Publications by Year: 2026

PURPOSE: Diabetic kidney disease (DKD) in type 1 diabetes has been shown to be strongly associated with insulin resistance, but this has not been previously explored using the euglycemic-hyperinsulinemic clamp. Therefore, we investigated insulin sensitivity in people with type 1 diabetes with and without DKD using M/I-values (mean glucose disposal rates [GDR]/mean plasma insulin) and compared GDRs to estimated GDR (eGDR)-formulae.

METHODS: In this pilot study, we studied 17 adult individuals with type 1 diabetes (ten with and seven without DKD) using euglycemic-hyperinsulinemic clamps and assessed correlations between GDR and eGDR values.

RESULTS: M/I-values were 62.5% lower in individuals with type 1 diabetes and DKD compared to those without DKD, albeit not statistically significant (0.16 ± 0.08 vs. 0.10 ± 0.08 mg/kg/min per mIU/L, P = 0.154). In the whole group (n = 17) eGDR by Williams et al. demonstrated the highest correlation with GDR (r = 0.35, P = 0.167), while eGDR by Januszewski et al. had the highest correlation in the DKD group (n = 10, r = 0.46, P = 0.177).

CONCLUSION: Our pilot study suggests the possibility of increased insulin resistance in people with type 1 diabetes and DKD.

BACKGROUND: Venous thromboembolism (VTE) remains a critical concern in plastic and reconstructive surgery (PRS) due to prolonged operative duration, perioperative immobility, and procedure-specific risks. While low-molecular-weight heparin (LMWH) has been the prophylactic standard, use of direct oral anticoagulants (DOACs) and aspirin (ASA) has been gaining traction. This study summarizes prophylactic practices in PRS.

METHODS: A systematic search of three databases was conducted. Studies evaluating ASA, DOACs, or LMWH prophylaxis in PRS with VTE, bleeding, or 30-day reoperation rates were included. Mixed anticoagulant regimens were excluded. Data on dosage, duration, and complication rates were extracted. A random-effect meta-analysis of proportions was conducted.

RESULTS: Of 884 studies screened, 7 met inclusion criteria, totaling 3,475 patients: ASA (n=402), DOACs (n=2056), and LMWH (n=802). Common regimens included ASA 325mg daily for 5 days and DOAC 10mg daily for 10 days; LMWH dosing varied. VTE rates were low across groups: 1.15% ASA, 0.3% DOACs, and 0.44% LMWH. Hematoma rates were similar for ASA (4.6%) and LMWH (4.5%), while DOACs had a higher rate (8.7%), largely influenced by an outlier. Reoperation rate was highest for ASA (16.9%), followed by DOACs (10.5%) and LMWH (8.0%).

CONCLUSION: Despite comparable VTE rates across agents, variability in bleeding and reoperation highlights the need for procedure-specific, individualized prophylaxis. ASA and LMWH may offer more predictable safety profiles, while DOACs remain promising but warrant further investigation LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

CRISPR-Cas enzymes must recognize a protospacer-adjacent motif (PAM) to edit a genomic site, greatly limiting the range of targetable sequences in a genome. Although engineering strategies to alter PAM specificity exist, they typically require labor-intensive, iterative experimentation. We introduce an evolution-informed deep learning model, Protein2PAM, to efficiently guide the design of Cas protein variants tailored to recognize specific PAMs. Trained on a dataset of over 45,000 CRISPR-Cas PAMs, Protein2PAM rapidly and accurately predicts PAM specificity directly from Cas proteins across type I, II and V CRISPR-Cas systems. Using in silico mutagenesis, the model identifies residues critical for PAM recognition in Cas9 without using structural information. We use Protein2PAM to computationally evolve Nme1Cas9, generating variants with broadened PAM recognition and up to a 50-fold increase in PAM cleavage rates compared to the wild type in vitro. Our machine learning approach allows Cas enzymes to target sequences that were previously inaccessible because of PAM constraints, potentially increasing target flexibility in personalized genome editing.

COVID-19 posed a significant threat to the mental health of the population in general and college students in particular, severely disrupting their daily routines due to protective measures and lockdown policies. The abrupt transition from in-person to online learning further introduced uncertainty regarding academic performance. To comprehensively assess the impacts of the pandemic on college students, this study collected longitudinal data from June 2020 to June 2021, involving 184 undergraduate students at Worcester Polytechnic Institute. The dataset includes demographic and socioeconomic status information of participants, measures of mental health outcomes, online student engagement, computer and Internet performance, daily activity diary, general indoor environment satisfaction, Fitbit data, sensor measured indoor environment quality, facial expression, and GPA. To our best knowledge, this dataset is also the first dataset that covers multimodal assessment of mental health outcomes, online learning, and potential influencing variables during COVID-19. Data was gathered through online surveys, video recordings, IoT indoor environmental sensors, and Fitbit wristbands.

Antibody-secreting cells (ASCs) play a central role in the pathophysiology of systemic lupus erythematosus (SLE). This single-arm, open-label, phase 2 clinical trial aims to evaluate the safety and efficacy of the ASC-depleting anti-CD38 monoclonal antibody daratumumab in patients with SLE (NCT04810754). The primary endpoint is the reduction in serum anti-double-stranded DNA (anti-dsDNA) antibody levels at week 12. Key secondary end points include safety, clinical efficacy, and immunologic changes. Ten female patients with active disease and inadequate responses to at least two immunosuppressive drugs have received eight subcutaneous injections of 1800 mg daratumumab weekly, with dexamethasone as premedication (20 mg for first two injections, then 10 mg). By week 12, anti-dsDNA antibody levels have been reduced by a median of 109.6 IU/ml (95% CI 38.1 - 274.5). The treatment resulted in rapid and sustained clinical improvements across all patients and organ domains, reflected by a 100% SRI-4 (Systemic Lupus Erythematosus Responder Index-4) response rate at week 12. Hypogammaglobulinemia occurred in 5/10 patients, requiring immunoglobulin substitution. Daratumumab treatment has depleted circulating ASCs, reduced type I interferon activity, and profoundly modulated the T-cell responses. These findings highlight the pivotal role of ASCs in SLE pathogenesis and support daratumumab as therapeutic option for SLE.

The lytic-latent balance is a major viral persistence strategy and obstacle to curing viral diseases, yet its mechanisms remain poorly understood. Following lytic infection in non-neuronal cells, herpes simplex virus (HSV) establishes latency specifically in neurons and is reactivated by stresses. Here we identify forkhead box (FOX) transcription factors that can strongly activate or repress replication of HSV-1 and other alphaherpesviruses, and show that neurons express activating Fox (e.g., Foxf) genes poorly but repressive Fox (Foxk) genes abundantly while non-neuronal or stressed neuronal cells exhibit higher expression of activating Fox genes. Remarkably, knockdown of Foxk1 or overexpression of activating Fox genes induces reactivation from latency in male mouse neuronal culture and in vivo. Of note, FOX proteins bind the viral genome globally and nonsequence-specifically and interact with epigenetic cofactors for gene regulation. FOXF1 interacts with CBP and P300 to acetylate and open viral chromatin. FOXK1 works with SIN3A, a cofactor of histone deacetylation, and MAX to suppress HSV-1 and antagonize activating FOX proteins. Therefore, the viral lytic-latent balance is controlled by the relative abundance of counteracting host transcription factors that recruit different epigenetic regulators to the viral genome.

OBJECTIVES: To examine the association between receipt of psychotherapy and behavior reduction among long-stay nursing home residents with Alzheimer's disease and related dementias (ADRD).

DESIGN: Retrospective cohort study using Minimum Data Set assessments linked to Medicare: Master Beneficiary Summary File, Part B Carrier, and Part D Event file (2017-2018).

SETTING AND PARTICIPANTS: All US Medicare- or Medicaid-certified nursing homes. Traditional Medicare beneficiaries enrolled in Medicare Parts B and D, aged ≥65 with ADRD and any problematic behaviors (physical, verbal, or other), stratified to residents with both ADRD and co-occurring psychiatric disorders, and ADRD only.

METHODS: The unit of analysis was 2 consecutive quarters with indication of a problematic behavior in the first. Outcomes were reductions in any, physical, verbal, or other behaviors. The treatment was receipt of psychotherapy in both quarters vs neither. Covariates included predisposing, enabling, and need factors. Propensity score weighting balanced resident characteristics, and generalized estimating equation logistic models were applied.

RESULTS: The cohort included 175,165 resident-quarter observations from 99,584 unique long-stay residents with ADRD and problematic behaviors. Psychotherapy was received in 9% of observations, most often in short (73%), quarterly (59%), or monthly (35%) sessions delivered by psychologists (56%) or social workers (34%). After weighting, psychotherapy was associated with greater likelihood of behavior reduction (ADRD + psychiatric disorders: 17%, P < .01; ADRD only: 33%, P < .05). In ADRD-only residents, psychotherapy was associated with 36% reduction in physical behaviors and 28% in verbal behaviors. In those with ADRD + psychiatric disorders, reductions were seen in physical (31%) and other behaviors (18%).

CONCLUSIONS AND IMPLICATIONS: Fewer than 10% of nursing home residents with ADRD and problematic behaviors received psychotherapy, yet its receipt was significantly associated with behavior reduction. Findings underscore the need to expand access to psychotherapy in nursing homes and to further investigate the psychotherapy characteristics that contribute to effectiveness.

Fuchs endothelial corneal dystrophy (FECD) is an age-related disorder characterized by excessive extracellular matrix (ECM) deposition and loss of corneal endothelial cells (CEnCs), eventually leading to corneal blindness. Despite known environmental and genetic contributors, the roles of aging and hormonal influences, particularly in the predominantly female population, remain underexplored in FECD. This study investigates the impact of chronic exposure to combined ultra-violet (UV-A) light and the oxidized estrogen metabolite 4-hydroxyestradiol (4-OHE2) on healthy CEnCs, primarily focusing on the cellular senescence pathway implicated in FECD pathogenesis. Our results show that prolonged exposure triggers G0/G1 cell cycle arrest through the p16-pRB pathway, inducing a senescence-mediated pro-secretory phenotype. The senescent cells in G0/G1 phase concurrently upregulated the fibrotic and extracellular matrix (ECM) markers indicating a complex relationship between senescence with fibrosis and ECM deposition. Additionally, multiplex analysis to detect senescence-associated secretory phenotype (SASP) after chronic exposure revealed significant upregulation of pathogenic factors such as IL-8 and IL-17, which were attenuated by SB225002 (anti-CXCR2) and secukinumab (anti-IL-17A). Senolytic cocktail of Dasatinib and Quercetin treatment alleviated fibrosis by selectively eliminating senescent cells and improved the survival of healthy cells. This study introduces a novel in vitro model of FECD, revealing the crucial role of cell cycle modulation, senescence and interleukins in the disease advancement and pathogenesis. The findings suggest that targeting senescence and cytokine-driven inflammation could be a promising therapeutic strategy for mitigating FECD progression.