Citations

ABSTRACT Background Long‐term health effects of thymectomy in adults remain uncertain. Previous reports suggested associations with increased mortality, cancer incidence, and autoimmune disease, although these findings may reflect differences in patient selection, surgical indication, or follow‐up duration. We aimed to examine long‐term outcomes following adult thymectomy. Methods We performed a propensity score‐matched retrospective study of patients who underwent thymectomy or comparator cardiothoracic procedures, with follow‐up extending to 10 years. Primary outcomes were all‐cause mortality, new‐onset malignancy, and autoimmune disease. Findings were compared with those reported in a recent study that has raised caution regarding thymic excision. Results We identified 425 patients who underwent thymectomy and 5401 controls who underwent coronary artery bypass or valve surgery. After matching, 398 patients remained in each group. Thymectomy was not associated with increased mortality at 5 years ( HR = 0.63; 95% CI , 0.38–1.04) or 10 years ( HR = 0.78; 95% CI , 0.54–1.13). Excluding reclassified thymic cancers, 5‐year extrathymic malignancy incidence was 2.3% versus 1.8% ( p = 0.54); no significant differences were observed in immune‐related disease. Mortality was higher among patients with thymic malignancy. Among MG patients, only one event occurred, precluding reliable estimation. Conclusions Thymectomy was not associated with excess mortality or malignancy at 10 years compared with matched cardiothoracic controls. Indication‐stratified analyses within the thymectomy cohort showed higher mortality for thymic malignancy, with insufficient events to assess outcomes in MG patients. These findings do not support a generalized survival penalty from thymectomy, though caution is warranted for incidental thymic removal.

OBJECTIVE Severe (level 3) hypoglycemia is a life-threatening complication of diabetes associated with substantial risk of recurrence and long-term morbidity. This study examined how adults with diabetes interpreted severe hypoglycemic events and why they declined participation in a community paramedicine program (Diabetes Rescue, Engagement, and Management [Diabetes-REM]) designed to prevent recurrence. RESEARCH DESIGN AND METHODS We conducted semistructured qualitative interviews with adults with type 1 or type 2 diabetes who experienced severe hypoglycemia requiring emergency medical services and declined enrollment in Diabetes-REM. Interviews explored hypoglycemia management experiences and reasons for nonparticipation and were explored using thematic analysis. RESULTS Sixteen adults (44% female; mean age 60 years, range 25–83) participated. Four interrelated themes emerged. First, participants normalized glucose variability as a baseline condition of diabetes and interpreted severe events as situational and correctable when a cause was identifiable, or as inevitable when it was not, rather than as evidence of increased risk. Second, participants relied on prevention systems encompassing habitual routines, caregiver involvement, and glucose-monitoring technologies. Third, severe episodes were frightening and disruptive but typically prompted adjustments to personal management over pursuit of additional clinical support. Finally, reasons for declining Diabetes-REM included time constraints (56%), perceived lack of benefit (25%), and privacy concerns or discomfort with home visits (25%). CONCLUSIONS Among adults who declined a community paramedicine hypoglycemia prevention intervention, severe events were absorbed into existing self-management frameworks rather than viewed as signals of increased risk. Programs targeting hypoglycemia recurrence should account for patients’ risk perceptions and existing management systems, positioning support as complementary rather than corrective.

Abstract Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72 -associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.

Abstract We describe a case of a child with macrolide-resistant Mycobacterium abscessus who initially had clinical improvement on a dual β-lactam regimen but continued to have positive cultures. Suitable phages active against the bacterial strain were identified, administered both systemically and directly to the ear, and were associated with microbiological remission.

As machine learning (ML)-based decision support tools proliferate in clinical practice, understanding how clinicians integrate personalized ML predictions alongside randomized controlled trial (RCT) evidence is critical. We designed a web-based clinical decision support system (CDSS) presenting survival and adverse event data from a simulated RCT and ML model across 12 synthetic multiple myeloma scenarios. In a within-subjects study with 32 physicians, we evaluated how clinicians synthesize competing evidence sources to make treatment decisions. When ML and RCT outputs were concordant, physicians reported greater confidence than with RCT data alone. When results were discordant, most physicians shifted toward the ML-supported treatment, often before reviewing any information about model training or validation, suggesting a tendency toward automation bias rather than algorithm avoidance. Despite reporting higher perceived reliability after viewing model quality disclosures, physicians were largely unable to describe the validation procedures they had reviewed. Taken together, these findings reveal that clinicians may over-rely on ML recommendations even when equipped with tools designed to support critical appraisal. We discuss implications for CDSS design, clinician training, and the institutional safeguards needed before ML-based systems are deployed in high-stakes oncology settings.

Background The pathophysiology of CS is complex and is associated with increased inflammation and impaired vascular tone. Corticosteroids are recommended in septic shock and have been proposed as a potential treatment for other types of shock. Objectives We sought to evaluate the clinical outcomes associated with early corticosteroid use in patients with cardiogenic shock (CS). Methods Using a nationally representative database including over 1000 hospitals, we identified adults ≥18 years of age admitted from 2015–2023 with a diagnosis of CS. Patients with adrenal insufficiency, chronic rheumatologic conditions, COVID-19 infection and acute COPD exacerbation were excluded. Using inverse probability treatment weighting (IPTW), we assessed for the association of receiving early corticosteroids (within the first 2 days of admission) versus no early corticosteroids and in-hospital mortality. Results Of the 167,721 identified patients with CS, the mean (SD) age was 65.5 (±15.2) years and 35.0% were women. A total of 13.2% received any corticosteroid within the first 2 days of admission. The most common corticosteroid was hydrocortisone (73.9%). Mortality for those receiving and not receiving early corticosteroids was 48.8% and 29.6% ( p < 0.001), respectively. After IPTW, early corticosteroid use remained associated with a 3.1% (95% confidence interval [CI]: 2.4% to 3.8%, p < 0.001) higher mortality. Among patients with CS and concomitant sepsis, 27.6% received early corticosteroids, which was similarly associated with a higher mortality (weighted mean 5.8% [95% CI: 4.6% to 7.0%, p < 0.001]). Conclusions Approximately 1 in 7 patients with CS received corticosteroids early during their admission, which was associated with higher in-hospital mortality.

ABSTRACT Metallo-beta-lactamase (MBL)-producing Enterobacterales are a global public health concern. Infections caused by these pathogens are often hard to treat, with few effective agents currently available. While aztreonam-avibactam only recently gained U.S. and European regulatory approval, laboratories have implemented laboratory-developed tests (LDTs) using existing aztreonam and ceftazidime-avibactam reagents. We sought to compare the performance of four phenotypic methods, up to three reagent manufacturers, and two media manufacturers. One hundred two MBL-producing Enterobacterales isolates were evaluated at two sites (Centers for Disease Control and Prevention [CDC] and Johns Hopkins University [JHU] School of Medicine). The performance of four methods was evaluated: broth disk elution (BDE), disk stacking (DS), gradient diffusion strip stacking (SS), and a strip-to-disk proximity (strip-disk) method, which were compared to reference broth microdilution (rBMD) tested in parallel. Respective category agreement for CDC and JHU was 92.2% and 96.1% for BDE, 51%–76.5% and 31%–49% for DS, 71.6%–86.3% and 83.3%–86.3% for SS, and 82.4%–87.3% and 80%–89.2% for the strip-disk method. The SS essential agreement ranged from 46.1% to 62.7% for JHU and 54.9% to 92.2% for CDC. Interlaboratory reproducibility was 93.1% for rBMD, 92.2% for BDE, 47.1%–53.1% for DS, 76.5%–80% for SS, and 87.3%–88.9% for strip-disk. BDE was the only method that exceeded acceptable performance of >90% accuracy and reproducibility. DS had the lowest and most variable performance between sites and among the different disk manufacturers used. LDTs for combination testing can be highly variable, and further work is needed to improve standardization and harmonization to achieve accurate and reliable results for clinical purposes. IMPORTANCE Carbapenem-resistant Enterobacterales are classified as an urgent public health threat in the Centers for Disease Control and Prevention’s 2019 Antibiotic Resistance Threats Report. Among the most concerning resistance mechanisms are carbapenemase enzymes encoded on mobile genetic elements, which can spread rapidly between bacteria. Of the various carbapenemases, metallo-beta-lactamases are particularly challenging, as they confer resistance to nearly all beta-lactams, and current treatment options remain limited. While aztreonam-avibactam has been U.S. Food and Drug Administration (FDA)-approved for treating certain infections with limited or no alternative treatment options, no FDA-cleared susceptibility test is yet available. In this context, laboratory-developed methods, such as combination testing of aztreonam and ceftazidime-avibactam, play a critical role in guiding therapy. Our study evaluates several of the more common laboratory-developed tests compared to reference broth microdilution and found that broth disk elution was the most accurate; in contrast, other methods had variable performance, some demonstrating limited reliability and being prone to overcalling resistance.

Background: Hypoplastic left heart syndrome (HLHS) is defined as “a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”. Without treatment, HLHS is usually lethal in the neonate. Many hypotheses have been advanced to explain the etiology of HLHS; however, no single theory appears to fully explain the phenotypic variability seen in HLHS. Furthermore, many of these theories offer no explanations regarding the precipitating events which lead to the development of HLHS. Objective: This review considers and critically evaluates the strengths and weaknesses of the leading theories proposed to explain the pathogenesis of HLHS—including hemodynamic disturbances, primary myocardial structural defects, valvar malformations, and genetic or epigenetic alterations that may provoke developmental and anatomic abnormalities. After presenting each model, we propose a novel, comprehensive, and data-driven framework which may assist researchers in developing models for the pathogenesis of the various subtypes of HLHS. Methods: Key findings from human fetal imaging, histopathology, genetic studies, and animal models were considered, as well as the hypothetical contribution of each in observed HLHS phenotypes. The rationales for these findings as causal factors initiating individual HLHS patterns, as well as how they might contribute to HLHS in general, were critically analyzed. Results: The flow theory is strongly supported by animal models and in utero interventions that demonstrate the impact of altered hemodynamics on cardiac morphogenesis. However, the flow theory fails to identify initial causes of disturbed flow or related histological features of HLHS like endocardial fibroelastosis. The myocardial and valve-first models suggest an important role in developmental defects, but do not necessarily have a strong experimental basis that provides explanations for how they mediate HLHS. Genetic studies in patients with HLHS have identified several candidate causal mutations. However, such genetic causes of HLHS exhibit incomplete phenotypic penetrance and clinical impact. A multifactorial framework attempts to integrate these diverse mechanisms and may provide the most coherent explanation that can accommodate the heterogeneity and variable presentation of HLHS. Such a framework may identify multiple forces that drive disease but does not provide useful pathways for future research about HLHS. Conclusions: No single hypothesis has fully explained how HLHS is initiated, progresses, and presents with the clinical conditions that are encountered by cardiac surgeons and cardiologists. The most current models suggest that the spectrum of HLHS reflects acomplex interaction between genetic susceptibility, flow-dependent cardiac remodeling, and environmental factors in utero. A multifactorial model integrates these diverse mechanisms and may provide the most coherent explanation for the various phenotypic variations in HLHS. Based on our analysis of the most current data and the strengths and weaknesses of the current theoretical frameworks, we propose a novel research strategy aimed at identifying specific cardiac progenitor cell populations whose dysregulation may represent a unifying explanation for the etiology of the various phenotypes of HLHS. Based on the arguments made throughout this manuscript that evaluate the various genetic, structural, and hemodynamic models of initiation of disease, we believe that the significant phenotypic variability across the spectrum of HLHS (i.e., the different anatomic subtypes for “classic” HLHS) most likely reflects different underlying etiologies and mechanisms. At the very least, it is very likely that the timing of the insult is critical in determining anatomic subtype. Based on the published data and the arguments within this manuscript, it seems naive to think that there is a single unifying mechanism explain all forms of HLHLS.

Staphylococcus aureus is a well-known pathogen responsible for a wide range of diseases with life-threatening consequences. Its public health burden continues to be significant due to pervasive colonization and growing antimicrobial-resistance (i.e., methicillin-resistant S. aureus, MRSA). In the present study we found that exposure of human bronchial epithelial (hBE) cells to spent culture supernatants of the MRSA strain USA300 induced an increase in mitochondrial ROS production and ATP release that was inhibited by pretreatment with the ROS scavenger glutathione (GSH). ATP secretion involved activation of probenecid-sensitive pannexin 1 channels and bafilomycin A1-dependent exocytosis. ATP exocytosis was inhibited by an antagonist peptide targeting the Receptor for Advanced Glycation End (RAGE) products suggesting that RAGE activation was involved in regulating vesicular ATP release. ATP secretion produced a sustained increase in intracellular Ca 2+ concentration which was dependent upon Ca 2+ uptake from the extracellular solution. Moreover, the sustained JE2-induced Ca 2+ response was not observed in spent supernatants from the less virulent S. aureus agrA mutants used to stimulate hBE cells whereas media from fadX and codY mutants produced responses similar to JE2. Furthermore, wildtype, fadX and codY supernatants evoked secretion of the type-2 inflammatory cytokine IL-33, whereas no response was elicited by media from the less virulent argA mutant. These findings indicate that exposure to secreted virulence factors from S. aureus induces oxidative stress in hBE cells that leads to ATP secretion, sustained Ca 2+ uptake and IL-33 secretion, which has been previously shown to induce type-2 inflammation in airways. This abstract was presented at the American Physiology Summit 2026 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.