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Background. The VPS35 p.D620N variant causes autosomal dominant Parkinson's disease (PD) and has been shown to activate the LRRK2 kinase pathway, resulting in increased Rab substrate phosphorylation in peripheral immune cells and elevated urinary bis(monoacylglycero)phosphate (BMP) levels. Recently, a VPS35 variant of unknown significance (c.959C>T; p.A320V) was described in two late-onset sporadic PD patients. Methods. We ascertained a family from the Canary Islands in which six siblings were chronically exposed to high doses of pesticides. Three siblings developed levodopa-responsive, akinetic-rigid PD, while the other three remained unaffected. Whole-exome sequencing was performed in the three affected siblings. The frequency of the resulting candidate variant was assessed in 23,327 PD patients and 9,235 controls from four independent cohorts. Members of this pedigree and unrelated controls were assessed for LRRK2 kinase activity in monocytes and neutrophils and BMP levels in urine. Results. The three affected siblings were all heterozygous for p.A320V, whereas the three unaffected siblings did not carry the variant. In the combined PD case-control cohort, p.A320V was identified in six patients and one control. However, unlike p.D620N, heterozygous carrier status for p.A320V was not associated with increased LRRK2 kinase activity or elevated urine BMP levels. Conclusions. While VPS35 p.A320V co-segregated with PD in this family, it did not exhibit the characteristic LRRK2-associated biomarker signature observed in VPS35 p.D620N carriers. It is possible that p.A320V exerts a subtle effect on VPS35 function that was not captured by the assays performed and that chronic pesticide exposure contributed to disease penetrance in this pedigree.

Abstract Purpose Validate the semiquantitative (SQ)-MRI score for chronic pancreatitis (CP) diagnosis in an independent, multicenter cohort. Methods We analyzed MRIs performed at baseline in 337 participants with acute (AP) or recurrent AP (RAP) and 67 with non-calcific chronic pancreatitis (NCCP) enrolled in the PROCEED study from 6/2017 to 3/2023. MRIs were performed at multiple clinical centers using site-specific clinical protocols and a variety of MRI vendors to evaluate the SQ-MRI score in a real-world setting. The SQ-MRI score was calculated using the T1 signal intensity ratio of the pancreas to the spleen (T1 score), arteriovenous enhancement ratio (AVR), and pancreatic body diameter (PBD). We adjusted for confounding by participant characteristics via propensity score weighting. Results Median AVR was higher in AP/RAP (1.18, IQR: 0.97–1.44) than in the NCCP group (1.03, IQR: 0.78–1.22, p = 0.007). Pancreatic body diameters were larger in AP/RAP than in the NCCP group − 7–14 mm (10% vs 25%), 14–20 mm (40% vs 54%), and > 20 mm (50% vs 21%), respectively ( p < 0.01). Median T1 score was higher in AP/RAP (1.18, IQR: 0.96–1.40) than in the NCCP group (1.04, IQR: 0.86–1.32, p = 0.10). Median SQ-MRI score in the AP/RAP group was significantly lower, 1.91 (IQR: 0.97, 2.95), than in the NCCP group, 2.74 (IQR: 2.04–4.03) ( p < 0.001). The propensity score-adjusted AUC for SQ-MRI to distinguish AP/RAP from NCCP was 0.64, which was higher than for individual parameters. Conclusion We have validated the SQ-MRI score in a multicenter cohort using an independent, real-world MRI dataset.

The NCCN Guidelines for Survivorship offer guidance for health care providers who care for survivors of adult-onset cancer. These guidelines include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from cancer and its treatment and provide a framework for care coordination. They also present guidance for helping cancer survivors to enhance their wellness and maintain a healthy lifestyle. This article summarizes the panel’s current recommendations and recent updates regarding anxiety, depression, distress, and trauma in cancer survivors.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of certain sites within the body. Pleural mesothelioma is the most common type and represents approximately 85% of mesotheliomas. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for evaluation and treatment in patients with pleural mesothelioma. The NCCN Guidelines will continue to be updated annually based on available clinical evidence and panel consensus.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-associated bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of male mouse femurs. In studies done in male mice, following three preclinical radiotherapy regimens of 30Gy (5 x 6Gy), 60Gy (5 x 12Gy) and a single dose of 24Gy, suppression of SASP by JAKi was efficacious in suppressing radiation-induced bone damage. In comparison and as shown before, the senolytic combination of D+Q was also able to alleviate radiation-associated bone loss. Early and intermittent suppression of SASP using JAK inhibitors in male mice alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression and reduced bone-marrow adiposity. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

Background and Goals: Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with cirrhosis and ascites, with additional risks posed by multidrug-resistant organisms (MDRO). This real-world study evaluated clinical outcomes in patients with SBP and the impact of MDRO. Methods: This study identified US adults with SBP receiving guideline-recommended treatment with antibiotics and albumin from January 2012 to June 2022. Antibiotic utilization trends, health care resource utilization, and clinical outcomes [in-hospital and ICU mortality and hospital and ICU length of stay (LOS)] were assessed and stratified by MDRO status. Results: A total of 10,956 patients with 12,570 encounters were identified. Median age was 57.0 years (IQR=49.0 to 65.0), and 62.4% were male; suspected MDRO infections occurred in 15% of encounters. Third-generation cephalosporins were used in 71.6%, 49.2% had acute kidney injury, and 20.0% and 7.2% had hepatorenal syndrome and hepatic encephalopathy, respectively. Median hospital LOS was 7.2 days (IQR=4.3 to 12.9), with 17.7% in-hospital mortality. ICU care was required in 14.5% of encounters, with a median ICU LOS of 3.6 days (IQR=1.7 to 6.7) and ICU mortality of 29.7%. MDRO infections were associated with increased in-hospital mortality (OR=2.24, P <0.001) and decreased hazard of hospital discharge (ie, prolonged LOS; HR=0.43, P <0.001). Receiving albumin within 24 hours of admission was associated with a 72% higher hazard of hospital discharge (ie, shorter LOS; HR=1.72, P <0.001). Conclusion: This study highlights the clinical and resource burden of SBP, emphasizing the impact of MDRO infections and the importance of timely albumin administration concordant with clinical guidelines.

OBJECTIVE Genetic variation in the glucagon-like peptide 1 receptor (GLP1R) has been implicated in type 2 diabetes (T2D) risk and treatment response. We investigated whether GLP1R R131Q, which was previously reported as a T2D-protective variant in genome-wide association studies, alters receptor signaling, β-cell function, and response to glucagon-like peptide 1 receptor agonists (GLP-1RAs). RESEARCH DESIGN AND METHODS Trajectory of β-cell function was evaluated in a 20-year community-based prospective cohort in Korea (n = 6,373), where participants underwent biennial 2-h 75-g oral glucose tolerance tests, and disposition index was used as surrogate marker. Pharmacogenetic response to GLP-1RAs was assessed in a hospital-based T2D cohort in Korea (n = 177). Hyperglycemic clamp studies (n = 17), human islet experiments (n = 21), and in vitro assays were conducted to characterize GLP1R R131Q effects on receptor signaling and islet function. RESULTS GLP1R R131Q was associated with slower decline in disposition index in individuals without T2D, with reductions from baseline of 30% in homozygous carriers, 35% in heterozygotes, and 37% in wild-type individuals. In people with T2D, each allele conferred an additional 0.53% or 5.8 mmol/mol reduction in HbA1c after 6 months of GLP-1RA treatment (P = 5.8 × 10−4). Hyperglycemic clamp and human islet experiments demonstrated allele-dependent enhancement of GLP-1RA–stimulated insulin secretion (P = 0.050 and P = 0.037, respectively). In vitro, GLP1R R131Q increased GLP-1RA–stimulated cAMP production with directional observations consistent with pathway bias. CONCLUSIONS GLP1R R131Q is a gain-of-function variant associated with preservation of β-cell function and enhanced glycemic response to GLP-1RA treatment, supporting further investigation as a candidate pharmacogenetic marker for precision diabetes care.

BACKGROUND: Accurate assessment of left ventricular outflow tract (LVOT) gradients is critical for hypertrophic cardiomyopathy management, yet Doppler-based measurements are technically demanding and require expertise. The objective of this work was to develop a multi-view deep learning model capable of classifying LVOT obstruction (>20 mm Hg) using routine 2-dimensional echocardiographic windows without reliance on Doppler imaging. METHODS: We trained and externally validated a cross-attention-based video-to-video fusion framework that integrated EchoPrime-derived video representations from 3 standard transthoracic echocardiographic views to classify LVOT gradients. RESULTS: Training was performed on a derivation cohort (N=1833) from a tertiary care system in the United States, with model performance evaluated on an internally held-out test set (N=275) and a Korean external validation cohort (N=46). Single-view baselines showed limited discrimination (external area under the receiver operating curves, 0.47–0.70). Conversely, the domain-specific foundational model (EchoPrime) achieved superior single-view performance (area under the receiver operating curves, 0.75–0.80 internal; 0.79–0.83 external), highlighting the importance of echo-specific pretraining and temporal modeling. The proposed multi-view fusion further enhanced predictive performance, with the late fusion model reaching an area under the receiver operating curve of 0.84 on the external cohort with significant population-shift. CONCLUSIONS: These results suggest LVOT physiology is encoded in routine 2-dimensional imaging and can be leveraged for clinically relevant gradient classification without Doppler input. The proposed artificial intelligence-guided strategy demonstrates substantial cost savings compared with the screen-all approach. By integrating complementary spatial-temporal information across multiple views, our approach generalizes robustly across populations and may enable real-time decision support, extend LVOT assessment to portable or resource-limited settings, and complement Doppler-based evaluation for longitudinal hypertrophic cardiomyopathy management.