Citations

Abstract Introduction Epicardial fat is known to be elevated in patients with type 2 diabetes mellitus (T2DM), but the clinical significance of this fat deposition is not fully understood. Purpose We assessed the epicardial adipose tissue in patients with T2DM and diabetic retinopathy (DR) without history of cardiovascular disease (CVD) when compared to healthy controls, and assessed the associations with cardiac function and severity of retinopathy. Methods 101 T2DM patients without history of CVD who underwent eye assessment for stages of retinopathy and 92 healthy controls underwent magnetic resonance imaging (MRI) for the assessment of epicardial & pericardial adipose tissue, cardiac function (left ventricular ejection fraction – LVEF, and strain), native T1 mapping, liver fat and liver iron corrected T1 (cT1). Results When compared to controls, DR had increased epicardial adipose tissue, lower LVEF, indexed LV end-diastolic & stroke volumes, impaired global longitudinal & circumferential strains, increased myocardial T1, liver fat and liver cT1 (all adjusted for age, gender and BMI). There were no significant differences in left atrial size, LV wall thickness, pericardial fat in DR, compared to controls after adjustment for age, gender and BMI. Increased epicardial fat was associated with reduced global longitudinal strain and severe (proliferative) retinopathy. Conclusions Patients with T2DM and retinopathy have elevated epicardial fat which is associated with reduced cardiac function, and presence of advanced retinopathy. T2DM with retinopathy without history of CVD may have underlying cardiac diseases and therefore should be considered for further cardiac evaluation. Epicardial fat may be a potential risk marker and therapeutic target in T2DM.Demographics and MRI parameters Epicardial adipose tissue and strains

Abstract Background Identification of the microorganisms causing infection in children with central nervous system infection is important. Conventional cerebrospinal fluid (CSF) tests may provide limited pathogen detection. CSF metagenomic next-generation sequencing (mNGS) may provide broader pathogen detection in a single assay. Methods Results of CSF mNGS testing performed at Mayo Clinic on patients and nonpatients between January 2024 and June 2025 were retrospectively analyzed. The subcohort of children treated at Mayo Clinic was analyzed to assess test performance as compared with conventional CSF diagnostics and potential clinical impact. Results In total 134 patients (138 CSF mNGS tests) from 22 US states and 2 international sites were included. Overall positivity was 16% with viruses representing most (59%) detections. In the Mayo Clinic subcohort (n = 15), test positivity was 27%: organisms included single detections of Streptococcus mitis group and HIV type 1, as well as 2 detections of Epstein-Barr virus, all confirmed by conventional tests. Positive results were associated with CSF pleocytosis (P = .026). Higher yield was observed in participants whose care was overseen by pediatric infectious diseases (PID) specialists (P = .026) and when a specimen hold strategy was applied (P = .033). Most results (87%) did not alter antimicrobial therapy, with 2 negative results contributing to antimicrobial de-escalation. Conclusions CSF mNGS demonstrated higher diagnostic yield in patients whose specimens showed CSF pleocytosis and in those who had PID consultation. Diagnostic stewardship strategies were applied, including specimen hold approaches and PID consultation.

Introduction: Underrepresented in family medicine (URiFM) physicians hold 14.42% of US family medicine faculty positions. Scholarship is critical to academic advancement. We explored family medicine department chairs’ racial allyship, their identification of scholarship barriers faced by URiFM faculty, and the existence of initiatives to increase scholarship. Methods: We used the 2022 Council of Academic Family Medicine Educational Research Alliance (CERA) Department Chair survey to examine the percentage of chair-perceived URiFM departmental faculty members and their scholarly productivity and chair-perceived barriers to productivity and initiatives. We measured chairs’ racial allyship. We calculated descriptive statistics, weighted means, and used regression to identify whether chair characteristics or allyship scores were associated with support of URiFM faculty scholarship initiatives and identification of the minority tax. Results: One hundred nine chairs completed the survey (response rate 48.4%); 13.76% identified as URiFM; 6.4% reported they perceived more than 50% of their faculty were URiFM; 90.8% of chairs did not report programs supporting URiFM scholarship; and 44.9% described URiFM faculty scholarly output as minimal or none. Department chairs’ mean allyship score was 2.59 (SD = 0.80) out of 5. Chairs ranked lack of research skills and lack of funding for protected time higher than the minority tax from a list of scholarship barriers. We found no association between chair allyship scores, chair characteristics, total department full-time equivalents, and the existence of a URiFM faculty scholarly support program. Discussion: Despite chairs reporting low URiFM faculty scholarly output, few departments have a dedicated support program. Chair allyship scores were not associated with identification of scholarship barriers or existence of scholarship programs.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Abstract Background New insights into community-acquired pleural infection microbiology may enable development of more rapid and accessible diagnostics that can streamline treatment. This study systematically compared molecular approaches for pathogen detection in pleural fluid from patients with such infections. Considering the need for rapid results with minimum hands-on time and test complexity, off-label use of the cassette-based, random-access BIOFIRE Joint Infection Panel (BF-JIP, bioMérieux) with and without supplementary in-house polymerase chain reaction (PCR) assays was evaluated. Methods Pleural fluids from 162 subjects from the Mayo Clinic (Rochester, Minnesota) and Haukeland University Hospital (Bergen, Norway), where molecular tests are routinely used for analyzing pleural fluid, were studied. The performance of the BF-JIP was compared to 16S rRNA gene PCR followed by Sanger and/or next-generation sequencing (16S rRNA gene PCR/sequencing), an in-house PCR panel specifically designed for pleural space infections, and culture. Results The BF-JIP supplemented with 3 in-house PCR assays targeting Fusobacterium nucleatum group, Streptococcus intermedius/constellatus, and Aggregatibacter aphrophilus detected 96.8% of pleural infections, providing complete microbial profiles in 70.1%. In comparison, the detection rate of 16S rRNA gene PCR/sequencing was 92.2%, providing complete microbial profiles in 87.0%. Culture detected bacteria in only 31.9% of pleural fluids, providing complete microbial profiles in 15.3%. Conclusions These results underscore the importance of molecular approaches in diagnosing pleural space infections and demonstrate the feasibility of panel-based PCR-based diagnostics for these sometimes-complex infections. The BF-JIP, designed for testing synovial fluid, could be modified to provide a useful diagnostic for testing pleural fluid.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

BACKGROUND & OBJECTIVE Sleep-disordered breathing (SDB) may be a remediable contributor to abnormal cognitive outcomes for children with myelomeningocele. We investigated the frequency of SDB among neonates with fetal vs postnatal myelomeningocele repair. METHODS In this nine-center, prospective, observational study, neonates with myelomeningocele born at more than 30 weeks gestational age underwent a 10-hour bedside polysomnogram at at least 35 weeks postmenstrual age, before hospital discharge. The primary outcome was SDB severity, reflected by the apnea-hypopnea index (AHI; number of respiratory events per hour of sleep). Decisions regarding surgical timing (fetal vs postnatal), technique (open fetal vs fetoscopic approach), and SDB treatment were made by the clinical teams. RESULTS Among 173 infants, 92/173 (53%) had SDB (median AHI 22.5, IQR 12.2–44.2). In unadjusted analysis, AHI was higher among the 90 neonates with fetal repair vs 83 with postnatal surgery (median 29, IQR 14–49, vs 19, IQR 10–36, P = .008). In propensity-adjusted multivariable models, prematurity was independently associated with AHI, whereas surgical timing (fetal vs postnatal) was not. Hindbrain herniation, myelomeningocele level, and clinical need for ventriculoperitoneal shunt did not predict AHI in adjusted models. Supplemental oxygen was commonly prescribed, for 44% of fetal vs 39% of postnatal myelomeningocele repair infants (P = .5). CONCLUSIONS SDB affects more than half of neonates with myelomeningocele. The higher AHI after fetal surgery could stem from the elevated incidence of prematurity in this group. As SDB is treatable and has a potential impact on neurodevelopment, routine screening could become an integral part of a strategy to optimize long-term medical and neurodevelopmental outcomes.

Abstract Exercise training improves cardiovascular health and reduces the risk for future cardiovascular events and mortality. However, emerging evidence suggests that Masters athletes may have a higher prevalence of cardiovascular abnormalities, such as atrial arrhythmias, coronary atherosclerosis, aortic dilatation, and myocardial fibrosis, compared to their less active peers. The clinical management of Masters athletes may be challenging as available guidelines for such conditions are generally based on data derived from symptomatic sedentary patients, limiting their applicability to highly trained individuals. Other unique challenges in the clinical assessment of Masters athletes include differences in symptomatic presentations compared to sedentary individuals, potential resistance to the initiation of pharmacologic treatment, and the increasing availability of consumer wearable health data that may provide relevant information on their cardiovascular health status. The purpose of this joint EAPC/ESC and ACC Clinical Consensus Statement is to provide an in-depth update on the current state of knowledge on abnormal cardiovascular findings in Masters athletes. We present an expert-based approach on the diagnostic assessment, management, and prognosis of (i) atrial fibrillation, (ii) bradyarrhythmias, (iii) ventricular arrhythmias, (iv) coronary atherosclerosis, (v) aortic dilatation, (vi) myocardial fibrosis, and (vii) exercise-induced arrhythmogenic cardiomyopathy. Clinical challenges, areas of ongoing controversy, and uncertainty and the potential underlying mechanisms are discussed. We also present future perspectives and research directives to further refine current best practice strategies. This includes the need for clinical outcome studies, dedicated randomized controlled trials in athletes, and international registries with diverse populations and longitudinal follow-up to evaluate the natural history of cardiac abnormalities and facilitate development of evidence-based approaches in the clinical management of Masters athletes with cardiovascular abnormalities.

Abstract Background Phage therapy has emerged as a generally safe approach, as demonstrated in preclinical and clinical studies. However, data on efficacy, including optimal dosing frequency, remain limited. MRSE is a leading cause of foreign body-associated osteomyelitis and a potential target for phage therapy. Here, the activity of phage K alone and in combination with vancomycin (VAN), administered once (QD) or three times (TID) daily, against biofilms formed by two orthopedic infection-associated MRSE isolates on orthopedic screws was evaluated.Fig 1.in vitro multi-dose assay of methicillin-resistant S. epidermidis biofilm-coated cortical bone screws.IDRL, Infectious Diseases Research Laboratory; DMEM, Dulbecco's Modified Eagle Medium; PBS, phosphate-buffered saline; CFU, colony-forming units. Created in https://BioRender.comFig 2.Quantities of biofilm on screws after 24 hours of treatment.*Log10 CFU/cm² of biofilm on screws before treatments. Biofilm burden of the MRSE isolates prior to treatment ranged from 5.7 to 6.3 log10 CFU/cm². A Kruskal-Wallis test was performed to evaluate the statistical significance of biofilm reduction between treatment groups. The minimum inhibitory concentration (MIC), minimum biofilm inhibitory concentration (MBIC), and minimum biofilm bactericidal concentration (MBBC) of vancomycin for both IDRL-9410 and IDRL-9403 were 2, 2, and &gt;128 µg/mL, respectively. Methods MRSE IDRL-9410 and IDRL-9403 biofilms were formed on titanium cortical bone screws (D 1.5 mm, L 4 mm, surface area 0.33 cm²) in 0.2 mL of tryptic soy broth containing 10⁶ CFU/mL (Fig 1); testing was performed in triplicate on two separate days. After 24 hours, screws were rinsed with PBS and randomly assigned to: Dulbecco’s Modified Eagle Medium (DMEM); vancomycin (VAN, 20 μg/mL) in DMEM; phage K (10⁹ PFU/mL) in DMEM; or VAN and phage K in DMEM. Every 8 hours, screws from the TID groups were transferred to new plates containing fresh treatment, with QD groups left in the original material. 24 hours post-treatment, screws were quantitatively cultured. Bactericidal activity was defined as ≥ 3 log₁₀ CFU/cm² reduction compared to the DMEM group, and synergy as ≥ 2 log₁₀ CFU/cm² reduction in the combination group compared to VAN or phage alone. Results After 24 hours, bactericidal activity was observed for QD and TID VAN-phage K groups against IDRL-9410 (p &lt; 0.05 and p &lt; 0.01, respectively) and IDRL-9403 (both p &lt; 0.01). Synergy was observed in the VAN-phage K QD group, with a 2.2 log₁₀ CFU/cm² reduction for IDRL-9410 compared to VAN alone (Fig 2). 3.0 and 5.3 log₁₀ CFU/cm² reductions were observed in the VAN TID groups for IDRL-9410 and IDRL-9403, respectively, compared to the DMEM group (both p &lt; 0.01). There was no statistically significant difference in biofilm reduction between the QD and TID groups for phage K alone or VAN-phage K for either strain. Conclusion Combination treatment with phage K and VAN, administered QD or TID, showed greater biofilm reduction compared to phage K alone. Increasing phage dosing frequency did not enhance biofilm reduction under the conditions studied. Disclosures Robin Patel, MD, a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection: a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection|MicuRx Pharmaceuticals and bioMérieux: Grant/Research Support|PhAST, Day Zero Diagnostics, DEEPULL DIAGNOSTICS, S.L., Nostics, HealthTrackRx, bioMérieux and CARB-X: Advisor/Consultant|Up-to-Date and the Infectious Diseases Board Review Course: Honoraria

Abstract Background Staphylococcus aureus is a challenging pathogen which causes a multiplicity of human diseases around the globe, acquired in the community and healthcare settings alike. Treatment of S. aureus infection can be challenging and is further compromised by antimicrobial resistance. Understanding of its pathogenesis, transmission pathways and the dynamics of its genome evolution and associated adaptations is incomplete. One strategy to assess genome evolution is to assess codon bias. Historically, studies have focused on the consequences of coding changes; assessing silent mutations in the form of synonymous codon usage bias represents a novel approach to studying genetic adaptation.Figure 1.Principal component analysis (PCA) (A) and sPLS-DA (B) separate S. aureus from complex mates.sPLS-DA component 1 relies on a hypothetical protein, identified here by its NCTC 8325 genomic coordinates, as important for separating S. aureus from complex mates (C). Methods Here, the codon bias of 2,872 genes was queried against all publicly available complete S. aureus plasmids and genomes. Using public BioSample data, genomes were sorted by disease state (e.g., bacteremia, pulmonary infection) and geographical collection site. Results Isolates from Nairobi, Kenya were most different from other isolates, suggesting that geographical isolation may shape codon bias signature. In addition, codon bias of two MSCRAMM proteins implicated in human disease - SdrC and FnBPB - varied between isolation sources, suggesting a role for codon bias in S. aureus genetic adaptation to selective pressures of infection. Additionally, codon bias out-performed coding and nucleic acid mutational metrics in separating members of the S. aureus complex, S. aureus, Staphylococcus argenteus, Staphylococcus schweitzeri, and Staphylococcus roterodami; Fig 1, sparse partial least squares analysis (sPLS-DA) mean AUC codon: 0.89762, nucleic acid: 0.82266, codon bias: 0.9996 (relying on hypothetical protein NC_007795.1:516850-517419). Conclusion This analysis suggests that codon bias in S. aureus is a source of genetic adaptation that can be used to separate strains by geographical isolation source, and separate S. aureus sensu stricto from other S. aureus complex members. Disclosures Nicholas Bedard, MD, Stryker: Advisor/Consultant Robin Patel, MD, a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection: a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection|MicuRx Pharmaceuticals and bioMérieux: Grant/Research Support|PhAST, Day Zero Diagnostics, DEEPULL DIAGNOSTICS, S.L., Nostics, HealthTrackRx, bioMérieux and CARB-X: Advisor/Consultant|Up-to-Date and the Infectious Diseases Board Review Course: Honoraria