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Importance Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. Objective To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. Design, Setting, and Participants This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. Exposures Amount and intensity of physical activity. Main Outcomes and Measures The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient’s exercise category. Results Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. Conclusions and Relevance Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Key Points Hepatorenal syndrome type 1 (HRS-1) is an often fatal, but potentially reversible, kidney failure in patients with decompensated cirrhosis. Treatment with terlipressin in patients with HRS-1 is associated with a reduction in the need for RRT. Background Hepatorenal syndrome type 1 (HRS-1)—also known as hepatorenal syndrome-AKI (HRS-AKI)—is a rapidly progressing and usually fatal, but potentially reversible, kidney failure occurring in patients with decompensated cirrhosis. A large proportion of patients with HRS-1 require renal replacement therapy (RRT). Terlipressin demonstrated efficacy in reversing HRS and improving renal function in patients with HRS-1 in three phase III, randomized, clinical trials (RCTs; i.e. , OT-0401, REVERSE, and CONFIRM). However, these RCTs were not designed to evaluate the effect of terlipressin on the requirement of RRT. In this study, the effect of terlipressin on RRT requirements in the pooled phase III patient population was assessed. Methods For this retrospective analysis, data from patients who participated in the OT-0401, REVERSE, and CONFIRM studies were integrated in the largest-to-date randomized database ( N =608). Results The need for RRT was significantly decreased in patients in the terlipressin group versus the placebo group by day 30 (28.1% versus 35.9%, respectively; P = 0.040) and day 60 (30.1% versus 37.9%, respectively; P = 0.045) in the pooled population and also postliver transplantation (LT) at day 60 (20.5% versus 40.3%, respectively; P = 0.008) and day 90 (25.3% versus 43.1%, respectively; P = 0.018). More patients were alive and RRT-free by day 90 in the overall population (36.9% versus 28.5%; P = 0.030) and among patients who received an LT (60.0% versus 39.7%; P = 0.010). Random assignment to receive terlipressin was an independent positive predictor of avoidance of RRT ( P = 0.042); while higher baseline serum creatinine (sCr) level and Child-Pugh scores were negatively associated with RRT avoidance ( P < 0.001 and P = 0.040, respectively). Conclusions Terlipressin decreased the requirement of RRT compared with placebo among patients with HRS-1, including those receiving LT. A lower sCr level at the beginning of therapy was associated with avoidance of RRT.

We convened an expert panel to develop evidence-based guidelines for the evaluation, treatment, and prevention of nonfreezing cold injuries (NFCIs; trench foot and immersion foot) and warm water immersion injuries (warm water immersion foot and tropical immersion foot) in prehospital and hospital settings. The panel graded the recommendations based on the quality of supporting evidence and the balance between benefits and risks/burdens according to the criteria published by the American College of Chest Physicians. Treatment is more difficult with NFCIs than with warm water immersion injuries. In contrast to warm water immersion injuries that usually resolve without sequelae, NFCIs may cause prolonged debilitating symptoms, including neuropathic pain and cold sensitivity.

AbstractBackgroundDiscrete spot scanning (DSS) is the commonly used method for proton pencil beam scanning (PBS). There is lack of data on the dose‐driven continuous scanning (DDCS).PurposeTo investigate delivery benefits and dosimetric implications of DDCS versus DSS for PBS systems.MethodsThe irradiation duty factor, beam delivery time (BDT), and dose deviation were simulated for eight treatment plans in prostate, head and neck, liver, and lung, with both conventional fractionation and hypofractionation schemes. DDCS results were compared with those of DSS.ResultsThe DDCS irradiation duty factor (range, 11%–41%) was appreciably improved compared to DSS delivery (range, 4%–14%), within which, hypofractionation schemes had greater improvement than conventional fractionation. With decreasing stop ratio constraints, the DDCS BDT reduction was greater, but dose deviation also increased. With stop ratio constraints of 2, 1, 0.5, and 0, DDCS BDT reduction reached to 6%, 10%, 12%, and 15%, respectively, and dose deviation reached to 0.6%, 1.7%, 3.0%, and 5.2% root mean square error in PTV DVH, respectively. The 3%/2‐mm gamma passing rate was greater than 99% with stop ratio constraints of 2 and 1, and greater than 95% with a stop ratio of 0.5. When the stop ratio constraint was removed, five of the eight treatment plans had a 3%/2‐mm gamma passing rate greater than 95%, and the other three plans had a 3%/2‐mm gamma passing rate between 90% and 95%.ConclusionsThe irradiation duty factor was considerably improved with DDCS. Smaller stop ratio constraints led to shorter BDTs, but with the cost of larger dose deviations. Our finding suggested that a stop ratio of 1 constraint seems to yield acceptable DDCS dose deviation.

Abstract Background/Aims Flares following COVID-19 vaccination are an emerging concern among patients with rare rheumatic disease like idiopathic inflammatory myositis (IIMs), whereas data and understanding of this is rather limited. We aimed to study the prevalence, characteristics and determinants of IIM flares following COVID-19 vaccination. Methods CoVAD (COVID-19 Vaccination In Autoimmune Diseases) surveys are global patient self-reported e-surveys from 109 countries conducted in 2021 and 2022. Flares of IIM were defined by 4 definitions; a. patient self-reported, b. physician and immunosuppression (IS) denoted, c. sign directed (new erythematous rash, or worsening myositis or arthritis), d. MCID worsening of PROMISPF10a score between the patients who had taken both surveys. Descriptive statistics and multivariate regression were used to describe the predictors of flare. Cox-regression analysis was used to differentiate flares by IIM subtypes. Results Among the 1,278 IIM patients, aged 63 (50-71) years, 276 (21.5%) were dermatomyositis, 237 (18.5%) IBM, 899 (70.3%) were female and most were Caucasian (80.8%). Flares of IIM were seen in 123/1278 (9.6%), 163/1278 (12.7%), 112/1278 (8.7%), and 16/96 (19.6%) by definitions a-d respectively with median time to flare being 71.5 (10.7-235) days. Muscle weakness (69.1%), and fatigue (56.9%) were the most common symptoms of flare. The predictors of self-reported flare were: inactive/disease in remission prior to first dose of vaccine (OR = 4.3, 95%CI=2.4-7.6), and anxiety disorder (OR = 2.2, 95%CI=1.1-4.7). Rituximab use (OR = 0.3, 95%CI=0.1-0.7) and IBM (OR = 0.3, 95%CI=0.1-0.7) were protective. Physician defined flares were seen more often in females, mixed ethnicity, and those with asthma, ILD, and anxiety disorder (OR ranging 1.6-7.0, all p &lt; 0.05). Notably, overlap myositis (OM) had higher HR for flare compared to polymyositis (HR = 2.3, 95%CI=1.2-4.4, p = 0.010). Conclusion Nearly one in ten individuals with IIM develop flares after vaccination, more so among women, those with overlap myositis, and inactive disease prior to vaccination. Formal definition of flares in IIM is needed. Disclosure L. Gupta: None. N. R: None. Z. Griger: None. V. Agarwal: None. P. Sen: None. M. Joshi: None. S. Saha: None. K. Jagtap: None. O. Distler: Honoraria; Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. E. Nikiphorou: Honoraria; Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly. Grants/research support; Pfizer and Lilly. A. Tan: Honoraria; Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB. S. Shinjo: None. N. Ziade: Honoraria; Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre. M. Milchert: None. I. Parodis: Honoraria; Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG. M. Kuwana: None. A. Makol: None. J. Pauling: None. C. Wincup: None. J. Lilleker: Honoraria; Sanofi Genzyme, Roche, and Biogen. A. Nune: None. J. Day: Grants/research support; CSL Limited. H. Chinoy: Consultancies; Novartis, Eli Lilly, Orphazyme, Astra Zeneca. Honoraria; UCB, and Biogen. Grants/research support; Eli Lilly and UCB. V. Agarwal: None. R. Aggarwal: Consultancies; Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, and Roivant.

Abstract Background/Aims Post COVID-19 syndrome (PCS) is an emerging cause of morbidity and poor quality of life in COVID-19 survivors. We aimed to assess the prevalence, risk factors, outcomes, and association with disease flares of PCS in patients with autoimmune rheumatic diseases (AIRDs) and non-rheumatic autoimmune diseases (nrAIDs), both vulnerable groups understudied in the current literature using data from the 2nd COVID-19 Vaccination in Autoimmune Diseases (COVAD) global multicentre patient self-reported e-survey. Methods The survey was circulated from February to July 2022 by the international COVAD Study Group (157 collaborators from 106 countries), and demographics, comorbidities, AIRD/nrAID status, COVID-19 history, vaccination details, and PROMIS physical and mental function were recorded. PCS was defined as symptom resolution time &gt;90 days following acute COVID-19. Predictors of PCS were analysed using regression models for the different groups. Results 7666 total respondents completed the survey. Of these, 2650 respondents with complete responses had positive COVID-19 infection, and 1677 (45.0% AIRDs, 12.5% nrAIDs, 42.5% HCs) completed the survey &gt;90 days post acute COVID-19. Of these, 136 (8.1%) had PCS. Prevalence of PCS was higher in AIRDs (10.8%) than healthy controls HCs (5.3%) (OR: 2.1; 95%CI: 1.4-3.1, p = 0.002). Across the entire cohort, a higher risk of PCS was seen in women (OR: 2.9; 95%CI: 1.1-7.7, p = 0.037), patients with long duration of AIRDs/nrAIDs (OR 1.01; 95%CI: 1.0-1.02, p = 0.016), those with comorbidities (OR: 2.8; 95%CI: 1.4-5.7, p = 0.005), and patients requiring oxygen supplementation for severe acute COVID-19 (OR: 3.8; 95%CI: 1.1-13.6, p = 0.039). Among patients with AIRDs, comorbidities (OR 2.0; 95%CI: 1.08-3.6, p = 0.026), and advanced treatment (OR: 1.9; 95%CI: 1.08-3.3, p = 0.024), or intensive care (OR: 3.8; 95%CI: 1.01-14.4, p = 0.047) for severe COVID-19 were risk factors for PCS. Notably, patients who developed PCS had poorer PROMIS global physical [15 (12-17) vs 12 (9-15)] and mental health [14 (11-16) vs 11 (8-14)] scores than those without PCS. Conclusion Individuals with AIRDs have a greater risk of PCS than HCs. Associated comorbid conditions, and advanced treatment or intensive care unit admission for severe COVID-19 confer a higher risk of PCS. It is imperative to identify risk factors for PCS for immediate multidisciplinary management in anticipation of poor physical and mental health. Disclosure L. Gupta: None. P. Sen: None. N. R: None. M. Joshi: None. S. Saha: None. K. Jagtap: None. V. Agarwal: None. O. Distler: Consultancies; Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. E. Nikiphorou: Honoraria; Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly. Grants/research support; Pfizer and Lilly. A. Tan: Honoraria; Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB. S. Shinjo: None. N. Ziade: Honoraria; Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre. M. Milchert: None. I. Parodis: Honoraria; Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG. M. Kuwana: None. A. Makol: None. J.D. Pauling: None. C. Wincup: None. J. Lilleker: Honoraria; Sanofi Genzyme, Roche, and Biogen. A. Nune: None. J. Day: Grants/research support; CSL Limited. H. Chinoy: Consultancies; Novartis, Eli Lilly, Orphazyme, Astra Zeneca. Honoraria; UCB, and Biogen. Grants/research support; Eli Lilly and UCB. V. Agarwal: None. R. Aggarwal: Consultancies; Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, and Roivant.

Abstract Objectives Disease flares in the post–coronavirus disease 2019 (COVID-19) vaccination period represent a prominent concern, though risk factors are poorly understood. We studied these flares among patients with idiopathic inflammatory myopathies (IIMs) and other autoimmune rheumatic diseases (AIRDs). Methods The COVAD-1 and -2 global surveys were circulated in early 2021 and 2022, respectively, and we captured demographics, comorbidities, AIRDs details, COVID-19 infection history and vaccination details. Flares of IIMs were defined as (a) patient self-reported, (b) immunosuppression (IS) denoted, (c) clinical sign directed and (d) with &gt;7.9-point minimal clinically significant improvement difference worsening of Patient-Reported Outcomes Measurement Information System (PROMIS) PROMISPF10a score. Risk factors of flares were analysed using regression models. Results Of 15 165 total respondents, 1278 IIMs (age 63 years, 70.3% female, 80.8% Caucasians) and 3453 AIRDs were included. Flares of IIM were seen in 9.6%, 12.7%, 8.7% and 19.6% patients by definitions (a) to (d), respectively, with a median time to flare of 71.5 (10.7–235) days, similar to AIRDs. Patients with active IIMs pre-vaccination (OR 1.2; 95% CI 1.03, 1.6, P = 0.025) were prone to flares, while those receiving rituximab (OR 0.3; 95% CI 0.1, 0.7, P = 0.010) and AZA (OR 0.3, 95% CI 0.1, 0.8, P = 0.016) were at lower risk. Female gender and comorbidities predisposed to flares requiring changes in IS. Asthma (OR 1.62; 95% CI 1.05, 2.50, P = 0.028) and higher pain visual analogue score (OR 1.19; 95% CI 1.11, 1.27, P &lt; 0.001) were associated with disparity between self-reported and IS-denoted flares. Conclusion A diagnosis of IIMs confers an equal risk of flares in the post–COVID-19 vaccination period to AIRDs, with active disease, female gender and comorbidities conferring a higher risk. Disparity between patient- and physician-reported outcomes represents a future avenue for exploration.

We read with great interest the manuscript by Brassetti et al. recently published in your journal and hope it will encourage discussion and debate around the optimization of the surgical management of patients with penile cancer (PECa) [...]

Abstract High grade glioma (HGG) represents a group of devastating diseases with dismal prognosis. Surgical resection of the contrast enhancing (CE) region of HGG remains the mainstay of treatment, but recurrence inevitably arises from the unresected non-contrast enhancing (NE) region, surgically inaccessible due to cancer cell invasion into healthy brain tissue. Due to its critical role in recurrence, understanding of the NE region is central to the improvement of clinical outcomes. We reveal the biological characteristics of this region through image localized multi-regional sampling. We linked microenvironmental characteristics measured by multi-parametric MRI to genomic mutations and transcriptional phenotypes using mixed effect modeling which allowed us to control for individualized patient effects. We first confirmed that T2 is a significant indicator of IDH mutation status in the NE region, being the first description of such a relationship in a HGG cohort. We found the combination of EGFR amplification and CDKN2A homozygous loss was associated with a significantly lower mean diffusivity (MD) compared to double wild type tumors in the NE region, indicating the presence of greater cellular packing and proliferation in EGFR amplification/CDKN2A loss regions. Finally, using single cell pathway based tumor classifications, we showed that nK2, a DSC-MRI metric representing cell size heterogeneity, correlated positively with neuronal signature and negatively with glycolytic/plurimetabolic signature within the NE tumor, indicating that glycolytic/plurimetobolic tumors possessed a high amount of cell size heterogeneity compared to neuronal samples. This hypothesis was supported using digital reference object (DRO) modeling which confirmed that cell size and heterogeneity drove the differential nK2 signal between neuronal and glycolytic/plurimetabolic samples. We identified immune cell infiltrate as one possible mechanism of increased cell size heterogeneity using transcriptomic signature analysis which found more immune cell signatures within glycolytic/plurimetobolic tumors compared to neuronal. Collectively this study demonstrates the central role of multi-parametric MRI as a non-invasive measure of tumor biology and a tool for understanding the clinically critical NE region which can then inform new therapies targeting this region of HGG recurrence. Citation Format: Matthew Flick, Taylor Weiskittel, Kevin Meng-Lin, Fulvio D'Angelo, Francesca Caruso, Shannon Ensign, Mylan Blomquist, Luija Wang, Christopher Sereduk, Gustavo De Leon, Ashley Nespodzany, Javier Urcuyo, Ashlynn Gonzalez, Lee Curtin, Kyle Singleton, Aliya Anil, Natenael Simmineh, Erika Lewis, Teresa Noviello, Reyna Patel, Panwen Wang, Junwen Wang, Jennifer Eschbacher, Andrea Hawkins-Daarud, Pamela Jackson, Kris Smith, Peter Nakaji, Bernard Bendok, Richard Zimmerman, Chandan Krishna, Devi Patra, Naresh Patel, Mark Lyons, Matthew Neal, Kliment Donev, Maciej Mrugala, Alyx Porter, Scott Beeman, Yuxiang Zhou, Leslie Baxter, Christopher Plaisier, Jing Li, Hu Li, Anna Lasorella, Chad Quarles, Kristin Swanson, Michele Ceccarelli, Antonio Iavarone, Nhan Tran, Leland Hu. Multi-parametric MRI maps regional heterogeneity of high grade glioma phenotypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5621.