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Allensworth, Rebecca Haw. The Licensing Racket: How We Decide Who Is Allowed to Work, and Why It Goes Wrong
No full textUnique pore architecture underlies constitutive gating of human retinal TRPM1
No full textTransient receptor potential melastatin 1 (TRPM1), a Ca ²⁺ -permeable nonselective cation channel essential for retinal ON bipolar cell signaling and night vision, and implicated in congenital night blindness, has remained structurally and functionally poorly characterized. Here we report the first cryo-electron microscopy structure of human TRPM1 in conducting state. Although the channel assembles as a tetramer, it adopts an unexpected clockwise domain-swapped pore module with rotational geometry inverse to that observed in previously characterized 6-TM tetrameric channels. This inverted topology is accompanied by extensive remodeling of the S5-P-S6 module, dilation of the selectivity filter, expansion of the central cavity, and splaying of S6 to form a wide intracellular gate. Single-channel recordings reveal constitutive activity consistent with the conductive state captured. Together, these findings uncover a new 6-TM fold in tetrameric channel and provide a framework for understanding TRPM1 gating and disease-associated dysfunction.Transient receptor potential melastatin 1 (TRPM1), a Ca ²⁺ -permeable nonselective cation channel essential for retinal ON bipolar cell signaling and night vision, and implicated in congenital night blindness, has remained structurally and functionally poorly characterized. Here we report the first cryo-electron microscopy structure of human TRPM1 in conducting state. Although the channel assembles as a tetramer, it adopts an unexpected clockwise domain-swapped pore module with rotational geometry inverse to that observed in previously characterized 6-TM tetrameric channels. This inverted topology is accompanied by extensive remodeling of the S5-P-S6 module, dilation of the selectivity filter, expansion of the central cavity, and splaying of S6 to form a wide intracellular gate. Single-channel recordings reveal constitutive activity consistent with the conductive state captured. Together, these findings uncover a new 6-TM fold in tetrameric channel and provide a framework for understanding TRPM1 gating and disease-associated dysfunction
Suicidality at Epilepsy Diagnosis and Future Treatment Resistance in Adults With Focal Epilepsy
No full textPsychiatric disturbances are common in epilepsy and are associated with increased risk of premature mortality, lower quality of life, and poor response to antiseizure medications (ASMs).
To evaluate the role of psychiatric disturbances at the time of epilepsy diagnosis in predicting risk of future treatment resistance in focal epilepsy.
The Human Epilepsy Project (HEP) is a prospective, observational, international, and multicenter cohort study with follow-up for up to 6 years. Participants with newly diagnosed focal epilepsy, enrolled within 4 months of initiating ASM treatment, between the ages 18 and 60 years, and without significant other comorbidities were recruited during the open period of 2012 to 2020. Data analysis was performed from January to September 2025.
Presence of a psychiatric diagnosis.
Presence of psychiatric diagnosis (mood/anxiety disorders) measured by Mini International Neuropsychiatric Interview (MINI) and/or suicidality measured by Columbia-Suicide Severity Rating Scale (C-SSRS) at enrollment. Treatment response included the following outcomes: treatment resistant (TR), defined as failure of first 2 adequate ASM trials (ongoing seizures at/above therapeutic doses); treatment sensitive (TS), defined by a minimum period of seizure freedom on first 2 adequate ASM trials (12 months/3-fold greatest pretreatment seizure-free interval, whichever is longer); and indeterminate (neither TR/TS).
Of 376 enrolled adults, 347 (median [IQR] age at seizure onset, 33 [23-44] years; 209 female [60.2%]) completed the MINI and C-SSRS at enrollment. Of these individuals, 191 (55%) were TS, 83 (24%) TR, and 73 (21%) indeterminate. The rate of psychiatric disturbance (mood/anxiety disorder; suicidality) at epilepsy diagnosis was 38% (n = 133). Fifty-seven (16%) had mood/anxiety disorder(s) without suicidality, and 75 (22%) expressed suicidality with or without a psychiatric disorder. Suicidality at epilepsy diagnosis was associated with greater than 2-fold risk of developing TR (relative risk [RR], 2.02; 95% CI, 1.32-3.09; P = .001). There were no significant overall associations between mood/anxiety disorders and TR. Suicidality alone significantly increased TR probability from 16.3% (95% CI, 11.3%-21.3%) in those with no psychiatric disturbance to 47.1% (RR, 2.89; 95% CI, 1.65-5.05; P < .001). Anxiety disorder alone increased TR probability to 32.9% (RR, 2.02; 95% CI, 1.10-3.71; P = .02), although this was not statistically significant after correcting for multiple comparisons. There was no significant change in TR probability when mood disorder alone was present; however, presence of mood disorder with suicidality increased TR probability to 39.6% (RR, 2.43; 95% CI, 1.26-4.68; P = .008).
Results of this cohort study reveal that suicidality at the time of focal epilepsy diagnosis was associated with future drug resistance and may be a marker of more severe neuropathology. Psychiatric screening at time of diagnosis may facilitate early identification of patients at risk for treatment refractory epilepsy syndromes
Lower and Biliary Disorders of Gut-Brain Interaction: Child/Adolescent
No full textRome V provides updated criteria for pediatric disorders of gut-brain interaction (DGBI), replacing age-based subdivisions with a classification based on regions and symptom patterns: abdominal pain disorders, defecation and anorectal disorders, and discomfort disorders. New entities were introduced including biliary pain syndrome, centrally mediated abdominal pain syndrome, functional abdominal bloating, and proctalgia fugax. The term "infantile colic" has been replaced with "infant distress syndrome." Existing criteria for irritable bowel syndrome, functional constipation, and nonretentive fecal incontinence were revised to improve diagnostic clarity and reflect current clinical understanding. Rome V also acknowledges that DGBIs may coexist with other conditions producing gastrointestinal symptoms. These updates are intended to support a more consistent diagnostic framework and guide appropriate management strategies for children and adolescents
Thalamic Stimulation for Drug-Resistant Focal Epilepsy: A Case Report and Focused Literature Review of RNS Lead Revision
No full textResponsive neurostimulation (RNS) is a well-established therapy for drug-resistant focal epilepsy. While thalamic targets are increasingly explored in complex cases, revision surgeries remain rare and technically challenging due to imaging artifacts from implanted hardware. Here, we present a case of thalamic lead revision and review the existing literature on RNS revisions to contextualize its feasibility and outcomes. This report highlights both the clinical rationale/outcome of CM lead augmentation and a practical image-fusion strategy for trajectory planning in the setting of implant-related imaging artifact.
We report a case of RNS revision in a 30-year-old woman with multifocal drug-resistant epilepsy who underwent re-implantation targeting the centromedian (CM) thalamic nucleus using a novel image fusion approach. To assess existing evidence, a focused literature review was conducted using PubMed with predefined inclusion criteria: studies reporting RNS lead revision in patients with epilepsy. Relevant data on demographics, indication for revision, targets, and outcomes were extracted.
The patient underwent safe implantation of a thalamic lead following a preoperative co-registration of historical contrast-enhanced MRI with perioperative imaging. At 6 months, the patient showed a significant reduction in seizure frequency. In our review, 12 articles were screened, of which 4 met inclusion criteria. All reported lead revision for inadequate seizure control or lead malfunction. Three of the four patients had favorable outcomes, including one seizure-free and two with ≥50% seizure reduction. No complications were reported. No study described thalamic lead placement or the use of image fusion for trajectory planning.
RNS lead revision may be a viable strategy in patients with suboptimal seizure control. Our case is the first to describe revision involving thalamic targeting with advanced imaging techniques. Although data remain limited, growing clinical experience suggests that revising RNS systems, including to thalamic targets, can enhance seizure outcomes in selected patients. Further prospective data are needed to guide patient selection and targeting strategies
Trial Design and Objectives for Patients With Prostate Cancer: Recommendations From the Prostate Cancer Working Group 4
No full textThe continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer.
We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer.
PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework.
PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator-naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients
PRRT for well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
No full textNeuroendocrine tumors (NETs) are rare, heterogeneous neoplasms with varying prognoses and management approaches. Peptide receptor radionuclide therapy (PRRT), targeting tumors expressing somatostatin receptors, delivers cytotoxic radiation to tumor cells. While PRRT has demonstrated efficacy in advanced, well-differentiated NETs, the optimal sequencing with other therapies remains an area of active research.
This review explores PRRT's role in NET management, focusing on its mechanisms, clinical efficacy, safety profile, and its integration into a multi-modal treatment strategy. We also examine evidence on the sequencing of PRRT with surgery, liver directed therapy, chemotherapy and targeted therapies to optimize treatment outcomes.
We conducted a comprehensive review of recent clinical trials, cohort studies, and expert consensus guidelines to assess PRRT's place in the treatment paradigm. Factors influencing treatment sequencing, such as tumor type, receptor expression, disease burden, and patient-specific characteristics, are also discussed.
PRRT has proven effective for patients with advanced, somatostatin receptor-positive NETs, especially for inoperable tumors or those progressing after other therapies. While PRRT plays a vital role in management, its sequencing with other treatments remains complex, with evidence supporting its use both early and late in treatment based on individual patient factors.
Optimizing its sequencing with other treatments requires further research but offers potential for improved outcomes. A personalized, multidisciplinary approach is essential for maximizing PRRT's benefits in NET management. This review article summarizes current evidence and describes patient specific circumstances, enabling treating provider to make informed PRRT sequencing decisions
Sigma-1 receptor regulates HIV-1 and methamphetamine-induced endothelial/pericyte barrier impairment via strain-specific inflammatory responses and mitochondrial dysregulation
No full textBackgroundMethamphetamine (METH) use disorder (MUD) is a frequent comorbidity among people with HIV-1 (PWH). While both METH and HIV-1 independently disrupt the brain microvascular system and promote neuroinflammation, the molecular mechanisms underlying their synergistic neurotoxicity remain unclear. The sigma-1 receptor (Sigma-1R) signaling pathway has been suggested as a potential target in METH misuse; however, its involvement in the impact of METH and/or HIV-1 infection on brain pericytes remains unknown.MethodsTranswell co-cultures of human brain microvascular endothelial cells (HBMECs) and human brain vascular pericytes (HBVPs) were employed to assess the impact of combined METH exposure and infection with HIV-1 on barrier integrity. Moreover, mitochondrial functions, inflammatory mediators, oxidative stress markers, and the expression of interferon-stimulated genes were analyzed.ResultsHBVP infection with the CXCR4-tropic HIV-1 strain NL4-3, but not the CCR5-tropic JR-CSF strain, disrupted endothelial/pericyte barrier permeability, reduced transendothelial electrical resistance (TEER), and lowered claudin-5 expression, effects alleviated by pretreatment with Sigma-1R antagonist S1RA (10 µM). S1RA suppressed interleukin-6 (IL-6) release without affecting increased ROS levels and mitigated HIV-1 NL4-3 and METH co–induced proton leak and mitochondrial network fragmentation in a DRP1 phosphorylation–dependent manner. Importantly, METH enhanced replication of HIV-1 NL4-3, a process modulated by the CXCR4/CCL2 signaling pathway rather than Sigma-1R.ConclusionsThe obtained results identify Sigma-1R antagonism as a potential therapeutic strategy to protect microvascular integrity in the context of HIV-1 infection and METH misuse. In addition, they reveal distinct mechanisms that may underly microvascular dysfunction in PWH who experience MUD
