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Abstract Context The effects of COVID-19 on the thyroid axis remain uncertain. Recent evidence has been conflicting, with both thyrotoxicosis and suppression of thyroid function reported. Objective We aimed to detail the acute effects of COVID-19 on thyroid function and determine if these effects persisted on recovery from COVID-19. Design A cohort observational study was conducted. Participants and Setting Adult patients admitted to Imperial College Healthcare National Health Service Trust, London, UK, with suspected COVID-19 between March 9 to April 22, 2020, were included, excluding those with preexisting thyroid disease and those missing either free thyroxine (FT4) or thyrotropin (TSH) measurements. Of 456 patients, 334 had COVID-19 and 122 did not. Main Outcome Measures TSH and FT4 measurements were recorded at admission, and where available, in 2019 and at COVID-19 follow-up. Results Most patients (86.6%) presenting with COVID-19 were euthyroid, with none presenting with overt thyrotoxicosis. Patients with COVID-19 had a lower admission TSH and FT4 compared to those without COVID-19. In the COVID-19 patients with matching baseline thyroid function tests from 2019 (n = 185 for TSH and 104 for FT4), TSH and FT4 both were reduced at admission compared to baseline. In a complete case analysis of COVID-19 patients with TSH measurements at follow-up, admission, and baseline (n = 55), TSH was seen to recover to baseline at follow-up. Conclusions Most patients with COVID-19 present with euthyroidism. We observed mild reductions in TSH and FT4 in keeping with a nonthyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.

Background Since 2013, the number of violent crimes and offences by sharp instruments have increased continually, following a previous decrease, with majority of cases occurring among young people and in London. There is limited understanding surrounding the drivers influencing this change in trends, with mostly American-based research identifying risk factors. Methods The aim of this review is to identify and synthesise evidence from a range of literature to identify risk factors associated with weapon-related crime, for young people (aged 10–24 years) within the UK. A search strategy was generated to conduct a systematic search of published and grey literature within four databases (EMBASE, Medline, PsycINFO, and OpenGrey), identifying papers within a UK-context. Abstracts and full texts were screened by two independent reviewers to assess eligibility for inclusion, namely study focus in line with the objectives of the review. Weight of Evidence approach was utilised to assess paper quality, resulting in inclusion of 16 papers. Thematic analysis was conducted for studies to identity and categorise risk factors according to the WHO ecological model. Results No association was found between gender or ethnicity and youth violence, contrasting current understanding shown within media. Multiple research papers identified adverse childhood experiences and poor mental health as positively associated with youth and gang violence. It was suggested that community and societal risk factors, such as discrimination and economic inequality, were frequently linked to youth violence. A small number of studies were included within the review as this is a growing field of research, which may have led to a constrained number of risk factors identified. Due to heterogeneity of studies, a meta-analysis could not be conducted. As many studies displayed positive results, publication bias may be present. Conclusions Several risk factors were identified, with evidence currently heterogeneous with minimal high-quality studies. However, findings highlight key areas for future research, including the link between poor mental health and knife-crime, and the trajectory into gangs. Risk factors should help identify high-risk individuals, targeting them within mitigation strategies to prevent involvement within crime. This should contribute to efforts aimed at reducing the rising crime rates within UK. Systematic review registration number CRD42019138545 . Registered at PROSPSERO: 16/08/2019.

BACKGROUNDHypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODSUsing psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTSMC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSIONThese data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATIONClinicalTrials.gov NCT04179734.FUNDINGThis is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001).

Background An estimated 2.6 million newborns died in 2016; over 98.5% of deaths occurred in low- and middle-income countries (LMICs). Neonates born preterm and small for gestational age are particularly at risk given the high incidence of infectious complications, cardiopulmonary, and neurodevelopmental disorders in this group. Quality improvement (QI) initiatives can reduce the burden of mortality and morbidity for hospitalised newborns in these settings. We undertook a systematic review to synthesise evidence from LMICs on QI approaches used, outcome measures employed to estimate effects, and the nature of implementation challenges. Methods We searched Medline, EMBASE, WHO Global Health Library, Cochrane Library, WHO ICTRP, and ClinicalTrials.gov and scanned the references of identified studies and systematic reviews. Searches covered January 2000 until April 2017. Search terms were “quality improvement”, “newborns”, “hospitalised”, and their derivatives. Studies were excluded if they took place in high-income countries, did not include QI interventions, or did not include small and sick hospitalised newborns. Cochrane Risk of Bias tools were used to quality appraise the studies. Results From 8110 results, 28 studies were included, covering 23 LMICs and 65,642 participants. Most interventions were meso level (district and clinic level); fewer were micro (patient-provider level) or macro (above district level). In-service training was the most common intervention subtype; service organisation and distribution of referencing materials were also frequently identified. The most commonly assessed outcome was mortality, followed by length of admission, sepsis rates, and infection rates. Key barriers to implementation of quality improvement initiatives included overburdened staff and lack of sufficient equipment. Conclusions The frequency of meso level, single centre, and educational interventions suggests that these interventions may be easier for programme planners to implement. The success of some interventions in reducing morbidity and mortality rates suggests that QI approaches have a high potential for benefit to newborns. Going forward, there are opportunities to strengthen the focus of QI initiatives and to develop improved, larger-scale, collaborative research into implementation of quality improvement initiatives for this high-risk group. Trial registration PROSPERO CRD42017055459 .

Paediatric acute liver failure (PALF) is a rare but devastating condition with high mortality. An exaggerated inflammatory response is now recognised as pivotal in the pathogenesis and prognosis of ALF, with cytokine spill from the liver to systemic circulation implicated in development of multi-organ failure associated with ALF. With advances in medical management, especially critical care, there is an increasing trend towards spontaneous liver regeneration, averting the need for emergency liver transplantation or providing stability to the patient awaiting a graft. Hence, research is ongoing for therapies, including extracorporeal liver support devices, that can bridge patients to transplant or spontaneous liver recovery. Considering the immune-related pathogenesis and inflammatory phenotype of ALF, plasma exchange serves as an ideal liver assist device as it performs both the excretory and synthetic functions of the liver and, in addition, works as an immunomodulatory therapy by suppressing the early innate immune response in ALF. After a recent randomised controlled trial in adults demonstrated a beneficial effect of high-volume plasma exchange on clinical outcomes, this therapy was incorporated in European Association for the Study of Liver (EASL) recommendations for managing adult patients with ALF, but no guidelines exist for PALF. In this review, we discuss rationale, timing, practicalities, and existing evidence regarding the use of plasma exchange as an immunomodulatory treatment in PALF. We discuss controversies in delivery of this therapy as an extracorporeal device, and practicalities of use of plasma exchange as a ‘hybrid’ therapy alongside other extracorporeal liver assist devices, before finally reviewing outstanding research questions for the future.

ObjectivesTo determine if increased exposure to clinical specialties at medical school is associated with increased interest in pursuing that specialty as a career after foundation training.DesignA retrospective observational study.Setting31 UK medical schools were asked how much time students spend in each of the clinical specialties. We excluded two schools that were solely Graduate Entry, and two schools were excluded for insufficient information.Main outcome measuresTime spent on clinical placement from UK undergraduate medical schools, and the training destinations of graduates from each school. A general linear model was used to analyse the relationship between the number of weeks spent in a specialty at medical school and the percentage of graduates from that medical school entering each of the Core Training (CT1)/Specialty Training (ST1) specialties directly after Foundation Year 2 (FY2).ResultsStudents spend a median of 85 weeks in clinical training. This includes a median of 28 weeks on medical firms, 15 weeks in surgical firms, and 8 weeks in general practice (GP). In general, the number of training posts available in a specialty was proportionate to the number of weeks spent in medical school, with some notable exceptions including GP. Importantly, we found that the number of weeks spent in a specialty at medical school did not predict the percentage of graduates of that school training in that specialty at CT1/ST1 level (ß coefficient=0.061, p=0.228).ConclusionsThis study found that there was no correlation between the percentage of FY2 doctors appointed directly to a CT1/ST1 specialty and the length of time that they would have spent in those specialties at medical school. This suggests that curriculum adjustments focusing solely on length of time spent in a specialty in medical school would be unlikely to solve recruitment gaps in individual specialties.

Continuous Renal Replacement Therapy (CRRT) machines are used off-label in patients less than 20 kg. Infant and neonates-dedicated CRRT machines are making their way into current practice, but these machines are available only in select centres. This study assesses the safety and efficacy of CRRT using adult CRRT machines in children ≤ 10 kg and to determines the factors affecting the circuit life in these children. Design: Retrospective cohort study of children ≤ 10 kg who received CRRT (January 2010-January 2018) at a PICU in a tertiary care centre in London, UK. Primary diagnosis, markers for illness severity, CRRT characteristics, length of PICU admission and survival to PICU discharge were collected. Descriptive analysis compared survivors and non-survivors. A subgroup analysis compared children ≤ 5 kg to children 5–10 kg. Fifty-one patients ≤ 10 kg received 10,328 h of CRRT, with median weight of 5 kg. 52.94% survived to hospital discharge. Median circuit life was 44 h (IQR 24–68). Bleeding episodes occurred with 6.7% of sessions and hypotension for 11.9%. Analysis of efficacy showed a reduction in fluid overload at 48 h ( P  = 0.0002) and serum creatinine at 24 and 48 h ( P  = 0.001). Blood priming was deemed to be safe as serum potassium decreased at 4 h ( P  = 0.005); there was no significant change in serum calcium. Survivors had a lower PIM2 score at PICU admission ( P  < 0.001) and had longer PICU length of stay ( P  < 0.001).     Conclusion : Pending neonatal and infant dedicated CRRT machines, CRRT can be safely and effectively applied to children weighing ≤ 10 kg using adult-sized CRRT machines. What is Known: • Continuous Renal Replacement Therapy can be used for a variety of renal and non-renal indications to improve outcomes for children in the paediatric intensive care unit. These include, persistent oliguria, fluid overload, hyperkalaemia, metabolic acidosis, hyperlactatemia, hyperammonaemia, and hepatic encephalopathy. • Young children ≤ 10 kg are most often treated using standard adult machines, off-label. This potentially places them at risk of side effects due to high extracorporeal circuit volumes, relatively higher blood flows, and difficulty in achieving vascular access. What is New: • This study found that standard adult machines were effective in reducing fluid overload and creatinine in children ≤ 10 kg. This study also assessed safety of blood priming in this group and found no evidence of an acute fall in haemoglobin or calcium, and a fall in serum potassium by a median of 0.3 mmol/L. The frequency of bleeding episodes was 6.7%, and hypotension requiring vasopressors or fluid resuscitation occurred with 11.9% of treatment sessions. • These findings suggest that adult CRRT machines are sufficiently safe and efficacious for routine use in PICU for children ≤ 10 kg and suggest that further research is undertaken, regarding the routine rollout of dedicated machines.

Background To describe how using a combined approach of community-based participatory research and intervention mapping principles could inform the development of a tailored complex intervention to improve management of asthma for South Asian (SA) children; Management and Interventions for Asthma (MIA) study. Methods A qualitative study using interviews, focus groups, workshops, and modified intervention mapping procedures to develop an intervention planning framework in an urban community setting in Leicester, UK. The modified form of intervention mapping (IM) included: systematic evidence synthesis; community study; families and healthcare professionals study; and development of potential collaborative intervention strategies. Participants in the community study were 63 SA community members and 12 key informants; in-depth semi-structured interviews involved 30 SA families, 14 White British (WB) families and 37 Healthcare Professionals (HCPs) treating SA children living with asthma; prioritisation workshops involved 145 SA, 6 WB and 37 HCP participants; 30 participants in finalisation workshops. Results Two key principles were utilised throughout the development of the intervention; community-based participatory research (CBPR) principles and intervention mapping (IM) procedures. The CBPR approach allowed close engagement with stakeholders and generated valuable knowledge to inform intervention development. It accounted for diverse perceptions and experiences with regard to asthma and recognised the priorities of patients and their families/caregivers for service improvement. The ‘ACT on Asthma’ programme was devised, comprising four arms of an intervention strategy: education and training, clinical support, advice centre and raising awareness, to be co-ordinated by a central team. Conclusions The modified IM principles utilised in this study were systematic and informed by theory. The combined IM and participatory approach could be considered when tailoring interventions for other clinical problems within diverse communities. The IM approach to intervention development was however resource intensive. Working in meaningful collaboration with minority communities requires specific resources and a culturally competent methodology.

Background Our study aimed to evaluate to what extent Zero2 Expo's ‘Birthing a Better Future’, a co‐created multimedia exhibition, was effective in raising awareness on the importance of the first 1001 days of life and explore what refinements would help to optimize the impact of future exhibitions. Methods We conducted a mixed‐methods evaluation of the exhibition delivered in the John Radcliffe Hospital, Oxford. Through convenience sampling, 14 participants were selected to participate in 12 structured interviews and 19 participants completed a questionnaire. Interviews were thematically analysed alongside quantitative analysis of questionnaire responses through Likert scales. Results The majority (78.6%, n = 11/14) of participants who completed the questionnaire either agreed or strongly agreed that the exhibition raised their awareness about the first 1001 days of life. This was supported by the analysis of interviews. The use of art was found to provoke an emotional engagement from participants. Participants felt that the length of the written pieces and location of the exhibition were important factors for designers to consider in future exhibitions. Conclusion This study demonstrated that multimedia exhibitions, combining science with art, may be an effective way to raise awareness of public health messages. Engaging with key stakeholders will be an essential step in order to improve future public health exhibitions. Public Contribution When designing the study, the public reviewed the study tools, which were refined based on their feedback. At every phase of the study, members of the public who are artists co‐created the exhibition content.

Paediatric acute liver failure (PALF) is a rare but devastating condition with high mortality. An exaggerated inflammatory response is now recognised as pivotal in the pathogenesis and prognosis of ALF, with cytokine spill from the liver to systemic circulation implicated in development of multi-organ failure associated with ALF. With advances in medical management, especially critical care, there is an increasing trend towards spontaneous liver regeneration, averting the need for emergency liver transplantation or providing stability to the patient awaiting a graft. Hence, research is ongoing for therapies, including extracorporeal liver support devices, that can bridge patients to transplant or spontaneous liver recovery. Considering the immune-related pathogenesis and inflammatory phenotype of ALF, plasma exchange serves as an ideal liver assist device as it performs both the excretory and synthetic functions of the liver and, in addition, works as an immunomodulatory therapy by suppressing the early innate immune response in ALF. After a recent randomised controlled trial in adults demonstrated a beneficial effect of high-volume plasma exchange on clinical outcomes, this therapy was incorporated in European Association for the Study of Liver (EASL) recommendations for managing adult patients with ALF, but no guidelines exist for PALF. In this review, we discuss rationale, timing, practicalities, and existing evidence regarding the use of plasma exchange as an immunomodulatory treatment in PALF. We discuss controversies in delivery of this therapy as an extracorporeal device, and practicalities of use of plasma exchange as a 'hybrid' therapy alongside other extracorporeal liver assist devices, before finally reviewing outstanding research questions for the future.