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Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Abstract Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep‐rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14–15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.

Summary The American Society of Clinical Psychopharmacology convened a 45-member international expert task force to identify circumstances supporting the deprescribing of core psychotropic medications for major depressive disorder (MDD) and bipolar disorders. Three Delphi survey rounds plus a selective literature review identified points of consensus (predefined as ≥75% agreement) about when antidepressant, antipsychotic, mood stabiliser and sedative-hypnotic deprescribing is warranted. Twenty out of 32 statements (63%) achieved consensus across seven thematic areas. In MDD, panellists favoured discontinuing antidepressants when mechanisms of action are duplicative, adequate trials produce ≤25% improvement or loss of prior efficacy cannot be regained through dose increases or augmentations. Indefinite antidepressant maintenance in MDD was favoured after three or more lifetime episodes. In bipolar disorder, antidepressant deprescribing was favoured in the setting of rapid cycling, mixed features or emerging mania/hypomania symptoms; and discouraged if prior antidepressant cessation led to relapse. In nonpsychotic mood disorders, panellists favoured deprescribing antipsychotics that caused significant weight gain or tardive dyskinesia over adding pharmacological antidotes. Deprescribing to achieve an eventual medication-free status was considered inappropriate, in bipolar type 1, but not necessarily bipolar type 2 disorder. Although individualised circumstances necessarily inform psychopharmacology management, clinical presentations that misalign with existing pharmacotherapies may signal the desirability of cautious deprescribing.

ABSTRACT Background and Aims Women now comprise over half of US medical school matriculants yet remain underrepresented in academic leadership, including emergency medicine (EM). Leadership training within medical education is variable, particularly in communication, conflict management, negotiation, and operations. Concurrently, large language models (LLMs) are emerging as accessible tools to support leadership skill development. This study aimed to develop and evaluate an AI‐augmented leadership skills workshop designed to address the leadership gap for women in academic emergency medicine. Materials and Methods The Academy for Women in Academic Emergency Medicine (AWAEM) developed and piloted a leadership development workshop at the 2025 Society for Academic Emergency Medicine Annual Meeting. The curriculum integrated evidence‐based leadership frameworks with experiential small‐group learning and structured demonstrations of LLM use. Educational strategies included brief didactics, reflection on lived leadership challenges, peer discussion, and guided LLM‐supported simulation of leadership conversations. Pre‐workshop and postworkshop surveys and qualitative feedback were collected to assess participant confidence and perceived utility. Results Participants demonstrated increased confidence in navigating power‐differential conversations and initiating negotiations following the workshop. There was greater reported intent to apply leadership frameworks and to utilize LLMs for leadership‐related tasks. Qualitative feedback highlighted themes of empowerment, practical applicability, and the importance of a psychologically safe, gender‐informed learning environment. Participants identified LLMs as a novel and accessible adjunct to traditional leadership development resources. Discussion and Conclusions An AI‐augmented, experiential leadership workshop is a feasible and scalable approach to addressing persistent leadership development gaps for women in academic emergency medicine. Integrating LLM‐supported practice with established leadership frameworks may enhance learner confidence and engagement. This model offers a practical strategy to support leadership skills for women physicians needed to navigate systemic barriers and advance into leadership roles.

ABSTRACT Background Chemotherapy‐induced peripheral neuropathy (CIPN), characterized by loss of sensation and impaired physical function, is a prevalent and debilitating side effect of chemotherapy, affecting 30%–50% of breast cancer survivors (BCS) with effects lasting years after treatment completion. Mindfulness‐based interventions are shown to be efficacious in reducing symptoms in neuropathies. This subgroup analysis examined the effect of Mindfulness‐Based Stress Reduction on Breast Cancer (MBSR(BC)) compared to Breast Cancer Education Support (BCES) or Usual Care (UC) on CIPN among BCS who received chemotherapy or chemotherapy and radiation. Methods BCS ( n = 114) were randomly assigned to the 6‐week MBSR(BC) ( n = 48), BCES ( n = 52), or UC ( n = 14) regimen. Demographic and clinical data were assessed at baseline, and CIPN was assessed using the Chemotherapy‐Induced Peripheral Neuropathy assessment tool (CIPNAT) at baseline, 6, 12, and 26 weeks. Between‐ and within‐group differences were evaluated and change over time was compared between groups. Results BCS (mean age = 52.7 years, range: 28–81 years) were primarily White and non‐Hispanic ( n = 78, 68%). The pattern of effect sizes was similar for CIPNAT symptoms and interference with improvements in CIPN for MBSR(BC) and BCES groups overtime. For both groups, the effects were larger compared to the UC. Differences tended to increase over time with significant effects observed between MBSR(BC) and UC, and between BCES and UC at weeks 12 and 26. Conclusions The findings indicate that MBSR(BC) and BCES may effectively reduce CIPN symptoms among BCS compared to UC. MBSR(BC) and BCES programs are effective non‐pharmacological interventions for CIPN that may translate into practice.

ABSTRACT Background A randomized phase II screening trial of gemcitabine, nab‐paclitaxel, and cisplatin with a medically supervised ketogenic diet (MSKD) versus usual diet (non‐MSKD) was conducted in patients with treatment‐naive metastatic pancreatic ductal adenocarcinoma (PDAC). Methods Patients with untreated metastatic PDAC were randomized 1:1 to MSKD or non‐MSKD while receiving gemcitabine, nab‐paclitaxel, and cisplatin on days 1 and 8 of a 21‐day cycle. The MSKD was guided by a remote health care team and daily ketone (beta‐hydroxybutyrate) levels, with goal beta‐hydroxybutyrate of 0.5 to 3.0 mM. The primary endpoint was progression‐free survival (PFS) using a one‐sided alpha level of 0.20. Secondary endpoints included overall survival (OS), safety, and quality of life (QOL). Changes in microbiome were an exploratory endpoint. Findings Overall, there were 32 evaluable patients. In the MSKD arm, 15 of 16 patients achieved nutritional ketosis; the median proportion of days in ketosis was 39.4%. The median PFS was 8.5 months in MSKD patients and 6.2 months in non‐MSKD patients: hazard ratio, 0.53 (95% CI, 0.21–1.37); one‐sided p = .096. The median OS was 13.7 months with MSKD and 10.2 months in the non‐MSKD arm: hazard ratio, 0.58 (95% CI, 0.25–1.37); one‐sided p = .107). All MSKD‐related adverse events were grade 1‐2. There were no significant differences in grade ≥3 chemotherapy‐related adverse events between the arms. MSKD patients had no decline in QOL and had significant enrichment of beneficial taxa in the microbiome ( p < .05, log‐fold change ≥2). Conclusions The MSKD is feasible in patients with PDAC and, although not powered for definitive outcomes, shows trends in improved PFS and OS when combined with gemcitabine, nab‐paclitaxel, and cisplatin, without added toxicity or detriment to QOL. Larger studies are required to confirm these findings and establish the value of the MSKD in pancreatic cancer treatment.

OBJECTIVE Electrical stimulation mapping is a widely used technique to determine functional localization for medically refractory epilepsy. Sites where stimulation interferes with naming are often focal regions of the frontal and temporal cortex. The extent to which these crucial sites remain in the same location over time in an individual adult patient has not yet been established. The aim of this study was to determine whether cortical naming sites identified using stimulation mapping are stable in their anatomical location over time in adult patients with medically refractory epilepsy. METHODS Twenty-two patients who underwent electrical stimulation mapping for medically refractory epilepsy during surgical interventions separated by more than 1 year between 1967 and 2005 were included. A median of 8.35 years elapsed between mappings. The mean age at the first operation was 27.7 (range 10–39) years. Fourteen patients were female. Mapping occurred under two different conditions: intraoperatively in procedures conducted under local anesthesia or extraoperatively through implanted grid electrodes. A Bayesian hierarchical model of language site locations across repeated interventions was used to assess the stability of locations of stimulation-evoked interference in language naming. RESULTS Sites where electrical stimulation interferes with language naming were separated by a median of 0.6 cm between the 2 mappings. Eighty-six percent of the mapped sites related to language naming at the second operation were within 1.5 cm of a site identified at the first operation, 61% within 1 cm, and 36% within 0.5 cm. However, in 2 patients, none of the identified language naming sites at the second operation were within 1.5 cm of the sites from the first operation. CONCLUSIONS This unique, long-term series of neurosurgical mappings reveals that language naming sites in the cortex of adult patients with epilepsy show substantial long-term stability over many years. However, rare relocation of these sites does occur in some patients over many years.