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Basic Science and Pathogenesis
Get PDFBACKGROUND: Alzheimer's disease (AD) is a complicated neurodegenerative disorder influenced by dynamic interactions among clinical, microbial, and other complex underlying mechanisms. The Alzheimer's Disease Analysis Model Generation 1 (ADAM-1) is an innovative multi-agent large language model (LLM) framework proposed to deal with the complications of analyzing diverse and multi-modal datasets. ADAM-1 integrates clinical datasets, microbiome profiles, and existing Alzheimer's publications using retrieval-augmented generation (RAG) techniques supporting AI agents to enhance diagnostic and analytical capabilities offering unified and comprehensive insights into Alzheimer's disease prognosis.
METHOD: The study incorporates a multi-modal dataset with paired clinical and gut microbiome data from 102 nursing home residents, including 64 healthy controls (HC) and 38 individuals with AD, collected across four facilities in central Massachusetts as part of one of our previous studies. ADAM-1, built on the GPT-4o-mini-2024-07-18 model, integrates three AI agents designed for Alzheimer's binary classification: a computational agent for generating descriptive statistics, a summarization agent for synthesizing insights from the data and knowledge database, and a classification agent for performing binary predictions based on prior outputs. The knowledge database comprises 80,909 Alzheimer's-focused publications from PubMed. Classification performance was assessed using F1 scores across 15 randomized seeds, with comparisons to XGBoost as the baseline model. The study was conducted using Python 3.10.14 on an Ubuntu 24.04.1 LTS workstation with four 3090 GPUs.
RESULT: For Alzheimer's classification, ADAM-1 achieved a mean F1 score comparable to that of XGBoost (p = 0.0967, t-test) while demonstrating significantly reduced F1 score variance (p = 0.0083, F-test), indicating more stable performance across evaluations using 15 randomized seeds. The reduced variance in F1 scores emphasizes the reliability of ADAM-1 in handling relatively small sample data, a common scenario in clinical translational research.
CONCLUSION: ADAM-1 offers a robust and consistent platform for multi-modal data analysis in Alzheimer's research. The system's human-machine interaction through natural language queries enhances data interpretability, expanding and broadening researchers' insights in analyzing such complex datasets. Future versions of ADAM will include blood biomarkers and neuroimaging thus enabling more comprehensive and precise diagnostics, advancing the understanding of the complicated and dynamic underlying mechanisms of Alzheimer's disease progression.No embarg
Optimization of VE607 to generate analogs with improved neutralization activities against SARS-CoV-2 variants
Get PDFSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a threat to human health, particularly among immunocompromised and elderly individuals, given their heightened vulnerability to coronavirus disease 2019 (COVID-19)-associated morbidity and mortality. Recently, omicron subvariants such as KP.3.1.1 and XEC have emerged with an enhanced ability to evade humoral immunity. The development of new strategies against these variants of concern remains an intense area of research. The small molecule VE607 is an entry inhibitor that targets the Spike glycoprotein and delays virus spread in vivo. To improve the potency of this new class of SARS-CoV-2 entry inhibitors, we generated and characterized VE607 analogs and identified candidates with enhanced activity against variants, including KP.3.1.1 and XEC. Promising analogs exhibited higher inhibitory potency than the original compound and stabilized the receptor-binding domain in its "up" conformation. Among these, DY-III-281 also reduced viral burden and delayed death in SARS-CoV-2-challenged K18-hACE2 transgenic mice. Furthermore, combining DY-III-281 with a non-neutralizing antibody engineered for Fc-enhanced functions exhibited an additive effect in reducing SARS-CoV-2-induced disease burden in mice. Our findings support the continued development of small-molecule entry inhibitors, alone or in combination with antibody-based therapies, as a promising strategy to counteract emerging SARS-CoV-2 variants.
Importance: Mutations in the Spike glycoprotein drive viral evolution and confer resistance to current vaccines and some therapeutic interventions against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we report new analogs of the SARS-CoV-2 small-molecule entry inhibitor VE607. These analogs exhibited improved potency against emerging SARS-CoV-2 variants, including KP.3.1.1 and XEC. One analog, DY-III-281, delayed viral replication in SARS-CoV-2WA1-challenged K18-hACE2 transgenic mice, suggesting that small-molecule compounds targeting viral entry might be useful in fighting evolving SARS-CoV-2 variants.No embarg
Differential associations of the stages of pressure and stasis ulcers and social engagement among nursing home residents
No full textBackground: Social engagement is an important determinant of health in older adults. Skin ulcers may adversely impact social engagement among nursing home residents. This study sought to quantify the differential associations between pressure and stasis ulcers and social engagement among long-stay US nursing home residents.
Methods: Cross-sectional, nationally representative data was obtained from the Minimum Data Set 2.0 on US nursing home residents aged ≥ 50 years with an annual assessment between Oct 1, 2009 and Sept 30, 2010. Adjusted prevalence ratios (aPR) of low social engagement among residents with the four stages of pressure and stasis ulcers and 95 % confidence intervals (CI) were estimated from multivariable Poisson models using a generalized estimating equation approach to account for residents nested within nursing homes.
Results: Among the 771,634 residents, 4.5 % had pressure ulcers, and 1.1 % had stasis ulcers. The presence of pressure ulcers, regardless of the stage, was associated with an increased risk of low social engagement (stage 1 aPR: 1.05 (95 % CI: 1.03-1.07); stage 4 aPR: 1.07 (95 % CI: 1.05-1.08)). Residents with stage 1 to 3 stasis ulcers were less likely than those without any skin ulcers to have low social engagement. In contrast, those with stage 4 stasis ulcers had an increased prevalence of low social engagement (aPR: 1.10 (95 % CI: 1.06-1.14)).
Conclusion: Social engagement should be monitored and addressed in residents with skin ulcers. Since pressure and stasis ulcers have different etiologies and treatment modalities, they should be considered separately in the empirical work on their association with social engagement.No embarg
Safety and efficacy of preoperative embolization in the treatment of brain arteriovenous malformations with perinidal aneurysms and single draining vein: a multicenter study with propensity score-weighting
No full textBackground and objectives: Arteriovenous malformations (AVMs) with perinidal aneurysms and single draining vein are associated with an elevated risk of rupture and increased procedural complexity. The role of preoperative embolization in this high-risk anatomical subset remains unclear. This study aimed to evaluate the safety and efficacy of microsurgery with preoperative embolization, compared with microsurgery alone in patients with such AVMs.
Methods: We conducted a multicenter retrospective analysis of an AVM registry from the MISTA (Multicenter International Study for Treatment of Brain AVMs) consortium and included AVMs with perinidal aneurysms and a single draining vein. Baseline characteristics, angiographic outcomes, functional outcomes, and complication rates were compared. Propensity score weighting (PSW) using the covariate balancing method was applied to adjust for baseline differences.
Results: Out of a total of 1919 patients, 65 met the inclusion criteria; 45 patients underwent preoperative embolization followed by microsurgery, and 20 underwent microsurgery alone. After adjustment, complete obliteration rates were similar between groups (OR 0.87, 95% CI 0.04 to 16.33, P=0.92), as were rates of functional independence at discharge and follow-up. Overall complication, symptomatic complication, and mortality rates did not differ significantly between groups. However, permanent complications were significantly lower in patients with preoperative embolization (OR 0.06, 95% CI 0.004 to 0.84, P=0.03).
Discussion: In patients with AVMs featuring perinidal aneurysms and single draining vein, preoperative embolization followed by microsurgery was associated with fewer permanent complications and no increase in adverse outcomes compared with microsurgery alone. However, given the small number of events, this finding should be interpreted cautiously.No embarg
Comaneci-assisted embolization of wide-necked aneurysms: results from the SUCCESS postmarket US study
Get PDFBackground: Wide-necked intracranial aneurysms present unique challenges for endovascular treatment. The Comaneci device is a novel temporary bridging device designed to assist coil embolization without parent vessel occlusion.
Methods: The SUccess in Comaneci-assist Coils Embolization Surveillance Study (SUCCESS) was a multicenter, prospective, postmarket surveillance study conducted at 17 US centers. Ninety consecutive patients with wide-necked intracranial aneurysms were treated with Comaneci-assisted coiling. The primary effectiveness endpoint was successful aneurysm occlusion (Raymond-Roy class I/II) at procedure end. Primary safety endpoints included periprocedural events within 24 hours and clinical outcomes at discharge and 30 days.
Results: Of 90 enrolled patients (mean age 63 years, 63% female), 32 (36%) presented with ruptured aneurysms. Most common locations were anterior communicating (33%), internal carotid (20%), and posterior communicating arteries (19%). Successful occlusion was achieved in 85.6% of cases at procedure end and 94.7% at 6 months. Good clinical outcome (modified Rankin Scale (mRS) 0-2) was maintained from baseline (73%) through 30 days (81%) and 6 months (83%). Thromboembolic events occurred in 5.5% of cases, all asymptomatic. Device-related complications were minimal, with coil entanglement in 0.3% of deployed coils and no instances of deployment/retrieval failure. All-cause mortality was 4.4%, confined to the ruptured aneurysm cohort.
Conclusions: The SUCCESS study demonstrates high rates of successful aneurysm occlusion with Comaneci-assisted coiling, with occlusion rates persisting through 6 month follow-up. The safety profile was favorable, with low rates of thromboembolic events compared with other assist techniques. These results support the use of the Comaneci device for wide-necked aneurysm treatment in both ruptured and unruptured settings.
Trial registration number: NCT04518670.No embarg
Using intervention mapping to develop training for US dental providers to recommend the HPV vaccine
No full textIntroduction: Iowa has the highest incidence of oropharyngeal cancer (OPC) in the US, and human papillomavirus (HPV) is the most common cause of that disease. An HPV vaccine is approved for OPC prevention, but its uptake is low. We identified dental offices as novel settings in which the HPV vaccine can be recommended to patients, and we describe our use of the Intervention Mapping (IM) framework to develop an intervention that prepares dental providers to recommend the vaccine to parents of patients aged 9-17.
Methods: Our planning group used IM to engage in (1) needs assessment, which involved surveying dental hygienists (n = 470) and interviewing dental hygienists (n = 19) and dentists (n = 20); (2) method and (3) theory identification; and (4) intervention development, (5) implementation, and (6) evaluation, resulting in our "Educate, Recommend, Refer" intervention.
Results: The needs assessment showed dental providers were willing to learn more about the HPV vaccine but needed training to confidently recommend it. We chose training methods that increase self-efficacy, in accordance with behavior change theory. Multiple health behavior theories and frameworks also prompted our development of supporting materials, that encouraged participants to engage in vaccine promotion, as well as an evaluation plan.
Conclusion: IM guided our integration of theory, existing evidence, and stakeholder input to create an intervention that comprehensively addressed the needs of our target audience and overcame limitations of other similar interventions. Presenting intervention development in accordance with the IM framework also gives practitioners clear information for its replication or adoption.No embarg
Rlim coordinates diurnal regulation of food intake and thermogenesis [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Energy homeostasis in mice is maintained through coordinated activity among hypothalamic nuclei that regulate food intake and thermogenesis. These processes must adapt to the sleep-wake cycle, yet the underlying pathways, cell types, and molecular mechanisms governing their diurnal regulation remain poorly understood. We show that mice lacking the E3 ubiquitin ligase are lean and resistant to diet-induced obesity, owing to reduced food intake and enhanced brown adipose tissue (BAT) thermogenesis. We identify GABAergic neurons in the suprachiasmatic nucleus (SCN)-components of the central circadian clock-as mediators of these effects. Specifically, in RIP-Cre neurons governs daily thermogenic rhythms, while in vasoactive intestinal peptide (VIP)-expressing neurons modulates diurnal feeding behavior. Thus, is a key regulator of diurnal rhythms controlling energy balance.No embarg
Evaluation of an Integrated Digital and Mobile Intervention for COPD Exacerbation [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and healthcare utilization, with frequent exacerbations contributing to emergency department visits and hospitalizations. This study evaluates a multimodal, community-based digital health intervention's association with changes in acute care utilization among patients with COPD to develop preliminary estimates of intervention effects.
Methods: In this decentralized, nonrandomized pilot clinical trial, participants with moderate to severe COPD were offered biometric monitoring, symptom tracking, on-demand MIH services, and a digital pulmonary rehabilitation program. Outcomes were compared between intervention participants and a weighted synthetic control group using full optimal matching. Weighted odds ratios derived from regression models were used to estimate intervention effect size. The primary outcome was hospitalization during the study period. Secondary outcomes included 30 and 90-day readmission rates, emergency department visits, and hospital length of stay.
Results: In total, 88 participants from the intervention arm (mean age 67, 50% female) were compared to a weighted synthetic control of 14,492 participants (weighted mean age 66, 48.7% female). We observed that participants in the intervention arm had a trend toward decreased hospitalization with an OR of 0.69 (CI 0.44-1.03, p=0.066). The intervention was also associated with 61% decreased odds of 30-day readmission after an index admission compared to controls (OR: 0.39, 95% CI: 0.16-0.95, p = 0.04). Trends toward reductions in ED visits and hospital length of stay were also observed.
Conclusions: A combined digital and mobile health approach to COPD management was associated with reductions in acute care utilization. These findings support further investigation into hybrid care models to enhance COPD self-management and improve patient outcomes. Future research should evaluate scalability, cost-effectiveness, and long-term clinical impact.No embarg
Employment Outcomes among People with Disabilities: Youth and Young Adult Employment Determinants
Get PDFA systematic scoping review of research published between 2000 and 2020 on employment of people with disabilities, that was funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR), was conducted by CeKTER (NIDILRR Grant #90DPEM0004, 2020–2025) researchers. All papers comparing people with disabilities to those without were excluded from the systematic scoping review. Among over 100 publications reviewed there was a wide and very disparate array of findings with numerous variables used and varying research questions. This result belies summative findings. There are numerous ways of organizing the disparate findings. This brief is part of a series of findings from the center’s systematic scoping review. In this brief we report on findings about determinants impacting the employment outcomes among youth and young adults with disabilities. Please note that all comparisons are always about corresponding peers with disabilities.The contents of this product were funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR), Grant #90DPEM0004 (The Center on Knowledge Translation for Employment Research, 2020-2025). NIDILRR is a Center within the Administration for Community Living (ACL). ACL in the Department of Health and Human Services (HHS). The contents of this product do not necessarily represent the policy of NIDILRR, ACL, or HHS and you should not assume endorsement by the Federal Government.No embarg
Risk-Based Services, Reoffending, and Rethinking Service Approaches for Justice-Involved Youth
Get PDFThe Youth Protective Factors Study is an unprecedented, multistate, multiyear examination of which risk and protective factors are most significant when it comes to reoffending—especially for serious offenses—among youth ages 10 to 23 in the juvenile justice system. This brief is the third in a series that shares key findings from the study to inform juvenile justice supervision, case planning, and service strategies aimed at improving public safety and youth outcomes.
Read the first brief, "Youth Reoffending: Prevalence and Predictive Risk Factors in Two States", here: https://doi.org/10.13028/219x-vs03
Read the second brief, "Protective Factors and Strength-Based Services: Impacts on Long-Term Youth Reoffending", here: https://doi.org/10.13028/21g7-nh83
Learn more about the Youth Protective Factors Study on our website, https://www.umassmed.edu/lawandpsychiatry/law-and-psychiatry-research/NIJ-Youth-Protective-Factor-Study/.This grant was funded by the National Institute of Justice #2020-JF-FS-0005. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice.No embarg