 2020 and 2021 were matched to non-infected controls. Seventeen gastrointestinal and eight hepatobiliary outcomes as well as nine other digestive abnormalities following SARS-CoV-2 infection were identified and compared with controls., Results: The discovery cohort revealed heightened risks of gastrointestinal diseases (HR 1.15; 95% CI 1.08-1.22), hepatobiliary diseases (HR 1.30; 95% CI 1.09-1.55), and other digestive abnormalities (HR 1.05; 95% CI 1.01-1.10) beyond the first 30 days of infection, after exposure-driven propensity score-matching. The risk was pronounced according to the COVID-19 severity. The SARS-CoV-2 vaccination was found to lower the risk of gastrointestinal diseases but did not affect hepatobiliary diseases and other digestive disorders. The results derived from validation cohorts were consistent. The risk profile was most pronounced during the initial 3 months; however, it persisted for >6 months in validation cohorts, but not in the discovery cohort., Conclusion: The incidence of gastrointestinal disease, hepatobiliary disease, and other digestive abnormalities increased in patients with SARS-CoV-2 infection during the post-acute phase.

Aim: To map and explore primary research about factors related to retention, turnover and turnover intention among migrant nurses., Background: Understanding retention and turnover among migrant nurses is essential, especially in the context of nursing shortage. There is a range of factors motivating nurses to emigrate; however, factors related to retention and turnover among migrant nurses in the host country are unclear., Methods: This review utilised Arksey and O'Malley's methodological framework for scoping reviews, and is reported with the PRISMA-ScR checklist. Four electronic databases were searched-CINAHL, PsycINFO, ProQuest and PubMed-to identify primary research published between January 2000 and May 2022. Titles and abstracts were reviewed against the inclusion and exclusion criteria, and then full-text versions were reviewed. Data extracted were summarised, and results synthesised., Results: Fifteen studies were included, with studies mainly from the Middle East, the United Kingdom and the United States. Personal, organisational, financial, political and environmental factors were found to influence retention and turnover among migrant nurses., Conclusion: Retention and turnover rates among migrant nurses vary among host countries. The factors identified are related to each other; hence, retention and turnover among migrant nurses are best understood in the context of their source country, host country and individual circumstances. IMPLICATIONS FOR NURSING POLICY, SOCIAL POLICY, AND HEALTH POLICY: Host countries must promote strategies that foster retention, such as reviewing immigration policies to support long-term immigration and family unity. Organisations employing migrant nurses need to consider the presence of a social network to facilitate adaptation and integration. It is also recommended that source countries address the reasons for emigration and initiate policies encouraging return migration, including providing merit to overseas experience. International nursing organisations should call for an examination of the conditions of migrant nurses to ensure equality across all source countries., (© 2023 The Authors. International Nursing Review published by John Wiley & Sons Ltd on behalf of International Council of Nurses.)

The bidirectional effect of hyperuricemia on chronic kidney disease (CKD) underscores the importance of hyperuricemia as a risk factor for CKD. We evaluated the effect of hyperuricemia on the presence and development of CKD after considering genetic background by calculating polygenic risk scores (PRSs). We employed genome-wide association study summary statistics-excluding the United Kingdom Biobank (UKB) datasets among published CKD Gen Consortium papers-to calculate the PRSs for CKD in white background subjects. To validate PRS performance, we divided the UKB into two datasets to validate and test the data. We used logistic regression analysis to evaluate the association between hyperuricemia and CKD, and performed Kaplan-Meier survival analysis exclusively for subjects with available follow-up data. In total, 438,253 clinical data and 4,307,940 single nucleotide polymorphisms from 459,155 samples were included. We observed a significant positive association between PRS and CKD and the presence and development of CKD. Hyperuricemia significantly increased CKD risk (adjusted odds ratio 1.55, 95% confidence interval 1.48-1.61). The impact of hyperuricemia on CKD was maintained irrespective of PRS range. In addition, negative interaction between hyperuricemia and PRS for CKD was found. Survival analysis indicates that the presence of hyperuricemia significantly increased the risk of CKD development. The PRS for CKD thoroughly reflects the risk of CKD development. Hyperuricemia is a significant indicator of CKD risk, even after incorporating the genetic risk score for CKD. Irrespective of genetic risk, patients with a prospective risk of developing CKD require uric acid monitoring and management., (© 2024. The Author(s).)

Previous research has not investigated the persistent cutaneous immune-related adverse events (cirAEs) related to long COVID to investigate the long-term sequelae. This multinational study, using a propensity-matched overlap weighting method, utilizes large national claims-based cohorts, using ICD-10 code diagnosis, focusing on patients aged ≥20 years from three countries: South Korean, Japanese, and the British cohorts. To estimate the risk of cirAEs in long COVID, the persistence or emergence of cirAEs occurring 4 weeks after the initial SARS-CoV-2 infection, we employed a Cox proportional hazard regression model. The Korean cohort (n = 5,937,373; mean age 49.2 years [SD: 13.2]), the Japanese cohort (n = 4,307,587; 42.5 years [13.6]), and the UK cohort (n = 395,435; 71.0 years [8.07]) were presented. An increased risk of cirAEs in long COVID was observed (HR, 1.10; 95% CI, 1.06-1.14) in Korean cohort, while a similar association was observed in Japanese and UK cohorts. The long-term risk of cirAEs in long COVID was higher in more severe COVID-19 cases (1.31; 1.22-1.39). Unlike the increased risk of cirAEs in long COVID, COVID-19 vaccination attenuated the risk, especially with two or more doses (1.03; 0.95-1.11) or heterologous regimens (0.98; 0.76-1.27). The time attenuation effect indicated a sustained risk for up to 6 months postinfection (<3 months: 1.13 [1.07-1.19]; 3-6 months: 1.14 [1.06-1.22]). SARS-CoV-2 infection is associated with an increased risk of cirAEs in the aspect of long COVID. Vaccination might reduce this risk, highlighting the need for preventive strategies in long COVID management., (© 2024 Wiley Periodicals LLC.)

Sexual violence (SV) experienced by higher education students is a prevalent public health problem. Collecting data on SV through self-report surveys in higher education institutions (HEIs) is essential for estimating the scope of the problem, the first step to adequately resourcing and implementing prevention and response programming and policies. However, in the United Kingdom, data is limited. We used data from the cross-sectional Oxford Understanding Relationships, Sex, Power, Abuse and Consent Experiences survey, administered to all students at a university in the United Kingdom in May 2021 ( n  = 25,820), to estimate the past year prevalence of SV. We analyzed data from respondents who answered at least one question on SV ( n  = 1,318) and found that 20.5% of respondents experienced at least one act of attempted or forced sexual touching or rape, and 52.7% of respondents experienced at least one act of sexual harassment (SH). We found that women experienced the highest rates of SV. Attempted forced sexual touching was far more common than forced sexual touching, or rape. Sexist remarks or jokes were the most common act of SH. Most acts of SV took place at the university. These findings reveal that the prevalence of SV in HEIs in the United Kingdom could be far higher than what is experienced in the general population. While this study reflects the context in only one institution, it underlines the need for continued monitoring to develop rigorous, evidence-based, and targeted prevention and response strategies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article.

This study aimed to investigate the association between residential greenness and tinnitus and the potential interaction between greenness and genetic predisposition to tinnitus. The normalized difference vegetation index (NDVI) is used to measure residential greenness. The tinnitus is defined based on self-reported. In the cross-sectional analyses, logistic regression models are used for the baseline sample of the United Kingdom Biobank cohort. In the secondary analysis, a Cox proportional hazard model is used for a subsample of participants who completed the tinnitus questionnaire at follow-up. In the cross-sectional analysis including 106471 participants, higher residential greenness is associated with lower odds of tinnitus for each interquartile range increase in continuous NDVI, with an adjusted odds ratio of 0.97 (95% confidence interval: 0.95 to 0.99) for tinnitus. A similar association is observed in the longitudinal analysis, with an adjusted hazard ratio of 0.92 (95% confidence interval: 0.86 to 0.98) for the association of NDVI increased per interquartile range with incident tinnitus. Moreover, there is a significant interaction between greenness and genetic predisposition to tinnitus (P < 0.05). This study suggested that residential greenness is negatively associated with tinnitus. Greenness and genetic predisposition to tinnitus are found to have a significant interaction., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

As mounting evidence suggests a higher incidence of adverse consequences, such as disruption of the immune system, among patients with a history of COVID-19, we aimed to investigate post-COVID-19 conditions on a comprehensive set of allergic diseases including asthma, allergic rhinitis, atopic dermatitis, and food allergy. We used nationwide claims-based cohorts in South Korea (K-CoV-N; n = 836,164; main cohort) and Japan (JMDC; n = 2,541,021; replication cohort A) and the UK Biobank cohort (UKB; n = 325,843; replication cohort B) after 1:5 propensity score matching. Among the 836,164 individuals in the main cohort (mean age, 50.25 years [SD, 13.86]; 372,914 [44.6%] women), 147,824 were infected with SARS-CoV-2 during the follow-up period (2020-2021). The risk of developing allergic diseases, beyond the first 30 days of diagnosis of COVID-19, significantly increased (HR, 1.20; 95% CI, 1.13-1.27), notably in asthma (HR, 2.25; 95% CI, 1.80-2.83) and allergic rhinitis (HR, 1.23; 95% CI, 1.15-1.32). This risk gradually decreased over time, but it persisted throughout the follow-up period (≥6 months). In addition, the risk increased with increasing severity of COVID-19. Notably, COVID-19 vaccination of at least two doses had a protective effect against subsequent allergic diseases (HR, 0.81; 95% CI, 0.68-0.96). Similar findings were reported in the replication cohorts A and B. Although the potential for misclassification of pre-existing allergic conditions as incident diseases remains a limitation, ethnic diversity for evidence of incident allergic diseases in post-COVID-19 condition has been validated by utilizing multinational and independent population-based cohorts., (© 2024. The Author(s).)

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Purpose: Exposure to parental mental ill-health and poverty in childhood impact health across the lifecourse. Both maternal and paternal mental health may be important influences, but few studies have unpicked the complex interrelationships between these exposures and family poverty for later health., Methods: We used longitudinal data on 10,500 children from the nationally representative UK millennium cohort study. Trajectories of poverty, maternal mental health, and secondary caregiver mental health were constructed from child age of 9 months through to 14 years. We assessed the associations of these trajectories with mental health outcomes at the age of 17 years. Population-attributable fractions were calculated to quantify the contribution of caregivers' mental health problems and poverty to adverse outcomes at the country level., Results: We identified five distinct trajectories. Compared with children with low poverty and good parental mental health, those who experienced poverty and poor primary or secondary caregiver mental health (53%) had worse outcomes. Children exposed to both persistent poverty and poor caregiver mental health were at markedly increased risk of socioemotional behavioural problems (aOR 4.2; 95% CI 2.7-6.7), mental health problems (aOR 2.5; CI 1.6-3.9), and cognitive disability (aOR 1.7; CI 1.1-2.5). We estimate that 40% of socioemotional behavioural problems at the age of 17 were attributable to persistent parental caregivers' mental health problems and poverty., Discussion: More than half of children growing up in the UK are persistently exposed to either one or both of poor caregiver mental health and family poverty. The combination of these exposures is strongly associated with adverse health outcomes in the next generation., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Although trauma is increasingly recognized as a major risk factor for psychosis and for its link to treatment outcomes, the landscape of trauma-related practices in specialized early psychosis services in the United States and other countries remains only poorly characterized. Research documenting the perspectives of frontline providers is also lacking. The primary goals of this study were to document the state of trauma-related policy implementation in early intervention in psychosis (EIP) programs and to gather provider perspectives., Methods: This was a mixed-methods project involving an international EIP provider survey, followed by in-depth provider interviews. The survey was disseminated in Australia, Canada, Chile, the United Kingdom, and the United States. In total, 164 providers, representing 110 unique sites, completed the survey. Frequencies were calculated for responses to survey items, and open-ended responses were analyzed with a systematic content analysis., Results: The survey findings suggested low implementation rates for a variety of assessment and support practices related to trauma and trauma-informed care. Coding of open-ended responses revealed numerous concerns and uncertainties among providers regarding the relationship between trauma and psychosis and the state of the EIP field., Conclusions: An expansion of research and service development aimed at better meeting the trauma-related needs of young people with psychosis is essential, with implications for EIP outcomes and service user and staff experiences., Competing Interests: The authors report no financial relationships with commercial interests.

Background: Stroke is a significant health issue in the United States, and identifying biomarkers for the prevention and functional recovery after an acute stroke remains the highest priority. This study aims to identify circulating metabolite signatures that may be associated with stroke pathophysiology by performing discovery and validation studies., Methods: We performed targeted metabolomics profiling of 420 participants of the discovery dataset of Metabolome in an Ischemic Stroke Study (MISS) using high-throughput nuclear magnetic resonance (NMR) spectroscopy. A validation study of significantly altered metabolites was conducted using an independent cohort of 117,988 participants from the UK Biobank, whose metabolomics profiles were generated using the same NMR technology., Results and Conclusion: Our study identified 16 metabolites to be significantly perturbed during acute stroke. Amino acid phenylalanine was significantly increased, while glutamine and histidine were significantly lowered in stroke. Serum levels of apolipoprotein A-1, HDL particles, small HDL particles, essential fatty acids, and phosphatidylcholine were reduced, while ketone bodies like 3-hydroxybutyrate and acetoacetate were markedly increased in stroke. Based on the robust validation in a large independent UK Biobank dataset, some of these analytes may become clinically meaningful biomarkers to predict or prevent stroke in humans., Competing Interests: Declaration of competing interest We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2023. Published by Elsevier Ltd.)

Background: In older people living with frailty, polypharmacy can lead to preventable harm like adverse drug reactions and hospitalization. Deprescribing is a strategy to reduce problematic polypharmacy. All stakeholders should be actively involved in developing a person-centred deprescribing process that involves shared decision-making., Objective: To co-design an intervention, supported by a logic model, to increase the engagement of older people living with frailty in the process of deprescribing., Design: Experience-based co-design is an approach to service improvement, which uses service users and providers to identify problems and design solutions. This was used to create a person-centred intervention with the potential to improve the quality and outcomes of the deprescribing process. A 'trigger film' showing older people talking about their healthcare experiences was created and facilitated discussions about current problems in the deprescribing process. Problems were then prioritized and appropriate solutions were developed. The review located the solutions in the context of current processes and procedures. An ideal care pathway and a complex intervention to deliver better care were developed., Setting and Participants: Older people living with frailty, their informal carers and professionals living and/or working in West Yorkshire, England, UK. Deprescribing was considered in the context of primary care., Results: The current deprescribing process differed from an ideal pathway. A complex intervention containing seven elements was required to move towards the ideal pathway. Three of these elements were prototyped and four still need development. The complex intervention responded to priorities about (a) clarity for older people about what was happening at all stages in the deprescribing process and (b) the quality of one-to-one consultations., Conclusions: Priorities for improving the current deprescribing process were successfully identified. Solutions were developed and structured as a complex intervention. Further work is underway to (a) complete the prototyping of the intervention and (b) conduct feasibility testing., Patient or Public Contribution: Older people living with frailty (and their informal carers) have made a central contribution, as collaborators, to ensure that a complex intervention has the greatest possible potential to enhance the experience of deprescribing medicines., (© 2022 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Never a monarch nor head of state, Queen Caroline of Ansbach (1683-1737) is among the legendary women rulers of England and Great Britain alongside Queens Elizabeth I and II, Queen Victoria, and Lady Margaret Thatcher. As queen consort, she was the acknowledged power behind the throne of her husband, King George II (1683-1760), working with Robert Walpole, the first Prime Minister of England. George accepted her intellectual superiority and backstage dominance even before he acceded to the throne in 1727. "[He had] no pretensions toward intellect and [was] basically interested in little more than military glory, political power, and a wife who would do her duty by providing him with male heirs," wrote popular historian John Van de Kiste. After they were wed in 1705, Caroline carried out her task with a remarkable fecundity: a male heir, Frederick Louis, in 1707, followed by Anne (1709), Amelia (1711), Caroline (1713), George William (1717), William (1721), Mary (1723), and Louise (1724). With good reason she believed that her influence over George came from his sexual attraction to her. It was a conceit that proved to be her undoing as she strove to hide from common knowledge an unsightly umbilical hernia. The rupture caused her death in 1737 at age 54. It strangulated, perforated, and spilled feculent succus entericus and fetid fluid onto the royal bed, a vivid example of the consequences of an untreated surgical condition.

To assess the global research landscape in the field of Posterior urethral valve (PUV), a scientometric study was conducted to determine the quantity and quality of the research output and get insight into the key research areas and pattern of collaboration in the research community., Methods: Primary data was acquired from the Scopus® database. Various parameters like the total research productivity, citations, citations per publication, citations per year, citations per publication per year, the scientific output of countries, institutions, authors, and journals were calculated. Key research areas were inferred by examining the top-cited articles (citations >150). Collaborative maps were generated by calculating co-authorship links amongst countries and authors using VOSviewer software., Results: One thousand seven hundred fourteen results were found published from 1913 to 2019, receiving a total of 27,253 citations, authored by 5138 authors from 125 countries. The top three countries were the United States of America (USA), India, and the United Kingdom (UK). The leading institutes were the Children's Hospital Boston, USA (n = 48), All India Institute of Medical Sciences (AIIMS, Delhi), India (n = 38), and Great Ormond Street Hospital, UK (n- = 27). The journals which published the most articles on PUV were the Journal of Urology (n = 278), Journal of Pediatric Urology (n = 121), followed by Urology (n = 86). Leading authors were Glassberg, K. L and Bajpai M (n = 17, each), Canning DA & Kajbafzadeh, AM (n = 16, each), followed by Peters CA with 14 manuscripts. The top-cited documents (n = 10) received 2104 citations and were published between 1986 and 2010. The key areas of interest found were "long-term outcomes" (n = 4) and "fetal surgery" (n = 2). The most productive countries were also the most collaborative countries (the USA and UK)., Conclusion: In the research landscape of PUV, the USA, Children's Hospital Boston, and Glassberg, K. L, along with Bajpai, M were the top contributors in terms of the country, organization, and authors, respectively. The "Journal of Urology" and "Pediatric Nephrology" stands out in terms of bibliometric parameters considered. The hotspot topics based on the number of citations received were "long-term outcomes" and "fetal surgery" in PUV. The most productive countries were also the most collaborative countries (the USA and UK)., (Copyright © 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Introduction: Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Here we describe the development of such a protocol, based upon the UK Biobank, and its validation with a travelling heads study. A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI), and arterial spin labelling (ASL), was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N = 8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King's College London). Over 2,000 Imaging Derived Phenotypes (IDPs), measuring both data quality and regional image properties of interest, were automatically estimated by customised UKB image processing pipelines (S2 File). Components of variance and intra-class correlations (ICCs) were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. Considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, although there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data., Conclusion: These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonisation of data collected from sites using scanners supplied by different manufacturers. These acquisition and analysis protocols are now in use for MRI assessments of post-COVID patients (N = 700) as part of the ongoing COVID-CNS study., Competing Interests: EB serves on the scientific advisory board of Sosei Heptares and as a consultant for Boehringer Ingelheim, GlaxoSmithKline, and Monument Therapeutics. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To determine how early-life risk factors explain socioeconomic inequalities in persistent asthma in adolescence., Methods: We did a causal mediation analysis using data from 7487 children and young people in the UK Millennium Cohort Study. Persistent asthma was defined as having a diagnosis reported at any two or more time points at 7, 11 or 14 years. The main exposure was maternal education, a measure of early-life socioeconomic circumstances (SECs), used to calculate the relative index of inequality. We assessed how blocks of perinatal (maternal health behaviours, infant characteristics and duration of breastfeeding, measured at 9 months) and environmental risk factors (family housing conditions; potential exposure to infections through childcare type and sibling number, and neighbourhood characteristics, measured at 3 years) mediated the total effect of childhood SECs on persistent asthma risk, calculating the proportion mediated and natural indirect effect (NIE) via blocks of mediators., Results: At age 14 the overall prevalence of persistent asthma was 15%. Children of mothers with lower educational qualifications were more likely to have persistent asthma, with a clear social gradient (degree plus: 12.8% vs no qualifications: 20.3%). The NIE gives the effect of SECs acting only via the mediators and shows a 31% increased odds of persistent asthma when SECs are fixed at the highest level, and mediators at the level which would naturally occur at the lowest SECs versus highest SECs (NIE OR 1.31, 95% CI 1.04 to 1.65). Overall, 58.9% (95% CI 52.9 to 63.7) of the total effect (OR 1.70, 95% CI 1.20 to 2.40) of SECs on risk of persistent asthma in adolescence was mediated by perinatal and environmental characteristics., Conclusions: Perinatal characteristics and the home environment in early life are more important in explaining socioeconomic inequalities in persistent asthma in British adolescents than more distal environmental exposures outside the home., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pollen food syndrome (PFS) is a highly prevalent food allergy affecting pollen-sensitized children and adults. Sufferers experience allergic symptoms when consuming raw plant foods, due to the homology between the pollen allergens and unstable proteins in these foods. The triggers involved can vary depending on the pollen sensitization, which in turn is affected by geographical location. The British Society of Allergy and Clinical Immunology (BSACI) Standards of Care Committee (SOCC) identified a need to develop a guideline for the diagnosis and management of PFS in the United Kingdom (UK). Guidelines produced by the BSACI use either the GRADE or SIGN methodology; due to a lack of high-quality evidence these recommendations were formulated using the SIGN guidelines, which is acknowledged to be less robust than the GRADE approach. The correct diagnosis of PFS ensures the avoidance of a misdiagnosis of a primary peanut or tree nut allergy or confusion with another plant food allergy to non-specific lipid transfer proteins. The characteristic foods involved, and rapid-onset oropharyngeal symptoms, mean PFS can often be diagnosed from the clinical history alone. However, reactions involving tree nuts, peanuts and soya milk or severe/atypical reactions to fruits and vegetables may require additional diagnostic tests. Management is through the exclusion of known trigger foods, which may appear to be simple, but is highly problematic if coupled with a pre-existing food allergy or for individuals following a vegetarian/vegan diet. Immunotherapy to pollens is not an effective treatment for PFS, and although oral or sublingual immunotherapy to foods seems more promising, large, controlled studies are needed. The typically mild symptoms of PFS can lead to an erroneous perception that this condition is always easily managed, but severe reactions can occur, and anxiety about the onset of symptoms to new foods can have a profound effect on quality of life., (© 2022 John Wiley & Sons Ltd.)

Rationale: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results., Objectives: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences., Methods: We used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections ( Pseudomonas aeruginosa , Staphylococcus aureus ) and treatments (rhDnase, hypertonic saline, inhaled antibiotics)., Results: We included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK., Conclusions: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation., Competing Interests: Competing interests: DKS, SC and DT-R were supported by the Strategic Research Centre 'CF-EpiNet: Harnessing data to improve lives' funded by the Cystic Fibrosis Trust. DT-R is funded by the MRC on a Clinician Scientist Fellowship (MR/P008577/1). RS was supported by grants from the Cystic Fibrosis Foundation (SZCZES18AB0) and NIH/NHLBI (R01 HL141286). CHG was supported by grants from the Cystic Fibrosis Foundation, the NIH (UM1 HL119073, P30 DK089507, U01 HL114589, UL1 TR000423) and the FDA (R01 FD003704). RHK is supported by a UKRI Future Leaders Fellowship (MR/S017968/1)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: To identify clinical and biochemical characteristics associated with 7- & 30-day mortality and intensive care admission amongst diabetes patients admitted with COVID-19., Research Design and Methods: We conducted a cohort study collecting data from medical notes of hospitalised people with diabetes and COVID-19 in 7 hospitals within the Mersey-Cheshire region from 1 January to 30 June 2020. We also explored the impact on inpatient diabetes team resources. Univariate and multivariate logistic regression analyses were performed and optimised by splitting the dataset into a training, test, and validation sets, developing a robust predictive model for the primary outcome., Results: We analyzed data from 1004 diabetes patients (mean age 74.1 (± 12.6) years, predominantly men 60.7%). 45% belonged to the most deprived population quintile in the UK. Median BMI was 27.6 (IQR 23.9-32.4) kg/m 2 . The primary outcome (7-day mortality) occurred in 24%, increasing to 33% by day 30. Approximately one in ten patients required insulin infusion (9.8%). In univariate analyses, patients with type 2 diabetes had a higher risk of 7-day mortality [p < 0.05, OR 2.52 (1.06, 5.98)]. Patients requiring insulin infusion had a lower risk of death [p = 0.02, OR 0.5 (0.28, 0.9)]. CKD in younger patients (<70 years) had a greater risk of death [OR 2.74 (1.31-5.76)]. BMI, microvascular and macrovascular complications, HbA1c, and random non-fasting blood glucose on admission were not associated with mortality. On multivariate analysis, CRP and age remained associated with the primary outcome [OR 3.44 (2.17, 5.44)] allowing for a validated predictive model for death by day 7., Conclusions: Higher CRP and advanced age were associated with and predictive of death by day 7. However, BMI, presence of diabetes complications, and glycaemic control were not. A high proportion of these patients required insulin infusion warranting increased input from the inpatient diabetes teams., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Llanera, Wilmington, Shoo, Lisboa, Jarman, Wong, Nizza, Sharma, Kalathil, Rajeev, Williams, Yadav, Qureshi, Narayanan, Furlong, Westall and Nair.)

Aim: In the UK, injectable medicines are often prepared and administered by nurses following the Injectable Medicines Guide (IMG). Our earlier study confirmed a higher frequency of correct administration with user-tested versus standard IMG guidelines. This current study aimed to model the cost-effectiveness of user-testing., Methods: The costs and cost-effectiveness of user-testing were explored by modifying an existing probabilistic decision-analytic model. The adapted model considered administration of intravenous voriconazole to hospital inpatients by nurses. It included 11 error types, their probability of detection and level of harm. Model inputs (including costs) were derived from our previous study and other published data. Monte Carlo simulation using 20,000 samples (sufficient for convergence) was performed with a 5-year time horizon from the perspective of the 121 NHS trusts and health boards that use the IMG. Sensitivity analyses were undertaken for the risk of a medication error and other sources of uncertainty., Results: The net monetary benefit at £20,000/quality-adjusted life year was £3,190,064 (95% credible interval (CrI): -346,709 to 8,480,665), favouring user-testing with a 96% chance of cost-effectiveness. Incremental cost-savings were £240,943 (95% CrI 43,527-491,576), also favouring user-tested guidelines with a 99% chance of cost-saving. The total user testing cost was £6317 (95% CrI 6012-6627). These findings were robust to assumptions about a range of input parameters, but greater uncertainty was seen with a lower medication error risk., Conclusions: User-testing of injectable medicines guidelines is a low-cost intervention that is highly likely to be cost-effective, especially for high-risk medicines., (© 2021. The Author(s).)

Objectives: Implementation of guidelines into clinical practice is challenging and complex. This study aims to (1) identify the training needs and capacity requirements, and (2) explore the impact on healthcare utilisation and asthma-related quality of life of implementing both spirometry and fraction of exhaled nitric oxide in diagnosis of asthma among children in the UK primary care., Methods: Ten UK general practitioner practices and a total of 612 children (5-16 years) with diagnosed or suspected asthma were invited to participate in this prospective observational study. The total times that the trainer and trainee clinical staff spent on developing the training package, providing and receiving, and performing and interpreting the two tests as part of routine child asthma review were collected, and costs were calculated. We compared healthcare utilisation and asthma-related and general health-related quality of life data between the 6 months before and after the asthma review guided by objective tests., Results: The average training cost for the 27 primary care clinical members was £1395. The average cost to implement and deliver the test-guided asthma review among the 612 included children was £22. In the 6 months following the tests-guided asthma review, both unplanned primary care attendance, and hospital admissions were reduced, and the asthma-related health status increased significantly., Conclusion: This study provides robust cost estimates of the resources needed to implement the National Institute for Health and Care Excellence asthma guideline. It also demonstrates the potential to save healthcare costs and improve health status among asthmatic children by implementing this guideline., Competing Interests: Competing interests: EAG: consultancy work for Boehringer ingelheim in November 2016 and for Anaxsys in July 2018 with money paid to the institution (University of leicester), investigator-led research grant from Circassia and Gilead, research collaboration with Medimmune and travel grants from Vertex., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mean retirement age for UK doctors is 59.6 years, giving the average OMFS consultant approximately 20 years of practice. Current pension tax regulations, new consultant posts typically restricted to a maximum of 10 sessions (40 hours), increasing proportions of consultants working less than full time (LTFT), all combined with the backlog of elective care created by COVID-19 will create a significant gap between workforce capacity and clinical demand. The age of current OMFS consultants was estimated using the date of their primary medical/dental qualification. Changes in job plans were estimated using data from the BAOMS Workforce Census and from recently advertised posts. Reports of unfilled posts were collated by OMFS Regional Specialty Professional Advisors (RSPAs). First degree dates were identified for 476 OMFS substantive consultant posts. Estimated current average age of OMFS consultants was 52.7 years (minimum 35.9, maximum 72.1), 75th centile age 59.0 and 23% of the current consultant workforce above the average retirement age for doctors. The 10 sessions of new OMFS consultants posts is significantly less than existing consultants' average of 12.1 sessions (48.4 hours). Unfilled consultant posts in Great Britain are 13% of the total compared to 20% in Northern Ireland and Ireland. Many (23%) of the OMFS consultant workforce are above average retirement age. Forty-hour contracts; new consultants working LTFT; and early loss of senior colleagues because of pension pressure will reduce NHS' capacity to treat OMFS disorders and injuries. This paper suggests increasing consultant posts, increasing trainee numbers, and actively retaining senior surgeons to maintain capacity., (Copyright © 2021 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: To examine the live birth and other outcomes reported with and without preimplantation genetic testing for aneuploidy (PGT-A) in the United Kingdom (UK) Human Embryology and Fertilization Authority (HFEA) data collection., Methods: A retrospective cohort analysis was conducted following freedom of information (FoI) requests to the HFEA for the PGT-A and non-PGT-A cycle outcomes for 2016-2018. Statistical analysis of differences between PGT-A and non-PGT-A cycles was performed. Other than grouping by maternal age, no further confounders were controlled for; fresh and frozen transfers were included., Results: Outcomes collected between 2016 and 2018 included total number of cycles, cycles with no embryo transfer, total number of embryos transferred, live birth rate (LBR) per embryo transferred and live birth rate per treatment cycle. Data was available for 2464 PGT-A out of a total 190,010 cycles. LBR per embryo transferred and LBR per treatment cycle (including cycles with no transfer) were significantly higher for all PGT-A vs non-PGT-A age groups (including under 35), with nearly all single embryo transfers (SET) after PGT-A (significantly more in non-PGT-A) and a reduced number of transfers per live birth particularly for cycles with maternal age over 40 years., Conclusion: The retrospective study provides strong evidence for the benefits of PGT-A in terms of live births per embryo transferred and per cycle started but is limited in terms of matching PGT-A and non-PGT-A cohorts (e.g. in future studies, other confounders could be controlled for). This data challenges the HFEA "red traffic light" guidance that states there is "no evidence that PGT-A is effective or safe" and hence suggests the statement be revisited in the light of this and other new data., (© 2021. The Author(s).)

Background: Self-report measures of alcohol problems are commonly included in studies evaluating treatment and recovery from alcohol use disorder (AUD), but no prior study has examined the replicability of the measurement of alcohol problems across studies with various measures and diverse samples. Further, it is unclear which items may be better indicators of alcohol problems for patient subgroups. In the present study, we integrated data from four large alcohol treatment studies to develop a commensurate measure of alcohol problems using moderated nonlinear factor analysis (MNLFA)., Methods: Data were from the COMBINE study, Project MATCH, the Relapse Replication and Extension Project (RREP), and the United Kingdom Alcohol Treatment Trial (UKATT), yielding a total sample size of 4414. MNLFA was carried out on the Drinker Inventory of Consequences (COMBINE, MATCH, RREP) and Alcohol Problems Questionnaire (UKATT)., Results: We successfully created a 78-item commensurate measure of alcohol problems and examined differential item functioning (DIF) by study membership, time, and socio-demographic characteristics. Sixty-two items demonstrated intercept DIF, suggesting differences in rates of item endorsement for clients with the same underlying levels of alcohol problems across patient subgroups. Six items demonstrated loading DIF, suggesting differences in the extent to which the items were indicative of alcohol problems across patient subgroups., Conclusions: The self-reported measurement of alcohol problems replicates across measures and diverse samples. Items with DIF have clinical implications for the treatment of AUD. Finally, MNLFA scores can be used to test substantive research questions across these studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In 2008, to create a rapid route for information transfer in relation training and recruitment for OMFS trainees, the British Association of Oral and Maxillofacial Surgeons (BAOMS) created a website to "Register Your Interest in OMFS" (RYIO). From 2011 a Mentoring and Support Programme (MSP) was created to provide focussed guidance for trainees aiming for specialty training. This paper reviews the effectiveness and cost of these programmes. Between 2008 and 2020, 1744 individuals used RYIO on 2715 occasions. Of these registrations, 1772 were by dentists, 193 dental students, 589 doctors and 161 medical students. 2354 were from UK and Ireland and 351 from the rest of the world. 188 registrants subsequently became UK OMFS trainees or specialists. All registrants valued the information provided. In response to RYIO trainee feedback the new 'Taste of OMFS 2020' programme was created. The MSP was originally called the Junior Trainee Programme (JTP). The MSP scheme provides a layer of mentorship/support which runs parallel to the medical/dental training post or period of study. Of 180 members of MSP, 72 have obtained specialty training posts in OMFS. There are 88 current members. Full information is available on the BAOMS website www.baoms.org.uk. Reviewing both programmes, participant feedback is excellent with tangible results whilst cost effectiveness is high., (Copyright © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this manuscript is to compare characteristics, management, and outcomes of patients with severe Traumatic Brain Injury (TBI) between Australia, the United Kingdom (UK) and Europe., Methods: We enrolled patients with severe TBI in Victoria, Australia (OzENTER-TBI), in the UK and Europe (CENTER-TBI) from 2015 to 2017. Main outcome measures were mortality and unfavourable outcome (Glasgow Outcome Scale Extended <5) 6 months after injury. Expected outcomes were compared according to the IMPACT-CT prognostic model, with observed to expected (O/E) ratios and 95% confidence intervals., Results: We included 107 patients from Australia, 171 from UK, and 596 from Europe. Compared to the UK and Europe, patients in Australia were younger (median 32 vs 44 vs 44 years), a larger proportion had secondary brain insults including hypotension (30% vs 17% vs 21%) and a larger proportion received ICP monitoring (75% vs 74% vs 58%). Hospital length of stay was shorter in Australia than in the UK (median: 17 vs 23 vs 16 days), and a higher proportion of patients were discharged to a rehabilitation unit in Australia than in the UK and Europe (64% vs 26% vs 28%). Mortality overall was lower than expected (27% vs 35%, O/E ratio 0.77 [95% CI: 0.64 - 0.87]. O/E ratios were comparable between regions for mortality in Australia 0.86 [95% CI: 0.49-1.23] vs UK 0.82 [0.51-1.15] vs Europe 0.76 [0.60-0.87]). Unfavourable outcome rates overall were in line with historic expectations (O/E ratio 1.32 [0.96-1.68] vs 1.13 [0.84-1.42] vs 0.96 [0.85-1.09])., Conclusions: There are major differences in case-mix between Australia, UK, and Europe; Australian patients are younger and have a higher rate of secondary brain insults. Despite some differences in management and discharge policies, mortality was less than expected overall, and did not differ between regions. Functional outcomes were similar between regions, but worse than expected, emphasizing the need to improve treatment for patients with severe TBI., Competing Interests: Declaration of Competing Interest AIRM declares consulting fees from PresSura Neuro, Integra Life Sciences, and NeuroTrauma Sciences. DKM reports grants from the UK National Institute for Health Research, during the conduct of the study; grants, personal fees, and non-financial support from GlaxoSmithKline; personal fees from Neurotrauma Sciences, Lantmaanen AB, Pressura, and Pfizer, outside of the submitted work. ES reports personal fees from Springer, during the conduct of the study. DJC is an Australian NHMRC Practitioner Fellow and reports grants from the NHMRC and consulting fees to Monash University from PresSura Neuro. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the risk of major adverse cardiac and cerebrovascular events (MACCEs) and all-cause death of patients with controlled hypertension and suggest the benefits of physical activity in their prognosis., Methods: People aged 40-69 years from the prospective UK Biobank cohort (UKB, n=220 026) and the retrospective Korean National Health Insurance Service cohort (KNHIS, n=3 593 202) were included in this observational cohort study, excluding those with previous cerebrocardiovascular diseases or hypertension without treatment. The study groups were stratified into normotension, controlled hypertension (patients with hypertension with systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg) and uncontrolled hypertension groups. The outcomes were MACCEs and all-cause mortality, analysed by Cox regression analysis., Results: We included 161 405/18 844/39 777 and 3 122 890/383 828/86 484 individuals with normotension/controlled hypertension/uncontrolled hypertension state from the UKB and KNHIS cohorts, respectively. The controlled hypertension group showed significantly higher risk of MACCEs (UKB: adjusted HR 1.73 (95% CI 1.55 to 1.92); KNHIS: 1.46 (95% CI 1.43 to 1.49)) and all-cause mortality (UKB: adjusted HR 1.28 (95% CI 1.18 to 1.39); KNHIS: 1.29 (95% CI 1.26 to 1.32)) than individuals with normotension. The controlled hypertension group not involved in any moderate or moderate-to-vigorous physical activity showed high risk of adverse outcomes, which was comparable with or even higher than the risk of patients with uncontrolled hypertension who were engaged in physical activity., Conclusions: Controlled hypertension is associated with residual risks of adverse outcomes. Clinicians may encourage physical activity for patients with controlled hypertension, not being reassured by their achieved target blood pressure values., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The syndrome of spontaneous preterm birth (sPTB) presents a challenge to mechanistic understanding, effective risk stratification, and clinical management. Individual associations between sPTB, self-reported ethnic ancestry, vaginal microbiota, metabolome, and innate immune response are known but not fully understood, and knowledge has yet to impact clinical practice. Here, we used multi-data type integration and composite statistical models to gain insight into sPTB risk by exploring the cervicovaginal environment of an ethnically heterogenous pregnant population (n = 346 women; n = 60 sPTB < 37 weeks' gestation, including n = 27 sPTB < 34 weeks). Analysis of cervicovaginal samples (10-15+6 weeks) identified potentially novel interactions between risk of sPTB and microbiota, metabolite, and maternal host defense molecules. Statistical modeling identified a composite of metabolites (leucine, tyrosine, aspartate, lactate, betaine, acetate, and Ca2+) associated with risk of sPTB < 37 weeks (AUC 0.752). A combination of glucose, aspartate, Ca2+, Lactobacillus crispatus, and L. acidophilus relative abundance identified risk of early sPTB < 34 weeks (AUC 0.758), improved by stratification by ethnicity (AUC 0.835). Increased relative abundance of L. acidophilus appeared protective against sPTB < 34 weeks. By using cervicovaginal fluid samples, we demonstrate the potential of multi-data type integration for developing composite models toward understanding the contribution of the vaginal environment to risk of sPTB.

Background: Convalescent plasma containing neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is under investigation for coronavirus disease 2019 (COVID-19) treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomized controlled trial that potentially influence treatment outcomes., Methods: SARS-CoV-2 RNA in nasopharyngeal swabs collected pretreatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H., Results: Of 1274 subjects, 90% were PCR positive with viral loads 118-1.7 × 1011IU/mL. Median viral loads were 40-fold higher in those IgG seronegative (n = 354; 28%) compared to seropositives (n = 939; 72%). Frequencies of B.1.1.7 increased from <1% in November 2020 to 82% of subjects in January 2021. Seronegative individuals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8 × 106 and 2.0 × 105 IU/mL, respectively; P = 2 × 10-15)., Conclusions: High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads, and antibody status define subgroups for analysis of treatment efficacy., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background and Purpose: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals., Methods: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy., Results: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07-1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04-1.21]; total cholesterol: 1.23 [1.06-1.43]; HDL-C, 0.93 [0.89-0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals., Conclusions: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.

As adult height is linked to various health outcomes, further investigation of its causal effects on kidney function later in life is warranted. This study involved a cross-sectional observational analysis and summary-level Mendelian randomization (MR) analysis. First, the observational association between height and estimated GFR determined by creatinine (eGFRcreatinine) or cystatin C (eGFRcystatinC) was investigated in 467,182 individuals aged 40-69 using UK Biobank. Second, the genetic instrument for adult height, as reported by the GIANT consortium, was implemented, and summary-level MR of eGFRcreatinine and CKDcreatinine in a CKDGen genome-wide association study was performed (N = 567,460), with multivariable MR being adjusted for the effects of genetic predisposition on body mass index. To replicate the findings, additional two-sample MR using the summary statistics of eGFRcystatinC and CKDcystatinC in UK Biobank was performed (N = 321,405). In observational analysis, adult height was inversely associated with both eGFRcreatinine (per 1 SD, adjusted beta -1.039, standard error 0.129, P < 0.001) and eGFRcystatinC (adjusted beta -1.769, standard error 0.161, P < 0.001) in a multivariable model adjusted for clinicodemographic, anthropometric, metabolic, and social factors. Moreover, multivariable summary-level MR showed that a taller genetically predicted adult height was causally linked to a lower log-eGFRcreatinine (adjusted beta -0.007, standard error 0.001, P < 0.001) and a higher risk of CKDcreatinine (adjusted beta 0.083, standard error 0.019, P < 0.001). Other pleiotropy-robust sensitivity MR analysis results supported the findings. In addition, similar results were obtained by two-sample MR of eGFRcystatinC (adjusted beta -1.303, standard error 0.140, P < 0.001) and CKDcystatinC (adjusted beta 0.153, standard error 0.025, P < 0.001) in UK Biobank. In conclusion, the results of this study suggest that a taller adult height is causally linked to worse kidney function in middle-aged to elderly individuals, independent of the effect of body mass index., Competing Interests: The authors have declared that no competing interests exist.

Background: Further investigation of the causal effects of psychologic wellbeing on kidney function is warranted., Methods: In this Mendelian randomization (MR) study, genetic instruments for positive affect, life satisfaction, depressive symptoms, and neuroticism were introduced from a previous genome-wide association study meta-analysis of European individuals. Summary-level MR was performed using the CKDGen data of European ancestry ( n =567,460), and additional allele score-based MR was performed in the individual-level data of White British UK Biobank participants ( n =321,024)., Results: In summary-level MR with the CKDGen data, depressive symptoms were a significant causative factor for kidney function impairment (CKD OR, 1.45; 95% confidence interval, 1.07 to 1.96; eGFR change [%] beta -2.18; 95% confidence interval, -3.61 to -0.72) and pleiotropy-robust sensitivity analysis results supported the causal estimates. A genetic predisposition for positive affect was significantly associated with better kidney function (CKD OR, 0.69; 95% confidence interval, 0.52 to 0.91), eGFR change [%] beta 1.50; 95% confidence interval, 0.09 to 2.93) and sensitivity MR analysis results supported the finding for CKD outcome, but was nonsignificant for eGFR. Life satisfaction and neuroticism exposures showed nonsignificant causal estimates. In the UK Biobank with covariate-adjusted allele score MR analysis, allele scores for positive affect and life satisfaction were causally associated with reduced risk of CKD and higher eGFR. In contrast, neuroticism allele score was associated with increased risk of CKD and lower eGFR, and depressive symptoms allele score was associated with lower eGFR, but showed nonsignificant association with CKD., Conclusions: Health care providers in the nephrology field should be aware of the causal linkage between psychologic wellbeing and kidney function., (Copyright © 2021 by the American Society of Nephrology.)

The COVID-19 pandemic has spread rapidly throughout the world. In the UK, the initial peak was in April 2020; in the county of Norfolk (UK) and surrounding areas, which has a stable, low-density population, over 3200 cases were reported between March and August 2020. As part of the activities of the national COVID-19 Genomics Consortium (COG-UK) we undertook whole genome sequencing of the SARS-CoV-2 genomes present in positive clinical samples from the Norfolk region. These samples were collected by four major hospitals, multiple minor hospitals, care facilities and community organizations within Norfolk and surrounding areas. We combined clinical metadata with the sequencing data from regional SARS-CoV-2 genomes to understand the origins, genetic variation, transmission and expansion (spread) of the virus within the region and provide context nationally. Data were fed back into the national effort for pandemic management, whilst simultaneously being used to assist local outbreak analyses. Overall, 1565 positive samples (172 per 100 000 population) from 1376 cases were evaluated; for 140 cases between two and six samples were available providing longitudinal data. This represented 42.6 % of all positive samples identified by hospital testing in the region and encompassed those with clinical need, and health and care workers and their families. In total, 1035 cases had genome sequences of sufficient quality to provide phylogenetic lineages. These genomes belonged to 26 distinct global lineages, indicating that there were multiple separate introductions into the region. Furthermore, 100 genetically distinct UK lineages were detected demonstrating local evolution, at a rate of ~2 SNPs per month, and multiple co-occurring lineages as the pandemic progressed. Our analysis: identified a discrete sublineage associated with six care facilities; found no evidence of reinfection in longitudinal samples; ruled out a nosocomial outbreak; identified 16 lineages in key workers which were not in patients, indicating infection control measures were effective; and found the D614G spike protein mutation which is linked to increased transmissibility dominates the samples and rapidly confirmed relatedness of cases in an outbreak at a food processing facility. The large-scale genome sequencing of SARS-CoV-2-positive samples has provided valuable additional data for public health epidemiology in the Norfolk region, and will continue to help identify and untangle hidden transmission chains as the pandemic evolves.

Background: Further exploration of the possible effects of vegetable intake on kidney function is warranted., Objective: We aimed to study the causality of the association between vegetable intake and kidney function by implementing Mendelian randomization (MR) analysis., Methods: This study comprised a cross-sectional dietary investigation using UK Biobank data and MR analysis. For the cross-sectional investigation, 432,732 participants aged 40-69 y from the UK Biobank cohort were included. Self-reported vegetable intake was the exposure, and the outcomes were the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). Next, we included 337,138 participants of white British ancestry in the UK Biobank, and a genome-wide association study (GWAS) was performed to generate a genetic instrument. For MR, we first performed polygenic score (PGS)-based 1-sample MR. In addition, 2-sample MR was performed with CKDGen GWAS for kidney function traits, and the inverse variance weighted method was the main MR method., Results: Higher vegetable intake was cross-sectionally associated with a higher eGFR (per heaped tablespoon increase; β: 0.154; 95% CI: 0.144, 0.165) and lower odds of CKD (OR: 0.975; 95% CI: 0.968, 0.982). A PGS for vegetable intake was significantly associated with a higher eGFR [per ordinal category increase (0, 1-3, 4-6, ≥7 tablespoons per day); β: 4.435; 95% CI: 2.337, 6.533], but the association with CKD remained nonsignificant (OR: 0.468; 95% CI: 0.143, 1.535). In the 2-sample MR, the causal estimates indicated that a higher genetically predicted vegetable intake was associated with a higher eGFR (percent change; β: 3.071; 95% CI: 0.602, 0.560) but nonsignificantly associated with the risk of CKD (OR: 0.560; 95% CI: 0.289, 1.083) in the European ancestry data from the CKDGen., Conclusions: This study suggests that higher vegetable intake may have a causal effect on higher eGFRs in the European population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Urban wastewater systems (UWSs) are a main receptacle of excreted antibiotic resistance genes (ARGs) and their host microorganisms. However, we lack integrated and quantitative observations of the occurrence of ARGs in the UWS to characterize the sources and identify processes that contribute to their fate. We sampled the UWSs from three medium-size cities in Denmark, Spain, and the United Kingdom and quantified 70 clinically important extended-spectrum β-lactamase and carbapenemase genes along with the mobile genetic elements and microbial communities. Results from all three countries showed that sewage-especially from hospitals-carried substantial loads of ARGs (10 6 -10 7 copies per person equivalent), but these loads progressively declined along sewers and through sewage treatment plants, resulting in minimal emissions (10 1 -10 4 copies per person equivalent). Removal was primarily during sewage conveyance (65 ± 36%) rather than within sewage treatment (34 ± 23%). The extended-spectrum β-lactamase and carbapenemase genes were clustered in groups based on their persistence in the UWS compartments. The less-persistent groups were associated to putative host taxa (especially Enterobacteriaceae and Moraxellaceae), while the more persistent groups appeared horizontally transferred and correlated significantly with total cell numbers and mobile genetic elements. This documentation of a substantial ARG reduction during sewage conveyance provides opportunities for antibiotic resistance management and a caution for sewage-based antibiotic resistance surveillance.

Objectives: To examine whether the school toilet environment at age 13, including bullying at toilets, is associated with female lower urinary tract symptoms (LUTS) at ages 13 and 19, as little is known about the association among school toilet environment, voiding behaviors, and LUTS in adolescent girls., Methods: The sample comprised 3962 female participants from the Avon Longitudinal Study of Parents and Children. At age 13, participants reported on 7 school toilet environment characteristics and a range of LUTS items. At age 19, participants completed the Bristol Female Lower Urinary Tract Symptoms questionnaire., Results: All toilet environmental factors were associated with at least 1 LUTS outcome at age 13. Holding behavior was associated with all school toilet environmental factors, with odds ratios ranging from 1.36 (95% confidence interval [CI]: 1.05, 1.76) for dirty toilets to 2.38 (95% CI: 1.60, 3.52) for feeling bullied at toilets. Bullying was associated with all daytime LUTS symptoms and nocturia; odds ratios ranged from 1.60 (95% CI: 1.04, 2.07) for nocturia to 2.90 (95% CI: 1.77, 4.75) for urgency. Associations between age 13 school toilets and age 19 LUTS were in the same direction as age 13 LUTS., Conclusion: This is the first examination of associations between school toilets and LUTS. Toileting environments were cross-sectionally associated with LUTS in adolescent girls. While further work is needed to determine whether these associations are causal, school toilet environments are modifiable and thus a promising target for LUTS prevention., (Copyright © 2020. Published by Elsevier Inc.)

Background: The effects of specific macronutrients on kidney function independent of total calorie intake have rarely been studied, although the composition of macronutrient intake has been reported to affect health outcomes., Objectives: We aimed to investigate the effects of macronutrient intake ratios on the risk of chronic kidney disease (CKD) by Mendelian randomization (MR) analysis., Methods: The study was an observational cohort study mainly based on the UK Biobank and including MR analysis. First, we evaluated the relative baseline macronutrient composition-that is, the number of calories from each macronutrient divided by total calorie intake-of the diets of UK Biobank participants, and we used Cox regression to assess the incidence of end-stage kidney disease (ESKD) in 65,164 participants with normal kidney function [estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2]. We implemented a genetic instrument for relative fat, protein, and carbohydrate intake developed by a previous genome-wide association study (GWAS) and performed MR analysis. Two-sample MR was performed with the summary statistics from independent CKDGen GWAS for kidney function traits (n = 567,460), including CKD (eGFR <60 mL/min/1.73 m2) and log-transformed eGFR., Results: The median relative macronutrient intake composition at baseline was 35% fats, 15% protein, and 50% carbohydrates. Higher relative protein intake in subjects with normal kidney function was significantly associated with a lower risk of incident ESKD (HR: 0.54; 95% CI: 0.30, 0.95) in the observational investigation. Two-sample MR indicated that increased relative fat intake causally increased the risk of kidney function impairment [CKD (OR: 1.94; 95% CI: 1.39, 2.71); log eGFR (β: -0.036; 95% CI: -0.048, -0.024)] and that higher relative protein intake was causally linked to a lower CKD risk [CKD (OR: 0.50; 95% CI: 0.35, 0.72); log eGFR (β: 0.044; 95% CI: 0.030, 0.058)]., Conclusions: A desirable macronutrient composition, including high relative protein intake and low relative fat intake, may causally reduce the risk of CKD in the general population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Aims: The coronavirus disease 2019 (COVID-19) pandemic has created significant challenges to healthcare globally, necessitating rapid restructuring of service provision. This questionnaire survey was conducted amongst adult heart failure (HF) patients in the United Kingdom (UK), to understand the impact of COVID-19 upon HF services., Methods and Results: The survey was conducted by the Pumping Marvellous Foundation, a UK HF patient charity. 'Survey Monkey' was used to disseminate the questionnaire in the Pumping Marvellous Foundation 's online patient group and in 10 UK hospitals (outpatient hospital and community HF clinics). There were 1050 responses collected (693/1050-66% women); 55% (579/1050) were aged over 60 years. Anxiety level was significantly higher regarding COVID-19 (mean 7 ± 2.5 on anxiety scale of 0 to 10) compared with anxiety regarding HF (6.1 ± 2.4; P < 0.001). Anxiety was higher amongst patients aged ≤60 years about HF (6.3 ± 2.2 vs. 5.9 ± 2.5 in those aged >60 years; P = 0.005) and COVID-19 (7.3 ± 2.3 vs. 6.7 ± 2.6 those aged >60 years; P < 0.001). Sixty-five per cent of respondents (686/1050) reported disruption to HF appointments (cancellation or postponement) during the lockdown period. Thirty-seven per cent reported disruption to medication prescription services, and Thirty-four per cent reported inability to access their HF teams promptly. Thirty-two per cent expressed reluctance to attend hospital (25% stated they would only attend hospital if there was no alternative, and 7% stated that they would not attend hospital at all)., Conclusions: The COVID-19 pandemic has caused significant anxiety amongst HF patients regarding COVID-19 and HF. Cancellation or postponement of scheduled clinic appointments, investigations, procedures, prescription, and monitoring services were implicated as sources of anxiety., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Endometriosis and restless leg syndrome (RLS) are both chronic conditions that can negatively affect a woman's quality of life. A higher prevalence of RLS is seen in women and particularly in those who are pregnant, suggesting a possible ovarian hormonal influence. Endometriosis is a common (affecting 1 in 10 women) estrogen driven gynecological condition, and the prevalence of RLS in women with symptoms or a diagnosis of endometriosis is unknown., Methods: A prospective, cross-sectional, observational self-completed questionnaire study was distributed to 650 pre-menopausal women attending the gynecological department at Liverpool Women`s Hospital over a period of 4 months. 584 questionnaires were returned and 465 completed questionnaires were included in the final dataset. Data on RLS-associated (The International Restless Leg Syndrome Study Group rating scale) and endometriosis-associated (modified-British Society of Gynaecological Endoscopists pelvic pain questionnaire) symptoms were collected., Results: Women who reported a prior surgical diagnosis of endometriosis had a greater risk of having a prior formal diagnosis of RLS (OR 4.82, 95% CI 1.66,14.02) and suffering RLS symptoms (OR 2.13, 95% CI 1.34-3.39) compared with those without a diagnosis. When women with either a formal surgical diagnosis or symptoms associated with endometriosis were grouped together, they also have a significantly increased risk of having either a formal diagnosis or symptoms suggestive of RLS (OR 2.49, 95% CI 1.30, 3.64). In women suffering with endometriosis-associated symptoms, the cumulative endometriosis-associated symptom scores demonstrated a modest positive correlation with RLS severity scores (r=0.42 95% CI 0.25 to 0.57)., Conclusions: This is the first study highlighting an association between the symptoms relevant to the two chronic conditions RLS and endometriosis, showing that women with a reported prior surgical diagnosis or symptoms suggestive of endometriosis have a significantly higher prevalence of a prior formal diagnosis or symptoms suggestive of RLS. This data will help in facilitating the discovery of novel therapeutic targets relevant to both conditions. The simultaneous treatment of these conditions could potentially lead to improvement in the overall quality of life for these women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tempest, Boyers, Carter, Lane and Hapangama.)