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Sparing the periprostatic neurovascular bundles during robot-assisted radical prostatectomy (RARP) improves postoperative erectile function and early urinary continence recovery. The NeuroSAFE technique, a standardised frozen section analysis, enables accurate real-time detection of positive surgical margins during nerve-sparing, increasing the likelihood of successful nerve preservation. However, the impact of the technique on patient outcomes remains uncertain. We aimed to assess the effect of NeuroSAFE-guided RARP versus standard RARP on erectile function and urinary continence. NeuroSAFE PROOF was a multicentre, patient-blinded, randomised, controlled phase 3 trial done at five National Health Service hospitals in the UK. Key eligibility criteria were a diagnosis of non-metastatic prostate cancer deemed suitable to undergo RARP, good erectile function (defined as a score of ≥22 on the first 5 items of the International Index of Erectile Function [IIEF]) without medical erectile function assistance, and no previous prostate cancer treatment. No age limits were applied. Participants were randomly assigned (1:1) to standard RARP or NeuroSAFE-guided RARP using block randomisation, stratified by site. Masking of participants to allocation was maintained throughout, but patients were informed of their nerve-sparing status after the operation. Due to the nature of the intervention, operating teams were aware of treatment group. Nerve-sparing was guided by a preoperative plan in the standard RARP group and by intraoperative NeuroSAFE assessment in the NeuroSAFE group. The primary outcome was erectile function at 12 months, assessed using the IIEF-5 score, in the modified intention-to-treat population, which included all randomly assigned participants who had surgery. Secondary endpoints were urinary continence scores at 3 and 6 months, evaluated using the International Consultation on Incontinence Questionnaire (ICIQ), and the erectile function domain of the IIEF (IIEF-6) scores at 12 months. The trial is registered at ClinicalTrials.gov, NCT03317990. Between Jan 6, 2019, and Dec 6, 2022, 407 patients were recruited, of whom 381 had surgery (190 participants in the NeuroSAFE group and 191 participants in the standard RARP group), and were included in the modified intention-to-treat population. Data for the primary outcome (IIEF-5 score at 12 months) were available for 344 participants (173 in the NeuroSAFE group and 171 participants in the standard RARP group). Median follow-up was 12·3 months (IQR 11·8–12·7). At 12 months, the mean IIEF-5 score was 12·7 (SD 8·0) in the NeuroSAFE group versus 9·7 (7·5) in the standard RARP group (adjusted mean difference 3·18 [95% CI 1·62 to 4·75]; p<0·0001). At 3 months, the ICIQ score was significantly lower in the NeuroSAFE group than the standard RARP group (adjusted mean difference –1·41 [95% CI –2·42 to –0·41]; p=0·006). At 6 months, no significant difference in ICIQ score was observed between groups (adjusted mean difference –0·37 [95% CI –1·35 to 0·62]; p=0·46). At 12 months, the mean IIEF-6 score was higher in the NeuroSAFE group than in the standard RARP group (15·3 [SD 9·7] vs 11·5 [SD 9·0]; adjusted mean difference 3·92 [95% CI 2·01 to 5·83]; p<0·0001). Serious adverse events occurred in six (3%) of 190 patients in the NeuroSAFE group, and and in five (3%) of 191 patients in the standard RARP group. All adverse events were postoperative complications; no serious adverse events or deaths were attributed to the study intervention. The use of NeuroSAFE to guide nerve-sparing during RARP improves patient-reported IIEF-5 scores at 12 months and short-term urinary continence. The erectile function benefit is enhanced in patients who would not otherwise have undergone bilateral nerve-sparing by standard practice. National Institute of Healthcare Research, JP Moulton Charitable Foundation, UCLH Charity, St Peters Trust, and Rosetrees Trust.

The dynamics and adaptive capacity of social-ecological systems are heavily contingent on system structure, which is established through geography, institutions, interactions, and movement. Contrasting views of system structure, as hierarchies and single-level networks respectively, have tended to emphasize the role of either top-down or lateral (peer-to-peer) connections. The concept of a heterarchy aims to capture both top-down and lateral connections on orthogonal axes and has been proposed as a way of unifying alternative approaches to measuring structure, but it has not been fully operationalized for quantifying and comparing system structures. We developed a simple approach to consistently quantifying heterarchical structure across different kinds of networks. We first calculated suitable metrics, including modularity and a hierarchy score, for a wide range of both simulated and real-world systems including food webs, biological, infrastructure, and social networks. Metrics were corrected for differences in size and magnitude. The results were then visualized as a heterarchy matrix. We compared the angle (degrees) and Euclidian distance of each simulated and real-world network from the center of the matrix between network groups. All networks showed distinct placement on the heterarchy matrix. Relative to one another, food webs were laterally polycentric, social networks were mainly pyramidal and coordinated polycentric, and biological networks were pyramidal and laterally polycentric. Our test of concept, although relatively basic, provides strong evidence that system structure cannot be fully understood as purely laterally connected or purely hierarchical. System resilience requires a trade-off between modularity, aiding redundancy and collaboration; and hierarchy, aiding efficient action. Our approach has the potential to provide a robust, accessible methodology to quantify system structure that allows for universal contextualization, a key step within fields such as resilience and sustainability science.

Background Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations’ Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. Main body Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. Conclusion These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that – in any context – a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.

We conducted a controlled before-and-after trial to evaluate the impact of an onsite urban sanitation intervention on the prevalence of enteric infection, soil transmitted helminth re-infection, and diarrhea among children in Maputo, Mozambique. A non-governmental organization replaced existing poor-quality latrines with pour-flush toilets with septic tanks serving household clusters. We enrolled children aged 1–48 months at baseline and measured outcomes before and 12 and 24 months after the intervention, with concurrent measurement among children in a comparable control arm. Despite nearly exclusive use, we found no evidence that intervention affected the prevalence of any measured outcome after 12 or 24 months of exposure. Among children born into study sites after intervention, we observed a reduced prevalence of Trichuris and Shigella infection relative to the same age group at baseline (<2 years old). Protection from birth may be important to reduce exposure to and infection with enteric pathogens in this setting.

Flow supports psychological wellbeing. But where do optimal experiences of flow occur? Existing studies of flow activities are increasingly outdated and don't account for changing patterns of time use. Further, the physical environments where flow experiences happen have not been empirically examined. This research explores flow activities and environments within a UK-based (Study 1, n = 4000) and international (Study 2, n = 839) sample. Commonly reported flow activities were largely consistent with existing research, with activities such as work, sport, reading, arts, and contemplative practices being frequently mentioned. Flow environments were varied, but the home and nature were prominent themes. Whilst certain flow activities tended to be reported alongside certain flow environments (e.g. sports outdoors and computer in residential spaces), others (e.g. art, music, reading) were not associated with specific locations. Together, findings consolidate understandings of the common sites of flow and provide preliminary insights into the role physical environments might play in supporting flow.

Safely managed drinking water is critical to prevent diarrhoeal diseases, including cholera, but evidence on the effectiveness of piped water supply in reducing these diseases in low-income and complex emergency settings remains scarce. We conducted a trial of water supply infrastructure improvements in Uvira (DRC). Our primary objective was to estimate the relationship between a composite index of water service quality and the monthly number of suspected cholera cases admitted to treatment facilities and, as a secondary analysis, the number of cases confirmed by rapid diagnostic tests. Other exposures included the quantity of supplied water and service continuity. We used Poisson generalised linear models with generalised estimating equations to estimate incidence rate ratios. Associations between suspected cholera incidence and water service quality (RR 0·86, 95% CI 0·73-1·01), quantity (RR 0·80, 95% CI 0·62-1·02) and continuity (RR 0·81, 95% CI 0·77-0·86) were estimated. The magnitudes of the associations were similar between confirmed cholera incidence and water service quality (RR 0·84, 95% CI 0·73-0·97), quantity (RR 0·76, 95% CI 0·61-0·94) and continuity (RR 0·75, 95% CI 0·69-0·81). These results suggest that an additional 5 L/user/day or 1.2 hour per day of water production could reduce confirmed cholera by 24% (95% CI 6-39%) and 25% (95% CI 19-31%), respectively. Ensuring a sufficient and continuous piped water supply may substantially reduce the burden of endemic cholera and diarrhoeal diseases but evaluating this rigorously is challenging. Pragmatic strategies are needed for public health research on complex interventions in protracted emergency settings. The trial is registered in ClinicalTrials.gov ID NCT02928341. https://classic.clinicaltrials.gov/ct2/show/NCT02928341.

ObjectivesThe aim of this study was to test whether household environmental hygiene and behavioural conditions moderated associations between diarrhoea and enteric pathogen detection in infants 5 months of age in Kenya and pathogen sources, including latrine access, domestic animal co-habitation and public food sources.DesignCross-sectional study utilising enrolment survey data of households participating in the Safe Start cluster-randomised controlled trial .SettingKisumu, Kenya.ParticipantsA total of 898 caregivers with 5-month (22 week ± 1 week) aged infants were enrolled in the study and completed the enrolment survey.Primary and secondary outcome measuresOutcomes were (1) caregiver-reported 7-day diarrhoea prevalence and (2) count of types of enteric viruses, bacteria and parasites in infant stool. Exposures and effect modifiers included water access and treatment, cohabitation with domestic animals, sanitation access, handwashing practices, supplemental feeding, access to refrigeration and flooring.ResultsReported handwashing after handling animals (adjusted odds ratio (aOR)=0.20; 95% CI=0.06 to 0.50) and before eating (aOR=0.44; 95% CI=0.26 to 0.73) were strongly associated with lower risk of caregiver-reported diarrhoea, while cohabitation with animals (aOR=1.54; 95% CI=1.01 to 2.34) living in a household with vinyl-covered dirt floors (aOR=0.60; 95% CI=0.45 to 0.87) were strongly associated with pathogen codetection in infants. Caregiver handwashing after child (p=0.02) or self-defecation (p=0.03) moderated the relationship between shared sanitation access and infant exposure to pathogens, specifically private latrine access was protective against pathogen exposure of infants in households, where caregivers washed hands after defecation. In the absence of handwashing, access to private sanitation posed no benefits over shared latrines for protecting infants from exposure.ConclusionOur evidence highlights eliminating animal cohabitation and improving flooring, postdefecation and food-related handwashing, and safety and use of cow milk sources as interventions to prevent enteric pathogen exposure of young infants in Kenya.Trial registration numberNCT03468114

Monocyte-derived alveolar macrophages drive lung injury and fibrosis in murine models and are associated with pulmonary fibrosis in humans. Monocyte-derived alveolar macrophages have been suggested to develop a phenotype that promotes lung repair as injury resolves. We compared single-cell and cytokine profiling of the alveolar space in a cohort of 35 patients with post-acute sequelae of COVID-19 who had persistent respiratory symptoms and abnormalities on a computed tomography scan of the chest that subsequently improved or progressed. The abundance of monocyte-derived alveolar macrophages, their gene expression programs, and the level of the monocyte chemokine CCL2 in bronchoalveolar lavage fluid positively associated with the severity of radiographic fibrosis. Monocyte-derived alveolar macrophages from patients with resolving or progressive fibrosis expressed the same set of profibrotic genes. Our findings argue against a distinct reparative phenotype in monocyte-derived alveolar macrophages, highlighting their utility as a biomarker of failed lung repair and a potential target for therapy. Misharin, Sala and colleagues show that in patients with lung fibrosis after COVID-19, monocyte-derived alveolar macrophages activate an inflammatory and fibrotic program that was similar in patients with either resolving or progressing fibrosis.

[...]interventions often demand a large investment of time and financial resources from those least able to bear the costs, and underestimate or overlook the structural challenges faced by people living in poverty. [...]the true costs of these so-called low-cost approaches are often born by women as the de-facto water managers or caregivers who are tasked with additional responsibilities, reinforcing gender inequalities.14 International attention focuses almost exclusively on low-income and middle-income countries (LMICs), suggesting WASH is no longer a truly global concern. [...]the cost of achieving universal access to at least safely managed WASH services will be immense but so too are the potential benefits. [...]the Commission will make concrete recommendations for reform focused on the establishment of national systems that are capable of both professionalised delivery of WASH services for all and responding to key challenges such as climate change and rapid urbanisation.