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Background: A Spanish nurse posted a video on TikTok criticizing the requirement of a certain level of Catalan to work in the public health system of Catalonia (Spain). The video went viral, eliciting reactions from social media users, politicians, and professional nursing organizations. This study aims to evaluate the reputational damage suffered by the nurse, her hospital, and the nursing profession, with the goal of proposing actions to prevent, avoid, or manage similar situations., Methodology: A sequential exploratory mixed-methods design was used to analyse the content of the video, its impact on the press and social media, and the management of the communication crisis by the hospital and nursing organizations involved., Results: The nurse exercised her right to freedom of expression. However, her choice to convey the message, wearing the uniform that identified her as a staff member of a specific hospital, and her criticism of the language level requirement, led to reputational damage after the video spread via the press and Twitter/X. The hospital's reputation was affected due to the nurse being identified as one of its employees. In contrast, the reputation of the nursing profession was not significantly harmed, as multiple information sources suggested the incident was isolated. The creation of a safe, self-regulatory framework and training in social media and communication management are proposed as measures for healthcare centres, nursing organizations, and academic institutions to implement., Conclusions: The reputations of both the nurse and her hospital were impacted. A methodological model for analysing similar situations is proposed.

Background: There is strong interest in the evaluation of longer-term outcome metrics for congenital heart diseases (CHDs); however, registries focus on postoperative metrics., Methods and Results: Informed by user online discussion forums and scoping of national data, we selected sentinel CHDs and long-term outcome metrics suitable for routine monitoring. We then developed sentinel CHD phenotypes and algorithms for identifying treatment pathway procedures using clinical codes. Finally, we calculated the metrics within a retrospective national cohort analysis. The 9 selected sentinel CHDs had a higher-than-average prevalence, typically involved surgery in infancy, and were associated with an increased risk of late mortality. The selected metrics of survival and reinterventions at 1, 5, and 10 years were both important and feasible. The cohort included 29 319 (41.3% of all operated CHD births) English and Welsh children born with sentinel CHDs in 2000 to 2022. Example metrics at age 10 years included: survival-hypoplastic left heart syndrome: 57.6% (95% CI, 54.9%-60.4%), functionally univentricular heart: 86.7% (95% CI, 84.6%-88.9%), transposition of the great arteries: 93.1% (95% CI, 92.2%-93.9%), pulmonary atresia: 81.0% (95% CI, 79.1%-82.9%), atrioventricular septal defect: 88.5% (95% CI, 87.5%-89.5%), tetralogy of Fallot: 95.1% (95% CI, 94.4%-95.8%), aortic stenosis: 94.4% (95% CI, 93.3%-95.6%), coarctation: 96.7% (95% CI, 96.2%-97.3%), and ventricular septal defect: 96.9% 95% CI, (96.4%-97.3%); and (2) cumulative incidence of reintervention-hypoplastic left heart syndrome : 54.5% (95% CI, 51.5%-57.3%), functionally univentricular heart: 57.3% (95% CI, 53.9%-60.5%), transposition of the great arteries: 20.9% (95% CI, 19.5%-22.3%), pulmonary atresia: 66.8% (95% CI, 64.2%-69.1%), atrioventricular septal defect: 21.6% (20.3%-23.0%), tetralogy of Fallot: 26.6% (95% CI, 25.2%-28.0%), aortic stenosis: 31.2% (95% CI, 28.8%-33.6%), coarctation: 19.8% (95% CI, 18.6%-21.1%), and ventricular septal defect: 6.1% (95% CI, 5.5%-6.8%)., Conclusions: It is feasible to report important long-term outcomes of survival and reintervention for sentinel CHDs using routinely collected procedure records, adding value to national audit.

Background: Reinterventions may influence the outcomes of children with functionally single-ventricle (f-SV) congenital heart disease., Methods and Results: We undertook a retrospective cohort study of children starting treatment for f-SV between 2000 and 2018 in England, using the national procedure registry. Patients were categorized based on whether they survived free of transplant beyond 1 year of age. Among patients who had transplant-free survival beyond 1 year of age, we explored the relationship between reinterventions in infancy and the outcomes of survival and Fontan completion, adjusting for complexity. Of 3307 patients with f-SV, 909 (27.5%), had no follow-up beyond 1 year of age, among whom 323 (35.3%) had ≥1 reinterventions in infancy. A total of 2398 (72.5%) patients with f-SV had transplant-free survival beyond 1 year of age, among whom 756 (31.5%) had ≥1 reinterventions in infancy. The 5-year transplant-free survival and cumulative incidence of Fontan, among those who survived infancy, were 93.4% (95% CI, 92.4%-94.4%) and 79.3% (95% CI, 77.4%-81.2%), respectively. Both survival and Fontan completion were similar for those with a single reintervention and those who had no reinterventions. Patients who had >1 additional surgery (adjusted hazard ratio, 3.93 [95% CI, 1.87-8.27] P <0.001) had higher adjusted risk of mortality. Patients who had >1 additional interventional catheter (adjusted subdistribution hazard ratio, 0.71 [95% CI, 0.52-0.96] P =0.03) had a lower likelihood of achieving Fontan., Conclusions: Among children with f-SV, the occurrence of >1 reintervention in the first year of life, especially surgical reinterventions, was associated with poorer prognosis later in childhood.

Aims: To examine determinants of access to treatment, outcomes and hospital utilization in patients undergoing secundum atrial septal defect (ASD) closure in adulthood in England and Wales., Methods and Results: Large retrospective cohort study of all adult patients undergoing secundum ASD closures in England and Wales between 2000/01 and 2016/17. Data were from population-based official data sets covering congenital heart disease procedures, hospital episodes and death registries.Out of 6 541 index closures, 79.4% were transcatheter (median age 47 years, IQR 34-61) and 20.6% were surgical (40 years, 28-52). The study cohort was predominantly female (66%), with socio-ethnic profile similar to the general population.Mortality in hospital was 0.2% and at one year 1.0% (95%CI 0.8%-1.2%). Risk of death was lower for transcatheter repairs, adjusting for age, sex, year of procedure, comorbidities and cardiac risk factors (in-hospital adjusted-OR 0.09, 95%CI 0.02-0.46, one-year adjusted-HR 0.5, 0.3-0.9). There was excess mortality one year after ASD closure compared to matched population data.Median (IQR) peri-procedural length of stay was 1.8 (1.4-2.5) and 7.3 (6.2-9.2) days for transcatheter and surgical closures, respectively. Hospital resource use for cardiac reasons started the year before repair (median 2 inpatient and 2 outpatient-only days) and decreased post-repair (zero inpatient and one outpatient days during the first two years)., Conclusion: This national study confirms that ASD closure in adults, by surgical or transcatheter methods, is provided independently of ethnic or socioeconomic differences, it is low (but not no) risk and appears to reduce future cardiac hospitalisation even in older ages., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Regulation of mRNA translation is a crucial step in controlling gene expression in stressed cells, impacting many pathologies, including heart ischemia. In recent years, ribosome heterogeneity has emerged as a key control mechanism driving the translation of subsets of mRNAs. In this study, we investigated variations in ribosome composition in human cardiomyocytes subjected to endoplasmic reticulum stress induced by tunicamycin treatment. Our findings demonstrate that this stress inhibits global translation in cardiomyocytes while activating internal ribosome entry site (IRES)-dependent translation. Analysis of translating ribosome composition in stressed and unstressed cardiomyocytes was conducted using mass spectrometry. We observed no significant changes in ribosomal protein composition, but several mitochondrial ribosomal proteins (MRPs) were identified in cytosolic polysomes, showing drastic variations between stressed and unstressed cells. The most notable increase in polysomes of stressed cells was observed in MRPS15. Its interaction with ribosomal proteins was confirmed by proximity ligation assay (PLA) and immunoprecipitation, suggesting its intrinsic role as a ribosomal component during stress. Knock-down or overexpression experiments of MRPS15 revealed its role as an activator of IRES-dependent translation. Furthermore, polysome profiling after immunoprecipitation with anti-MRPS15 antibody revealed that the "MRPS15 ribosome" is specialized in translating mRNAs involved in the unfolded protein response.

Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial., (© 2024. The Author(s).)

Competing Interests: Disclosures The study was approved by the UK National Health Service Stanmore Research Ethics Committee (Reference 18/LO/1688) and the need for patient consent was waived.

Objectives: Long-term survival is an important metric for health care evaluation, especially in functionally single-ventricle (f-SV) congenital heart disease (CHD). This study's aim was to evaluate the relationship between center volume and long-term survival in f-SV CHD within the centralized health care service of England and Wales., Methods: This was a retrospective cohort study of children born with f-SV CHD between 2000 and 2018, using the national CHD procedure registry, with survival ascertained in 2020., Results: Of 56,039 patients, 3293 (5.9%) had f-SV CHD. Median age at first intervention was 7 days (interquartile range [IQR], 4, 27), and median follow-up time was 7.6 years (IQR, 1.0, 13.3). The largest diagnostic subcategories were hypoplastic left heart syndrome, 1276 (38.8%); tricuspid atresia, 440 (13.4%); and double-inlet left ventricle, 322 (9.8%). The survival rate at 1 year and 5 years was 76.8% (95% confidence interval [CI], 75.3%-78.2%) and 72.1% (95% CI, 70.6%-73.7%), respectively. The unadjusted hazard ratio for each 5 additional patients with f-SV starting treatment per center per year was 1.04 (95% CI, 1.02-1.06), P < .001. However, after adjustment for significant risk factors (diagnostic subcategory; antenatal diagnosis; younger age, low weight, acquired comorbidity, increased severity of illness at first procedure), the hazard ratio for f-SV center volume was 1.01 (95% CI, 0.99-1.04) P = .28. There was strong evidence that patients with more complex f-SV (hypoplastic left heart syndrome, Norwood pathway) were treated at centers with greater f-SV case volume (P < .001)., Conclusions: After adjustment for case mix, there was no evidence that f-SV center volume was linked to longer-term survival in the centralized health service provided by the 10 children's cardiac centers in England and Wales., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Reports of long-term mortality and reintervention after transposition of the great arteries with intact ventricular septum treatment, although favorable, are mostly limited to single-center studies. Even less is known about hospital resource utilization (days at hospital) and the impact of treatment choices and timing on outcomes., Objectives: The purpose of this study was to describe survival, reintervention and hospital resource utilization after arterial switch operation (ASO) in a national dataset., Methods: Follow-up and life status data for all patients undergoing ASO between 2000 and 2017 in England and Wales were collected and explored using multivariable regressions and matching., Results: A total of 1,772 patients were identified, with median ASO age of 9.5 days (IQR: 6.5-14.5 days). Mortality and cardiac reintervention at 10 years after ASO were 3.2% (95% CI: 2.5%-4.2%) and 10.7% (95% CI: 9.1%-12.2%), respectively. The median time spent in hospital during the ASO spell was 19 days (IQR: 14, 24). Over the first year after the ASO patients spent 7 days (IQR: 4-10 days) in hospital in total, decreasing to 1 outpatient day/year beyond the fifth year. In a subgroup with complete risk factor data (n = 652), ASO age, and balloon atrial septostomy (BAS) use were not associated with late mortality and reintervention, but cardiac or congenital comorbidities, low weight, and circulatory/renal support at ASO were. After matching for patient characteristics, BAS followed by ASO and ASO as first procedure, performed within the first 3 weeks of life, had comparable early and late outcomes, including hospital resource utilization., Conclusions: Mortality and hospital resource utilization are low, while reintervention remains relatively frequent. Early ASO and individualized use of BAS allows for flexibility in treatment choices and a focus on at-risk patients., Competing Interests: This study is supported by the Health Foundation, an independent charity committed to bringing about better health and health care for people in the United Kingdom (Award number 685009). D.M. Dorobantu is supported by a PhD Studentship (grant MR/N0137941/1 for the GW4 BIOMED DTP), awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the 10.13039/501100000265Medical Research Council (MRC)/UKRI, unrelated to this work. The views expressed are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research, or Department of Health. The Linking AUdit and National datasets in Congenital HEart Services (LAUNCHES) project received ethical approval from the Health Research Authority (reference: IRAS 246796) and the Confidentiality Advisory Group (reference: 18/CAG/0180). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Objective: The study objective was to provide a detailed overview of health resource use from birth to 18 years old for patients with functionally single ventricles and identify associated risk factors., Methods: All patients with functionally single ventricles treated between 2000 and 2017 in England and Wales were linked to hospital and outpatient records using data from the Linking AUdit and National datasets in Congenital HEart Services project. Hospital stay was described in yearly age intervals, and associated risk factors were explored using quantile regression., Results: A total of 3037 patients with functionally single ventricles were included, 1409 (46.3%) undergoing a Fontan procedure. During the first year of life, the median days spent in hospital was 60 (interquartile range, 37-102), mostly inpatient days, mirroring a mortality of 22.8%. This decreases to between 2 and 9 in-hospital days/year afterward. Between 2 and 18 years, most hospital days were outpatient, with a median of 1 to 5 days/year. Lower age at the first procedure, hypoplastic left heart syndrome/mitral atresia, unbalanced atrioventricular septal defect, preterm birth, congenital/acquired comorbidities, additional cardiac risk factors, and severity of illness markers were associated with fewer days at home and more intensive care unit days in the first year of life. Only markers of early severe illness were associated with fewer days at home in the first 6 months after the Fontan procedure., Conclusions: Hospital resource use in functionally single ventricle cases is not uniform, decreasing 10-fold during adolescence compared with the first year of life. There are subsets of patients with worse outcomes during their first year of life or with persistently high hospital use throughout their childhood, which could be the target of future research., (© 2023 The Authors.)

Internal ribosome entry sites (IRESs) drive translation initiation during stress. In response to hypoxia, (lymph)angiogenic factors responsible for tissue revascularization in ischemic diseases are induced by the IRES-dependent mechanism. Here, we searched for IRES trans -acting factors (ITAFs) active in early hypoxia in mouse cardiomyocytes. Using knock-down and proteomics approaches, we show a link between a stressed-induced nuclear body, the paraspeckle, and IRES-dependent translation. Furthermore, smiFISH experiments demonstrate the recruitment of IRES-containing mRNA into paraspeckle during hypoxia. Our data reveal that the long non-coding RNA Neat1 , an essential paraspeckle component, is a key translational regulator, active on IRESs of (lymph)angiogenic and cardioprotective factor mRNAs. In addition, paraspeckle proteins p54 nrb and PSPC1 as well as nucleolin and RPS2, two p54 nrb -interacting proteins identified by mass spectrometry, are ITAFs for IRES subgroups. Paraspeckle thus appears as a platform to recruit IRES-containing mRNAs and possibly host IRESome assembly. Polysome PCR array shows that Neat1 isoforms regulate IRES-dependent translation and, more widely, translation of mRNAs involved in stress response., Competing Interests: AG, ER, FD, FH, FM, JA, FP, IA, EB, OB, CF, AH, PV, EL, FT, BG, AP No competing interests declared, (© 2022, Godet, Roussel et al.)

Objective: This study assessed the transfer of patients from paediatric cardiac to adult congenital heart disease (ACHD) services in England and the factors impacting on this process., Methods: This retrospective cohort study used a population-based linked data set (LAUNCHES QI data set: 'Linking Audit and National datasets in Congenital Heart Services for Quality Improvement') including all patients born between 1987 and 2000, recorded as having a congenital heart disease (CHD) procedure in childhood. Hospital Episode Statistics data identified transfer from paediatric to ACHD services between the ages of 16 and 22 years., Results: Overall, 63.8% of a cohort of 10 298 patients transferred by their 22nd birthday. The estimated probability of transfer by age 22 was 96.5% (95% CI 95.3 to 97.7), 86.7% (95% CI 85.6 to 87.9) and 41.0% (95% CI 39.4 to 42.6) for severe, moderate and mild CHD, respectively. 166 patients (1.6%) died between 16 and 22 years; 42 of these (0.4%) died after age 16 but prior to transfer. Multivariable ORs in the moderate and severe CHD groups up to age 20 showed significantly lower likelihood of transfer among female patients (0.87, 95% CI 0.78 to 0.97), those with missing ethnicity data (0.31, 95% CI 0.18 to 0.52), those from deprived areas (0.84, 95% CI 0.72 to 0.98) and those with moderate (compared with severe) CHD (0.30, 95% CI 0.26 to 0.35). The odds of transfer were lower for the horizontal compared with the vertical care model (0.44, 95% CI 0.27 to 0.72). Patients who did not transfer had a lower probability of a further National Congenital Heart Disease Audit procedure between ages 20 and 30 compared with those who did transfer: 12.3% (95% CI 5.1 to 19.6) vs 32.5% (95% CI 28.7 to 36.3)., Conclusions: Majority of patients with moderate or severe CHD in England transfer to adult services. Patients who do not transfer undergo fewer elective CHD procedures over the following decade., 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.)

The global distribution and presence of plastic, at all levels of the water column, has made plastic debris one of today's greatest environmental challenges. The ingestion and entanglement of plastic-containing marine debris has been documented in more than 60% of all cetacean species. In light of the increasing pressure on cetaceans, and the diversity of factors that they face, the aim of this work is to provide evidence of the impact of plastic debris on stranded cetaceans, in terms of ingestion and entanglement, in the Balearic Islands for the first-time. Detailed examinations, necropsies, and plastic debris analysis were performed on 30 of the 108 cetaceans stranded between 2019 and 2022. Specimens belonging to five different species, Stenella coeruleoalba , Tursiops truncatus , Grampus griseus , Balaenoptera physalus , and Physeter macrocephalus , were evaluated. Ten percent of the cetaceans (N = 3) presented plastic debris in their stomach, with one case of obstruction and perforation. Fishery gear fragments (ropes and nets) were found in two adults of T. truncatus , whereas packaging debris (plastic bag, packing straps, and plastic sheets) were found in a juvenile P. macrocephalus . Plastic items analysed by Fourier transform infrared spectroscopy (FT-IR) reported three polymer types: polypropylene, polyamide, and high-density polypropylene. A total of seven cases of entanglement were recorded during the study, affecting four different species ( S. coeruleoalba , T. truncatus , P. macrocephalus , and Megaptera novaeangliae ). Only two individuals were freed from the nets, although one died after a week, whereas the rest were already found dead. In conclusion, data collected in the present study provided evidence of plastic ingestion and entanglement in cetaceans of the Balearic Islands for the first-time, thus highlighting the need for the regular examination of stranded cetaceans (as they are top predators) in future research to better understand the effects of these pollutants.

Plastic waste has become ubiquitous pollutants in seas and oceans and can affect a wide range of species. For some marine species, plastic debris could pose a considerable threat through entanglement, ingestion, and habitat degradation and loss. Sea turtles are one of the most sensitive species, as their migratory behaviour and multifaceted life cycles make these reptiles especially vulnerable to the negative effects of plastic debris. The present study aimed to assess the amount and composition of plastic debris ingested by loggerhead turtles (Caretta caretta, Linnaeus, 1758) in the Balearic Islands Sea, thusly providing new information to complete the knowledge for this topic. In this work, 45 stranded dead C. caretta specimens were necropsied, and their digestive tract content analysed for the presence of plastic debris. Plastic objects were observed in 27 individuals (60.0%), with an average of 12.7 ± 4.7 plastic items per turtle. Litter in the faecal pellet was also monitored in 67 living individuals, observing plastic elements in 46 (68.7%) of the specimens, reporting an average of 9.7 ± 3.3 plastic elements per individual. Overall, 785 plastic items were found, measured, weighed and categorized according to size, colour, shape, and type of polymer. The main elements ingested were plastic sheets that were found in 65.3% of the turtles analysed, being white (42.7%) and transparent (29.2%) the most predominant colours. Most elements were macroplastics (59.3%), while microplastics were not found. Fourier Transform Infrared Spectrometry (FT-IR) analysis showed that high-density polyethylene and polypropylene were the main polymer plastics, representing 42.3% and 33.8% of the total, respectively. In conclusion, the high occurrence of plastic debris determined in the present study evidenced for the first time plastic ingestion in loggerhead turtles in the Balearic Islands, and highlights C. caretta as a bioindicator organism for marine pollution., 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 © 2022 Elsevier B.V. All rights reserved.)

Objective: Given the paucity of long-term outcome data for complex congenital heart disease (CHD), we aimed to describe the treatment pathways and survival for patients who started interventions for functionally univentricular heart (FUH) conditions, excluding hypoplastic left heart syndrome., Methods: We performed a retrospective cohort study using all procedure records from the National Congenital Heart Diseases Audit for children born in 2000-2018. The primary outcome was mortality, ascertained from the Office for National Statistics in 2020., Results: Of 53 615 patients, 1557 had FUH: 55.9% were boys and 67.4% were of White ethnic groups. The largest diagnostic categories were tricuspid atresia (28.9%), double inlet left ventricle (21.0%) and unbalanced atrioventricular septal defect (AVSD) (15.2%). The ages at staged surgery were: initial palliation 11.5 (IQR 5.5-43.5) days, cavopulmonary shunt 9.2 (IQR 6.0-17.1) months and Fontan 56.2 (IQR 45.5-70.3) months. The median follow-up time was 10.8 (IQR 7.0-14.9) years and the 1, 5 and 10-year survival rates after initial palliation were 83.6% (95% CI 81.7% to 85.4%), 79.4% (95% CI 77.3% to 81.4%) and 77.2% (95% CI 75.0% to 79.2%), respectively. Higher hazards were present for unbalanced AVSD HR 2.75 (95% CI 1.82 to 4.17), atrial isomerism HR 1.75 (95% CI 1.14 to 2.70) and low weight HR 1.65 (95% CI 1.13 to 2.41), critical illness HR 2.30 (95% CI 1.67 to 3.18) or acquired comorbidities HR 2.71 (95% CI 1.82 to 4.04) at initial palliation., Conclusion: Although treatment pathways for FUH are complex and variable, nearly 8 out of 10 children survived to 10 years. Longer-term analyses of outcome based on diagnosis (rather than procedure) can inform parents, patients and clinicians, driving practice improvements for complex CHD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To link five national data sets (three registries, two administrative) and create longitudinal healthcare trajectories for patients with congenital heart disease (CHD), describing the quality and the summary statistics of the linked data set., Design: Bespoke linkage of record-level patient identifiers across five national data sets. Generation of spells of care defined as periods of time-overlapping events across the data sets., Setting: National Congenital Heart Disease Audit (NCHDA) procedures in public (National Health Service; NHS) hospitals in England and Wales, paediatric and adult intensive care data sets (Paediatric Intensive Care Audit Network; PICANet and the Case Mix Programme from the Intensive Care National Audit & Research Centre; ICNARC-CMP), administrative hospital episodes (hospital episode statistics; HES inpatient, outpatient, accident and emergency; A&E) and mortality registry data., Participants: Patients with any CHD procedure recorded in NCHDA between April 2000 and March 2017 from public hospitals., Primary and Secondary Outcome Measures: Primary: number of linked records, number of unique patients and number of generated spells of care. Secondary: quality and completeness of linkage., Results: There were 143 862 records in NCHDA relating to 96 041 unique patients. We identified 65 797 linked PICANet patient admissions, 4664 linked ICNARC-CMP admissions and over 6 million linked HES episodes of care (1.1M inpatient, 4.7M outpatient). The linked data set had 4 908 153 spells of care after quality checks, with a median (IQR) of 3.4 (1.8-6.3) spells per patient-year. Where linkage was feasible (in terms of year and centre), 95.6% surgical procedure records were linked to a corresponding HES record, 93.9% paediatric (cardiac) surgery procedure records to a corresponding PICANet admission and 76.8% adult surgery procedure records to a corresponding ICNARC-CMP record., Conclusions: We successfully linked four national data sets to the core data set of all CHD procedures performed between 2000 and 2017. This will enable a much richer analysis of longitudinal patient journeys and outcomes. We hope that our detailed description of the linkage process will be useful to others looking to link national data sets to address important research priorities., 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.)

Background: Whether long coronavirus disease pertains to children as well is not yet clear. Methods: The authors performed a survey in children suffering from persistent symptoms since initial infection. A total of 510 children infected between January 2020 and January 2021 were included. Results: Symptoms such as fatigue, headache, muscle and joint pain, rashes and heart palpitations and issues such as lack of concentration and short-term memory problems were particularly frequent and confirm previous observations, suggesting that they may characterize this condition. Conclusion: A better comprehension of long coronavirus disease is urgently needed.

The European Medical Agency (EMA) has issued a draft guideline on the quality and equivalence of topical products. The equivalence for complex semisolid formulations involves several steps: the same quantitative content, the same microstructure, the same release, and permeation profile. In this paper, several batches of a low strength topical product, which we used as a reference/comparator product, were evaluated according to the recommendations of the EMA draft guideline. The batches were 0.025% capsaicin emulsions from the same manufacturer that were evaluated in terms of droplet size, X-ray diffraction patterns, rheology, release, and permeation profile. The generated data revealed a large batch-to-batch variability, and if the EMA guideline was applied, these batches would not be considered equivalent, although they were produced by the same manufacturer. The result of this work illustrates the difficulties in obtaining equivalence according to the current draft guidelines. It also highlights that the equivalence guidelines should consider the variability of the comparator product, and in our opinion, the guidelines should allow for claiming equivalence by comparing the limits in the variability of the data generated for the comparator product with the limits in the variability of the data generated for the intended equivalence product.

Background: We can improve healthcare services by better understanding current provision. One way to understand this is by linking data sets from clinical and national audits, national registries and other National Health Service (NHS) encounter data. However, getting to the point of having linked national data sets is challenging., Objective: We describe our experience of the data application and linkage process for our study 'LAUNCHES QI', and the time, processes and resource requirements involved. To help others planning similar projects, we highlight challenges encountered and advice for applications in the current system as well as suggestions for system improvements., Findings: The study set up for LAUNCHES QI began in March 2018, and the process through to data acquisition took 2.5 years. Several challenges were encountered, including the amount of information required (often duplicate information in different formats across applications), lack of clarity on processes, resource constraints that limit an audit's capacity to fulfil requests and the unexpected amount of time required from the study team. It is incredibly difficult to estimate the resources needed ahead of time, and yet necessary to do so as early on as funding applications. Early decisions can have a significant impact during latter stages and be hard to change, yet it is difficult to get specific information at the beginning of the process., Conclusions: The current system is incredibly complex, arduous and slow, stifling innovation and delaying scientific progress. NHS data can inform and improve health services and we believe there is an ethical responsibility to use it to do so. Streamlining the number of applications required for accessing data for health services research and providing clarity to data controllers could facilitate the maintenance of stringent governance, while accelerating scientific studies and progress, leading to swifter application of findings and improvements in healthcare., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Increases in longevity combined with a policy emphasis on caring for older people in their own homes could have widened or narrowed the survival gap between care home and community-dwelling resident older people. Knowledge of pre-COVID-19 trends in this gap is needed to assess the longer-term impacts of the pandemic. We provide evidence for England on recent trends in 1, 2 and 3-year mortality amongst care home residents aged 65+ compared with similar community-dwelling residents. We use the Clinical Practice Research Datalink, a nationally representative primary care database. For each of the ten years from 2006 to 2015, care home and community-dwelling residents aged 65+ were identified and matched in the ratio 1:3, according to age, gender, area deprivation and region. Cox survival analyses were used to estimate mortality risks for care home residents in comparison with similar community-dwelling people, adjusting for age, gender, area deprivation and region. The study sample consisted of ten overlapping cohorts averaging 5495 care home residents per cohort. Adjusted mortality risks increased over the study period for care home residents while decreasing slightly for matched community-dwelling residents. The relative risks (RRs) of mortality associated with care home residence were higher for younger ages and shorter follow-up periods, in all years. Over the decade, the RRs increased, most at younger ages and for shorter follow-up periods (e.g. for the age group 65-74 years, 1-year average RR increased by 61% from 5.4 to 8.8, while for those aged 85-94 years and over, 3-year RR increased by 22% from 1.3 to 1.6). Thus the survival gap between older care home and community-dwelling residents has been widening, especially at younger ages. In due course, it will be possible to establish to what extent the COVID-19 pandemic has resulted in further growth in this gap., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigate the impact of exogenous local conditions which favor high market concentration on supply, price and quality in local markets for care homes for older people in England. We extend the existing literature in: (i) considering supply capacity as a market outcome alongside price and quality; (ii) taking account of the chain structure of care home supply and differences between the nursing home and residential care home sectors; (iii) using an econometric approach based on reduced form relationships that treats market concentration as a jointly determined outcome of a complex market. We find that areas susceptible to a high degree of market concentration tend to have greatly restricted supply of care home places and (to a lesser extent) a higher average public cost, than areas susceptible to low degree of market concentration. There is no significant evidence that conditions favoring high market concentration affect average care home quality., (© 2021 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Objective: To assess the use of fourth-generation rapid diagnostic tests in identifying acute infection of Human Immunodeficiency Virus (HIV)., Methods: BCN Checkpoint promotes sexual health among men who have sex with men (MSM), with a focus on diagnosing HIV early, initiating combined antiretroviral treatment (cART) promptly, and recommending regular repeat testing for those who have tested negative. This cross-sectional study included all test results obtained at the centre between 25 March 2016 and 24 March 2019. The Alere™ HIV Combo (now rebranded to Determine™ HIV Ultra, from Abbott) was used to detect p24 antigen (p24 Ag) and/or immunoglobulin M (IgM) and G (IgG) antibodies to HIV-1/HIV-2 (HIV Ab). Rapid polymerase chain reaction (PCR) confirmatory testing and Western blot (WB) were performed for clients with a positive rapid test result. Confirmed HIV cases were promptly referred to the HIV unit for care and cART prescription., Results: A total of 12,961 clients attended BCN Checkpoint during the study and 27,298 rapid tests were performed. 450 tests were found to be reactive, of which 430 confirmed as HIV-positive, representing a prevalence of 3.32%. Four confirmed cases (0.93%) were detected as "p24 Ag only", nine (2.09%) as "both p24 and HIV Ab" and 417 (96.98%) as "HIV Ab only". The "p24 Ag only" group had a 1-log higher viral load than the other groups and initiated treatment on the following working day. Overall, there were 20 false-positive results (0.07% and 4.44% of total and reactive tests, respectively), of which 10 positive for "p24 Ag only" and 10 for "HIV Ab only"., Conclusions: Four Acute HIV Infections (AHI), with very high viral loads, have been detected with the "p24 Ag only" while the HIV Ab were still absent. Referral to the HIV unit and initiation of cART on the following working day contributed to improving persons' health and to reduce HIV transmission chain., Competing Interests: We would like to declare explicitly that none of the authors or members of the BCN Checkpoint Working Group have or had during the last five years any financial or nonfinancial competing interests with the company Abbott Laboratories. Therefore, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

In cancer, the lymphatic system is hijacked by tumor cells that escape from primary tumor and metastasize to the sentinel lymph nodes. Tumor lymphangiogenesis is stimulated by the vascular endothelial growth factors-C (VEGFC) after binding to its receptor VEGFR-3. However, how VEGFC cooperates with other molecules to promote lymphatics growth has not been fully determined. We showed that lymphangiogenesis developed in tumoral lesions and in surrounding adipose tissue (AT). Interestingly, lymphatic vessel density correlated with an increase in circulating free fatty acids (FFA) in the lymph from tumor-bearing mice. We showed that adipocyte-released FFA are uploaded by lymphatic endothelial cells (LEC) to stimulate their sprouting. Lipidomic analysis identified the monounsaturated oleic acid (OA) as the major circulating FFA in the lymph in a tumoral context. OA transporters FATP-3, -6 and CD36 were only upregulated on LEC in the presence of VEGFC showing a collaborative effect of these molecules. OA stimulates fatty acid β-oxidation in LECs, leading to increased AT lymphangiogenesis. Our results provide new insights on the dialogue between tumors and adipocytes via the lymphatic system and identify a key role for adipocyte-derived FFA in the promotion of lymphangiogenesis, revealing novel therapeutic opportunities for inhibitors of lymphangiogenesis in cancer.

Hepatitis B virus (HBV) chronic infection is responsible for almost 900.000 deaths each year, due to cirrhosis or hepatocellular carcinoma (HCC). Ten HBV genotypes have been described (A-J). HBV genotype F and H circulate in America. HBV genotypes have been further classified in subgenotypes. There is a strong correlation between the genetic admixture of the American continent and the frequency of genotypes F or H: a high frequency of these genotypes is found in countries with a population with a higher ratio of Amerindian to African genetic admixture. The frequency of occult HBV infection in Amerindian communities from Latin America seems to be higher than the one found in other HBV-infected groups, but its association with American genotypes is unknown. There is growing evidence that some genotypes might be associated with a faster evolution to HCC. In particular, HBV genotype F has been implicated in a frequent and rapid progression to HCC. However, HBV genotype H has been associated to a less severe progression of disease. This study reviews the diversity and frequency of autochthonous HBV variants in the Americas and evaluates their association to severe progression of disease. Although no significant differences were found in the methylation pattern between different genotypes and subgenotypes of the American types, basal core promoter mutations might be more frequent in some subgenotypes, such as F1b and F2, than in other American subgenotypes or genotype H. F1b and probably F2 may be associated with a severe presentation of liver disease as opposed to a more benign course for subgenotype F4 and genotype H. Thus, preliminary evidence suggests that not all of the American variants are associated with a rapid progression to HCC., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Recent reports have shown that small and big felines could be infected by SARS-CoV-2, while other animals, like swines and mice, are apparently not susceptible to this infection. These findings raise the question of the role of cell factors associated with early stages of the viral infection in host selectivity. The cellular receptor for SARS-CoV-2 is the Angiotensin Converting Enzyme (ACE2). Transmembrane protease serine 2 (TMPRSS2) has been shown to prime the viral spike for its interaction with its receptor. GRP78 has also been proposed as a possible co-receptor. In this study, we used several bioinformatics approaches to bring clues in the interaction of ACE2, TMPRSS2, and GRP78 with SARS-CoV-2. We selected several mammalian hosts that could play a key role in viral spread by acting as secondary hosts (cats, dogs, pigs, mice, and ferrets) and evaluated their predicted permissiveness by in silico analysis. Results showed that ionic pairs (salt bridges, N-O pair, and long-range interactions) produced between ACE2 and the viral spike has an essential function in the host interaction. On the other hand, TMPRSS2 and GRP78 are proteins with high homology in all the evaluated hosts. Thus, these proteins do not seem to play a role in host selectivity, suggesting that other factors may play a role in the non-permissivity in some of these hosts. These proteins represent however interesting cell targets that could be explored in order to control the virus replication in humans and in the intermediary hosts., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In Barcelona, Spain prior to 2006, HIV testing was mostly limited to formal healthcare facilities with no incidence data reported. A community-based organization (BCN Checkpoint) was established to increase HIV testing in a peer-led community location to generate incidence data in men who have sex with men and transgender women. Three community engagement interventions were conducted between 2009 and 2017 as follows: 2009-2011 (peer-led point-of-care testing for HIV), 2012-2014 (12-monthly HIV testing with an emphasis on testing in partnerships), 2015-2017 (three-monthly HIV testing with rapid referral for antiretroviral initiation). Between 2009 and 2017 a predominantly cisgender male (99.4%) and Spanish national (62.4%) population with mean age of 34.8 years had 49,630 visits. Mean visit number increased from 1.69 in the first to 2.07 in the last three-year period. HIV incidence fell from 4.17 (95% confidence interval [CI]: 3.53-4.93) per 100 person-years in 2009-2011 to 1.57 (95% CI: 1.30-1.89) per 100 person-years in 2015-2017. This represents a 62% reduction (incidence rate ratio: 0.38, 95% CI: 0.29-0.48) between the first and third study period (p < 0.001). These early interventions may have contributed to the reduction seen in HIV incidence in this cohort.

Hypoxia, a major inducer of angiogenesis, triggers major changes in gene expression at the transcriptional level. Furthermore, under hypoxia, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here, we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 mouse cardiomyocytes: most genes are induced at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) that is able to bind RNA and to activate the FGF1 IRES in hypoxia, but which tends to inhibit several IRESs in normoxia. VASH1 depletion has a wide impact on the translatome of (lymph)angiogenesis genes, suggesting that this protein can regulate translation positively or negatively in early hypoxia. Translational control thus appears as a pivotal process triggering new vessel formation in ischemic heart., Competing Interests: FH, AG, FD, FT, ER, FP, LD, IA, LL, AH, YS, AP, EL, BG, AP No competing interests declared, (© 2019, Hantelys et al.)

This study focuses on actions at the political and administrative level in Spain in relation to the implementation of pre-exposure prophylaxis (PrEP). We analysed a whole range of different formal initiatives taken by the political and administrative actors involved. The information was obtained from official public data sources. As of February 2018, PrEP had not been implemented. The decision is dependent on both state and regional governments. The Ministry of Health and some Autonomous Regions are working on different interventions, but without providing an implementation timetable. The political parties have kept a very low profile in terms of initiatives related to the implementation of PrEP. From a legal point of view, proceedings are passing back and forth with the extension of the patent. The role of intergovernmental and interdepartmental institutions is very important for the implementation of PrEP in Spain., (Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.)