Citations

Sympathetic control of human blood pressure is mechanistically regulated by α 2 -adrenergic receptors distributed throughout the nervous system and cardiovascular end-targets. Recently, we discovered the sympathoinhibitory effects of central α 2 -adrenergic mechanisms on human sympathetic neuronal emission patterns. However, our knowledge remains incomplete regarding the impact of α 2 -adrenergic mechanisms on beat-by-beat transduction of muscle sympathetic nerve activity (MSNA) bursts to changes in blood pressure and heart rate (HR). Based on evidence of α 2 -adrenergic receptors within central and peripheral sympathetic neural sites and on the vasculature, this study tested the hypothesis that activation of α 2 -adrenergic receptors with dexmedetomidine (DEX) would reduce sympathetic transduction to blood pressure. In eight healthy participants (5 females; 28 ± 7 years), diastolic blood pressure (DBP; brachial arterial catheter), HR (ECG), and MSNA (peroneal microneurography) were recorded during a 5-minute supine baseline (BSL) and an intravenous DEX infusion consisting of a loading dose (10 minutes at 0.225 μg/kg/hr) and a maintenance dose (~0.15 μg/kg/hr). Signal averaging quantified sympathetic transduction to DBP and HR for 12 cardiac cycles following integrated MSNA bursts. We also quantified sympathetic transduction to DBP using a transduction gain estimate derived from the slope of the linear relationship between the peak DBP response and the number of cardiac cycles until peak DBP response. Data (mean ± SD) are reported for the 5-minute BSL and the last 5-minute period during the DEX infusion. Mixed-effects modeling and t -tests were performed. Non-parametric tests were performed for non-normally distributed data. DEX reduced resting MAP (BSL: 92 ± 7, DEX: 82 ± 6 mmHg: p < 0.001) but did not affect resting HR (BSL: 62 ± 14, DEX: 61 ± 14 bpm; p = 0.853). DEX reduced resting integrated MSNA burst frequency (BSL: 14 ± 6, DEX: 4 ± 3 bursts/min; p = 0.001) and total integrated MSNA (BSL: 663 ± 252, DEX: 188 ± 142 AU/min; p < 0.001). DEX attenuated the DBP transduction response, particularly for the cardiac cycle associated with peak DBP during BSL (cardiac cycle 6: BSL: 4.3 ± 3.2, DEX: 3.3 ± 2.0 mmHg; p = 0.025) and prolonged the time to peak DBP transduction (BSL: 6 ±1, DEX: 10 ± 3 cardiac cycles; p = 0.014). Also, DEX reduced DBP transduction gain (BSL: 1.6 ± 2.4, DEX: 0.9 ± 1.3 mmHg/cardiac cycle; p = 0.029). By contrast, DEX did not affect the mean transduction of MSNA bursts to changes in HR (BSL: 3.2 ± 3.1, DEX: 3.9 ± 4.6 mmHg; p = 0.668). These data suggest that α 2 -adrenergic mechanisms distributed among central and peripheral sympathetic neural regions and the cardiovascular system influence moment-to-moment sympathetic regulation of blood pressure homeostasis, but not HR, in humans. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Biological sex impacts baroreflex control of integrated muscle sympathetic nerve activity (MSNA), yet our knowledge remains incomplete regarding sex differences in baroreflex regulation of the differently sized APs contributing to variations in MSNA burst frequency and size. We hypothesized that sex differences in baroreflex control of sympathetic action potential (AP) discharge contribute to higher resting AP activity in males compared to females. We measured diastolic blood pressure (DBP; Finometer or brachial arterial catheter) and MSNA (peroneal microneurography and continuous wavelet transform, APs normalized to 10 clusters) in 24 healthy individuals (aged 18-30, 12 females) during a 5-minute supine baseline. Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and DBP. Sympathetic AP baroreflex sensitivity gain was measured as the slope of the linear relationship between AP clusters per burst and DBP. Analyses were performed during DBP rises and falls to explore baroreflex hysteresis. Mixed-effects analyses and t-tests were performed. Data are reported as mean ± SD. In the aggregate cohort, baroreflex control of medium-sized APs exhibited hysteresis. Compared to rises in DBP, DBP falls were associated with greater AP firing probabilities (cluster 3; DBP rise: 20 ± 11, DBP fall: 26 ± 12%; p < 0.01) and greater AP baroreflex gains (cluster 3; DBP rise: -4.36 ± 2.43, DBP fall: -5.32 ± 3.09 %/mmHg; p < 0.01). In the aggregate cohort, baroreflex hysteresis was not detected for small- or large-sized AP clusters (both p ≥ 0.56). Similar observations were detected for medium-sized APs in male (M) and female (F) cohorts when analyses were stratified by sex. Compared to females, males exhibited greater medium-sized AP firing probabilities during DBP rises (cluster 3; M: 23 ± 12, F: 16 ± 8%; p < 0.01) and falls (cluster 3; M: 32 ± 13, F: 20 ± 8%; p < 0.01). However, AP baroreflex gains were not different between sexes during DBP rises (cluster 3; M: -4.87 ± 2.05, F: -3.84 ± 2.75%/mmHg; p = 0.13) and falls (cluster 3; M: -5.87 ± 2.25, F: -4.76 ± 3.77 %/mmHg; p = 0.15). In the aggregate cohort, the number of AP clusters per burst and the AP baroreflex sensitivity gain were not different between rises and falls in DBP. However, compared to females, males demonstrated a greater number of AP clusters per burst during DBP rises (M: 4 ± 0.9, F: 3 ± 0.6 clusters/burst; p < 0.01) and falls (M: 4 ± 0.8, F: 3 ± 0.7 clusters/burst; p < 0.01). No sex differences in AP baroreflex sensitivity gain were detected during DBP rises (M: -0.08 ± 0.09, F: -0.30 ± 0.07 clusters/burst/mmHg; p = 0.14) or falls (M: -0.08 ± 0.08, F: -0.02 ± 0.08 clusters/burst/mmHg; p = 0.09). These data suggest that 1) hysteresis exists in baroreflex regulation of medium-sized but not small or large sympathetic APs firing under baseline conditions and 2) in line with earlier integrated MSNA studies, compared to females, males demonstrate greater resting sympathetic outflow from greater sympathetic AP discharge and more AP clusters firing per burst in periods of rising and falling DBPs. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Aim Develop an AI-generated Global Surgery podcast series tailored to healthcare professionals’ needs in specific countries, focussing on Uganda as a pilot. This precision education model addresses disparities in global surgical education, historically driven by high-income countries (HICs). Podcasts were chosen for their scalability, accessibility, and self-directed learning. Method Building on prior data from our international trainee-based needs assessment (145 survey respondents from 18 countries; 94 from Low-and-Middle-Income-Countries, LMICs; 51 from High-Income-Countries, HICs). Generative AI (ChatGPT 4.0, OpenAI) and prompt engineering were used to develop a global surgery curriculum from survey data from Ugandan respondents (selected because Uganda had one of the highest response rates, n=31). The resultant curriculum was then adapted into a podcast format featuring country-specific themes using NotebookLM (Google), using a format of exercises, case studies, and expert interviews. Results The preliminary outputs of the survey and podcasts highlight diverse country-specific priorities; for HICs these include access to resources, research opportunities, and infrastructure development; for LMICs they emphasise the burden of surgical disease, use of local case studies, and foundational concepts in global surgery. Conclusions By tailoring content to regional needs and leveraging storytelling to foster engagement, podcasts can complement traditional curricula to address gaps in access and relevance. Limitations include current AI-generative software offering only US accents, which may not suit learners elsewhere, reflecting concerns about HICs bias in AI-generated content. Future research will validate the podcasts through focus groups with Ugandan surgical trainees, and explore speech-processing for regional accents, or blending human voice with AI-generated transcripts.

ABSTRACT Background This medical center migrated from alcohol to sotradecol foam sclerotherapy (SFS) because of perceived improved efficacy in managing symptomatic kidney and liver cysts. We report technical aspects, change in short- and long-term cyst volumes, patient-reported outcomes, safety and applications of the technique. Methods In this retrospective observational study, cases from January 2017 to December 2021 had TKCV/TLCV (per Targeted Kidney or Liver or Cyst analysis) segmented using a deep-learning algorithm and cyst segmentation software (pre-, post-procedure and longitudinally). TKCV/TLCV % change were evaluated using the one-sample Wilcoxon signed rank test. For analyses involving changes in cyst volumes, the median % change in cyst volume per patient was assessed. Longitudinal changes in cyst volumes were assessed using linear mixed models. Changes in quality of life (QOL) [Linear Analog Self-Assessment (LASA), Polycystic Liver Disease Quality of life Questionnaire (PLD-Q) and 12-item short-form (SF12)] were also assessed. Results There were 102 SFS sessions (38 kidney, 58 liver, 6 combined liver/kidney cysts) performed on 77 unique individuals included for analysis. Median [interquartile range (IQR)] % reductions in TKCV were –92.0% (IQR –98.2%, –82.7%, P &lt; .001) and for TLCV were –83.1% (IQR –93.5%, –52.9%, P &lt; .001). Among patients with multiple kidney procedures (n = 7), median % reduction in TKCV was –94.3% (IQR –96.6%, –92.4%, P = .023). For patients with multiple liver procedures (n = 11), median % reduction in TLCV was –63.3% (IQR –85.2%, –28.3%, P = .004). Results were similar among the four patients undergoing multi-stage procedures (n = 1 kidney, n = 3 liver). When measured longitudinally, both liver and kidney cyst volumes declined to levels near 0 mL by 1 year follow-up and remained stable several years later. LASA physical domain and PLD-Q QOL scores improved post-SFS procedure. Conclusion SFS led to substantial long-term reductions in TKCV/TLCV and improved QOL. SFS can augment cyst volume reduction in addition to tolvaptan (kidney cysts) and octreotide (liver cysts). In some individuals with large symptomatic cysts, multiple SFS procedures were safe and effective in reducing TLCV/TKCV and improving symptoms.

Pediatric central nervous system tumors are the leading cause of cancer-related deaths in children. The five-year survival rate for high-grade glioma in children is less than 20%. The development of new treatments is dependent upon multi-institutional collaborative clinical trials requiring reproducible and accurate centralized response assessment. We present the results of the BraTS-PEDs 2023 challenge, the first Brain Tumor Segmentation (BraTS) challenge focused on pediatric brain tumors. This challenge utilized data acquired from multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. BraTS-PEDs 2023 aimed to evaluate volumetric segmentation algorithms for pediatric brain gliomas from magnetic resonance imaging using standardized quantitative performance evaluation metrics employed across the BraTS 2023 challenges. The top-performing AI approaches for pediatric tumor analysis included ensembles of nnU-Net and Swin UNETR, Auto3DSeg, or nnU-Net with a self-supervised framework. The BraTS-PEDs 2023 challenge fostered collaboration between clinicians (neuro-oncologists, neuroradiologists) and AI/imaging scientists, promoting faster data sharing and the development of automated volumetric analysis techniques. These advancements could significantly benefit clinical trials and improve the care of children with brain tumors.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

AbstractBackgroundGastric cancer with synchronous peritoneal metastases is a debilitating disease with limited treatment options. This article describes an update of the 2018 Chicago Consensus guidelines addressing the management of gastric cancer with synchronous peritoneal metastases in line with the most recent evidence.MethodsA clinical management pathway was updated through two rounds of a Delphi consensus to assess agreement levels with pathway blocks. Supporting evidence underwent evaluation using a rapid literature review. Meta‐analyses were performed as appropriate.ResultsOverall, the level of evidence in this disease subset was low to moderate. Of 124 participants in the first round, 109 (88%) responded in the second round. Strong consensus (>90%) was achieved in six of eight blocks (75%) in rounds 1 and 2. A multidisciplinary preoperative assessment and diagnostic laparoscopy should be offered to all patients, whereas patients with a high burden of disease or progression should undergo nonsurgical management. Patients with stable/responsive disease and a low peritoneal carcinomatosis index should subsequently be offered treatment with regional therapeutic interventions and cytoreductive surgery. In patients who are cytology‐positive, systemic therapy can be used to convert them to cytology‐negative, with subsequent surgery offered according to the patient's goals of care. Meta‐analysis of observational and randomized control trials revealed a survival benefit with the addition of intraperitoneal chemotherapy to cytoreductive surgery (hazard ratio, 0.52).ConclusionsThe consensus‐driven clinical pathway for gastric cancer with synchronous peritoneal metastases offers vital clinical guidance for practitioners. There is a growing body of high‐quality evidence to support management strategies, and future clinical trials are eagerly awaited.

Objectives: Esophageal cancer (EC) often presents with dysphagia due to tumor obstruction. Esophageal stenting has the potential of palliating dysphagia, improving nutrition, preventing aspiration, and improving quality of life (QoL) but may be associated with risks. The present systematic review and guidelines are intended to assist treatment decision-making when considering stent placement in patients with EC based on the available evidence. Methods: Using the population, intervention, comparator, outcome, timing and study design framework, the evidence was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included prospective phase II-III trials and retrospective analyses published between January 1, 2010 and December 3, 2024 in the Ovid Medline database. These references were assessed by American Radium Society (ARS) Appropriate Use Criteria (AUC) methodology. RAND-UCLA consensus methodology was used to rate the appropriateness of the use of stents. Results: ARS AUC recommendations include (1) esophageal stenting is usually not appropriate in patients with early-stage EC in whom upfront surgery is planned; (2) esophageal stenting is usually not appropriate in patients with locally-advanced EC in whom neoadjuvant/perioperative therapy and esophagectomy or definitive chemoradiation is planned; (3) esophageal stenting may be appropriate in the setting of metastatic EC, especially in patients with short life expectancy with limited treatment options; (4) esophageal stenting is usually not appropriate for benign stricture following curative-intent therapy; (5) esophageal stenting is usually not appropriate for locally recurrent tumor in the setting of prior radiation; and (6) esophageal stenting is usually appropriate for management of tracheoesophageal fistula before curative-intent treatment. Conclusions: This ARS AUC summary provides guidelines for the use of esophageal stents in patients with EC provides based on available evidence.

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P &lt; 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (&gt;10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.