Citations

ABSTRACT Immune checkpoint‐inhibitors (ICIs) have revolutionized and significantly improved cancer care through remarkable efficacy, but significant adverse effects have been observed. Among these, ICI‐induced myocarditis with myositis/myasthenia gravis overlap syndrome represents a life threatening, severe immune‐related adverse event that clinicians need to be aware of and be able to diagnose rapidly given its aggressive course. We present two patients who were treated with ICIs and subsequently developed said syndrome. Both patients experienced significant cardiac and neuromuscular manifestations and despite high‐dose intravenous steroids, intravenous immunoglobulin, and other adjunctive therapies, both patients rapidly deteriorated and elected to withdraw care. Additionally, we review the pathophysiology, diagnosis and management of ICI‐induced myocarditis with myositis/myasthenia gravis overlap syndrome. Overall, the overlap syndrome has a poor prognosis and high mortality rates requiring prompt recognition, discontinuation of ICIs and initiation of immunosuppressive therapies.

ABSTRACT Gain-of-function mutations in the transient receptor potential 6 (TRPC6) channel have recently been recognized as risk factors for both doxorubicin (DOX)-induced cardiomyopathy. Functional evaluation of TRPC6 missense variants is therefore important for cancer patients undergoing anthracycline treatment. However, traditional electrophysiological methods are labor-intensive and time-consuming. In this study, we compared the functional responses of TRPC6 missense variants to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, using molecular docking and patch clamp recording techniques. For the wild-type (WT) TRPC6 structure (PDB ID: 6UZ8), OAG exhibited a binding energy of -4.49 kcal/mol and a dissociation constant (Kd) of 0.511 mM. Twenty TRPC6 missense variants were identified from cancer patients in the Mayo Clinic database. Of these, fifteen variants had resolvable structures, nine of which displayed increased Kd values and six decreased Kd values compared to WT in molecular docking analysis. Patch clamp recordings revealed that TRPC6 WT and mutant channels were inactive at baseline but were activated upon 50 μM OAG stimulation, except two loss-of-function variants. Moreover, a 24-h treatment with 0.5 μM DOX significantly enhanced OAG-induced channel activation. All three variants identified in patients with heart failure demonstrated gain-of-function properties in both electrophysiological measurements and in-silico predictions. Importantly, the results obtained from molecular docking and patch clamp recordings were strongly correlated, showing an 82% concordance, higher than the predictions from AlphaMissense. These findings indicate that our computational analysis provides a rapid and reliable method for predicting the functional impact of TRPC6 missense variants, which may aid clinical decision-making in cancer patients receiving chemotherapy.

Background: Femoroacetabular impingement (FAI) is a common cause of hip pain in young, active athletes. American football players place high demands on the hip due to the sport's requirements for pivoting, cutting, and loading in deep flexion. Although arthroscopic treatment of FAI in professional National Football League (NFL) players has shown favorable outcomes, football-specific outcomes in non-NFL athletes remain limited. Purpose: To report the return-to-sport (RTS) rates and functional outcomes at a minimum 2-year follow-up for active American football players competing at multiple levels after primary hip arthroscopy for FAI. Study Design: Case series; Level of evidence, 4. Methods: An institutional database was queried to identify all active American football players who underwent primary hip arthroscopy with labral repair between 2010 and 2023. Demographic characteristics, radiographic parameters, procedure details, complications, and reoperations were collected. Follow-up was completed at a minimum of 2 years to obtain updated patient-reported outcome measures (PROMs) as well as football-specific data, including current participation and RTS status. PROMs were reported as mean ± standard deviation, and categorical variables, including RTS, were reported as frequencies. Pre- versus postoperative PROMs were compared using t tests or Mann-Whitney U tests to assess outcomes. Results: In total, 49 hips in 38 male football players (age, 18.1 years; range, 14-26 years) were included. Most athletes played at the high school (74%) or college level (21%). A total of 51% played as linemen. Labral repair was performed in all cases. At a mean 7.6 years, mean modified Harris Hip Score was 90 ± 13, Hip Outcome Score–Activities of Daily Living was 95 ± 7, and Hip Outcome Score–Sport was 89 ± 17. Overall mean surgery satisfaction was 8.7 ± 1.7 (out of 10). Significant postoperative improvements were observed in all PROMs ( P ≤ .002). Twelve players (32%) did not attempt RTS due to other nonmedical factors and were excluded from return to sport analysis. A total of 23 (88%) players achieved RTS, and 3 players (12%) did not. Two players (8%) cited other injuries, and 1 player (4%) continued to have hip limitations. Four hips (8%) underwent reoperation at a mean 4.9 years postoperative. Conclusion: Amateur American football players undergoing primary hip arthroscopy for FAI demonstrated excellent patient-reported outcomes and a high RTS rate of 88%, when excluding those who did not return for nonmedical reasons, at a mean 7.6-year follow-up. Notable positional differences were observed across multiple levels of play. Although outcomes were generally favorable, both medical and nonmedical factors could limit return to sport, particularly among high school and college athletes.

FRACTURE MRI demonstrated strong agreement with conventional radiography and CT in evaluating key bone tumor characteristics, including lesion type, location, and matrix content.

Abstract Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. However, not all patients with t(11;14)(CCND1;IGH) respond to treatment, and some progress early after initial response. To investigate this, we examined 44 whole-genome and whole-exome sequencing data samples from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 patients with MM. The presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired prevenetoclax and postvenetoclax treatment samples, postvenetoclax progression was recurrently driven by the selection of genomic events in the BCL2/MCL1 and RAS pathways and of high-risk features (eg, loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.

Key Points Experimental autosomal dominant polycystic kidney disease is associated with longitudinal changes in the kidney micro-RNA and mRNA profiles. Alterations in cellular transport, a feature of CKD, and a common biological process within polycystic kidney disease models and human autosomal dominant polycystic kidney disease, is present from early stages. Early versus late micro-RNA expression changes in autosomal dominant polycystic kidney disease could be targeted for a more tailored therapeutic intervention in the disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development and enlargement of bilateral kidney cysts, which often leads to kidney failure. This study comprehensively characterized the expression profile of micro-RNAs (miRNAs) and their target genes in Pkd1 RC/RC mice and further compared them with other murine models of polycystic kidney disease (PKD) and a model of CKD and individuals with ADPKD. Methods Pkd1 RC/RC and wild-type (WT) mice ( n =10 each, five males and five females) were studied at 1, 6, and 12 months. At each time point, kidney volume was determined in vivo (magnetic resonance imaging), followed by ex vivo histomorphometric analyses. In randomly selected Pkd1 RC/RC and WT mouse kidneys ( n =5/genotype, at 1 and 12 months), miRNA-sequencing (seq) was performed, followed by mRNA-seq, integrated (miRNA-seq/mRNA-seq analysis), and functional analysis of miRNA target genes. Venn diagrams were constructed to identify overlapping and novel differentially expressed (DE) miRNAs in Pkd1 RC/RC and other commonly used murine models of PKD, diabetic kidney disease, and individuals with ADPKD. Results miRNA-seq analysis identified 41 and 181 miRNAs DE in Pkd1 RC/RC versus WT kidneys at 1 and 12 months, respectively, which were confirmed by quantitative PCR. Target genes of miRNAs DE in Pkd1 RC/RC at early stages encoded for proteins mainly implicated in cell proliferation and α -ketoglutarate ( α -KG) transport, whereas those DE at late stages encoded for transport proteins involved in proinflammatory and metabolic processes. Urine α -KG concentration ( 1 H nuclear magnetic resonance spectroscopy), its fractional excretion, and tissue levels were higher in Pkd1 RC/RC during the entire course of the disease and associated with decreased protein expression of α -KG transporters sodium-coupled dicarboxylate transporter 3 and organic anion transporter 1. We further identified common DE miRNAs among murine models of PKD, diabetic kidney disease, and previous reports in individuals with ADPKD, as well as several novel miRNAs DE in early and late Pkd1 RC/RC kidneys, which have not been previously reported in either other murine models of PKD or patients with ADPKD. Conclusions Our study demonstrates that the renal miRNA expression profile changes longitudinally with the progression of the disease and might suggest that the post-transcriptional regulation of α -KG transport could represent a novel early feature of the disease.

This Viewpoint discusses the practice of molecular testing for the classification of thyroid nodules and explores related questions regarding automation, transparency, and clinical reasoning.

Background This study aimed to evaluate outcomes of different antibiotic durations in patients with severe diverticulitis. Methods Initial electronic medical record review identified 2437 adult patients who underwent sigmoid colectomy. Manual chart review identified 133 patients who underwent sigmoid resection and proximal diversion for Hinchey stage 3 or 4 diverticulitis. Patients who received a short antibiotic course (SAC, ≤5 days) were compared with those who received a long antibiotic course (LAC, >5 days). The primary composite outcome included superficial, incisional, organ-space infections or death within 30 days post procedure. Results A total of 53 SAC patients and 55 LAC patients were identified. The composite outcome occurred more frequently in LAC patients than in SAC patients (40% vs 15%; P = .005). Organ-space infection occurred more frequently in LAC patients than in SAC patients (31% vs 13%; P = .04). Conclusions Extended duration of antibiotics after adequate source control does not improve outcomes even in the setting of extensive intra-abdominal contamination.

This paper summarizes the presentations and panel discussion provided at Plenary Panel #2 on the first day of the 16 th World Congress of the International Radiation Protection Association (IRPA) jointly organized with the 69th Annual Meeting of the Health Physics Society (HPS) in Orlando/Florida in July 2024. International organizations that play a key role in radiation protection and are close in contact with IRPA by official agreements or even MoU’s (Memorandum of Understanding) presented highlights of their projects in radiation protection as well as results. Topical issues on their current work program as seen in a list of statements, including future efforts, were presented and discussed. The needs of practitioners were stressed for recognition by the representatives of the international organizations to be included in their projects. Requested and presented topics were: • Key challenges for radiation protection practitioners in the next 10 y. • Potential effects of emerging science on radiation protection. • Challenges for implementation of IAEA Safety Standards in low- and middle-income countries. • Challenges in occupational radiation protection. • Broadening the process of optimization. • Impact of emerging technologies on radiation protection. • Ensuring radiation protection workforce for the future.