Citations

Abstract Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.

Abstract Background Calculated LDL cholesterol (LDL-C) is a standard component of the lipid panel and an important risk factor in managing atherosclerotic cardiovascular disease (ASCVD). Due to the assumptions in the derivation of the Friedwald formula, fasting (≥8 hours) and triglyceride levels ≤400mg/dL have long been recommended. More recent data have shown that in most cases fasting has minimal effect on results, leading to the endorsement of non-fasting lipid panels for routine evaluation of ASCVD risk in clinical practice guidelines. Furthermore, newer equations (e.g. Sampson-NIH) allow for more accurate estimation of LDL-C even in the presence of hypertriglyceridemia. Mayo Clinic has implemented the Sampson-NIH LDL-C calculation and removed fasting/non-fasting designation from lipid panel orders. We hypothesized that the change to fasting designation would allow more afternoon draws for routine lipid panels and that increased non-fasting collections may increase triglyceride levels, but that the Sampson-NIH equation would prevent bias in LDL-C estimation. In order to test these hypotheses, we analyzed patient data from 1 year prior and 1 year post-implementation. Methods Results of lipid panels performed for one year preceding (n=334,719) and one year after (n=381,804) removal of the fasting/non-fasting designation and implementation of Sampson-NIH equation were collected. Median, 10th, and 90th percentile of draw time, triglyceride, and LDL-C calculated by either Sampson-NIH or Friedwald formulas were compared by quantile regression. Results Draw times shifted post-implementation at the 10th percentile (7:06 vs. 7:10, p<0.0001), median (8:49 vs. 9:08, p<0.0001) and 90th (12:02 vs. 13:46, p<0.0001). No difference in median triglyceride measurement was observed between pre-and post-implementation (110mg/dL), but slight differences were observed in the 10th and 90th percentile values (60 vs 59mg/dL and 224 vs 229mg/dL, p<0.0001). No difference was observed in 10th, 50th, or 90th percentile LDL values when calculated by Sampson-NIH equation (56, 99, 153mg/dL); however, if the Friedwald formula is used, a slight shift is observed in the 10th and 50th percentile LDL values (54 vs. 53, 97 vs. 96; p<0.0001) but not the 90th (150mg/dL). Conclusions Changing to the Sampson/NIH formula for LDL-C and removing fasting vs. non-fasting designation from routine lipid panels had minimal effect on reported triglyceride and LDL-C values, while allowing increased flexibility in draw time and reporting of LDL-C on patients with triglycerides ≥400mg/dL. Patients with TG ≥400mg/dL represented 1.7% of the dataset overall, including 5,387 patients before the change in which LDL-C could not be reported and 6,697 patients in the year post-implementation for whom LDL-C was reported based on the Sampson-NIH formula. Using an equation that is robust in patients with elevated triglyceride levels and removing fasting requirements from routine lipid panels allows greater flexibility and convenience for patients while allowing for more even distribution of phlebotomy workload and reporting of LDL-C results for patients with hypertriglyceridemia without evidence of clinically significant bias in reported results.

Abstract INTRODUCTION Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). Improvements in neuro-oncology practice and research have seen increased diagnosis of brain tumors. However, to our knowledge, there have been no previous projects on brain tumor genetics in SSA. To understand the feasibility of developing brain tumor biobanking and registries, this project aims to start by mapping out the current neuro-oncology capacity in terms of workforce and available services. METHODOLOGY We will conduct a descriptive questionnaire-based online survey among a cross section of neuro-oncology practitioners spread across SSA countries. The dissemination of the survey questionnaire will be facilitated by the Society for Neuro-oncology in SSA (SNOSSA). The Google designed questionnaire will capture information on the distribution, and number of available neuro-oncology care practitioners, capacity for brain tumor diagnosis and management, cancer registration, tumor biobanking, and research. CLINICAL IMPACT AND CONCLUSION This study will generate robust data from SSA, which can be used to improve future research and promote advocacy towards brain tumor diagnosis and management. This work will also serve as a pilot study for subsequent research that will focus on the development of brain tumor-specific registries and biorepositories in SSA.

In the ever-evolving healthcare landscape, hospitals routinely grapple with daily disruptions and unforeseen events affecting resources and capacity. This paper explores the implementation and impact of the Rochester Hospital Operations Command Center (RHOCC) as a strategic response to challenges faced by the Mayo Clinic Hospital campuses in Rochester. The RHOCC, developed with an expedited timeline in response to capacity issues, exacerbated by COVID-19, serves as a centralised hub for real-time monitoring, coordination and decision-making related to patient flow. The process of establishing the command centre involved role identification, skill set determination, location of important personnel in an organised central space and vendor selection to develop the necessary infrastructure. Dashboards were developed to provide real-time actionable insights into external transfers, surgical and other planned admissions, emergency department status, patient throughput and discharges. These dashboards include colour-coded keys highlighting thresholds related to patient flow metrics and are used to facilitate daily huddles and enhance transparency and data-driven decision-making among hospital stakeholders. The outcomes of implementing the RHOCC include improved efficiency and collaboration, as well as a significantly enhanced ability to proactively respond to factors affecting census. The development of a command centre — driven by leadership endorsement and a commitment to continuous improvement — emerges as a transformative strategy in healthcare innovation. The RHOCC’s approach of building capability, fostering inclusion and articulating a vision of providing superior care while driving impactful improvements, positions it as a leading force in creating operational efficiencies to define healthcare delivery.

Our previous study suggests that glial-derived neurotrophic factor (GDNF) is involved in allergen-induced airway hyperreactivity and remodeling in vivo. Here, we show that GDNF has no direct effects in remodeling of human airway smooth muscle (ASM) but GDNF dysregulates mitochondrial morphology in human ASM in the context of asthma.

Background: Surgical management of failed metacarpophalangeal (MCP) arthroplasties includes revision arthroplasty and arthrodesis. The purpose of this study was to review the indications and outcomes of arthrodesis as a salvage procedure for failed MCP arthroplasties. Methods: This was a retrospective cohort study of all patients undergoing salvage MCP arthrodesis at a single institution from 1990 to 2020. Patient charts were reviewed for patient demographics, indication for salvage, surgical technique, revision rate, and time to radiographic union. Patient-reported outcomes, including the Michigan Hand Outcomes Questionnaire and an MCP-specific questionnaire detailing pain, functional, appearance, and patient satisfaction, were also collected. Results: Eleven digits in 9 patients (6 women, 3 men, median age of 66) with median 36-month follow-up were included. The majority (91%) of patients also had concomitant soft tissue deformities, including joint contractures, extension lag, and collateral ligament insufficiency. The overall revision rate following arthrodesis was 45% with 3 digits requiring one revision each, and 2 digits undergoing 3 revisions. The overall union rate was 91% with median time to union of 4 months from most recent arthrodesis. Patient-reported outcomes obtained from 4 patients demonstrated improvements in pain and function. Conclusion: Despite a high revision rate of 45%, salvage MCP arthrodesis following arthroplasty has a high eventual union rate of 91% and is associated with improved pain and function based on 4 patients’ experiences. Arthrodesis as a salvage procedure for failed MCP arthroplasties should be considered in patients with persistent joint instability and functionally limiting soft tissue deformities.

Coronary CT angiography (CCTA) is now endorsed by all major cardiology guidelines for the investigation of chest pain and assessment for coronary artery disease (CAD) in appropriately selected patients. CAD is a leading cause of morbidity and mortality. There is extensive literature to support CCTA diagnostic and prognostic value both for stable and acute symptoms. It enables rapid and cost-effective rule-out of CAD, and permits quantification and characterization of coronary plaque and associated significance. In this comprehensive review, we detail the road traveled as CCTA evolved to include quantitative assessment of plaque stenosis and extent, characterization of plaque characteristics including high-risk features, functional assessment including fractional flow reserve-CT (FFR-CT), and CT perfusion techniques. The state of current guideline recommendations and clinical applications are reviewed, as well as future directions in the rapidly advancing field of CT technology, including photon counting and applications of artificial intelligence (AI).

Objectives: The purpose of this study was to characterize content posted by orthopaedic surgeons on social media (SM) while investigating patient perceptions of this content from various regions of the United States. Analysis was included regarding how this content may influence the respondents’ healthcare decisions. Methods: SM posts by orthopaedic surgeons were reviewed and categorized. A patient survey was written to assess respondent SM usage practices as well as respondent perceptions of these categories. The survey was administered in the clinic of 13 separate orthopaedic surgeons via QR code. Survey results were analyzed for differences in SM utilization. Patient responses were assessed to judge perception of social medial content types. Results: There were 674 completed patient surveys. The 18-24 (89.3%) and 25-34 (87.6%) age groups were more likely to report daily use (p=0.002), but SM utilization was high among all age groups. 23% of patients reported using SM to see information about their healthcare at least once per month, 38% of patients reported reviewing the SM account of a physician at least once per month, and 23% of patients reported that they were likely or very likely to view the SM account of their own physician. 26% of patients reported that SM content is likely or very likely to influence which physician they see. Patients held the most consistently positive view of posts educating patients regarding common injuries, discussing sports team coverage, providing patient testimonials, and posts illustrating examples of imaging used to diagnose and treat patients. Patients held consistently neutral views of posts educating colleagues, discussing research and presentations at national meetings, displaying aspects of surgeons’ personal lives, and supporting marginalized groups. Several post categories elicited negative or highly polarized responses including those discussing research publications, showing surgical techniques or pictures/videos taken during surgery, or political statements. Conclusions: SM is an increasingly useful tool to help physicians interact with patients or build a practice. Physicians who wish to interact with patients should consider posting content viewed most positively including posts educating patients, discussing sports team coverage, and patient testimonials. Content that is viewed less favorably should be posted sparingly or with a sensitive tag. The most effective way to reach large patient populations appears to be through Instagram, Facebook, Tik Tok, Snapchat, and LinkedIn, in that order. Further ongoing study is required to understand the differences between physician SM content focused on interacting with patients compared to content focused on interacting with other physicians.

Abstract Aims Degenerative mitral stenosis (DMS) is due to degenerative mitral annular calcification (MAC) and valvular calcification. However, DMS impacts on the outcome, and therefore, potential treatment needs are poorly known. We aimed at evaluating survival after DMS diagnosis by Doppler echocardiography in routine practice. Methods and results A cohort of 2937 (75 ± 12 years, 67% women) consecutive patients were diagnosed between 2003 and 2014 with DMS (diastolic mean gradient ≥ 5 mmHg), with analysis of short- and long-term survival. All patients had overt mitral annular/valvular degenerative calcification without rheumatic involvement. Mean gradient was 6.5 ± 2.4 mmHg, and DMS was considered mild in 50%, moderate in 44%, and severe in 6%. DMS was associated with left atrial enlargement (52 ± 23 mL/m2) and elevated pulmonary pressure (49 ± 16 mmHg) despite generally normal ejection fraction (61 ± 13%). DMS was associated with frequent comorbid conditions (74% hypertension, 58% coronary disease, and 52% heart failure) and humoural alterations (haemoglobin 11.3 ± 1.8 g/dL and creatinine 1.5 ± 1.4 mg/dL). One-year mortality was 22%, most strongly related to older age, higher comorbidity, and abnormal haemoglobin/creatinine but only weakly to DMS severity (with anaemia 42% irrespective of DMS severity, P = 0.99; without anaemia 18, 23, and 28% with mild, moderate, and severe DMS, respectively, P < 0.0004). Long-term mortality was high (56% at 5 years) also mostly linked to aging and weakly to DMS severity [with anaemia P = 0.90; without anaemia: adjusted-hazard ratio: 1.30 (1.19–1.42), P < 0.0001, for moderate vs. mild DMS and 1.63 (1.34–1.98), P < 0.0001, for severe vs. mild DMS]. Conclusion DMS is a condition of the elderly potentially resulting in severe mitral obstruction and haemodynamic alterations. However, DMS is frequently associated with severe comorbidities imparting considerable mortality following diagnosis, whereas DMS severity is a weak (albeit independent) determinant of mortality. Hence, patients with DMS should be carefully evaluated and interventional/surgical treatment prudently considered in those with limited comorbidity burden, particularly without anaemia. Keywords: Degenerative Mitral Stenosis; Outcome; Natural history; Ecocardiography; Mitral Stenosis.

ObjectiveDe novo variants in cullin‐3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient‐derived T‐cells.ResultsWe assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss‐of‐function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin‐protein conjugates in vitro. Notably, we show that 4E‐BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient‐derived cells.InterpretationOur study further refines the clinical and mutational spectrum of CUL3‐associated NDDs, expands the spectrum of cullin RING E3 ligase‐associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2025;97:76–89