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Abstract Metagenomics can provide insight into the microbial taxa present in a sample and, through gene identification, the functional potential of the community. However, taxonomic and functional information are typically considered separately in downstream analyses. We develop interpretable machine learning (ML) approaches for modelling metagenomic data, combining the biological representation of species with their associated genetically encoded functions within models. We apply our methods to investigate soil organic carbon (SOC) stocks. First, we combine a diverse global set of soil microbiome samples with environmental data, improving the predictive performance of classic ML and providing new insights into the role of soil microbiomes in global carbon cycling. Our network analysis of predictive taxa identified by classical ML models provides context for their ecological significance, extending the focus beyond just the most predictive taxa to ‘hidden’ features within the model that might be considered less predictive using standard methods for explainability. We next develop unique graph representations for individual microbiomes, linking microbial taxa to their associated functions directly, enabling predictions of SOC via deep graph convolutional neural networks (DGCNNs). Interpretation of the DGCNNs distinguished between the importance of functions of key individual species, providing genome sequence differences, e.g., gene loss/acquisition, that associate with SOC. These approaches identify several members of the Verrucomicrobiaceae family and a range of genetically encoded functions, e.g., related to carbohydrate metabolism, as important for SOC stocks and effective global SOC predictors. These relatively understudied but widespread organisms could play an important role in SOC dynamics globally.

Previous published studies have shown an improvement of penile hemodynamic parameters after low-intensity extracorporeal shockwave therapy (Li-ESWT). However, the clinical significance of these findings remains unclear, and definitive selection criteria for Li-ESWT based on preexisting comorbidities have yet to be established. This was an observational study of 113 patients with ED, evaluated between January 2019 and December 2021 in Andrology Unit at the Department of Urology and Renal Transplantation, University of Foggia (Foggia, Italy). Penile dynamic Doppler was performed to evaluate vascular parameters and 5-item version of the International Index of Erectile Dysfunction (IIEF-5) questionnaire was administered to assess the severity of ED. This was repeated 1 month after treatment. Patients with a peak systolic velocity (PSV) 30 cm s−1 at posttherapeutic penile dynamic Doppler. A clinically significant IIEF-5 score improvement was observed in 7 patients, 21 patients, and 2 patients with mild-to-moderate, moderate, and severe pretreatment ED, respectively. No different outcomes were assessed based on smoking habits, previous pelvic surgery, or use of oral phosphodiesterase-5 inhibitor (PDE5i). On the other side, only 1 (6.7%) in 15 patients with diabetes mellitus showed an IIEF-5 score improvement after Li-ESWT. Shockwave treatment determined a significant increase in PSV and correlated IIEF-5 improvement in ED patients. This advantage seemed particularly evident for moderate ED and was not affected by smoking habits, previous pelvic surgery, and use of PDE5i. Conversely, diabetic patients did not benefit from the treatment.

Background & aimsPatients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers.MethodsMembers of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey.ResultsSurveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%).ConclusionsThe perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties.Impact and implicationsOver the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

Abstract Background Respiratory syncytial virus (RSV) affects 60–80% of children below 1 year and it’s the first cause of acute bronchiolitis. The aim of this study was to assess the trend and characteristics of hospitalizations for RSV infections in Italy. Methods This is a retrospective study based on the Italian Hospital Discharge Record (HDR) database. We analysed HDRs from June 2015 to May 2019, considering two groups of infants: Group 1 had a confirmed diagnosis of RSV; Group 2 had a diagnosis of acute bronchiolitis not RSV-coded. Results There were 67,746 overall hospitalizations (40.1% Group 1, and 59.9% Group 2). Hospitalization rate increased for Group 1 from 125 to 178 per 10,000 infants (+ 42.4%), and for Group 2 from 210 to 234 per 10,000 (+ 11.4%). The mean hospitalization length was 6.3 days in Group 1, longer than Group 2 (+ 1.0 day). A further analysis revealed that infants with heart disease or born premature had longer mean hospital stay compared to infants without risk factors (10.7 days versus 6.1 days, p

Objective: Our study's objective was to assess the incidence trends and healthcare resource utilization of hospitalizations for Tick-Borne Encephalitis (TBE) and associated costs in Italy in order to improve public awareness and preventive measures. Methods: This retrospective observational study was based on the Italian Ministry of Health's Hospital Discharge Record (HDR) database. Data were gathered across Italy from 2015 to 2019, selecting hospitalizations with ICD-9 code 063 related to TBE, both in primary and secondary diagnoses. For each year, we collected the following variables: number of hospitalizations, hospitalization rate, mortality rate, mean length of hospital stay, hospital ward, and cost of hospitalization. Results: There were a total of 237 hospitalizations from 2015 to 2019; 62 % of those were male. The lowest number of TBE hospitalizations was in 2015 (21 cases, corresponding to 0.35 per million inhabitants), the highest in 2019 (64 cases, 1.04 per million inhabitants). The summer months saw a greater than average number of hospitalizations. For the years analyzed, the cumulative number of cases peaked in June (54 cases), July (46 cases), and August (35 cases). There were only two deaths registered in our study sample. TBE cases were mostly localized in the North-Eastern regions of Italy. TBE incidence during the study period in the most affected areas were: Autonomous Province of Trento, ranging from 11.2 to 42.3 per million inhabitants, Autonomous Province of South Tyrol, from 0 to 21.1 per million inhabitants, and Veneto Region, from 2.6 to 4.5 per million inhabitants. In the study period, the average length of hospital stay was largely stable ranging from 10.6 days to 12.8 days, with related costs ranging from 5,813.7 € to 7,352.5 €. Conclusions: According to our data, the majority of TBE hospitalizations occur in North-East Italy with an increasing trend over the analyzed period. Even though Italy has fewer TBE cases than other neighboring European countries, the health and economic impact can be high in the affected areas.

Oxidative stress is one of the main mechanisms responsible for male infertility. Various conditions such as varicocele, obesity, advanced age, and lifestyle can lead to an increase in reactive oxygen species, causing an oxidative imbalance in the reproductive environment. Spermatozoa are sensitive to reactive oxygen species and require energy to carry out their main function of fertilizing the egg. Excessive reactive oxygen species can affect sperm metabolism, leading to immobility, impaired acrosome reaction, and cell death, thereby impairing reproductive success. This double-blind randomized study evaluated the effect of supplementation with L-carnitine, acetyl-L-carnitine, vitamins, and other nutrients on semen quality in 104 infertile patients with or without varicocele, while also investigating the impact of factors such as obesity and advanced age on treatment. Sperm concentration significantly increased in the supplemented group compared to the placebo group (P = 0.0186). Total sperm count also significantly increased in the supplemented group (P = 0.0117), as did sperm motility (P = 0.0120). The treatment had a positive effect on patients up to 35 years of age in terms of sperm concentration (P = 0.0352), while a body mass index (BMI) above 25 kg m−2 had a negative effect on sperm concentration (P = 0.0110). Results were not showing a net benefit in stratifying patients in accordance with their BMI since sperm quality increase was not affected by this parameter. In conclusion, antioxidant supplementation may be beneficial for infertile patients and has a more positive effect on younger patients with a normal weight.

Abstract Background The problem of mental ill-health in doctors is complex, accentuated by the COVID-19 pandemic, and impacts on healthcare provision and broader organisational performance. There are many interventions to address the problem but currently no systematic way to categorise them, which makes it hard to describe and compare interventions. As a result, implementation tends to be unfocussed and fall short of the standards developed for implementing complex healthcare interventions. This study aims to develop: 1) a conceptual typology of workplace mental health and wellbeing interventions and 2) a mapping tool to apply the typology within research and practice. Methods Typology development was based on iterative cycles of analysis of published and in-practice interventions, incorporation of relevant theories and frameworks, and team and stakeholder group discussions. Results The newly developed typology and mapping tool enable interventions to be conceptualised and/or mapped into different categories, for example whether they are designed to be largely preventative (by either improving the workplace or increasing personal resources) or to resolve problems after they have arisen. Interventions may be mapped across more than one category to reflect the nuance and complexity in many mental health and wellbeing interventions. Mapping of interventions indicated that most publications have not clarified their underlying assumptions about what causes outcomes or the theoretical basis for the intervention. Conclusion The conceptual typology and mapping tool aims to raise the quality of future research and promote clear thinking about the nature and purpose of interventions, In doing so it aims to support future research and practice in planning interventions to improve the mental health and wellbeing of doctors.

Abstract Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Background and objective: Percutaneous nephrolithotomy (PCNL) is the recommended treatment for large or complex renal stones. This study aims to evaluate the outcomes of mini PCNL in obese and nonobese patients and to compare the outcomes of mini and standard PCNL in the obese population. Methods: We retrospectively reviewed our PCNL database to identify patients who had undergone mini (Amplatz sheath size 17.5Ch) or standard (Amplatz sheath size ≥26Ch) PCNL between 2005 and 2022. First, we compared the outcomes of the two procedures in the obese (body mass index [BMI] ≥30) and nonobese (BMI

There is an ongoing need for biomarkers that could reliably predict the outcome of BC and that could guide the management of this disease. In this setting, we aimed to explore the prognostic value of the transcription factor P63 in patients with muscle-invasive bladder cancer (MIBC) having undergone radical cystectomy. The correlation between P63 expression and clinicopathological features (tumor stage, nodes involvement, patterns of muscularis propria invasion, papillary architecture, anaplasia, concomitant carcinoma in situ, lymphovascular invasion, perineural invasion, necrosis) and molecular subtyping (basal and luminal type tumors) was tested in 65 radical cystectomy specimens and matched with cancer-specific survival (CSS) and overall survival (OS). P63-negative tumors displayed significantly higher rates of pattern 2 of muscularis propria invasion (50% vs. 14%, p = 0.002) and variant histology (45% vs. 19%, p = 0.022) compared to P63-positive ones. According to the combined expression of CK5/6 and CK20 (Algorithm #1), P63-positive and P63-negative tumors were mostly basal-like and double-negative, respectively (p = 0.004). Using Algorithm #2, based on the combined expression of CK5/6 and GATA3, the vast majority of tumors were luminal overall and in each group (p = 0.003). There was no significant difference in CSS and OS between P63-positive and P63-negative tumors, but the former featured a trend towards longer OS. Though associated with pathological features harboring negative prognostic potential, P63 status as such failed to predict CSS and OS. That said, it may contribute to better molecular subtyping of MIBC.

Despite advances in sequencing, lack of standardization makes comparisons across studies challenging and hampers insights into the structure and function of microbial communities across multiple habitats on a planetary scale. Here we present a multi-omics analysis of a diverse set of 880 microbial community samples collected for the Earth Microbiome Project. We include amplicon (16S, 18S, ITS) and shotgun metagenomic sequence data, and untargeted metabolomics data (liquid chromatography-tandem mass spectrometry and gas chromatography mass spectrometry). We used standardized protocols and analytical methods to characterize microbial communities, focusing on relationships and co-occurrences of microbially related metabolites and microbial taxa across environments, thus allowing us to explore diversity at extraordinary scale. In addition to a reference database for metagenomic and metabolomic data, we provide a framework for incorporating additional studies, enabling the expansion of existing knowledge in the form of an evolving community resource. We demonstrate the utility of this database by testing the hypothesis that every microbe and metabolite is everywhere but the environment selects. Our results show that metabolite diversity exhibits turnover and nestedness related to both microbial communities and the environment, whereas the relative abundances of microbially related metabolites vary and co-occur with specific microbial consortia in a habitat-specific manner. We additionally show the power of certain chemistry, in particular terpenoids, in distinguishing Earth's environments (for example, terrestrial plant surfaces and soils, freshwater and marine animal stool), as well as that of certain microbes including Conexibacter woesei (terrestrial soils), Haloquadratum walsbyi (marine deposits) and Pantoea dispersa (terrestrial plant detritus). This Resource provides insight into the taxa and metabolites within microbial communities from diverse habitats across Earth, informing both microbial and chemical ecology, and provides a foundation and methods for multi-omics microbiome studies of hosts and the environment.

Background & Aims: In France, bulevirtide (BLV) became available in September 2019 through an early access program to treat patients with HDV. The aim of this analysis was to evaluate the efficacy and safety of BLV in patients with HIV and HDV coinfection. Methods: Patients received BLV 2 mg ± pegylated interferon-α (pegIFNα) according to the physician’s decision. The primary endpoint (per-protocol analysis) was the virological response rate at Week 48, defined as the proportion of patients with undetectable serum HDV RNA or a HDV RNA decline >2 log10 IU/ml from baseline. Results: The characteristics of the 38 patients were as follows: 28 male, mean age 47.7 years, and mean baseline HDV RNA viral load 5.7 ± 1.2 log10 IU/ml. Median HIV viral load and mean CD4 count were 32 (30–65) copies/ml and 566 ± 307/mm3, respectively. Eight patients stopped treatment before Week 48. At Week 48, 10 of 19 patients (52.6%) in the 2 mg BLV group and five of seven patients (71.4%) in the 2 mg BLV + pegIFNɑ group had reached virological response (no HDV RNA available in four patients). At Week 48, seven of 19 patients in the 2 mg BLV group and three of six patients in the 2 mg BLV + pegIFNɑ group had a combined response (virological response and normal alanine aminotransferase level). Conclusions: Adults living with HIV coinfected with HDV can be treated by BLV with a virological response in more than 50% of patients. The combination of BLV and pegIFNɑ showed a strong virological response. Impact and implications: Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p

Feature selection is indispensable in microbiome data analysis, but it can be particularly challenging as microbiome data sets are high dimensional, underdetermined, sparse and compositional. Great efforts have recently been made on developing new methods for feature selection that handle the above data characteristics, but almost all methods were evaluated based on performance of model predictions. However, little attention has been paid to address a fundamental question: how appropriate are those evaluation criteria? Most feature selection methods often control the model fit, but the ability to identify meaningful subsets of features cannot be evaluated simply based on the prediction accuracy. If tiny changes to the data would lead to large changes in the chosen feature subset, then many selected features are likely to be a data artifact rather than real biological signal. This crucial need of identifying relevant and reproducible features motivated the reproducibility evaluation criterion such as Stability, which quantifies how robust a method is to perturbations in the data. In our paper, we compare the performance of popular model prediction metrics (MSE or AUC) with proposed reproducibility criterion Stability in evaluating four widely used feature selection methods in both simulations and experimental microbiome applications with continuous or binary outcomes. We conclude that Stability is a preferred feature selection criterion over model prediction metrics because it better quantifies the reproducibility of the feature selection method.

The increasing importance of treatment of lower urinary tract symptoms (LUTS), while avoiding side effects and maintaining sexual function, has allowed for the development of minimally invasive surgical therapies (MISTs). Recently, the European Association of Urology guidelines reported a paradigm shift from the management of benign prostatic hyperplasia (BPH) to the management of nonneurogenic male LUTS. The aim of the present review was to evaluate the efficacy and safety of the most commonly used MISTs: ablative techniques such as aquablation, prostatic artery embolization, water vapor energy, and transperineal prostate laser ablation, and nonablative techniques such as prostatic urethral lift and temporarily implanted nitinol device (iTIND). MISTs are becoming a new promise, even if clinical trials with longer follow-up are still lacking. Most of them are still under investigation and, to date, only a few options have been given as a recommendation for use. They cannot be considered as standard of care and are not suitable for all patients. Advantages and disadvantages should be underlined, without forgetting our objective: treatment of LUTS and re-treatment avoidance.

Background Nurses, midwives and paramedics are the largest collective group of clinical staff in the National Health Service and have some of the highest prevalence of psychological ill-health. Existing literature tends to be profession-specific and focused on individual interventions that place responsibility for good psychological health with nurses, midwives and paramedics themselves. Aim To improve understanding of how, why and in what contexts nurses, midwives and paramedics experience work-related psychological ill-health; and determine which high-quality interventions can be implemented to minimise psychological ill-health in these professions. Methods Realist synthesis methodology consistent with realist and meta-narrative evidence syntheses: evolving standards’ reporting guidelines. Data sources First round database searching in Medical Literature Analysis and Retrieval System Online Database ALL (via Ovid), cumulative index to nursing and allied health literature database (via EBSCO) and health management information consortium database (via Ovid), was undertaken between February and March 2021, followed by supplementary searching strategies (e.g. hand searching, expert solicitation of key papers). Reverse chronology screening was applied, aimed at retaining 30 relevant papers in each profession. Round two database searches (December 2021) targeted COVID-19-specific literature and literature reviews. No date limits were applied. Results We built on seven key reports and included 75 papers in the first round (26 nursing, 26 midwifery, 23 paramedic) plus 44 expert solicitation papers, 29 literature reviews and 49 COVID-19 focused articles in the second round. Through the realist synthesis we surfaced 14 key tensions in the literature and identified five key findings, supported by 26 context mechanism and outcome configurations. The key findings identified the following: (1) interventions are fragmented, individual-focused and insufficiently recognise cumulative chronic stressors; (2) it is difficult to promote staff psychological wellness where there is a blame culture; (3) the needs of the system often override staff well-being at work (‘serve and sacrifice’); (4) there are unintended personal costs of upholding and implementing values at work; and (5) it is challenging to design, identify and implement interventions to work optimally for diverse staff groups with diverse and interacting stressors. Conclusions Our realist synthesis strongly suggests the need to improve the systemic working conditions and the working lives of nurses, midwives and paramedics to improve their psychological well-being. Individual, one-off psychological interventions are unlikely to succeed alone. Psychological ill-health is highly prevalent in these staff groups (and can be chronic and cumulative as well as acute) and should be anticipated and prepared for, indeed normalised and expected. Healthcare organisations need to (1) rebalance the working environment to enable healthcare professionals to recover and thrive; (2) invest in multi-level system approaches to promote staff psychological well-being; and use an organisational diagnostic framework, such as the NHS England and NHS Improvement Health and Wellbeing framework, to self-assess and implement a systems approach to staff well-being. Future work Future research should implement, refine and evaluate systemic interventional strategies. Interventions and evaluations should be co-designed with front-line staff and staff experts by experience, and tailored where possible to local, organisational and workforce needs. Limitations The literature was not equivalent in size and quality across the three professions and we did not carry out citation searches using hand searching and stakeholder/expert suggestions to augment our sample. Study registration This study is registered as PROSPERO CRD42020172420. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020172420. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR129528) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary The National Health Service needs healthy, motivated staff to provide high-quality patient care. Nurses, midwives and paramedics experience poor psychological health (e.g. stress/anxiety) because of pressured environments and the difficulties of healthcare work. This study planned to better understand the causes of poor psychological ill-health in nurses, midwives and paramedics and find which interventions might help and why. We analysed the literature using a method called ‘realist review’ to understand how interventions work (or not), why, and for who. We tested our findings with patients, the public, nurses, midwives and paramedics in our stakeholder group. We reviewed over 200 papers/reports and identified five main findings: (1) existing solutions (interventions) are disjointed, focus mainly on the individual (not the system) and do not recognise enduring stressors enough; (2) when there is a blame culture it is difficult to encourage staff psychological well-being; (3) the needs of the system often override staff psychological well-being at work; (4) upholding and implementing personal and professional values at work can have negative personal costs; and (5) it is difficult to design, identify and implement solutions that work well for staff groups in different circumstances with varied causes of poor psychological health. Healthcare organisations should consider: (1) changing (rebalancing) the working environment to help healthcare professionals rest, recover and thrive; (2) investing in multiple-level system (not just individual) approaches to staff psychological well-being; (3) continuing to reduce stigma; (4) ensuring the essential needs of staff are prioritised (rest-breaks/hydration/hot food) as building blocks for other solutions; (5) addressing the blame culture, assuming staff are doing their best in difficult conditions; (6) prioritising staff needs, as well as patient needs. We will provide guidance and recommendations to policy-makers and organisational leaders to improve work cultures that tackle psychological ill-health and suggest new areas for research. Scientific summary Background The National Health Service (NHS) is the biggest employer in Europe and the world’s largest employer of highly skilled professionals with 1.6 million people. The NHS needs healthy, motivated staff to provide high-quality patient care; however, in recent years increasing workload, due to societal demand for healthcare services, combined with increasing external scrutiny of their work, has been associated with a high prevalence of psychological ill-health amongst staff. Due to budget constraints and staff shortages, pressure is building in the health and care system and this is taking its toll on staff and patients. In 2018, commentators described staff as ‘running on empty’ and the COVID-19 pandemic has only added to these pressures. The 2021 NHS staff survey reports that 47% of staff felt unwell because of work-related stress in the last 12 months, 55% went into work despite not feeling well enough to perform their duties in the last 3 months, 77% often felt they had unrealistic time pressures, 73% felt there were not enough staff to enable them to do their job properly and only 68% were happy with the standard of care provided by their organisation. Nurses, midwives and paramedics are the largest collective group of clinical staff in the NHS, comprising 29.3% of the NHS workforce and over 56% of the clinical workforce. Although there is a large body of literature on interventions that offer prevention, support or treatment to nurses, midwives and paramedics experiencing poor psychological health, this literature tends to be profession-specific and focused on individual interventions that place responsibility for good psychological health with nurses, midwives and paramedics themselves. There is a need for research that is sensitive to the complexities of psychological ill-health in nurses, midwives and paramedics and provides an understanding of the causes of poor psychological health in these three groups, thus identifying what is unique to each group or setting. Through this understanding, we will be able to design context-sensitive interventions that are more likely to address the pressing workforce problems faced by the NHS. Aims The overall aim of this research was to improve understanding of how, why and in what contexts nurses, midwives and paramedics experience work-related psychological ill-health; and determine which high-quality interventions can be implemented to minimise psychological ill-health in nurses, midwives and paramedics. Our specific aims were to (A1) understand when and why nurses, midwives, and paramedics develop psychological ill-health at work and provide examples of where and how it is most experienced; (A2) identify which strategies/interventions to reduce psychological ill-health work best for these staff groups, find out how they work and in what circumstances these are most helpful; (A3) design and develop resources for NHS managers/leaders so that they can understand how work affects the psychological health of nurses, midwives and paramedics; and what they can do to improve their psychological health in the workplace. Methods A realist synthesis methodology based on the realist and meta-narrative evidence syntheses: evolving standards’ reporting guidelines was adopted to search, identify, appraise and synthesise the literature (including primary and secondary empirical research, as well as editorials, theoretical and discussion papers, and key reports) to reach an ontologically deep understanding of causes and interventions to mitigate psychological ill-health in nurses, midwives and paramedics. A stakeholder group supported the project, meeting four times over the course of the project to confirm that our developing analysis was resonating with stakeholders and to make suggestions regarding important areas for improving understanding. The realist approach allowed us to synthesise evidence on organisational and structural contexts (e.g. community or hospital work) and profession-specific working practices (e.g. types of shift work, team or lone-working) within each of these three professional groups, but also differences and similarities between the groups (e.g. by specialty, setting). By illuminating differences in organisational factors, context and working practices (service architecture), we anticipated how these might influence the development of psychological ill-health and the uptake and success or otherwise of interventions aimed at supporting psychological wellness within and between these staff groups. This feature of the approach is particularly appealing because the causes and solutions to workplace psychological ill-health are complex and multifactorial. Due to the broad mandate, and the potential for locating insights across a diversity of literature in nursing, midwifery and paramedic professions, in February–March 2021, we undertook a broad first round of database searching using Medical Literature Analysis and Retrieval System Online Database ALL (via Ovid), cumulative index to nursing and allied health literature database (via EBSCO) and health management information consortium database (via Ovid), followed by more specific supplementary searching strategies (e.g. hand searching journals, expert solicitation of key papers). Subsequent database searches in December 2021 targeted COVID-19-specific literature, as well as literature reviews, to supplement that found in the first database search. We used reverse chronology quota screening to include a manageable, recent set of papers relating to each profession, and excluded literature focussing on physical health, students and patient well-being. All included papers were read multiple times and we extracted key information, including causes and interventions. We used an appraisal journaling technique to enable the multidisciplinary team to extract key insights, built on existing knowledge of the research literature and the NHS, and use these insights to formulate context-mechanism-outcome configurations (CMOcs). Multiple rounds of analysis in consultation with stakeholders allowed us to crystallise the key findings, and generate insights into the tensions facing nurses, midwives and paramedics, as well as a range of interventions that might support their workplace psychological ill-health and wellness. Results We built on seven key reports and included 75 papers in the first round (26 nursing, 26 midwifery, 23 paramedic) plus 44 expert solicitation papers, 29 literature reviews and 49 COVID-19 focused articles in the second round. We found that overall there are more similarities than differences in causes of psychological ill-health among nurses, midwives and paramedics; and very few interventions were profession-specific. Some causes may be more prevalent or exacerbated in certain professions, or roles within professions (rather than being profession-specific). In most cases it is the service architecture (organisational factors, context and working practices), that can increase risk rather than the profession itself. Our findings suggest that staff come into health care with high ideals, strong values and the desire to do a good job every day, yet many develop psychological ill-health as a result of their work. Through the realist synthesis and by surfacing 14 key tensions in the literature, we identified five key findings, supported by 26 CMOcs. The key findings (and 14 key tensions) were as follows: Interventions are fragmented, individual-focused and insufficiently recognise cumulative chronic stressors, with tensions between the below: T1: a focus on individuals versus a focus on systemic issues T2: a focus on acute episodes of trauma versus recognising and supporting chronic cumulative stressors. It is difficult to promote staff psychological wellness where there is a blame culture, with tensions between the below: T3: a lack of collective accountability, which blames individual staff for errors, versus a team/system-based approach T4: needing to raise concerns to improve conditions and patient safety versus fitness-to-practice processes becoming an oppressive force T5: encouraging staff to speak up versus the ‘deaf effect’ response from managers and hearers. The needs of the system often override staff well-being at work (‘serve and sacrifice’), with tensions between the below: T6: a professional culture that promotes a ‘serve and sacrifice’ ethos, which persuades staff to prioritise institutional needs, versus a culture that promotes self-care T7: supporting existing staff in the context of staff shortages versus perceived coercion to fill vacant shifts beyond contracted hours T8: the lived reality of staff shortages versus the wish to deliver high-quality patient care, which can result in moral distress (MD). There are unintended personal costs of upholding and implementing values at work and tensions between the below: T9: the reality of healthcare delivery versus the taught theory and values, which can lead to guilt and moral and emotional distress T10: the benefits of staff empathy to patients (ensuring quality care) versus the harms of staff empathy to staff (increasing risk of vicarious trauma or unhealthy/negative coping strategies). T11: the excessive requirements for emotional labour inherent in healthcare practice versus the need to improve workplace psychological ill-health. It is challenging to design, identify and implement interventions to work optimally for diverse staff groups with diverse and interacting stressors, with tensions between the below: T12: making staff wellness interventions mandatory versus voluntary T13: the need for spaces to debrief with managers/leaders so they hear and can thereby offer support versus the need for peer-led spaces for debriefing T14: the need to act and offer support versus providing interventions that are ineffective because they are too soon, reactive and/or single time point. Importantly, we identified that a multi-layered systems approach to psychological well-being is required; not a one-size-fits-all approach, but individualised, where everyday events as well as acute events, are acknowledged as impacting on staff psychological wellness. A psychologically safe culture, where good visible leaders enable and support staff to speak up and take accountability is needed to change the status quo. Initiatives such as the ‘Freedom to Speak up Guardians’ are promising but need adequate resources to learn from data, change culture and respond to concerns raised. Through the analysis, we learned that healthcare delivery and staff psychological health is a balancing act, with different considerations needing to be held in productive tension, such as needs of staff and the needs of patients. Our findings showed that nurses, midwives and paramedics tend to put patients first, often putting their own needs second, which can erode well-being in the face of intense and potentially traumatic work, and (counterintuitively) actually serve to compromise high-quality patient care. We identified that healthcare staff are selected and trained to hold strong professional values and codes of conduct. Yet, compassion and empathy can come at a high price for staff in terms of their own psychological health and not being able to deliver care in line with their values can cause guilt and MD or moral injury. We also identified the significant challenges of designing and embedding complex interventions within large organisations that meet the dynamic needs of diverse groups of healthcare staff, for example, considering who, when and how interventions are delivered, not just what they are. This implementation gap needs significant future attention in practice and research. Finally, the analysis of COVID-19 literature revealed that the pandemic had significantly impacted the psychological health of staff, in an almost entirely negative way, exacerbating and accelerating staff mental distress from already difficult pre-pandemic conditions. One of the few benefits that the pandemic offered was the focus on staff health and psychological well-being and adaptation and innovation of interventions to support staff, but many interventions had unintended negative consequences. Unfortunately, while most editorials and commentaries tended to call for multi-level, systems approaches, most empirical papers focused on single interventions, perhaps because these interventions are easier to design or evaluate. In other words, the practice and research effort seem to be focusing on what is easiest currently, rather than what is likely to be most effective. Therefore, in the future, more attention needs to be paid to how the primary, secondary and tertiary levels can work together to provide a systems approach to preventing, mitigating and treating psychological ill-health in staff. There is a focus on the traumatised (tip of the iceberg), rather than the essential needs of the majority and organisational prevention is under-represented. Some individual characteristics (e.g. ethnicity, sexual orientation and/or gender identity, and disability) deserve greater focus to improve understanding of causes and interventions. Our profession-specific analysis revealed a need for targeted interventions to support particular staff groups, especially minority groups and newly qualified staff, and at specific times when they may be at greater risk of psychological ill-health. Encouragingly, we also identified many ‘informal’ interventions, perhaps developed by front-line staff to plug gaps in current provision, some of which could be formalised. The strengths of our study were the use of realist methodology that uncovered rich insights, the cross-professional analysis, which provided unique perspectives, and the expertise offered by the multidisciplinary research team, advisory group and stakeholder group. In terms of limitations, the literature was not equivalent in size and quality across the three professions, the literature synthesised was not comprehensive, although it was appropriate to the methodology, and we did not carry out citation searches since hand searching and stakeholder/expert suggestions had proved an efficient way to identify papers. Conclusions Unequivocally our realist synthesis suggests the need to improve the systemic working conditions and the working lives of nurses, midwives and paramedics to improve their psychological well-being. Individual, one-off psychological interventions are unlikely to succeed alone. Psychological ill-health is highly prevalent in these staff groups (and can be chronic and cumulative as well as acute) and should be anticipated and prepared for, indeed normalised and expected. Our research has resulted in eight implications for healthcare practice suggesting a need for healthcare organisations to the following: rebalance the working environment to enable healthcare professionals to recover and thrive; invest in multi-level systems approaches to promote staff psychological well-being; continue to reduce stigma by implementing long-term plans and investment; focus on staff essential needs in order of priority; assume that staff are doing the best job they can in difficult circumstances, to counteract a blame culture; enable the needs of staff to be prioritised, to challenge a ‘serve and sacrifice’ ethos; identify and nurture future compassionate leaders; and use an evidence-based framework to self-assess and implement a systems approach to staff well-being, for example, the NHSE/I Health and Wellbeing Framework. Future research examining psychological ill-health in nurses, midwives and paramedics should build on our synthesis and seek to implement, refine and evaluate systemic interventional strategies. We recommend that interventions and evaluations are co-designed with front-line staff and staff experts by experience and tailored where possible to local organisational and workforce needs. Future interventions and research should focus on what is most needed, rather than what is easy to implement or evaluate, and significant attention should be paid to the implementation design and process. Study registration This study is registered as PROSPERO CRD42020172420. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020172420. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR129528) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information.

Abstract Excessive toxic lipid accumulation in hepatocytes underlies the development of non-alcoholic fatty liver disease (NAFLD), phenotypically characterized by necrosis and steato-fibrosis, whose molecular mechanism is not yet fully understood. Patients with NAFLD display an imbalanced palmitic (PA) to oleic acid (OA) ratio. Moreover, increasing experimental evidence points out a relevant involvement of the exosomal content in disease progression. Aim of the study was to highlight the PA/OA imbalance within circulating exosomes, the subsequent intracellular alterations, and the impact on NALFD. Liver cells were challenged with exosomes isolated from both healthy subjects and NAFLD patients. The exosomal PA/OA ratio was artificially modified, and biological effects were evaluated. A NAFLD-derived exosomal PA/OA imbalance impacts liver cell cycle and cell viability. OA-modified NAFLD-derived exosomes restored cellular viability and proliferation, whereas the inclusion of PA into healthy subjects-derived exosomes negatively affected cell viability. Moreover, while OA reduced the phosphorylation and activation of the necroptosis marker, Receptor-interacting protein 1 (phospho-RIP-1), PA induced the opposite outcome, alongside increased levels of stress fibers, such as vimentin and fibronectin. Administration of NAFLD-derived exosomes led to increased expression of Elongase 6 (ELOVL6), Stearoyl-CoA desaturase 1 (SCD1), Tumor necrosis factor α (TNF-α), Mixed-lineage-kinase-domain-like-protein (MLKL) and RIP-1 in the hepatocytes, comparable to mRNA levels in the hepatocytes of NAFLD patients reported in the Gene Expression Omnibus (GEO) database. Genetic and pharmacological abrogation of ELOVL6 elicited a reduced expression of downstream molecules TNF-α, phospho-RIP-1, and phospho-MLKL upon administration of NAFLD-derived exosomes. Lastly, mice fed with high-fat diet exhibited higher phospho-RIP-1 than mice fed with control diet. Targeting the Elongase 6–RIP-1 signaling pathway offers a novel therapeutic approach for the treatment of the NALFD-induced exosomal PA/OA imbalance.

Introduction: Urinary incontinence is a prevalent condition, especially in elderly men, with stress urinary incontinence (SUI) being a common cause after radical prostatectomy. The artificial urinary sphincter (AUS), particularly the AMS 800™ device, has been the gold-standard treatment for moderate-severe male SUI for decades. Despite some technical advancements and alternative devices like ZSI-375, Victo, and BR-SL-AS 904 being introduced, there is limited literature comparing their effectiveness to the AMS 800™. Methods: This literature review compares the AMS 800™ to the newer technologies in the management of SUI. We reviewed the current literature on urinary sphincter implant in male stress incontinence, including AMS 800™, ZSI-375, Victo, and BR-SL-AS 904. Findings: The AMS 800™ is a sophisticated system consisting of an inflatable cuff, a pressure-regulating balloon, and a control pump. Studies show continence rates ranging from 61% to 100% with AMS 800™ implants, with low infection rates and significant improvement in patients’ quality of life. The ZSI-375 sphincter is a unique single-piece cuff without an abdominal reservoir, simplifying implantation. Preliminary data show a social continence rate of 73% at six months, with lower complication rates than the AMS 800™. The VICTO® device offers adjustable pressure and a stress relief mechanism, providing conditional occlusion of the urethra. Early studies report a satisfaction rate of up to 94.2% and a complication rate of 17.6%. BR-SL-AS 904 is a newly proposed urinary sphincter, but due to the limited number of cases and a single study, its efficacy and complication rates remain uncertain. Conclusions: Overall, AMS 800™ remains the gold-standard treatment for SUI after radical prostatectomy. Alternative devices like ZSI-375 and VICTO® show promising results, but longer studies and more data are needed to establish their effectiveness and safety compared with the AMS 800™. Further research and ongoing monitoring are essential to address mechanical issues associated with AUS implants.