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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 professional quality of life of psychological therapy practitioners can be conceptualised within a compassion satisfaction and compassion fatigue framework. Compassion fatigue is purportedly separated into two components of burnout and secondary traumatic stress. Compassion fatigue can have detrimental impacts on therapy practitioners, organisations and patient care, whereas compassion satisfaction is associated with positive outcomes. Consequently, there is a need to explore factors that mitigate compassion fatigue and promote compassion satisfaction. This is particularly important for newly qualified psychological therapists who are reportedly at risk of compassion fatigue during the transition from pre- to post-qualified practice. Psychological flexibility is the central tenet within Acceptance and Commitment Therapy (ACT) and is purportedly a key resilience process that is associated with higher levels of compassion satisfaction and lower compassion fatigue for healthcare professionals generally. However, the evidence base is dominated by cross-sectional research and there is a need to explore these associations over a longitudinal trajectory for healthcare workers and specifically newly qualified psychological therapy practitioners. Therefore, this study aimed to examine whether psychological flexibility prospectively predicts levels of compassion fatigue (inclusive of burnout and secondary traumatic stress) and compassion satisfaction in newly qualified psychological therapy practitioners. The study employed a prospective cohort longitudinal design whereby fifty-six trainee psychological therapy practitioners (trainee Clinical Psychologists and Cognitive Behavioural Therapists) were recruited to complete an online survey of baseline measures pre-qualification. Participants completed the survey at two further timepoints post-qualification and data collection was completed over eight-months. The survey comprised a demographic questionnaire and measures of psychological flexibility, professional quality of life and wellbeing related to workplace factors. Multilevel modelling was used to predict levels of compassion satisfaction, burnout and secondary traumatic stress, based on baseline levels of psychological flexibility. The results revealed that higher prospective levels of psychological flexibility predicted higher levels of compassion satisfaction and lower levels of burnout and secondary traumatic stress across all timepoints. Further analysis also revealed that psychological flexibility as a predictor exhibited causal predominance over professional quality of life as a predictor. However, contrary to theoretical suggestions regarding the buffering role of psychological flexibility, in this instance where time and workplace factors related to workplace wellbeing was found to have a significant detrimental effect on some professional quality of life outcomes, psychological flexibility did not moderate these effects. Therefore, the study confirmed existing cross-sectional associations between psychological flexibility and professional quality of life for healthcare practitioners and goes further to provide insights regarding psychological flexibility as a prospective predictor of professional quality of life. Given existing evidence from interventional studies with alternative healthcare worker samples, it could be hypothesised that pre-qualification intervention to improve psychological flexibility would lead to positive post-qualification professional quality of life outcomes for therapy practitioners. This may potentially carry positive implications for practitioners, organisations and patient care. It would be beneficial for future researchers to confirm the aforementioned hypothesis through interventional studies. Furthermore, it may be possible to observe the buffering role of psychological flexibility should future studies impose a longer time series. Finally, it is recommended that further longitudinal research is undertaken to examine similar predictive associations with other healthcare worker samples considering the dominance of cross-sectional research.

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins. Mitofusins regulate mitochondrial fusion. Here the authors identify small molecules that activate or inhibit mitofusins’ activity and modulate mitochondrial fusion and functionality. Inhibition of mitochondrial fusion promotes minority MOMP, caspase-3/7 activation, and DNA damage.

Antimicrobial resistance (AMR) of infectious agents is a growing concern for public health organizations. Given the complexity of this issue and how widespread the problem has become, resources are often insufficient to address all concerns, thus prioritization of AMR pathogens is essential for the optimal allocation of risk management attention. Since the epidemiology of AMR pathogens differs between countries, country-specific assessments are important for the determination of national priorities. To develop a systematic and transparent approach to AMR risk prioritization in Canada. Relevant AMR pathogens in Canada were selected through a transparent multi-step consensus process (n=32). Each pathogen was assessed using ten criteria: incidence, mortality, case-fatality, communicability, treatability, clinical impact, public/political attention, ten-year projection of incidence, economic impact, and preventability. For each pathogen, each criterion was assigned a numerical score of 0, 1, or 2, and multiplied by criteria-specific weighting determined through researcher consensus of importance. The scores for each AMR pathogen were summed and ranked by total score, where a higher score indicated greater importance. A sensitivity analysis was conducted to determine the effects of changing the criteria-specific weights. The AMR pathogen with the highest total weighted score was extended spectrum B-lactamase-producing (ESBL) Enterobacteriaceae (score=77). When grouped by percentile, ESBL Enterobacteriaceae, Clostridium difficile, carbapenem-resistant Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus were in the 80-100th percentile. This assessment provides useful information for prioritising public health strategies regarding AMR resistance at the national level in Canada. As the AMR environment and challenges change over time and space, this systematic and transparent approach can be adapted for use by other stakeholders domestically and internationally. Given the complexity of influences, resource availability and multiple stakeholders, regular consideration of AMR activities in the public health realm is essential for appropriate and responsible prioritisation of risk management that optimises the health and security of the population.

is an emerging fungal pathogen causing outbreaks in healthcare facilities. Five distinctive genomic clades exhibit clade-unique characteristics, highlighting the importance of real-time genomic surveillance and incorporating genotypic information to inform infection prevention practices and treatment algorithms. Both active and passive surveillance were used to screen hospitalized patients. polymerase chain reaction (PCR) assay on inguinal-axillary swabs was performed on high-risk patients upon admission. All clinical yeast isolates were identified to the species level. isolates were characterized by both phenotypic antifungal susceptibility tests and whole-genome sequencing. From late 2019 to early 2022, we identified 45 patients with . Most had a tracheostomy or were from a facility with a known outbreak. Moreover, 7 patients (15%) were only identified through passive surveillance. Also, 8 (18%) of the patients had a history of severe COVID-19. The overall mortality was 18%. Invasive infections were identified in 13 patients (29%), 9 (69%) of whom had bloodstream infections. Patients with invasive infection were more likely to have a central line. All isolates were resistant to fluconazole but susceptible to echinocandins. Genomic analysis showed that 1 dominant clade-III lineage is circulating in Los Angeles, with very limited intrahost and interhost genetic diversity. We have demonstrated that a robust surveillance program can be established using both active and passive surveillance, with multidisciplinary efforts involving the microbiology laboratory and the hospital epidemiology team. In Los Angeles County, strains are highly related and echinocandins should be used for empiric therapy.

Doxorubicin remains an essential component of many cancer regimens, but its use is limited by lethal cardiomyopathy, which has been difficult to target, owing to pleiotropic mechanisms leading to apoptotic and necrotic cardiac cell death. Here we show that BAX is rate-limiting in doxorubicin-induced cardiomyopathy and identify a small-molecule BAX inhibitor that blocks both apoptosis and necrosis to prevent this syndrome. By allosterically inhibiting BAX conformational activation, this compound blocks BAX translocation to mitochondria, thereby abrogating both forms of cell death. When co-administered with doxorubicin, this BAX inhibitor prevents cardiomyopathy in zebrafish and mice. Notably, cardioprotection does not compromise the efficacy of doxorubicin in reducing leukemia or breast cancer burden in vivo, primarily due to increased priming of mitochondrial death mechanisms and higher BAX levels in cancer cells. This study identifies BAX as an actionable target for doxorubicin-induced cardiomyopathy and provides a prototype small-molecule therapeutic.

Although many components of the cell division machinery in bacteria have been identified 1 , 2 , the mechanisms by which they work together to divide the cell remain poorly understood. Key among these components is the tubulin FtsZ, which forms a Z ring at the midcell. FtsZ recruits the other cell division proteins, collectively called the divisome, and the Z ring constricts as the cell divides. We applied live-cell single-molecule imaging to describe the dynamics of the divisome in detail, and to evaluate the individual roles of FtsZ-binding proteins (ZBPs), specifically FtsA and the ZBPs EzrA, SepF and ZapA, in cytokinesis. We show that the divisome comprises two subcomplexes that move differently: stationary ZBPs that transiently bind to treadmilling FtsZ filaments, and a moving complex that includes cell wall synthases. Our imaging analyses reveal that ZBPs bundle FtsZ filaments together and condense them into Z rings, and that this condensation is necessary for cytokinesis. Live-cell single-molecule imaging of different Bacillus subtilis divisome proteins that interact with FtsZ (such as FtsA, EzrA, SepF and ZapA) reveals different subcomplexes with distinct motility: stationary FtsZ-binding proteins that bind transiently to treadmilling FtsZ filaments, and moving complexes containing cell wall synthases.

Mental health (MH) issues are the leading cause of mortality for young people, highlighting the importance of timely, high-quality, and affordable care. However, recent trends show a deceleration in the growth of youth mental health (YMH) services capacity in Australia. Meanwhile, digital interventions hold significant potential to sustain and enhance YMH outcomes. This study aimed to evaluate (1) the comparative impact of different services capacity growth trajectories on YMH outcomes and (2) whether digital interventions can offset rising demand and declining workforce capacity, to offer insights into strategic resource allocation for sustained improvements. Participatory system dynamics modeling was used to investigate the impact of MH services capacity growth trajectories and digital interventions on YMH outcomes, with simulation results projected for 2025-2035. The study focused on individuals aged 15-24 years from a culturally diverse, rapidly expanding urban population in Australia. Outcomes assessed included years lived with psychological distress and disorders, MH-related emergency department presentations, and self-harm hospitalizations. Among the services modeled, doubling the growth rates for specialized MH services had the greatest impact (8.4% reduction in cumulative years lived with symptomatic mental disorder). Doubling the growth rates for specialized MH service, headspace (headspace National Youth Mental Health Foundation Ltd), and referrals to online services, together, could significantly enhance YMH outcomes. Compared to baseline, this strategic investment approach is projected to reduce cumulative years spent with symptomatic mental disorders, cumulative MH-related emergency department presentations, and cumulative self-harm hospitalizations by 14%, 6.4%, and 4.1%, respectively, from 2025 to 2035. Digital interventions alone produced comparable impacts to specialized services, but critically, could not prevent worsening outcomes when specialized services experienced degrowth. Combining digital interventions with expansion of specialized services yielded best outcomes with reductions of 15%, 5.1%, and 4.4% in these indicators, respectively. The findings emphasize digital technologies as an effective interim and long-term solution to mitigate the slow and uncertain growth in the specialized MH workforce. However, simulation results showed that achieving sustained long-term improvements necessitates concurrent investment in expanding the specialized MH workforce, as digital interventions alone cannot compensate for degradation in specialized services capacity. A strategic combined approach offers the most effective pathway to improving YMH outcomes.

The effects of landscape fragmentation on nest predation and brood parasitism, the two primary causes of avian reproductive failure, have been difficult to generalize across landscapes, yet few studies have clearly considered the context and spatial scale of fragmentation. Working in two river systems fragmented by agricultural and rural-housing development, we tracked nesting success and brood parasitism in >2500 bird nests in 38 patches of deciduous riparian woodland. Patches on both river systems were embedded in one of two local contexts (buffered from agriculture by coniferous forest, or adjacent to agriculture), but the abundance of agriculture and human habitation within 1 km of each patch was highly variable. We examined evidence for three models of landscape effects on nest predation based on (1) the relative importance of generalist agricultural nest predators, (2) predators associated with the natural habitats typically removed by agricultural development, or (3) an additive combination of these two predator communities. We found strong support for an additive predation model in which landscape features affect nest predation differently at different spatial scales. Riparian habitat with forest buffers had higher nest predation rates than sites adjacent to agriculture, but nest predation also increased with increasing agriculture in the larger landscape surrounding each site. These results suggest that predators living in remnant woodland buffers, as well as generalist nest predators associated with agriculture, affect nest predation rates, but they appear to respond at different spatial scales. Brood parasitism, in contrast, was unrelated to agricultural abundance on the landscape, but showed a strong nonlinear relationship with farm and house density, indicating a critical point at which increased human habitat causes increased brood parasitism. Accurate predictions regarding landscape effects on nest predation and brood parasitism will require an increased appreciation of the multiple scales at which landscape components influence predator and parasite behavior.

E-cigarettes (electronic cigarettes) have been the most used tobacco product among US youth since 2014, reaching a plateau during the COVID-19 pandemic. Youth e-cigarette use is associated with negative health consequences such as impaired cognitive functioning. For many, the COVID-19 pandemic altered social interactions, harm perceptions, and product availability. This changed the frequency and locations in which youth use e-cigarettes. To better understand youth e-cigarette use, we need more information on factors that can alter e-cigarette use, specifically, how the pandemic changed e-cigarette use among youth. In 2020-2021, we conducted online, individual interviews with 19 youth (aged 13-17) e-cigarette users living in the US to explore how COVID-19 impacted their e-cigarette use. Youth described a progression of e-cigarette use from initial experimentation, regular social use, and ultimately to nicotine addiction demonstrated by individual use in isolation. Many youth initiated e-cigarette use due to influences by friends or family members. Youth discussed progression to social use, with social interactions as an important reason for use and an avenue for expanding one’s knowledge of e-cigarettes. After a period of time, youth began to recognize that the social interactions mattered less, suggesting to them that they had become addicted. This realization became more apparent during COVID-19, which changed how youth used e-cigarettes, especially around where use was occurring, health concerns, and use behavior and frequency. In our interviews, youth trajectory began with an initiation with family and friends, progressed to social use, and eventually developed to addiction, at which point social use was no longer the primary motivation for e-cigarette use. Understanding the trajectory of e-cigarette use will allow for effective interventions that reduce harm to youth from e-cigarette use.