Citations

ABSTRACT Background Evaluating fairness in artificial intelligence (AI) is essential before clinical implementation to prevent unintended harm across diverse patient populations. This study assesses performance differences of an image-based surgical site infection (SSI) detection model across age, gender, geography, race, and skin color. Methods Model development/validation study using retrospective, multicenter data across surgical subspecialties from adults who submitted an image of their incision via the electronic health record within 30 days of their procedure between 2019-2024. Area under receiver operating curve (AUROC) was compared by age (<55 vs. ≥55 years old), gender (male vs. female), geography (Rochester, Minnesota vs. Jacksonville, Florida vs. Scottsdale, Arizona vs. regional Minnesota/Wisconsin areas), race (White/Caucasian vs. non-White/Caucasian), and skin color (Fitpatrick I-III vs. IV-VI and Monk A-E vs. F-J). Results Training data contained 13,702 images from 4,274 patients between 2019-2022 (50.1% ≥55 years old; 63.2% female; 91.6% White/Caucasian; 58.5% Rochester, 17.3% Florida, 10.5% Arizona; 96.3% light skin tone), of which 1,348 images (9.8%) had an SSI. No differences in SSI detection existed for age, gender, race, or skin color (AUROC 0.83-0.87, p>0.09), however geographical differences were significant: lowest AUROC 0.83 (95% CI 0.77-0.88) vs. highest AUROC 0.87 (95% CI 0.84-0.89, p=0.01). Temporal validation using 4,242 images from 1,353 patients between 2022-2023 showed intact fairness across subgroups (ΔAUROC ≤0.06) except geography (ΔAUROC ≤0.16). Conclusions The model behaved fairly across age, gender, race, and skin color, however geographical differences persisted. These findings have practical implications underscoring the importance of evaluating bias in clinical AI before deployment.

Abstract Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Abstract The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

This is the first sham-controlled study to investigate the effects of leg heat therapy (HT) on walking performance, vascular function, and quality of life in patients with peripheral artery disease (PAD). Adherence to HT was high, and the treatment was well tolerated. Our findings revealed that HT applied with water-circulating trousers evokes a clinically meaningful increase in perceived physical function and reduces the serum concentration of the potent vasoconstrictor endothelin-1 in patients with PAD.

INTRODUCTION Patients with peripheral artery disease (PAD) are at a heightened risk of cardiovascular events and have markedly reduced vascular function and exercise tolerance. Heat therapy (HT) has emerged as a practical treatment to improve cardiovascular health in young individuals as well in patients with overt cardiovascular disease. We recently reported that a single 90 min session of HT applied to the legs of patients with PAD using water‐circulating trousers increases popliteal artery blood flow and reduces blood pressure and the circulating levels of the potent endogenous vasoconstrictor endothelin‐1 (ET‐1). The objective of the present study was to test the hypothesis that the repeated exposure to leg HT would lower blood pressure and ET‐1 levels and improve walking performance and conduit artery and cutaneous vascular function in patients with symptomatic PAD. METHODS Thirty‐two patients with symptomatic PAD (Age: 68± 8 years; Ankle‐brachial index: 0.67 ± 0.1) were assigned using a balanced randomized design to undergo 90 min of HT (48°C) or a thermoneutral treatment (33°C) 3 times per week for 6 consecutive weeks. The following outcomes were assessed at baseline and 3 and 6 weeks after the intervention: 1) resting ankle‐brachial index, 2) post‐occlusive reactive hyperemia in the popliteal artery (phase contrast magnetic resonance imaging), 3) leg cutaneous thermal hyperemia (laser Doppler flowmetry), 4) resting blood pressure every 5 min for 70 min, 5) 6‐min walk distance and 6) serum levels of ET‐1 and total nitrate (NOx). RESULTS Participants completed 17.7 ± 0.6 treatment sessions, resulting in a compliance rate of 98.7%. In the group exposed to HT, systolic blood pressure (SBP) decreased from baseline by ~3 mmHg at 6 weeks, while in the control group SBP increased by ~1 mmHg. A significant group by time interaction was observed for the changes in SBP from baseline to 6 weeks ( p=0.0049) with significant group differences at 20 min (Change in SBP: Control: 6.27 ± 15.5 vs. HT: −7.60 ± 13.6 mmHg, p=0.015 ) and 60 min (Change in SBP: Control: 4.13 ± 15.1 vs. HT: −7.33 ± 13.7 mmHg, p=0.0386 ). Similarly, serum ET‐1 levels decreased by ~15% from baseline to week 6 following exposure to HT, while a ~6% increase in this parameter occurred in the control group (Change in ET‐1: Control: 0.16 ± 0.6 vs. HT: −0.30 ± 0.4 pg/mL, p=0.035 – one outlier removed). Resting ABI, diastolic BP, 6MWT distance, hyperemic peak flow and cutaneous thermal hyperemia were not different between groups. CONCLUSION Exposure to repeated HT reduces systolic blood pressure and ET‐1 levels in patients with symptomatic PAD. These findings indicate that HT may be a practical and accessible nonpharmacological tool to reduce cardiovascular risk in PAD patients. Support or Funding Information American Heart Association Scientist Development grant (16SDG27600003).

AbstractDT388–GM-CSF, a targeted fusion toxin constructed by conjugation of human granulocyte-macrophage colony-stimulating factor (GM-CSF) with the catalytic and translocation domains of diphtheria toxin, is presently in phase I trials for patients with resistant acute myeloid leukemia. HL-60/VCR, a multidrug-resistant human myeloid leukemia cell line, and wild-type HL-60 cells were used to study the impact of DT388–GM-CSF on metabolism of ceramide, a modulator of apoptosis. After 48 hours with DT388–GM-CSF (10 nM), ceramide levels in HL-60/VCR cells rose 6-fold and viability fell to 10%, whereas GM-CSF alone was without influence. Similar results were obtained in HL-60 cells. Examination of the time course revealed that protein synthesis decreased by about 50% and cellular ceramide levels increased by about 80% between 4 and 6 hours after addition of DT388–GM-CSF. By 6 hours this was accompanied by activation of caspase-9, followed by activation of caspase-3, cleavage of caspase substrates, and chromatin fragmentation. Hygromycin B and emetine failed to elevate ceramide levels or induce apoptosis at concentrations that inhibited protein synthesis by 50%. Exposure to C6-ceramide inhibited protein synthesis (EC50∼5 μM) and decreased viability (EC50 ∼6 μM). Sphingomyelinase treatment depleted sphingomyelin by about 10%, while increasing ceramide levels and inhibiting protein synthesis. Diphtheria toxin increased ceramide and decreased sphingomyelin in U-937 cells, a cell line extremely sensitive to diphtheria toxin; exposure to DT388–GM-CSF showed sensitivity at less than 1.0 pM. Diphtheria toxin and conjugate trigger ceramide formation that contributes to apoptosis in human leukemia cells through caspase activation and inhibition of protein synthesis.