Citations

ABSTRACT Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in energy metabolism, DNA repair, and cellular signaling. While the effects of acute NAD depletion have been better characterized, the consequences of chronic NAD deficiency remain unclear. Here, we investigated the impact of chronic NAD depletion in cultured cells by removing the availability of nicotinamide (NAM), a key precursor for NAD synthesis, from the culture media. In NIH3T3 fibroblasts, NAM depletion caused a dramatic drop in intracellular NAD levels within 2 days. Remarkably, the cells remained viable even after 7–14 days of NAM depletion, despite NAD + levels falling to less than 10% of control conditions. This chronic NAD depletion led to distinct metabolic alterations. Mitochondrial basal respiration remained unchanged, but cells exhibited reduced spare respiratory and maximal capacities, along with significantly impaired glycolysis. Notably, NAD depletion triggered an interferon‐dependent inflammatory response, resembling viral infections. This was driven by cytosolic leakage of mitochondrial DNA (mtDNA) through voltage‐dependent anion channel 1 (VDAC1), which activated the cGAS‐STING signaling pathway. Inhibition of VDAC oligomerization with VBIT‐4, STING signaling with H‐151, or mtDNA depletion blocked the upregulation of interferon genes induced by NAM depletion. Similar interferon responses triggered by NAD depletion were observed in IMR90 human fibroblasts and HS5 stromal cells. Our findings reveal a novel link between chronic NAD deficiency, VDAC‐mediated mtDNA release to the cytoplasm, and the activation of the inflammatory response, providing new insight into how NAD decline affects cellular metabolic and inflammatory processes.

Objective: To assess trends in surgical approaches (robotic, laparoscopic, and open) for various procedures, including prostatectomy, nephrectomy, cystectomy, colectomy, proctectomy, pancreatectomy, hepatectomy, and esophagectomy, and predict the future of these surgical approaches. Summary Background Data: The rapid adoption of robotic surgery has raised critical questions about the future of traditional laparoscopic techniques. Understanding the trends and potential dominance of robotic surgery is essential for surgical training, healthcare infrastructure, and resource allocation. Methods: This retrospective observational study utilized data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) from 2012 to 2023. Vector Autoregressive modeling analyzed trends and predicted future patterns for robotic, laparoscopic, or open surgical approaches across the specified procedures. The study included all reported cases in the database where the surgical approach was specified. Results: The analysis revealed a continued shift towards robotic surgery, particularly dominant in urologic procedures and rapidly adopted for complex operations like hepatectomy and esophagectomy. Laparoscopy’s use is declining across most specialties, though it remains significant in colectomy. Open surgery persists at high rates, especially in pancreatic and rectal operations. Projections suggest robotic surgery will surpass laparoscopy in colectomy (44.5%) and proctectomy (38.3%) by 2026. Conclusions: The transition toward robotic surgery continues across specialties at varying rates. These findings have significant implications for surgical training, healthcare infrastructure, and resource allocation. The high rates of open surgery in certain procedures highlight opportunities for broader adoption of minimally invasive techniques.

AbstractBackground and AimsSex‐related hormones and proteins may underlie sex differences in alcohol use disorder characteristics and consequences. Previous reports suggest steroid sex hormones may influence alcohol consumption behaviors while proteins that regulate their circulation levels are rarely investigated. Following up on our earlier study of individual sex‐related hormones' associations with alcohol dependence (AD), this study measured the associations between the combinations of sex‐related hormones and proteins and AD in a larger sample.DesignSex‐stratified case‐control comparison and clustering of plasma sex‐related hormone and protein levels, plus a genome‐wide association study on the AD‐associated hormone and protein combinations.SettingAddiction treatment programs in the United States.ParticipantsFour hundred treatment‐seeking recently abstained AD patients (median = 24.5 days) and 388 age‐and‐sex‐matched controls from a community biobank (male:female ≈ 2:1).MeasurementsPlasma levels of total testosterone, estrone (E1), estradiol (E2), follicle‐stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG) and albumin.FindingsIn males, we found higher E2 [β = 0.13, Punadjusted < 0.001, false discovery rate (FDR) = 0.005], progesterone (β = 0.01, Punadjusted = 0.025, FDR = 0.054), LH (β = 0.12, Punadjusted = 0.017, FDR = 0.044) and albumin (β = 0.09, Punadjusted < 0.001, FDR = 0.005) in AD patients than controls; in females, we observed lower E1 (β = −0.24, Punadjusted = 0.024, FDR = 0.113) and progesterone (β = −1.86, Punadjusted = 0.026, FDR = 0.113) and higher albumin (β = 0.18, Punadjusted < 0.001, FDR = 0.001) in AD patients than controls. Three principal components (PCs), reflecting hormone signatures, were statistically significantly associated with AD in each sex: PC1 (TT, E2 and SHBG; β = −0.15, P = 0.016), PC3 (E1, progesterone and albumin; β = 0.28, P = 0.007) and PC4 (SHBG and albumin; β = 0.34, P = 0.001) in males; PC3 (progesterone and albumin; β = −0.38, P = 0.009), PC4 (TT and albumin; β = −0.49, P = 0.001) and PC5 (TT and progesterone; β = 0.54, P = 0.004) in females. Statistically significant SNP × group associations were found in females between PC4 and polymorphisms in RP51004I9.1 (top SNP: rs6082693; P = 5.41E‐12) and in males between PC3 and a genomic locus that contained SLC35E4, DUSP18 and OSBP2 (top SNP: rs13053277; P = 1.77E‐07).ConclusionsThree sex‐related hormone and protein signatures appear to be associated with alcohol dependence in each sex. Peripheral levels of sex‐related hormones and proteins, as well as their combinations, could be altered in people with alcohol dependence who have abstained for a few weeks compared with controls, and such differences may be sex‐specific.

Recent guidelines on biliary cannulation are lacking. This guideline is an initiative of the World Endoscopy Organization (WEO) with the involvement of a panel of experts from Asia, Europe, and America. Relevant clinical questions on four areas (post‐endoscopic retrograde cholangiopancreatography [ERCP] pancreatitis [PEP] prophylaxis, biliary cannulation techniques, sphincterotomy/papillary balloon dilation, and biliary cannulation in special circumstances) were developed and answered after systematic reviews of the literature and using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Successful biliary cannulation and sphincterotomy are cornerstones of ERCP and are indispensable for almost all therapeutic and advanced diagnostic procedures. However, adverse events, particularly PEP, may commonly occur and impair patients' outcomes. A high cannulation rate and a low rate of PEP are quality indicators for ERCP and should be the goal of all endoscopists. With this guideline we aimed to provide clinical practice advice applicable worldwide, regardless of resources and expertise availability. The main recommendations focus on specific aspects of ERCP, including pre‐, intra‐, and postprocedural measures to reduce the risk of PEP, the technique for an initial biliary cannulation attempt, options for cannulation in cases of difficult biliary access, alternatives to ERCP in case of failure (percutaneous‐ and endoscopic ultrasound‐guided), and biliary access in altered anatomy (periampullary diverticulum and postsurgical anatomy) and in the presence of duodenal stenosis.

Original Article Citation Mithani K, Niazi F, Suresh H, Alrumayyan Y, Rayco ER, Ochi A, Otsubo H, Kerr E, Breitbart S, LeBlanc-Millar A, Gadgil N, Raskin JS, Weil AG, Hadjinicolaou A, Iorio-Morin C, Weiss S, Jain P, Sham L, Donner E, Fasano A, Gorodetsky C, Ibrahim GM. Deep brain stimulation of the centromedian nucleus for drug-resistant epilepsy in children: Quality-of-life and functional outcomes from the CHILD-DBS registry. Epilepsia. 2025 Apr 1. doi: 10.1111/epi.18393. Epub ahead of print. PMID: 40167366. Objective: Deep brain stimulation of the centromedian nucleus of the thalamus (CM-DBS) is an investigational, off-label treatment for drug-resistant epilepsy (DRE) in children. Although emerging evidence supports its safety and efficacy for select indications, the effect of CM-DBS on quality of life and functional outcomes such as school attendance has not been studied. Here, we analyzed data from the prospective CHILD-DBS (Child and Youth Comprehensive Longitudinal Database for Deep Brain Stimulation) to examine the impact of CM-DBS on patient- and caregiver-reported outcomes. Methods: Twenty-two children and youth underwent bilateral CM-DBS. Caregiver–child dyads completed surveys related to seizure frequency, seizure severity, quality of life, and school attendance at baseline, 6 months, and 1 year postsurgery. Simulated volumes of tissue activation were analyzed to identify optimal stimulation targets associated with treatment outcome. Results: Of 22 children, 10 experienced ≥50% reduction in seizure frequency (mean reduction = 66.7 ± 17.3%), one exhibited a modest benefit (37.5% reduction), and the remaining 11 experienced no change. The majority (73% of patients) exhibited a clinically important reduction in seizure severity, including six children who did not demonstrate any change in seizure frequency. Only those who experienced a reduction in seizure frequency demonstrated significant improvements in general health and overall quality of life. Furthermore, we observed an increase in school attendance across participants 1 year after CM-DBS. Significance: CM-DBS can lead to reduction in seizure burden concurrent with improvements in quality of life and relevant functional outcomes in children with DRE. These findings further our understanding of the impact of CM-DBS on meaningful outcomes for children and caregivers.