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BackgroundStress and burnout are pervasive among physicians. Academic physicians who are female and physicians who are under-represented in medicine (URM) face inequities in the workplace and beyond. Understanding their experiences is crucial for workforce sustainability and diversity, especially given the disproportionate effects on these individuals and overall workforce capacity.ObjectiveTo qualitatively explore the perspectives of academic female and URM physicians and identify key themes affecting their careers and well-being.DesignSemi-structured interviews were conducted with 30 physicians at an urban academic health system. Interviews were audio-recorded, transcribed and thematically analysed using a general inductive approach. Interview guides were informed by prior literature and constructs.InterventionNone.Setting and participantsFemale and URM physicians from a large, academic medical centre were recruited via email. Participants self-reported demographic information, including sex, race, ethnicity and tenure.Outcomes and measuresThe primary outcomes encompassed the main themes identified through the analysis of interviews with female and URM physicians regarding their perspectives on well-being, mental health and academic medicine.Results30 female or URM physicians were interviewed (27 (90%) female; 14 (47%) black, Asian or multi-racial). Thematic analysis revealed four key themes: physician identity (URM, female, family), well-being in the workplace (emotional health, staffing burden, non-clinical responsibilities), barriers to accessing well-being resources (workplace environment, culture, overgeneralisation) and facilitators to well-being (physician camaraderie, leadership support). Physicians discussed how their identities influenced their experiences of well-being. They highlighted emotional health challenges, staffing burdens and administrative tasks contributing to stress. Barriers to accessing resources included workplace culture and broad-based interventions, while supportive leadership and camaraderie were identified as facilitators of access.ConclusionFemale and URM physicians face systemic challenges impacting their well-being and careers. These findings underscore the need to address systemic changes and specifically design programmes focused on promoting the well-being and inclusivity of female and URM physicians. Tailored interventions to these individuals, supportive leadership structures and collaborative working cultures are crucial for addressing these issues and sustaining a diverse physician workforce.

Importance Health care workers (HCWs) face significant mental health challenges when delivering care and over the span of their careers. Despite growing recognition of these issues, barriers such as stigma, structural limitations, and individual obstacles continue to impede progress in supporting HCWs mental health needs. Digital mental health platforms continue to expand in health systems as they offer novel approaches to address these gaps, but more evidence is needed to understand their reception among HCWs. Objective To examine the perceptions of HCWs regarding their mental health, explore barriers and facilitators to accessing mental health care, and assess their experiences with digital mental health interventions within the context of the pandemic. Design A qualitative study using semi-structured interviews with HCWs who participated in a prior randomized controlled trial (RCT) assessing the impact of a digital mental health platform on anxiety and depression. Setting A large, urban, academic health system. Participants A purposive sample of 64 HCWs, including physicians, nurses, technicians, administrative staff, and social workers, was recruited. Participants were selected from the upper and lower quartiles of anxiety and depression scores from the parent RCT to capture a range of mental health symptomatology. Outcomes and measures The study aimed to identify HCWs’ attitudes toward mental health care, barriers to utilizing professional resources, and their experiences with the digital mental health platform at the local institution. A thematic content analysis was used to analyze the interview data. Results Five major themes were identified: (1) the evolving mental health challenges during and after the pandemic, (2) individual barriers to accessing care, such as personal coping strategies and familial responsibilities, (3) structural barriers like workload and limited access to mental health clinicians, (4) experiences with digital mental health interventions, including text message-based assessments, and (5) recommendations for future digital health strategies to improve access and reduce stigma. Conclusion Digital mental health interventions provide a promising avenue to support HCWs by reducing stigma and improving access to mental health resources and clinicians. However, personalized and system-level changes are necessary to address the ongoing mental health challenges faced by the workforce.

The well-being of emergency medicine (EM) physicians significantly impacts health care systems, and patients. Understanding the interplay of factors contributing to EM physicians' mental health issues and burnout is essential for developing targeted support mechanisms. To investigate the individual, environmental, and structural factors influencing the mental health and burnout experienced by EM physicians, thereby informing potential strategies for intervention and support. A qualitative study using recorded and de-identified semi-structured interviews. Twenty EM residents and faculty physicians at a large urban academic health system. Interviews followed a semi-structured interview guide focusing on clinical work experiences and factors influencing well-being and mental health. Thematic analysis was applied. The study outlined underlying themes from the participants' responses, utilizing a general inductive approach. Four primary themes emerged with subthemes: (1) Individual Coping - detailing strategies for managing stress during and outside shifts, including long-term adjustments; (2) Interpersonal Factors - examining the interactions with patients, peers, and family; (3) Environmental Factors - highlighting the challenges posed by patient boarding and workload; and (4) Systemic Issues - addressing stigma in mental health, confidentiality, and the strain from public health crises. The study underscores the complex challenges impacting EM physicians' mental health and career longevity. It highlights the need for comprehensive interventions that move beyond resilience training and build upon interpersonal support and systemic health system reforms. Fostering a culture of workplace safety and implementing targeted resources to manage capacity strain are essential approaches for supporting the well-being of EM physicians.

Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.

Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Aβ expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Aβ peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD.

Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice. Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals.

Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A /p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5 /XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A /p21 expression and increased ERCC5 /XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174. Synopsis We found that the DNA damaging RNA Pol‐II inhibitor lurbinectedin strongly synergizes with the ATR inhibitor berzosertib in SCLC. This synergy is dependent on berzosertib allowing for continued cell cycle progression in the presence of lurbinectedin induced DNA damage. An unbiased screen revealed maximal synergy between lurbinectedin and the ATR inhibitor berzosertib in SCLC cells. Berzosertib augments lurbinectedin‐induced DNA damage while inhibiting cell cycle checkpoints leading to mitotic catastrophe. Synergy is reduced with high p21 expression as p21 causes G1 arrest. Synergy is increased with high XPG expression as lurbinectedin induced DNA damage is XPG dependent. The recalcitrant non‐neuroendocrine SCLC subtype has high XPG expression and low p21 expression leading to a unique vulnerability to the lurbinectedin‐berzosertib combination, we are currently exploring this combination in the clinic. Graphical Abstract We found that the DNA damaging RNA Pol‐II inhibitor lurbinectedin strongly synergizes with the ATR inhibitor berzosertib in small cell lung cancer. This synergy is dependent on berzosertib allowing for continued cell cycle progression in the presence of lurbinectedin induced DNA damage.

Maternal folic acid (FA) supplementation prior to and during gestation is recommended for the prevention of neural tube closure defects in the developing embryo. Prior studies, however, suggested that excessive FA supplementation during gestation can be associated with toxic effects on the developing organism. Here, we address whether maternal dietary folic acid supplementation at 40 mg/kg chow (FD), restricted to a period prior to conception, affects neurobehavioural development in the offspring generation. Detailed behavioural analyses showed reversal learning impairments in the Morris water maze in offspring derived from dams exposed to FD prior to conceiving. Furthermore, offspring of FD dams showed minor and transient gene expression differences relative to controls. Our data suggest that temporary exposure of female germ cells to FD is sufficient to cause impaired cognitive flexibility in the subsequent generation.

IntroductionSubependymomas are benign intraventricular tumours that most often occur asymptomatically and are found incidentally on autopsy. Symptomatic examples requiring surgical intervention are exceedingly rare.Case presentationA 55-year-old man with no history of neurological symptoms presented with multiple episodes of loss of consciousness and increasing headaches. MRI revealed a lobulated intraventricular mass centred at the right Foramen of Monro. Obstructive hydrocephalus with localised midline shift and a second lesion were noted. Right frontal craniotomy with total removal via transcortical resection was performed.DiscussionSymptomatic subependymomas generally present with signs of hydrocephalus due to obstruction of cerebrospinal fluid pathways. There is only one other reported case of multifocal subependymomas in a symptomatic patient. An example of multiple supratentorial subependymomas causing obstructive hydrocephalus has not been previously reported.ConclusionsMultiple subependymomas are rare. Judicious surgical management with full excision led to symptomatic improvement in our patient.

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we applied spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting an exceptionally poor prognosis. Together, our work provides the first comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.Competing Interest StatementThe authors have declared no competing interest.