Citations

ABSTRACT Novel β-lactam/β-lactamase inhibitors (βL/βLIs) are important therapies for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, the global extent of resistance to these agents and the impact of resistance on patient outcomes are unclear. We therefore evaluated patients with CRPA isolates at 35 hospitals (nine countries) from December 2018 to November 2019. Antimicrobial susceptibility testing was performed at a central laboratory by agar dilution for ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) and by broth microdilution for imipenem-relebactam (I/R). Characteristics and outcomes, including desirability of outcome rankings (DOOR), were compared between patients infected with isolates not susceptible vs susceptible to each agent. Of 800 CRPA isolates, susceptibility to C/T, CZA, and I/R was 69%, 67%, and 33%, respectively. USA isolates ( n = 526) were more frequently susceptible to these agents than isolates from other countries ( n = 274; C/T: 83% vs 42%; CZA: 77% vs 47%; I/R: 37% vs 23%; P < 0.001 for each comparison) and isolates with carbapenemases ( n = 157) were less frequently susceptible than isolates without carbapenemases ( n = 643; C/T: 7% vs 84%; CZA: 24% vs 77%; I/R: 6% vs 39%; P < 0.001 for each comparison). Thirty-day mortality and DOOR were similar overall in patients infected with isolates not susceptible vs susceptible to each βL/βLI. However, the adjusted probability of a better DOOR outcome for a randomly selected patient with bacteremia due to a C/T-not susceptible vs -susceptible isolate was 38.2% (95% confidence interval, 25.6%–52.7%). Resistance to novel βL/βLIs, especially I/R, is common in CRPA, particularly outside the USA and in carbapenemase-producing isolates. Additional treatment options are needed for CRPA infections.

Inverted sinonasal papilloma (ISP) and respiratory epithelial adenomatoid hamartoma (REAH) are sinonasal lesions with overlapping clinical, radiographic, and histologic features, making accurate diagnosis challenging. ISP is a benign but aggressive tumor with a propensity for local destruction, recurrence, and malignant transformation, whereas REAH is a hamartomatous lesion often arising in the olfactory cleft. We present four patients with lesions initially suspected to be ISP based on intraoperative frozen section but ultimately diagnosed as REAH on permanent pathology. All patients had polypoid sinonasal masses, frequently involving or adjacent to the olfactory cleft. Intraoperative frozen sections were often inconclusive or favored ISP, reflecting the difficulty of distinguishing these entities. Histologic analysis revealed that epithelial thickness served as a key morphologic feature differentiating ISP from REAH, with REAH exhibiting ciliated glandular proliferation and ISP characterized by hyperplastic epithelium with features of columnar and squamous differentiation. These patients underscore the diagnostic pitfalls of small biopsies and frozen sections, and highlight the importance of permanent specimens and collaboration with experienced pathologists. Accurate differentiation is critical, as management strategies differ substantially: ISP requires aggressive resection and long-term surveillance, while REAH may be treated with limited excision and minimal follow-up.

BACKGROUND AND OBJECTIVES: Craniopharyngiomas are complex intracranial tumors that pose significant challenges in surgical management. We aimed to develop risk-stratified surgical outcome benchmarks for adult patients undergoing endoscopic craniopharyngioma resection by using the Registry of Adenomas of the Pituitary and Related Disorders database to facilitate comparisons across institutions and guide clinical decision-making. METHODS: A retrospective cohort of adult patients (18 years and older) with craniopharyngioma undergoing a first-time endoscopic transnasal surgery across 14 academic centers in the United States was analyzed using data collected from 2011 to 2024. Patients were stratified into low-risk and high-risk cohorts based on criteria including age, body mass index, selected tumor characteristics (size, infundibular relationship, intraventricular extension), and previous radiation. Surgical outcomes were analyzed, and benchmarking ranges were defined using the established methodology. RESULTS: The overall cohort included 318 patients with a mean age of 50 years. Upon benchmarking analysis (50th-75th percentile performance), low-risk patients (n = 136) had a median length of stay of 4.0 to 6.0 days, 90-day readmission rates of 15.5% to 22.2%, skilled nursing facility discharge rates of <1.0%, postoperative cerebrospinal fluid leak incidence of <1.0% to 14.3%, gross total resection rates of 50.0% to 60.8%, new postoperative arginine vasopressin deficiency rates of 33.3% to 50.0%, and tumor progression/recurrence rates of <1.0% to 18.3% over a median follow-up period of 27.0 (IQR 10.5-56.5) months. Benchmarking ranges were proposed for each outcome to facilitate cross-institutional comparisons. CONCLUSION: Establishing surgical outcome benchmarks for adult patients undergoing craniopharyngioma resection using data from the Registry of Adenomas of the Pituitary and Related Disorders provides a framework for assessing surgical performance and guiding clinical decision-making. Benchmark ranges can inform institutional quality improvement efforts, perioperative risk stratification, and patient counseling regarding expected postoperative outcomes.

Introduction The WHO/UNICEF Nurturing Care Framework (NCF) features five domains necessary for child development—physical/mental health, responsive caregiving, adequate nutrition, security and safety and opportunities for early learning. We explored caregiver perspectives on the NCF in two African settings. Methods Between November 2023 and July 2024, 14 focus group discussions (FGDs) were conducted with caregivers living with and without HIV; eight with mothers in Gaborone, Botswana, and six with mothers and fathers in Nairobi, Kenya. FGDs were stratified by country, sex, HIV status and partnership status. Semi-structured interviews with interactive activities elicited caregiver perspectives on the NCF to identify the most ‘important’, ‘easiest’ and ‘challenging’ domains to fulfil. Thematic analyses identified key themes and compared perspectives. Results Our qualitative study included 101 caregivers, 55 from Kenya (30 mothers, 25 fathers) and 46 mothers from Botswana. Overall, caregivers identified physical/mental health as the ‘most important’ domain to fulfil for children and caregivers, noting how closely tied they were (“ If you have pain, that pain affects your child” ). The ‘most challenging’ domain was adequate nutrition in Botswana and security and safety in Kenya. The ‘easiest’ domains were responsive caregiving in Botswana and opportunities for early learning in Kenya. Kenyan caregivers noted that spiritual nourishment was also critical for well-being but missing from the NCF. Caregivers emphasised the importance of receiving social support with childcare. Caregivers living with HIV expressed similar views compared with caregivers without HIV, but mentioned that social isolation, stigma and treatment disruption impact their ability to provide adequate nurturing care. Conclusions Caregivers face unique parenting challenges depending on cultural environment. HIV disrupts caregivers’ health, which has important implications for raising children within families affected by HIV. Interventions that support caregivers’ abilities to fulfil all NCF domains and address challenges are essential to ensure children reach their developmental potential.

Chylous effusion is a complication most frequently seen in the iatrogenic setting secondary to thoracic surgery or other intervention. Management of this complication includes conservative measures, surgical exploration/ligation, and percutaneous thoracic duct embolization. This case presents a medically complex patient with persistent chylous effusions after thoracoscopic resection of a fluorodeoxyglucose (FDG) and Cu 64 DOTATATE-avid retrocrural lymph node. Initial conventional fluoroscopic lymphangiogram and thoracic duct embolization were unsuccessful. Subsequent magnetic resonance lymphangiography (MRL) more accurately localized the leak which was then marked with computed tomography-guided needle placement before conversion to fluoroscopically guided embolization. This case demonstrates the utility of MRL as a problem-solving tool for localizing hard-to-treat lymphatic leaks. MRL localized embolization is a safe and effective treatment for lymphatic leaks.

Background: Preliminary evidence examining ibogaine in neuropsychiatric and substance use disorders is accumulating. As patient interest and off-label use grow, clinicians require an understanding of emerging dosing strategies, investigational protocols, and reported adverse effects to appropriately counsel patients and contextualize potential risks and benefits. Methods: Databases were searched for human studies of ibogaine, noribogaine, or 5-MeO-DMT with relevant clinical outcomes, prioritizing randomized controlled trials (RCTs), microdosing paradigms, and sequential protocols. Results: Only three RCTs were identified. First, a double-blind pilot study in 20 cocaine-dependent adults found that a single 1800 mg dose of ibogaine was associated with reduced craving versus placebo over follow-up of up to 24 weeks. Second, an ascending-dose trial in 36 healthy volunteers showed that noribogaine doses of 3–60 mg were safe and well-tolerated, without opioid-agonist effects. Third, a randomized crossover trial in 27 opioid-dependent patients receiving noribogaine 60–180 mg demonstrated dose-dependent heart rate-corrected QT interval (QTc) prolongation with non-significant reductions in withdrawal symptoms. Thus, two RCTs enrolled substance-dependent populations, while one focused on safety and pharmacokinetics in healthy volunteers. Microdosing and escalating sequential protocols remain experimental, lack standardized definitions, and are supported only by preliminary observational data. Adverse effects include neurologic, psychiatric, and cardiac events, including QTc prolongation; fatalities have occurred in the presence of medical and substance use comorbidities. Conclusions: The available evidence is confined to case reports, observational analyses, and small early-phase or proof-of-concept studies. Given ibogaine’s cardiotoxicity and narrow therapeutic margin, clinical use cannot be recommended without confirmation from larger, well-controlled trials.

Background: Complex repairs of radial meniscal tears have shown increased fixation strength compared to conventional sutures. A simplified 2-suture hybrid and a novel dual tie-grip repair with interconnected vertical mattress sutures spanning the tear were tested and compared to all-inside double-horizontal and tie-grip repairs. Hypothesis: The dual tie-grip repair would increase the initial compression load across the tear and show the least cyclic displacement and highest failure strength. Study Design: Controlled laboratory study. Methods: A total of 40 porcine medial menisci were assigned to 4 repair groups: double-horizontal, hybrid, tie-grip, and dual tie-grip (10 per group). Results from tie-grip repairs were used to assess the effect of vertical mattress suture interconnection. After suture placement according to the described technique and fixation, the initial compressive load, stiffness, and relief displacement were measured. The repaired specimens underwent cyclic loading between 5 and 30 N over 1000 cycles (0.75 Hz), while cyclic stiffness and displacement were measured. Ultimate stiffness and load-to-failure were analyzed at 3.15 mm/s. Results: Analysis of variance revealed that dual tie-grip and hybrid repairs showed higher initial compressive load and relief displacement than the other techniques, with dual tie-grip repair reaching the highest values for both metrics (load: 19.3 ± 2.3 N [ P < .001]; displacement: 0.75 ± 0.19 mm [ P < .001]). The double-horizontal repair had the lowest initial stiffness ( P < .001). Cyclic displacement was lowest for the dual tie-grip repair and highest for the double-horizontal repair (both P < .001). All repaired specimens stiffened during cycling without intergroup differences. Analysis of covariance for stiffness over displacement revealed higher stabilization ( P < .040) with dual tie-grip repair and reduced stabilization ( P < .001) with double-horizontal repair. Despite comparable ultimate stiffness across groups, the dual tie-grip repair failed predominantly by suture rupture at the highest ultimate load (275.5 ± 26.2 N; P < .001), whereas the double-horizontal repair failed by tissue rupture the earliest (127.2 ± 15.9 N; P < .001). Conclusion: The dual tie-grip repair provided the highest initial compression across the radial meniscal tear, the lowest cyclic displacement, and the greatest load-to-failure among all techniques in a porcine cadaveric model. The simplified 2-suture hybrid repair showed higher initial compression than other repairs and comparable cyclic stability to the tie-grip repair. Clinical Relevance: The dual tie-grip repair provided high compression across the radial tear and strong resistance to cyclic displacement. Future clinical series assessing differences in healing rates among different repair groups are warranted.

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

ABSTRACT Aims Exercise capacity is a powerful predictor of cardiovascular risk. In patients unable to exercise, body composition analysis can potentially be used to estimate cardiorespiratory fitness. We developed a body composition “fitness” score, then validated its utility in two external populations. Methods and Results We included patients from four sites undergoing single photon emission computed tomography (SPECT) and twelve sites undergoing positron emission tomography (PET). We quantified body composition using deep learning. We evaluated associations between body composition and good exercise capacity (defined as completing ≥7 minutes on a Bruce protocol) then developed a body composition “fitness” score. We then assessed the associations of “fitness” score with exercise capacity and all-cause mortality in external populations. In total, 36471 patients were included with median age 67 (interquartile range 58 – 74). Median skeletal muscle density was higher among patients with good exercise capacity. In the external SPECT population, the body composition “fitness” score had higher prediction performance for good exercise capacity (AUC 0.771, 95% CI 0.752 – 0.789) than age (AUC 0.717, p<0.01). In the external PET population, high body composition “fitness” score was associated with lower cardiovascular death (adjusted hazard ratio 0.70, 95% CI 0.62 – 0.79, p<0.001). Conclusions We demonstrated that a comprehensive body composition “fitness” score could identify patients with good cardiorespiratory fitness. This approach transforms routinely acquired CT data into a surrogate marker of fitness which can be applied in patients undergoing PET, or other CT imaging, where exercise testing is not performed. Graphical Abstract Overview of study design. The overall population (n=36471) was split as outlined above. Body composition was analyzed from available computed tomography imaging. The distribution of body composition measures were analyzed in the combined single photon emission computed tomography (SPECT) populations. A body composition “fitness” score was derived to predict good exercise capacity in the internal population, with associations assessed in the two external testing populations.