Tag: nevin manimala

J Phys Chem B. 2026 Apr 15. doi: 10.1021/acs.jpcb.6c00165. Online ahead of print.

ABSTRACT

Electron transfer (ET) in protein receptor-ligand complexes is governed by environmental structure, memory, and fluctuation statistics. We investigate ET dynamics within a non-Markovian open-quantum-systems framework using a non-Markovian stochastic Schrödinger equation (NMSSE), contrasting the conventional harmonic (Gaussian) bath approximation with an anharmonic, non-Gaussian environment modeled by discrete Poisson (shot-noise) events. The model consists of a two-state donor-acceptor dimer coupled to a discrete vibrational mode and embedded in a structured protein-membrane environment. To represent anharmonicity beyond harmonic-bath theory, we introduce a finite-memory shot-noise description at the level of the second cumulant that implements instantaneous kicks on the coupled electronic-vibrational manifold. Ensemble-averaged trajectory simulations yield populations and coherences across broad parameter ranges. Three robust regimes emerge: (i) a weakly anharmonic regime, where many small events per correlation time render the compound-Poisson bath effectively Gaussian and harmonic, and non-Gaussian predictions are quantitatively close; (ii) an intermediate anharmonic regime, where intermittency and higher-order statistics become dynamically relevant, enhancing ET and qualitatively reshaping population and coherence dynamics, particularly at weak electronic coupling; and (iii) a strongly anharmonic sparse-event regime, where impulsive events drive pronounced, irregular energy exchange and the largest deviations from harmonic-bath behavior. These results delineate when harmonic approximations are sufficient and when explicit anharmonic, non-Gaussian bath models are required for faithful ET dynamics in biomolecular environments.

PMID:41984468 | DOI:10.1021/acs.jpcb.6c00165

JAMA Dermatol. 2026 Apr 15. doi: 10.1001/jamadermatol.2026.0605. Online ahead of print.

ABSTRACT

IMPORTANCE: Lifileucel is a first-in-class autologous tumor-infiltrating lymphocyte (TIL) therapy for advanced/metastatic melanoma with progression after anti-programmed cell death protein 1 (PD-1) therapy and/or BRAF inhibitor therapy, if BRAF V600 mutations are present. In the C-144-01 phase 2 trial of lymphodepleting chemotherapy, lifileucel, and interleukin 2 (IL-2), cutaneous eruption occurred in 37.2% of individuals. These eruptions remain clinically and prognostically unknown.

OBJECTIVE: To examine cutaneous toxic effects development in the setting of lifileucel therapy, abstract clinical and histopathologic eruption features, and test for association with objective radiographic tumor response.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was performed at Mass General Brigham (MGB)/Dana-Farber Cancer Institute (DFCI) that included all patients treated with lifileucel, outside of active clinical trials. The analysis was completed in December 2025.

EXPOSURES: All individuals received cyclophosphamide/fludarabine lymphodepletion, lifileucel, and 6 or fewer IL-2 infusions. Demographics, melanoma-specific factors (M stage, pre-TIL lactate dehydrogenase levels, and number of lines of prior systemic therapy), number of IL-2 doses received, eruption features, photography, and dermatopathologic findings were abstracted.

MAIN OUTCOMES AND MEASURES: Radiographic responses 30 to 41 days, 42 to 89 days, and 90 days or longer from TIL infusion per Response Evaluation Criteria in Solid Tumors (RECIST) were abstracted. Individuals were stratified as high IL-2 (4-6 doses) or low IL-2 (1-3 doses), for objective response rate (ORR) comparison as a descriptive sensitivity analysis. An unadjusted logistic regression modeled tumor response as a binary outcome with lifileucel-associated eruption occurrence as a binary predictor. Three adjusted models included IL-2 doses (age, sex, and demographic differences) and melanoma-specific factors as covariates.

RESULTS: Per retrospective electronic medical health record review, among 44 individuals (34.1% female individuals; mean [SD] age, 54.8 [14.5] years), treated with lifileucel (median, 4.5 IL-2 doses), 22 (50.0%) developed an associated cutaneous eruption while hospitalized, after a median of 4 post-TIL days. Photographs from 14 of 22 individuals (63.6%) with available images demonstrated central-predominant, frequently purpuric morbilliform eruptions. ORRs did not significantly differ by IL-2 stratification (high IL-2: 50.0% vs low IL-2: 37.5%; P = .53). Cutaneous eruption development was associated with a 42-day response across analyses (analysis 1: OR, 7.29; 95% CI, 1.91-27.86; P = .004; OR, 7.65; 95% CI, 1.79-32.69; P = .006; analysis 2: OR, 11.95; 95% CI, 1.90-75.39; P = .008; analysis 3: OR, 9.73; 95% CI, 2.12-44.74; P = .003); 30-day responses were statistically similarly associated. All 90-day cutaneous eruption response analyses did not detect statistical significance.

CONCLUSIONS AND RELEVANCE: In this cohort study, lifileucel treatment was frequently complicated by purpuric morbilliform eruptions, which were prognostically favorable and associated with short-term response. The lifileucel-associated eruption may be a peritreatment efficacy marker, assessable during the TIL treatment hospitalization prior to traditional 42-day restaging.

PMID:41984455 | DOI:10.1001/jamadermatol.2026.0605

Pain Ther. 2026 Apr 15. doi: 10.1007/s40122-026-00835-w. Online ahead of print.

ABSTRACT

INTRODUCTION: The objective of this study was to utilize real-world data from National Poison Data System (NPDS) to evaluate the relative risk of intentional use and subsequent outcomes following exposures to buprenorphine buccal film (BBF) compared to immediate-release (IR) and extended-release (ER) full agonist opioid (FAO) formulations, and buprenorphine transdermal patch (BTP).

METHODS: A cross-sectional study design compared exposures that involved BBF to those that involved IR FAO, ER FAO, and BTP using real-world data from NPDS. Data included individuals age 18 years and older involved in exposures managed by US poison centers from 2020 to 2023. Descriptive statistics were used to summarize study groups, exposures, and outcomes. Relative risk was calculated for exposure reasons and clinical outcomes using BBF as reference group.

RESULTS: Dataset included 276 BBF, 43,322 IR FAO, 2453 ER FAO, and 134 BTP exposures. Compared to BBF, significantly higher risks were found for both IR FAO and ER FAO for intentional abuse, intentional suspected suicide, significant medical outcome, hospital admission, and treated/evaluated and released level of care.

CONCLUSION: Findings from this study suggest that, compared to FAO, exposures to BBF managed by US poison centers were less likely to involve intentional abuse or suspected suicide, have a decreased risk of resulting in a life-threatening effect or death, and have a lower likelihood of subsequent hospital admission and emergency department visits. Along with published guidelines and medication labels (including boxed warnings), relative risks of intentional exposures and associated clinical outcomes should be considered when determining opioid therapy for pain management.

PMID:41984416 | DOI:10.1007/s40122-026-00835-w

J Hist Biol. 2026 Apr 15. doi: 10.1007/s10739-026-09854-x. Online ahead of print.

NO ABSTRACT

PMID:41984382 | DOI:10.1007/s10739-026-09854-x

Hepatol Res. 2026 Apr 15. doi: 10.1111/hepr.70187. Online ahead of print.

ABSTRACT

AIM: This study investigated the effects of the subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI) on the overall survival (OS) of patients with hepatocellular carcinoma (HCC).

METHODS: This study included 587 patients with HCC. The Cox proportional hazards model was used to identify independent prognostic factors. The optimal SATI cutoff value that yielded the most significant differences in OS was determined using the maximally selected statistics. Survival was estimated using the Kaplan-Meier method, and differences between survival curves were evaluated using the log-rank test.

RESULTS: SATI (hazard ratio, 0.99; 95% confidence interval, 0.98-0.99; p < 0.001) was significantly associated with improved OS after adjustment for potential confounders. The high-SATI group (≥ 41.1 cm²/m² for males and ≥ 48.9 cm²/m² for females) demonstrated significantly longer survival than those in the low-SATI group (p < 0.001; median survival: 87.0 vs. 40.4 months). The results of the decision tree analysis showed that patients with SATI ≥ 41.0 cm²/m² who received curative treatment demonstrated the best survival (median survival: 191.8 months). Subgroup analyses revealed that the survival advantage of the high-SATI group was consistent across most subgroups, except for patients with metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, body mass index > 25 kg/m², VATI ≥ 85 cm²/m², or hyperlipidemia.

CONCLUSIONS: In the absence of findings indicative of ectopic lipid accumulation, SAT accumulation is associated with an improved prognosis in patients with HCC.

PMID:41984354 | DOI:10.1111/hepr.70187

Clin Rheumatol. 2026 Apr 15. doi: 10.1007/s10067-026-08120-z. Online ahead of print.

ABSTRACT

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by profound metabolic perturbations and dysregulated crosstalk between immune cells and fibroblast-like synoviocytes (FLS). Phenylalanine (PHE), an aromatic amino acid, has been implicated in RA-related metabolic disorders, but its direct immunomodulatory effects on human primary FLS and peripheral blood lymphocytes remain unclear. This study aimed to identify RA-specific metabolic signatures via untargeted metabolomics and validate PHE’s functional role in regulating core pathogenic cells in RA.

METHODS: LC-MS/MS-based untargeted metabolomics was performed on serum from 123 RA patients (2010 ACR/EULAR criteria) and 106 age/sex-matched healthy controls. Differential metabolites and pathways were identified via multivariate statistical analysis (PCA, OPLS-DA) and KEGG enrichment. Primary FLS and peripheral blood lymphocytes were treated with 100 μmol/L PHE (matching RA serum levels). CCK-8, qPCR, multiplex cytokine detection and flow cytometry were used to assess cell viability, pro-inflammatory gene expression, cytokine secretion, and apoptosis.

RESULTS: Metabolomic profiling revealed clear separation between RA and controls, with significant enrichment in phenylalanine metabolism. Eight novel RA-specific biomarkers were identified. Functional validation showed that PHE significantly upregulated mRNA expression of IL-6, IL-8, CXCL12, and MMP3 in FLS (1.8-7.2-fold, all p < 0.01) and enhanced secretion of IL-6 (115 → 180 pg/mL), IL-8 (300 → 550 pg/mL), and CCL2 (3000 → 5500 pg/mL) (all p < 0.01). In lymphocytes, PHE promoted secretion of IL-1β, TNF-α, IL-6, and CXCL8 (all p < 0.001) and increased total apoptosis rate (8.3% → 18.7%, p < 0.01).

CONCLUSION: This study reveals distinct metabolic features in RA patients, confirming PHE as a key pro-inflammatory metabolite that modulates FLS and lymphocyte functions. Key Points • Serum untargeted metabolomics of an RA cohort identifies 8 novel biomarkers and core dysregulated pathways, including phenylalanine metabolism and acylcarnitine-mediated fatty acid β-oxidation. • Phenylalanine directly activates FLS, upregulating pro-inflammatory cytokines, chemokines, and matrix metalloproteinases, enhancing their tissue-destructive potential. • Phenylalanine promotes pro-inflammatory cytokine secretion and induces apoptosis in RA peripheral blood lymphocytes, disrupting immune homeostasis.

PMID:41984350 | DOI:10.1007/s10067-026-08120-z

Appl Health Econ Health Policy. 2026 Apr 15. doi: 10.1007/s40258-026-01043-5. Online ahead of print.

ABSTRACT

OBJECTIVES: Cardiovascular diseases (CVDs) are a leading contributor to morbidity, mortality, and healthcare spending in low- and middle-income countries (LMICs). Despite this burden, economic evidence on system-level interventions to strengthen hypertension and CVD care in sub-Saharan Africa remains limited. This study estimates the costs and budget impact of the Ghana Heart Initiative (GHI), a multi-component health systems strengthening intervention.

METHODS: We conducted a retrospective cost analysis from the health system perspective using an activity-based costing approach. We estimated the financial and economic costs incurred during the design (2018-2019) and initial implementation phase (2020-2022) of the GHI across 42 public health facilities in the Greater Accra Region. Costs were disaggregated by activity cluster and input category. We then projected the budget impact of hypothetical national scale-up under three implementation scenarios that varied in scope and cost-sharing assumptions. All costs were inflation-adjusted and reported in 2024 US dollars (US $).

RESULTS: The total economic cost of designing and implementing the GHI over 4 years was US$1.96 million, of which 91.5% was attributable to implementation activities. Human resources were the primary cost driver. Average annual economic costs were US$11,960 per health facility, US$997 per targeted health provider trained, and US$39.9 per outpatient attendee. Projected annual costs for nationwide scale-up ranged from US$12.1 million to US$30.1 million, depending on implementation scenario, with a streamlined service-delivery-only model representing a lower-bound estimate.

CONCLUSIONS: This study provides granular, activity-level cost estimates for a complex health system strengthening intervention targeting hypertension and CVD care. The findings offer policy-relevant inputs for budget planning and highlight how implementation choices influence the fiscal implications of scaling up system-level CVD interventions in LMICs.

PMID:41984319 | DOI:10.1007/s40258-026-01043-5

J Youth Adolesc. 2026 Apr 15. doi: 10.1007/s10964-026-02357-2. Online ahead of print.

NO ABSTRACT

PMID:41984318 | DOI:10.1007/s10964-026-02357-2

Ecohealth. 2026 Apr 15. doi: 10.1007/s10393-026-01792-8. Online ahead of print.

ABSTRACT

Kashin-Beck disease (KBD) is an endemic disease characterized by its complex etiology and severe impact on human health. It is also regarded as one of the most serious endemic disease in China. This study aimed to investigate the spatial correlation and determinants of this disease. Monitoring data of children and possible influencing factors were collected from 37 KBD regions in Gansu Province. The spatial autocorrelation method was used to describe the spatial aggregation of KBD, and the spatial regression analysis was used to explore the natural environment and socioeconomic factors influencing KBD incidence. The results showed that the X-ray detection rate of KBD demonstrated a significant negative spatial correlation, with Kangle county and its neighboring areas located in southcenter of Gansu Province were hot spots of KBD. The spatial lag model revealed that rainfall, the proportion of afforestation in cultivated land, and population density had negative effects on the X-ray detection rate of KBD. The prevalence of KBD in Gansu Province is determined by a combination of natural environment and socioeconomic factors. Precision prevention and control should be implemented by the specific conditions of each diseased region.

PMID:41984302 | DOI:10.1007/s10393-026-01792-8

Prog Orthod. 2026 Apr 15;27(1):17. doi: 10.1186/s40510-026-00621-6.

ABSTRACT

BACKGROUND: Digital treatment planning software in clear aligner (CA) therapy incorporates virtual simulations to generate planned tooth movements. While baseline tooth positions constitute one of the geometric inputs to digital setups, limited information is available regarding the association between pre-treatment positional asymmetry and the magnitude of planned movements, and how these associations vary by tooth and movement type.

METHODS: A retrospective analysis was conducted on 65 patients (390 anterior teeth) treated with Invisalign^®. Baseline malpositions of anterior teeth were measured using 3D digital models in ClinCheck^®, while planned movements-including rotation, angulation, extrusion, and intrusion-were extracted from the corresponding digital treatment plans. Baseline asymmetry between contralateral teeth was calculated to quantify movement complexity. General Linear Model (GLM) regression analyses were employed to assess the relationship between initial asymmetry and the magnitude of planned movements. Descriptive statistics and normality assessments were also performed.

RESULTS: In the 11-21 tooth pair, baseline asymmetry was significantly associated with planned extrusion (p = .002) and rotation (p < .001), but not intrusion (p = .190) or angulation (p = .270). For the 12-22 pair, significant associations were observed for intrusion (p = .008), angulation (p < .001), and rotation (p < .001), but not extrusion (p = .493). In the 13-23 pair, only extrusion was significantly associated with baseline differences (p < .001); no significant effects were observed for the other movement types.

CONCLUSION: Baseline positional asymmetry was associated with variation in planned extrusion, intrusion, and rotation movements within digital CA setups. These findings should be interpreted as descriptive associations rather than evidence of software-imposed constraints or internal planning strategies, and underscore the relevance of baseline geometry when interpreting digitally planned tooth movements.

PMID:41984292 | DOI:10.1186/s40510-026-00621-6