Citations

Abstract Objectives/Background This narrative review summarizes evidence implicating a role for the hypothalamus in the prodrome phase of a migraine attack. Prodrome is the earliest phase of the migraine attack. Understanding the migraine prodrome could lead to a better description of how migraine attacks are initiated and identification of targets for acute and preventive migraine treatment. The hypothalamus has been implicated in migraine prodrome via (1) localization of common prodrome symptoms to the hypothalamus; (2) identification of neurotransmitters, peptides, and hormones important in migraine pathophysiology for which the hypothalamus influences their production or release; and (3) brain neuroimaging studies identifying changes in hypothalamic activity and functional connectivity during the prodrome and preheadache phases of the migraine attack. Methods For this narrative review, PubMed was searched for relevant English language articles using the terms “hypothalamus, prodrome,” “hypothalamus, premonitory,” “hypothalamus, migraine,” “migraine, prodrome,” and “migraine, premonitory.” The PubMed search was performed on October 29, 2025. Full articles were chosen for review based on their relevance to the three areas defined just above: symptom localization, neuropeptide/neurotransmitter release, and brain imaging. Results Those with migraine commonly, and often consistently, experience prodrome symptoms, including hypersensitivities to visual and auditory stimuli, neck pain, fatigue, sleep–wake disturbances, changes in appetite, mood changes, and alterations in thermoregulation perception. Many of these symptoms can be localized to functions of hypothalamic subregions and nuclei. Several neuropeptides, neurotransmitters, and hormones that contribute to prodrome and other migraine attack symptoms, including calcitonin gene‐related peptide, dopamine, orexins, and pituitary adenylate cyclase‐activating polypeptide, are either produced by the hypothalamus or their release is mediated by the hypothalamus. Functional neuroimaging studies of spontaneous and triggered migraine attacks have identified increased hypothalamic activity and altered hypothalamic functional connectivity before migraine headache onset, including during the prodrome. Conclusion There is compelling evidence that the hypothalamus plays a role in the migraine prodrome and likely in migraine attack initiation. This is supported by many migraine prodrome symptoms localizing to hypothalamic function and functional neuroimaging studies demonstrating increased activity and altered connectivity of the hypothalamus during the prodrome phase. Further evidence and research are required to understand the hypothalamus' contribution relative to other brain regions.

Background Immune checkpoint inhibitor-based combinations represent the standard of care for advanced renal cell carcinoma. The OMNIVORE trial investigated a response-adaptive strategy, including treatment discontinuation in early nivolumab responders (Arm A) and salvage ipilimumab addition in non-responders (Arm B). Here we report outcomes with extended follow-up. Methods OMNIVORE was a phase II response-adaptive trial in which patients received induction nivolumab monotherapy. Patients achieving a confirmed complete or partial response discontinued nivolumab and entered observation (Arm A), while patients with stable disease or progressive disease received two doses of ipilimumab added to ongoing nivolumab (Arm B). This analysis characterizes long-term overall survival across the full study cohort and durability of response among patients who discontinued nivolumab following an early objective response. Results Of 83 patients who initiated treatment, 12 (14%) were allocated to Arm A and 57 (69%) to Arm B, with a median follow-up among living patients of 59.4 months (range 29.1–85.4 months) in Arm A and 31.4 months (range 4.6–62.6 months) in Arm B. The 3-year overall survival rate from nivolumab initiation was 64% (95% CI 51% to 74%) in the overall cohort, 83% (95% CI 48% to 96%) in Arm A, and 63% (95% CI 47% to 76%) in Arm B. Of the 12 Arm A patients, 6 (50%) remained off nivolumab at 1 year following treatment discontinuation, of whom 5 maintained responses beyond 43 months off therapy, with all remaining alive at last known follow-up, with overall survival ranging from 48.8 to 85.4 months from nivolumab initiation. Of the six patients who resumed treatment, only one achieved a durable complete response remaining on treatment at 83.2 months from nivolumab initiation. All 57 Arm B patients discontinued treatment with a median treatment duration of 3.7 months (range 1–24.8 months) and a median progression-free survival from nivolumab plus ipilimumab initiation of 4.6 months (95% CI 2.7 to 6.5 months). Conclusions With extended follow-up, a meaningful subset of patients achieving an early objective response to nivolumab maintained prolonged treatment-free survival following a short course of treatment. Salvage ipilimumab in nivolumab non-responders demonstrated limited benefit, reinforcing that upfront concurrent dual checkpoint blockade remains the preferred approach. Trial registration number NCT03203473 .

ABSTRACT Introduction Chronic gastroduodenal disorders remain challenging to manage, and new diagnostic approaches are needed to better delineate underlying causes and guide therapeutic decisions. Body Surface Gastric Mapping (BSGM) technologies combine high‐resolution gastric myoelectrical activity measurements with symptom and psychological profiling to provide mechanistic insights into gastric motor and sensory dysfunction. An International Working Group convened to derive the first consensus classification of BSGM phenotypes (the “Auckland Classification”). Methods A Technical Group conducted a systematic literature and clinical database review to identify objective test biomarkers and candidate disease mechanisms. Evidence was synthesized across 50 studies (primarily in gastroparesis, chronic nausea and vomiting, and functional dyspepsia), and BSGM phenotypes were mapped to existing treatment guidelines. Subsequently, iterative review and development of consensus was performed by a Consensus Group composed of international clinical experts familiar with BSGM. Eleven statements underlying the classification were then derived and circulated as a final survey to establish agreement. Results Six BSGM phenotypes were endorsed: three defined by myoelectrical abnormalities (Dysrhythmic, High Frequency, and Low Meal Response) and three by characteristic symptom associations (Sensorimotor, Continuous, and Delayed Onset Symptoms). Published studies plausibly linked these phenotypes to mechanisms including interstitial cell of Cajal depletion, vagal impairment, hypomotility, visceral hypersensitivity, gut‐brain dysregulation, and small bowel dysfunction. Phenotypes were also mapped to existing mechanism‐based treatment guidelines. Ten out of the eleven statements had > 80% agreement. Conclusions The Auckland Classification, derived by international consensus, presents a structured framework for BSGM‐defined patient phenotypes. Evidence and mechanism‐based treatment options are suggested for each phenotype to provide a foundation for research, further validation, and a pathway for integrating BSGM into clinical care.

Ehrlichiosis is a rare tick-borne zoonosis caused by Ehrlichia chaffeensis , E. ewingii and related species. In solid organ transplant recipients, immunosuppression can result in atypical presentations, delayed diagnosis and poor outcomes. The disease remains under-recognised among lung transplant recipients despite its potentially fatal course. A man in his early 70s with a history of bilateral lung transplantation for chronic obstructive pulmonary disease presented with a high-grade fever and shortness of breath. Bronchoalveolar lavage (BAL) culture grew Pseudomonas aeruginosa and meropenem was initiated. He subsequently developed severe thrombocytopenia, acute kidney injury and elevated liver transaminases. Disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP) were excluded, while haemophagocytic lymphohistiocytosis (HLH) was considered but not confirmed. His condition rapidly progressed to multiorgan failure requiring mechanical ventilation and haemodialysis. E. chaffeensis was identified postmortem by next-generation sequencing. This case highlights diagnostic challenges and the importance of early empiric doxycycline therapy in endemic areas.

Background: Smokers with multiple sclerosis (MS) experience worse disease, yet underlying mechanisms remain unknown. Smoking disrupts bile acid and tryptophan metabolism in non-MS populations; both pathways involve host–microbiome co-metabolism and have been linked to MS. Objective: Determine whether smoking perturbs these metabolic pathways in MS and whether such alterations statistically mediate smoking’s effect on MS severity. Methods: We analyzed serum bile acid, tryptophan, and tobacco-related metabolites across four independent MS cohorts ( N = 266) using discovery-replication analyses. Mixed-effects regression assessed replicating associations with current smoking and nicotine exposure. Mediation analyses tested if replicating metabolites were potential mediators between smoking and MS severity. Hypothesis-generating metagenomic analyses explored smoking-associated gut–microbial shifts and metabolite correlations. Results: Current smokers and nicotine-exposed MS subjects had reductions in bile acids and tryptophan metabolites, notably indolepropionate, a neuroprotective, anti-inflammatory gut–microbial metabolite. Lower indolepropionate statistically mediated ~20% of smoking’s adverse effect on MS severity. Metagenomic analyses identified potential smoking-enriched MS-linked taxa, and that indolepropionate broadly co-occurs with microbial networks (e.g. Lachnoclostridium appeared inversely associated with indolepropionate in smokers with MS). Conclusion: Tobacco exposure disrupts host–microbiome tryptophan and bile acid metabolism in persons with multiple sclerosis, with indolepropionate depletion partially mediating disease severity, highlighting a potential mechanistic pathway warranting further investigation in MS smokers.

Background Accreditation Council for Graduate Medical Education (ACGME) requires internal medicine (IM) residents to perform procedures considered “essential for the area of practice.” However, no guidelines or best practices exist for teaching these skills. To address this gap, a procedure training workshop (PTW) was developed. Methods IM residents attended a PTW where they practiced paracenteses, lumbar punctures (LPs), and central venous catheter (CVC) placement on ultrasound-compatible task trainers. The PTW was assessed using pre- and post-session tests and surveys. To evaluate translation into clinical practice, procedure volume, success rates, and immediate complications were tracked. Results Following implementation of the PTW, resident knowledge assessment scores increased from 67.4% to 84.1% (p < 0.001). More residents reported feeling “well-prepared” to perform or “teach others” procedures (CVC 69% from 31%, p < 0.01; LP 71% from 8%, p < 0.05; paracentesis 80% from 28%, p < 0.05) and able to perform all steps without assistance or model (CVC 54% from 28%; LP 49% from 17%, p < 0.01; paracentesis 66% from 25%, p < 0.01). Paracenteses increased from 71 (2020) to 119 (2021) to 143 (2024), while LPs increased from 87 (2020) to 156 (2021) to 135 (2024). Success rates remained stable across procedures: paracentesis (91.5% to 94.1% to 93.7%), LP (58.6% to 55.8% to 52.6%), and CVC placement (95.5% to 97.6% to 94.9%). Conclusions PTW is a valuable half-day session that equips early residents with essential procedural knowledge and hands-on practice that translates into sustained increases in bedside procedure volume.

Objective Digital health applications (health apps) are increasingly integrated in clinical care. Yet the information describing these apps varies across curated app repositories supporting prescription. We aimed to identify the information items used to describe health apps in repositories; and to quantify the completeness of publicly displayed app-entry information across repositories. Methods We conducted a cross-sectional study of seven national or international curated health app repositories: mHealthBelgium, DiGA, AppThera, ORCHA, GGD AppStore, MIND, and AppGuide. In January 2025, we randomly selected 140 health apps, with 20 apps per repository. For each app, one reviewer extracted the publicly available information displayed in the repository entry and inductively identified the information items reported (i.e., atomic information elements used to describe apps). These information items were then grouped into categories by an expert committee. We calculated, for each repository, the median number of items reported across apps, overall and by category. Results Health apps were described by 32 information items grouped into 10 categories: general information, regulatory information, compatibility, costs, indication, functions, evidence, user experience, data governance and security, and change history. The median number of items reported in repositories ranged from a median of 9/32 items, IQR 9 to 11 in MIND to 27/32, IQR 26 to 28 in DiGA. Only, three repositories (AppThera, DiGA and AppGuide) systematically reported information on the evidence supporting the apps for all listed apps. Conclusions Curated health app repositories differed in the information items presented to clinicians and patients. Incomplete reporting of clinically relevant information, particularly evidence and data governance, may limit informed app selection and prescription. Minimum reporting standards are needed to enable safe prescription and reliable integration of health apps into clinical practice.

Background/Objectives: Myelodysplastic syndromes (MDS) carry a highly variable prognosis, stratified by the Revised International Prognostic Scoring System (IPSS-R) and the Molecular IPSS (IPSS-M). CEBPA mutations define a favorable-risk subgroup in acute myeloid leukemia (AML), yet their prognostic significance in MDS has not been characterized. Methods: We analyzed 2442 patients from the International Working Group (IWG) 2022 multi-center MDS registry after pre-specified exclusions. Overall survival (OS) and leukemia-free survival (LFS) were compared between CEBPA-mutated (n = 66; 2.7%) and wild-type patients using Kaplan–Meier estimation and Cox proportional hazards regression, adjusting for age, sex, and IPSS-R score; pre-specified subgroup, sensitivity, competing-risk, and mutation subtype analyses were performed. Results:CEBPA-mutated patients had markedly inferior OS (median 17.2 versus 42.2 months; HR 2.05, 95% CI 1.50–2.79; p < 0.001). After IPSS-R adjustment, the hazard ratio remained adverse (HR 1.39, 95% CI 1.00–1.94; p = 0.053), with uniform directionality across all 13 evaluable subgroups and no significant interaction. Co-mutation adjustment for ASXL1 and STAG2 further attenuated the hazard ratio to HR 1.11 (95% CI 0.79–1.57; p = 0.54), suggesting part of the observed signal reflects co-mutation burden rather than an independent CEBPA effect. Competing-risk analysis suggested that the excess mortality is mediated through AML transformation (CEBPA-mutated versus wild-type subdistribution hazard ratio of 1.89, 95% CI 1.20–2.99; p = 0.006) rather than non-transformative MDS mortality (cause-specific HR 0.97; p = 0.890). Truncating mutations drove the adverse signal (HR 2.21; p = 0.023), while basic leucine zipper (bZIP) domain mutations showed no significant effect (HR 1.25; p = 0.470). Conclusions:CEBPA mutations identify a rare MDS subgroup with markedly inferior survival, driven by truncating loss-of-function mutations and associated with leukemic transformation; the AML-derived bZIP-favorable paradigm does not translate to MDS, and CEBPA mutation status merits a prospective study to assess clinical utility for risk stratification.