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PubMed2025

Integrating explainable AI with multiomics systems biology and EHR data mining for personalized drug repurposing in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by region- and patient-specific molecular heterogeneity, which hinders therapeutic design. In this study, we introduce PRISM-ML (PRecision-medicine using Interpretable Systems and Multiomics with Machine Learning), an open-source integrated analysis pipeline that combines interpretable machine learning with systems biology and electronic health record (EHR) data mining to elucidate the molecular diversity of AD and predict promising drug repurposing opportunities. First, we integrated and harmonized transcriptomic (bulk RNA-seq) and genomic (genome-wide association study) data from 2105 brain samples, each with matched data from the same individual (1363 AD patients, 742 controls; nine tissues), sourced from three independent studies. Random forest classifiers with SHapley Additive exPlanations (SHAP) identified patient-specific biomarkers; unsupervised clustering resolved 36 molecularly distinct "subtissues" (clusters of samples); and gene-gene co-expression networks prioritized 262 high-centrality bottleneck genes as putative regulators of dysregulated pathways. Next, knowledge graph-based drug repurposing predicted six FDA-approved drugs that simultaneously target multiple bottleneck genes and multiple AD-relevant pathways. Notably, in a large U.S. de-identified insurance-claims database (n = 364733), exposure to promethazine, one of the candidate drugs, was associated with a 57-62 % lower incidence of AD versus an active antihistamine comparator (adjusted hazard ratio 0.38; inverse-probability weighted 0.43; both p < 0.001), providing real-world support for its repurposing potential. In summary, PRISM-ML, as an explainable multi-omics analysis pipeline, is readily transferable to other complex diseases, advancing precision medicine.

Computational Biology↗

PubMed1979

Framing pictures: the role of knowledge in automatized encoding and memory for gist.

In general, frame theories are theories about the representation and use of knowledge for pattern recognition. In the present article, the general properties of frame theories are discussed with regard to their implications for psychological processes, and an experiment is presented which tests whether this approach yields viable predictions about the manner in which people comprehend and remember pictures of real-world scenes. Normative ratings were used to construct six target pictures, each of which contained both expected and unexpected objects. Eye movements were then recorded as subjects who anticipated a difficult recognition test viewed the targets for 30 sec each. Then, the subjects were asked to discriminate the target pictures from distractors in which either expected or unexpected objects had been changed. One consequence of the embeddedness of frame systems is that global frames may function as "semantic pattern detectors," so that the perceptual knowledge in them could be used for relatively automatic pattern recognition and comprehension. Thus, subjects might be able to identify expected objects by using automatized encoding procedures that operate on global physical features. In contrast, identification of unexpected objects (i.e., objects not represented in the currently active frame) should generally require more analysis of local visual details. These hypotheses were confirmed with the fixation duration data: First fixations to the unexpected objects were approximately twice as long as first fixations to the expected objects. On the recognition test, subjects generally noticed only the changes that had been made to the unexpected objects, despite the fact that the proportions of correct rejections were made conditional on whether the target objects had been fixated. These data are again consistent with the idea that local visual details of objects represented in the frame are not neccesary for identification and are thus not generally encoded. Further, since subjects usually did not notice when expected objects were deleted or replaced with different expected objects, it was concluded that if two events instantiate the same frame, they may often be indistinguishable, as long as any differences between them are represented as arguments in the frame. Thus, for the most part, the only information about an event that is episodically "tagged" is information which distinguishes that particular event from others of the same general class. The data reinforce the utility of a frame theory approach to perception and memory.

Discrimination Learning↗

PubMed1997

Multiple automatic base selection: protein-ligand docking based on incremental construction without manual intervention.

A possible way of tackling the molecular docking problem arising in computer-aided drug design is the use of the incremental construction method. This method consists of three steps: the selection of a part of a molecule, a so-called base fragment, the placement of the base fragment into the active site of a protein, and the subsequent reconstruction of the complete drug molecule. Assuming that a part of a drug molecule is known, which is specific enough to be a good base fragment, the method is proven to be successful for a large set of docking examples. In addition, it leads to the fastest algorithms for flexible docking published so far. In most real-world applications of docking, large sets of ligands have to be tested for affinity to a given protein. Thus, manual selection of a base fragment is not practical. On the other hand, the selection of a base fragment is critical in that only few selections lead to a low-energy structure. We overcome this limitation by selecting a representative set of base fragments instead of a single one. In this paper, we present a set of rules and algorithms to automate this selection. In addition, we extend the incremental construction method to deal with multiple fragmentations of the drug molecule. Our results show that with multiple automated base selection, the quality of the docking predictions is almost as good as with one manually preselected base fragment. In addition, the set of solutions is more diverse and alternative binding modes with low scores are found. Although the run time of the overall algorithm increases, the method remains fast enough to search through large ligand data sets.

Automation↗

PubMed2024

DNABERT-S: Pioneering Species Differentiation with Species-Aware DNA Embeddings.

We introduce DNABERT-S, a tailored genome model that develops species-aware embeddings to naturally cluster and segregate DNA sequences of different species in the embedding space. Differentiating species from genomic sequences (i.e., DNA and RNA) is vital yet challenging, since many real-world species remain uncharacterized, lacking known genomes for reference. Embedding-based methods are therefore used to differentiate species in an unsupervised manner. DNABERT-S builds upon a pre-trained genome foundation model named DNABERT-2. To encourage effective embeddings to error-prone long-read DNA sequences, we introduce Manifold Instance Mixup (MI-Mix), a contrastive objective that mixes the hidden representations of DNA sequences at randomly selected layers and trains the model to recognize and differentiate these mixed proportions at the output layer. We further enhance it with the proposed Curriculum Contrastive Learning (C2LR) strategy. Empirical results on 23 diverse datasets show DNABERT-S's effectiveness, especially in realistic label-scarce scenarios. For example, it identifies twice more species from a mixture of unlabeled genomic sequences, doubles the Adjusted Rand Index (ARI) in species clustering, and outperforms the top baseline's performance in 10-shot species classification with just a 2-shot training. Model, codes, and data is publicly available at https://github.com/MAGlCS-LAB/DNABERT_S.

Journal Article↗

PubMed2026

Effects of short-bout accumulated exercise on postprandial metabolism in adults: A systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the acute effects of short-bout accumulated exercise (SBAE) interrupting prolonged sedentary behaviour on postprandial glucose, insulin, and triglycerides in adults. METHODS: Systematic searches in PubMed, Web of Science, Embase, Cochrane Library, CINAHL, SPORTDiscus, and CNKI (inception to 10 December 2025) identified randomised crossover trials comparing SBAE (≤10 min/bout, inter-bout interval ≥30 min or adequate recovery) with continuous sedentary behaviour. Outcomes included postprandial glucose, insulin, and triglyceride AUCs. Standardised mean differences (SMD) were pooled using random-effects models. RESULTS: Thirty-one publications reporting data from 29 independent cohorts involving 573 unique participants (mean age 47.8 ± 20.3 years; 47.5% female; mean BMI 29.0 ± 5.1 kg/m²) were included. Compared with continuous sedentary behaviour, SBAE significantly reduced glucose AUC (SMD = -0.53, 95% CI: -0.71 to -0.34, P < 0.001) and insulin AUC (SMD = -0.58, 95% CI: -0.85 to -0.31, P < 0.001), but not triglyceride AUC (SMD = -0.17, 95% CI: -0.48 to 0.15, P = 0.306).Exploratory subgroup analyses showed statistically significant reductions in glucose and insulin for walking and for inter-bout intervals < 60 min, but not for standing alone or intervals ≥ 60 min. A statistically significant insulin-lowering effect was observed in obese individuals. CONCLUSION: SBAE acutely improves postprandial glucose and insulin control. Exploratory subgroup analyses showed statistically significant effects for walking and for inter-bout intervals < 60 min, but these comparisons are observational and no formal interaction test was conducted. These findings provide preliminary evidence for acute SBAE in sedentary populations, though long-term health effects and real-world generalisability require further investigation.

Adult↗

PubMed2025

DNABERT-S: pioneering species differentiation with species-aware DNA embeddings.

SUMMARY: We introduce DNABERT-S, a tailored genome model that develops species-aware embeddings to naturally cluster and segregate DNA sequences of different species in the embedding space. Differentiating species from genomic sequences (i.e. DNA and RNA) is vital yet challenging, since many real-world species remain uncharacterized, lacking known genomes for reference. Embedding-based methods are therefore used to differentiate species in an unsupervised manner. DNABERT-S builds upon a pre-trained genome foundation model named DNABERT-2. To encourage effective embeddings to error-prone long-read DNA sequences, we introduce Manifold Instance Mixup (MI-Mix), a contrastive objective that mixes the hidden representations of DNA sequences at randomly selected layers and trains the model to recognize and differentiate these mixed proportions at the output layer. We further enhance it with the proposed Curriculum Contrastive Learning (C2LR) strategy. Empirical results on 28 diverse datasets show DNABERT-S's effectiveness, especially in realistic label-scarce scenarios. For example, it identifies twice more species from a mixture of unlabeled genomic sequences, doubles the Adjusted Rand Index (ARI) in species clustering, and outperforms the top baseline's performance in 10-shot species classification with just a 2-shot training. AVAILABILITY AND IMPLEMENTATION: Model, codes, and data are publically available at https://github.com/MAGICS-LAB/DNABERT_S.

Sequence Analysis, DNA↗

PubMed2026

Temporal shifts in gyrA mutation types and sublineage replacement in ST11 Salmonella enterica serovar Enteritidis over a decade (2014-2023): A genomic epidemiological study in Guangxi, China.

The overuse or abuse of antibiotics drives the global health threat of antimicrobial resistance. Although bans on certain veterinary antibiotics, such as colistin, have proven effective, the impact of fluoroquinolone stewardship on the evolution of the foodborne pathogen Salmonella enterica serovar Enteritidis (S. Enteritidis) remains unclear. Here, we conducted a decade-long (2014-2023) retrospective longitudinal genomic epidemiological analysis of 441 ST11 S. Enteritidis isolates from Guangxi, China, alongside a global reference dataset of 4297 genomes. Our aim was to elucidate the effect of real-world antibiotic stewardship on the shift of gyrA point mutations and lineage distribution. Surveillance identified three global epidemic clade sublineages (GEC-L2, L3, L4), with the multidrug-resistant GEC-L4 (i.e., GC-c or MMC2), characterized by the gyrA mutation with amino acid substitution D87Y, being domestically dominant (70.07%, 309/441). Following China's 2016 ban on the veterinary use of critical fluoroquinolones, the proportion of the highly resistant GEC-L4 sublineage decreased continuously (from 86.84% in 2017 to 56.00% in 2023), while the less resistant GEC-L3 sublineage (i.e., GC-b or MMC1), mainly characterized by gyrA D87G, increased simultaneously (from 13.16% to 44.00%). This phenomenon might be attributed to the fact that the GEC-L4 sublineage exhibited a higher fitness cost compared with the GEC-L3 sublineage, as confirmed by the competition assay. A Random Forest Model validated that the gyrA mutation with amino acid substitution D87Y was the paramount feature for these sublineages' identification. In contrast, global data showed a continuous increase in gyrA mutations (from 8.63% in 2006 to 68.85% in 2024), primarily D87Y (from 1.44% to 31.15%) and D87N (from 4.32% to 22.95%), correlating with rising average fluoroquinolone consumption. This study provides direct genomic evidence that national-level antibiotic stewardship can drive the replacement of highly resistant sublineages with moderately resistant ones. These findings offer crucial scientific evidence for evaluating the impact of antibiotic management policies and inform strategies for the rational use of antimicrobials.

China↗

PubMed2026

SPEN inactivation drives resistance to androgen receptor pathway inhibitors in metastatic prostate cancer.

PURPOSE: Treatment intensification with androgen receptor pathway inhibitors (ARPIs) has become the standard of care for patients with metastatic prostate cancer. However, there remains an unmet need to identify biomarkers for treatment resistance. Here, we identify SPEN inactivation as a driver of ARPI resistance. EXPERIMENTAL DESIGN: Pre-clinical studies were performed in LNCaP and VCaP cell lines. Data from a nationwide prostate cancer clinico-genomic database were extracted. Log-rank test and Cox proportional hazards models were used to compare time to next treatment (TTNT) on ARPI with/without SPEN mutations. SPEN immunohistochemistry was performed on a rapid autopsy metastatic tissue microarray. RESULTS: SPEN was identified as a top enzalutamide resistance hit in an unbiased genome-wide loss-of-function screen. SPEN inactivation results in upregulation of cell cycle proliferation and basal/stem cell activity as well as increased translation of pro-oncogenic genes. In a large patient cohort (N=6828), SPEN mutations are enriched following treatment with ARPIs (2.1% to 3.6%, p=0.001) and correlate with shorter TTNT on ARPI in patients with metastatic hormone-sensitive prostate cancer (6.4 vs 29.7 months, HR 2.67, p=0.02). In a metastatic rapid autopsy cohort (N=181), low SPEN H-score is associated with shorter time on abiraterone (5.0 vs 7.9 months, p=0.023) in metastatic castration-resistant prostate cancer. CONCLUSIONS: In real-world cohorts, loss of SPEN function across genomic, transcriptomic, and protein levels is associated with reduced benefit from ARPI therapy in metastatic prostate cancer. These findings identify SPEN inactivation as a clinically relevant biomarker of ARPI resistance that warrants prospective evaluation to guide treatment selection.

Journal Article↗

PubMed2024

Increased risk of hearing loss associated with MT-RNR1 gene mutations: a real-world investigation among Han Taiwanese Population.

BACKGROUND: Previous studies have implicated inherited mutations in mitochondrial DNA (mtDNA) in sensorineural hearing loss (SNHL). However, the definitive association between mitochondrial 12S rRNA (MT-RNR1) variants and hearing loss in the population has not been well established, particularly in Asia. The objective of this retrospective cohort study was to assess the association between MT-RNR1 variants and the risk of SNHL in patients in Taiwan. METHODS: The cohort included 306,068 participants from Taiwan between January 2003 and December 2020. Participants were classified based on genetic variants, particularly mitochondrial mutations (rs267606618, rs267606619, rs267606617). MT-RNR1 variant cases were matched 1:10 with non-mutant patients by age, gender, and visit year, excluding those with pre-existing hearing loss. The primary endpoint was SNHL, identified using specific ICD-TM codes with a 90% positive predictive value. Medication exposure history was determined via self-report or electronic medical records in the hospital. Cox proportional hazard regression models were used to assess the association between MT-RNR1 variants and hearing loss, adjusting for various covariates. Kaplan-Meier survival curves and log-rank tests compared hearing loss incidence between groups. RESULTS: The mean age of the mtDNA variants group is 32.4 years, with a standard deviation of 19.2 years. The incidence density of hearing loss for the mutation group was 36.42 per 10,000 person-years (95% Confidence Interval [CI], 27.21-47.73), which was higher than the 23.77per 10,000 person-years (95% CI, 21.32-26.42) in the wild-type group (p = 0.0036). Additionally, diabetes mellitus was associated with an increased risk of developing SNHL in individuals with MT-RNR1 variants (adjusted hazard ratio = 1.76 [95% CI, 1.00-3.09], p < 0.05). CONCLUSION: This study highlights the increased risk of hearing loss in patients carrying MT-RNR1 variants, particularly those with diabetes mellitus. Future research that integrates genetic and clinical data is crucial for developing more precise interventions to monitor and treat hearing loss in this vulnerable population.

Adolescent↗

PubMed2025

Integration of Gene Expression and Digital Histology to Predict Treatment-Specific Responses in Breast Cancer.

Deep learning models applied to digital histology can predict gene expression signatures (GES) and offer a low-cost, rapidly available alternative to molecular testing at the time of diagnosis. We optimized transformer-based models to infer GES results and applied this approach to pre-treatment H&E-stained biopsies from 1,940 breast cancer patients treated with neoadjuvant chemotherapy in clinical trial and real-world cohorts. The most predictive histology-derived GES for pathologic complete response (pCR) in the I-SPY2 trial was validated in four external cohorts: CALGB 40601, CALGB 40603, a trial of durvalumab plus CT, and standard-of-care CT-treated patients from the University of Chicago. Among HER2-negative patients, a transformer-based model trained using a signature composed of estrogen-regulated genes, proliferation, apoptosis, and interferon response genes predicted pCR with an AUC of 0.794, outperforming models based on clinical features alone (AUC 0.704, p = 0.001), pathologist TIL assessment, and a model trained directly to predict response from I-SPY2 cases. Tertiles of this signature stratify patients into clinically relevant groups with increasing likelihood of complete response, with pCR rates ≥50% in the top tertile regardless of treatment or hormone receptor status. Additional transformer-based signature models predicted response to specific therapies (but not chemotherapy alone), including a HER2 signaling signature in IO-treated patients, and a claudin-low signature in bevacizumab treated patients. In HER2- cohorts with available gene expression data and histology, models trained on expression data performed similarly to digital histology predictions, but the combination of gene expression and histology outperformed histology alone. These findings suggest that histology-based GES provides additive information to RNA sequencing data and can inform precision treatment selection across breast cancer subtypes.

Journal Article↗

PubMed2026

Predicting training outcomes for developmental dyslexia from EEG data.

Developmental dyslexia (DD) is characterised by lower-than-average reading abilities and is diagnosed in approximately 10% of individuals. The societal barriers may limit professional fulfilment and psychological wellbeing of individuals with DD, calling for the development of effective interventions to counteract them. As DD is associated with challenges in both phonological and visuo-attentional domains, different longitudinal training approaches were developed to strengthen them. However, they require a considerable amount of personal, social and economic resources and the outcomes may vary depending on individual differences in behavioural and neurophysiological functionality. Hence, predicting training outcomes might help in developing personalised treatment protocols and optimising the use of resources. In the present work we applied machine learning to resting-state EEG to predict longitudinal training outcomes in adults with DD enrolled in a randomized clinical trial. In particular, one group received a visuo-attentional training combined with transcranial alternating current stimulation (tACS), another group received visuo-attentional training with sham/placebo stimulation, and the third group received a phonological training with sham/placebo stimulation. The improvement in text reading speed was associated with spectral power in low-beta and individual frequencies in the alpha (IAF) and beta (IBF) bands, while the improvement in pseudoword reading was associated with IBF. The findings highlight the potential of capturing neural markers of treatment responsiveness in DD. Future studies should focus on the generalisability of predictive models to real-world settings, while investigating whether specific EEG markers predict responsiveness to distinct remediation protocols, thus supporting the development of personalised interventions.

Humans↗

PubMed1993

The case for chaos in childhood epidemics. II. Predicting historical epidemics from mathematical models.

The case for chaos in childhood epidemics rests on two observations. The first is that historical epidemics show various 'fieldmarks' of chaos, such as positive Lyapunov exponents. Second, phase portraits reconstructed from real-world epidemiological time series bear a striking resemblance to chaotic solutions obtained from certain epidemiological models. Both lines of evidence are subject to dispute: the algorithms used to look for the fieldmarks can be fooled by short, noisy time series, and the same fieldmarks can be generated by stochastic models in which there is demonstrably no chaos at all. In the present paper, we compare the predictive abilities of stochastic models with those of mechanistic scenarios that admit to chaotic solutions. The main results are as follows: (i) the mechanistic models outperform their stochastic counterparts; (ii) forecasting efficacy of the deterministic models is maximized by positing parameter values that induce chaotic behaviour; (iii) simple mechanistic models are equal if not superior to more detailed schemes that include age structure; and (iv) prediction accuracy for monthly notifications declines rapidly with time, so that, from a practical standpoint, the results are of little value. By way of contrast, next amplitude maps can successfully forecast successive changes in maximum incidence one or more years into the future.

Child↗

PubMed2026

Diagnostic Performance of Machine Learning for Systemic Lupus Erythematosus: Systematic Review and Meta-Analysis.

BACKGROUND: Early and accurate diagnosis of systemic lupus erythematosus (SLE) and its organ involvement is essential. Previous reviews of machine learning (ML) in SLE combined heterogeneous tasks and validation strategies and may have overinterpreted model performance. OBJECTIVE: This study evaluated the diagnostic performance of ML and deep learning (DL) models for 3 clinically distinct SLE-related tasks: SLE classification or diagnosis, lupus nephritis (LN) diagnosis, and neuropsychiatric systemic lupus erythematosus (NPSLE) discrimination. We also assessed methodological quality and certainty of evidence. METHODS: PubMed, Embase, Cochrane Library, Web of Science, and IEEE Xplore were searched from January 2014 to April 2026. Eligible peer-reviewed diagnostic accuracy studies developed or validated ML or DL models for 1 of the 3 prespecified tasks, used an accepted reference standard, and provided data for a 2×2 contingency table. Bivariate random-effects meta-analyses with the Hartung-Knapp-Sidik-Jonkman adjustment were used to pool sensitivity and specificity. We reported 95% prediction intervals (PIs), assessed risk of bias using the Quality Assessment of Diagnostic Accuracy Studies for Artificial Intelligence tool (QUADAS-AI; Viknesh Sounderajah [Imperial College London]), and evaluated certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework for diagnostic test accuracy. RESULTS: Twenty-nine studies were included: 17 for SLE classification, 5 for LN diagnosis, and 7 for NPSLE discrimination. In the primary task-stratified analysis, pooled sensitivity was 0.91 (95% CI 0.86-0.94; 95% PI 0.56-0.99), and pooled specificity was 0.94 (95% CI 0.91-0.96; 95% PI 0.69-0.99), with low heterogeneity (I²=23.9% and 22.9%, respectively). DL models showed a sensitivity of 0.93 and specificity of 0.95, compared with 0.88 and 0.94 for traditional ML models. Certainty of evidence was high for most analyses but low for LN diagnosis because of inconsistency and imprecision. All studies were retrospective, and only 9 of 29 (31%) performed independent external validation. Overall risk of bias was high or unclear in 22 of 29 (75.9%) studies. No study reported model calibration, decision-curve analysis, or net clinical benefit. CONCLUSIONS: ML models showed promising diagnostic accuracy across 3 distinct SLE-related tasks, but wide PIs, limited external validation, and pervasive risk of bias restrict conclusions about real-world generalizability. Prospective multicenter studies with standardized tasks and reference standards, independent external validation, and formal assessment of calibration and clinical utility are required before clinical implementation.

Humans↗

PubMed1994

Use of transdermal nicotine in a state-level prescription plan for the elderly. A first look at 'real-world' patch users.

OBJECTIVE: To assess transdermal nicotine use patterns and outcomes in a population of low-income older smokers. DESIGN: A 6-month telephone follow-up survey of smokers filling prescriptions for transdermal nicotine in the first 3 months of 1992. SETTING: Pennsylvania's Pharmaceutical Assistance Plan for the Elderly, the nation's largest state-level prescription plan for the elderly. POPULATION: A total of 1070 noninstitutionalized male and female smokers aged 65 through 74 years. MAIN OUTCOME MEASURES: Self-reported physician/pharmacist advice and adjunctive treatments, concomitant smoking, and 6-month smoking abstinence. RESULTS: Respondents were predominantly long-term heavy smokers. They used nicotine patches for an average of 5 weeks, with few reporting use beyond 3 months or recalling bothersome side effects. Most of those with previous quit attempts rated quitting with the patch "easier." The 29% self-reported 6-month quit rate observed is encouraging. However, compliance with patch use guidelines was far from ideal in this high-risk population: only 54% of respondents received any initial advice or materials from their physicians or pharmacists, fewer than 2% took part in a formal clinic or one-to-one treatment program, and almost half (47%) smoked while using the patch, including 20% who smoked every day. Concomitant smoking was strongly associated with failure to achieve abstinence (P < .001). More frequent contact with physicians and/or pharmacists was associated with less concomitant smoking (P < .001) and higher quit rates (P = .005). CONCLUSIONS: This survey offers an important first look at problems and prospects for nicotine patch therapy in older adults, with implications for other groups as well. Prospective studies are needed to clarify optimal treatment regimens and adjuncts.

Administration, Cutaneous↗

PubMed2026

Real-World Experience With TRBC1 Immunohistochemistry Across Cutaneous T-Cell Lymphoma Subtypes: A Large Cohort Study.

T-cell receptor β-chain constant region 1 (TRBC1) immunohistochemistry identifies clonal αβ T-cell populations on tissue sections, but its real-world performance across cutaneous T-cell lymphoma (CTCL) and related infiltrates is uncharacterized. The analytic cohort comprised 665 biopsies (566 patients) with paired T-cell receptor (TCR) clonality testing, classified clinicopathologically as mycosis fungoides (MF; MF-Patch, MF-Plaque, MF-Tumor, and MF-Folliculotropic); MF or Sézary syndrome; primary cutaneous small or medium T-cell lymphoproliferative disorders (LPDs); other CTCL-cutaneous LPDs; or reactive. At the primary <15%/>85% threshold, TRBC1 IHC achieved 85.8% sensitivity (337/393), 79.8% specificity (217/272), 86.0% positive and 79.5% negative predictive value, and 83.3% accuracy. Sensitivity was lowest in MF-Patch (84.2%). Three-reader agreement (Fleiss κ = 0.943) fell to κ = 0.776 in 176 reflexed biopsies, with disagreement concentrated on MF-Patch and CD30-positive LPDs. Monotypic TRBC1 predicted neoplasia, with odds rising with infiltrate density: MF-Patch (odds ratio, 5.41), MF-Plaque (10.40), MF/Sézary syndrome with MF-Tumor (15.19), and CTCL-cutaneous LPD (18.16). Polytypic TRBC1 was associated with reactive disease (odds ratio, 53.65), effectively excluded clonality (negative likelihood ratio, 0.18), and was uniformly observed in an independent 270-biopsy reactive cohort. For observer-independent validation, digital image analysis-derived TRBC1 quantification (QuPath) was applied to a stratified random subset of 250 biopsies representative of the cohort's tumor-burden distribution. The digital read-tracked molecular clonality (85.1% sensitivity, 80.1% specificity against TCR; area under the curve, 0.842) agreed with the dermatopathologist's manual read in 87.6% of cases (κ = 0.752), with the data-derived cutoff matching the prespecified <15%/>85% threshold value. Discordance was directional for both manual scoring and digital quantification: in MF-Patch, 25 of 38 (65.8%) and 12 of 17 (70.6%) cases were polytypic with monoclonal TCR (false-negative-dominant); in reactive biopsies, 34 of 45 (75.6%) and 19 of 20 (95%) were monotypic with polyclonal TCR (false-positive-dominant). These findings support a TRBC1-first approach, reserving reflex TCR testing for borderline expression or clinicopathologic discordance, preserving diagnostic accuracy while reducing molecular testing and reimbursement-based costs.

Sézary syndrome↗

PubMed1993

The health care status of the diabetic population as reflected by physician claims to a major insurer.

BACKGROUND: Conventional epidemiologic data suggest that diabetic patients use more health care resources than nondiabetic patients, yet overall health care use by diabetic individuals has never been fully quantitated. We took a new approach to this issue based on the actual economics of the provision of health care to diabetic insured individuals. METHODS: The claims records in the Mutual of Omaha Current Trends database, which contains information on more than 400,000 individuals, were surveyed to identify patients with diabetes and create the contrast population of nondiabetic patients by exclusion. International Classification of Diseases, Ninth Revision, Clinical Modification, codes and Physicians' Current Procedural Terminology, Fourth Edition, codes were used to determine all diagnoses recorded and all physician services rendered to the contrast populations. Age- and sex-adjusted comparisons were performed using Mantel-Haenszel procedures to determine an adjusted odds ratio (AOR). RESULTS: A total of 13,304 diabetic individuals and 388,053 nondiabetic individuals who received health care services from January 1, 1988, to January 1, 1989, were identified. Diabetic insured individuals constituted 3.1% of the overall insured population yet accounted for 8.3% of the charges (P < .01). Inpatient charges accounted for 81% of total diabetic charges but only 61.5% of total nondiabetic charges (P < .001). Diabetic insured individuals had twice as many physician office visits (AOR = 1.87; 95% confidence interval [CI], 1.79 to 1.96), with 2.5 times more physician hospital visits [AOR = 2.50; 95% CI, 2.27 to 2.75). However, the increases in physician care were not uniformly distributed across the diagnostic spectrum. The frequencies of well-established complications of diabetes, such as ischemic heart disease (AOR = 3.32; 95% CI, 3.12 to 3.53), peripheral vascular disease (AOR = 3.14; 95% CI, 2.79 to 3.53), and eye disease (AOR = 3.10; 95% CI, 2.94 to 3.27), were threefold higher in the diabetic group, with parallel increases in related medical services, such as cardiac catheterization (AOR = 3.02; 95% CI, 2.27 to 4.0), vascular surgery (AOR = 2.94; 95% CI, 2.64 to 3.27), and ophthalmologic procedures (AOR = 2.94; 95% CI, 2.72 to 3.18). In contrast, most diagnostic categories showed little or no increase. For example, the frequency of neoplasms (AOR = 1.11; 95% CI, 1.03 to 1.19) was minimally increased, and the associated procedural concomitants of therapeutic radiology (AOR = 0.81; 95% CI, 0.47 to 1.39) and chemotherapy (AOR = 0.98; 95% CI, 0.60 to 1.60) were not increased in the diabetic group. CONCLUSIONS: Our most important new finding is that diabetic patients have neither an elevated risk for a wide spectrum of diseases nor an increase in the receipt of physician services for diagnostic categories without increased risk, despite more frequent physician encounters. We provide real-world risk estimates that help in calculating the effect of offering specific insurance to diabetic individuals or including them in group health plans. The techniques we have developed to analyze computerized claims databases in this way may serve to better quantify the true impact of chronic diseases on the health care system.

Adult↗

PubMed2026

2024-2025 BNT162b2 KP.2 COVID-19 full season vaccine effectiveness from vaccine registries linked to administrative claims in two states: A cohort study in non-immunocompromised adults.

BACKGROUND: Data on effectiveness of COVID-19 vaccinations during the 2024-2025 respiratory season are limited, particularly among those with underlying medical conditions (UMC). We estimated BNT162b2 KP.2 vaccine effectiveness (VE) against COVID-19-associated hospital admission, emergency department (ED), and urgent care (UC) visits in two U.S. states. METHODS: Retrospective cohort study of non-immunocompromised adults living in Louisiana or California, with ≥1 year prior continuous enrollment in insurance plans contributing to the HealthVerity claims database beginning August 22, 2024. The effectiveness of BNT162b2 KP.2 vaccine (2024-2025 formulation, hereafter referred to as BNT162b2), measured as a time-varying exposure against hospital admission, ED, or UC encounters with International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code U07.1 was calculated as 1 - adjusted hazard ratio using Cox proportional hazard models adjusted for age group, sex, state, insurance payor, presence or absence of UMCs, and pre-index healthcare utilization. Stratifications included those aged 65 years and older, those aged 18-64 years with UMCs, and those aged 18-64 years without UMCs. RESULTS: The cohort included 6,256,421 individuals (93% California, 7% Louisiana); 330,565 (5%) received the BNT162b2 vaccine. Vaccinated individuals were older and had more comorbidities, wellness visits, and prior influenza vaccination. Overall, 66% of the study population had ≥1 UMC; the most prevalent conditions were obesity (25%), history of immunocompromised conditions (23%), and mental health conditions (19%). COVID-19-related encounter rates for ED, UC or hospitalization were lower among vaccinated compared to unvaccinated persons (25.1 vs 36.3 per 100,000 person-months). Among all adults, VE was 37% against hospitalization, 12% against ED/UC encounters, and 16% against ED/UC/hospitalization encounters. Results were similar across age groups and UMCs. CONCLUSIONS: BNT162b2 provided protection against COVID-19-associated outcomes of ED, UC or hospitalization among non-immunocompromised U.S. adults, including those with UMCs, over the course of the 2024-2025 respiratory virus season, supporting continued vaccine recommendations. REGISTRATION: This study was posted on clinicaltrials.gov prior to analyses (NCT06923137).

Adolescent↗

PubMed2026

Real-world clinical utility of exome sequencing in pediatric drug-resistant epilepsy: Experience from a tertiary center in Thailand.

BACKGROUND: Genomic testing has increasingly contributed to the diagnosis and management of pediatric drug-resistant epilepsy (DRE), particularly in patients with suspected genetic etiologies. This study evaluated the diagnostic yield and real- world clinical utility of whole-exome sequencing (WES) in children with DRE. METHODS: Children with DRE and seizure onset before 15 years of age were enrolled between January 2020 and December 2023. Clinical data, including demographics, seizure characteristics, developmental history, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and prior investigations, were reviewed. WES was performed in all probands and, when available, their parents. Variants were interpreted according to standard guidelines. Clinical utility and 1-year seizure and developmental outcomes were assessed from follow-up records. RESULTS: Fifty-six patients (23 males, 33 females) were included. The median age at seizure onset was 1 year (interquartile range [IQR] 0.3-4 years), and 96.4% had developmental comorbidities. Pathogenic or likely pathogenic variants were identified in 39% (22/56), with the highest diagnostic yield in children with seizure onset before 3 years of age. Channelopathies accounted for most genetically solved cases (68%), predominantly involving sodium channel genes. Genetic diagnoses provided clinical utility in 73% (16/22) of solved cases by guiding treatment and precision management. At 1-year follow-up, genetically solved patients showed more favorable seizure and developmental outcomes than those with genetically unsolved patients. CONCLUSION: WES achieved a 39% diagnostic yield and substantial clinical utility in pediatric DRE, particularly in early-onset and channelopathy-related disorders. These findings support early molecular diagnosis to facilitate genotype-informed management in appropriately selected children. However, the more favorable developmental and seizure outcomes observed in genetically solved patients should be interpreted with caution, as they may have been influenced by multiple factors beyond genetic diagnosis. In resource-limited settings, careful clinical phenotyping remains essential for treatment decisions and for prioritizing children for genomic testing.

Clinical utility↗