Citations

Abstract Objective Given the importance AI in genomics and its potential impact on human health, the American Medical Informatics Association—Genomics and Translational Biomedical Informatics (GenTBI) Workgroup developed this assessment of factors that can further enable the clinical application of AI in this space. Process A list of relevant factors was developed through GenTBI workgroup discussions in multiple in-person and online meetings, along with review of pertinent publications. This list was then summarized and reviewed to achieve consensus among the group members. Conclusions Substantial informatics research and development are needed to fully realize the clinical potential of such technologies. The development of larger datasets is crucial to emulating the success AI is achieving in other domains. It is important that AI methods do not exacerbate existing socio-economic, racial, and ethnic disparities. Genomic data standards are critical to effectively scale such technologies across institutions. With so much uncertainty, complexity and novelty in genomics and medicine, and with an evolving regulatory environment, the current focus should be on using these technologies in an interface with clinicians that emphasizes the value each brings to clinical decision-making.

Abstract Background Biofilms formed by antibiotic-resistant bacteria in wound beds present unique challenges in terms of treating wound infections. In this work, the in vivo anti-biofilm activity of a novel electrochemical bandage (e-bandage) designed to continuously deliver low amounts of hypochlorous acid (HOCl) was evaluated against wound biofilm infections caused by a clinical isolate of Pseudomonas aeruginosa resistant to all antibiotic classes except aminoglycosides. Methods 5 mm skin wounds were created on the dorsal surface of Swiss-Webster mice and infected with 106 CFU of P. aeruginosa. Biofilms were allowed to form over 2 days, after which e-bandages with Tegaderm™ or Tegaderm only were placed on the wound beds. Specifically, mice were randomized to one of three experimental groups (n = 7-8): 1) Tegaderm only (control); 2) non-polarized e-bandage; 3) polarized e-bandage using a wearable potentiostat. After 48 hours, animals were sacrificed and 10 mm skin biopsies containing the wound and surrounding tissue were harvested for bacterial quantification. Histopathology was performed on H&E-stained sections of wound beds from each treatment group. Blood was screened with an inflammatory cytokine panel. Wound healing (% area reduction; digital measurement) and purulence (observational scoring) were assessed in pre- and post-treatment wounds. Results 48 hours of polarized e-bandage treatment resulted in a mean reduction of 1.86 log10 biofilm CFUs/g (p < 0.0001) vs non-polarized controls, and 2.18 log10 CFU/g reduction (p < 0.0001) vs Tegaderm only controls (polarized, 7.6 ± 0.66 log10 CFU/g; non-polarized, 9.45 ± 0.26 log+10 CFU/g; Tegaderm only, 9.78 ± 0.16 log10 CFU/g). Compared to Tegaderm only, purulence reduction and wound healing were significantly higher for both non-polarized (purulence - p < 0.0001; healing - p < 0.01 ) and polarized treatment (purulence - p < 0.0001; healing - p < 0.0001) groups, but were not significantly different from each other. Histopathology and blood inflammation panel testing showed no significant differences between groups. Conclusion An HOCl-producing e-bandage reduced P. aeruginosa in wound biofilms, representing a potential antibiotic-free strategy for the treatment of recalcitrant wound infections. Disclosures Audrey N. Schuetz, MD, Merck: Advisor/Consultant Robin Patel, MD, Abbott Laboratories: Advisor/Consultant|Adaptive Phage Therapeutics: Grant/Research Support|Adaptive Phage Therapeutics: Mayo Clinic has a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics.|BIOFIRE: Grant/Research Support|CARB-X: Advisor/Consultant|ContraFect: Grant/Research Support|Day Zero Diagnostics: Advisor/Consultant|HealthTrackRx: Advisor/Consultant|Mammoth Biosciences: Advisor/Consultant|Netflix: Advisor/Consultant|Oxford Nanopore Technologies: Advisor/Consultant|PhAST: Advisor/Consultant|See details: Patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic|See details: continued, patent on an anti-biofilm substance issued|TenNor Therapeutics Limited: Grant/Research Support|Torus Biosystems: Advisor/Consultant|Trellis Bioscience, Inc.: Advisor/Consultant

Ovarian cancer remains a devastating disease with 5 year survival rate in advanced stage of only 27%. Advanced stage tumors metastasize through continuous shedding of tumor cells into the peritoneal fluid, aided by the resistance of these cells to anoikis, a form of apoptosis normally triggered by loss of cell‐matrix interactions. We have previously shown that the serine protease inhibitor SPINK1 activates anoikis resistance in ovarian cancer cells via its protease inhibitory function; however, the specific relevant protease target(s) remain unknown. To find these targets, we have synthesized an activity‐based protein probe with a diphenylphosphonate warhead that covalently modifies serine proteases, with greatest specificity towards trypsin‐like proteases. We have used this probe to identify ovarian cancer cell secreted and membrane‐bound serine proteases possessing differential activity in the presence versus absence of SPINK1, using a proteomics approach. We are evaluating candidate proteases for involvement in anoikis resistance in ovarian cancer models. Our studies implicate a serine protease network in regulation of anoikis in ovarian cancer cells. By identifying critical proteases that control anchorage‐independent viability in ovarian cancer metastasis, we aim to elucidate important downstream pathways and ultimately develop therapeutic approaches that can intervene in mechanisms of anoikis resistance. Support or Funding Information Mayo Clinic Graduate School, Rochester MN

Abstract Low-grade meningiomas with subtotal resection carry significantly shorter recurrence-free survival rates than those with gross total resection. We report the natural history of a case of low-grade meningioma after subtotal resection and review the literature. We aim to highlight known global health disparities in oncology treatment by describing a case of meningioma progression following subtotal resection. A 40-year-old Kenyan woman presented locally with headache, nausea, and vision loss over approximately a six month time period. A 5 cm olfactory groove meningioma was discovered, and she subsequently underwent subtotal resection that was likely limited due to hemorrhagic complications. Over the following two years, she developed progressive dizziness, nausea, gait instability, difficulty performing tasks, and visual loss prompting medical evaluation at our institution. Physical examination demonstrated blindness, bilateral proptosis with severe vertical gaze palsy, and prominent frontal bossing. MRI Brain revealed a 9 cm enhancing mass arising from the cribriform plate with elevation of an ununited overlying frontal craniotomy flap and apparent meningoceles extending through the presumed osteotomy bilaterally. She underwent successful resection with pathology demonstrating CNS WHO Grade 1 meningioma. Her postoperative neurologic exam showed subtle improvement, specifically in regards to orientation questions. In this patient, bone flap displacement from prior craniotomy allowed significant interval tumor growth while minimizing mass effect on brain parenchyma. This case highlights global health disparities in low-grade meningioma management related to appropriate healthcare access in underserved patients.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Importance Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. Objective To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38. Design, Setting, and Participants Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks’ postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria. Interventions Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care. Main Outcomes And Measures The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38. Results Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, −6.9% [95% CI, −15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7. Conclusion and relevance Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials. Trial Registration ClinicalTrials.gov Identifier: NCT02980276 ; EudraCT: 2016-001644-19