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PubMed2026

Efficacy and safety of postoperative chewing gum for gastrointestinal recovery in children undergoing surgery: an updated systematic review and meta-analysis.

Chewing gum may stimulate gut motility through a "sham feeding" mechanism, but evidence in children is limited. We performed an updated systematic review and meta-analysis of randomized controlled trials comparing chewing gum plus usual care versus usual care alone in patients younger than 18 years undergoing any surgery. We searched five databases through June 2025. Primary outcomes were the time to first flatus, time to first defecation, and postoperative length of stay (LOS). Certainty was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Ten studies (n = 649) were included: abdominal surgery (5), spinal fusion (3), and tonsillectomy (2). Chewing gum may result in little to no difference in the time to first flatus (MD - 3.58 h, 95% CI - 8.08 to 0.91) or first defecation (MD - 3.23 h, 95% CI - 6.63 to 0.18), both with low certainty. LOS evidence was very uncertain (MD - 0.18 days, 95% CI - 0.70 to 0.33). Subgroup analyses suggested shorter LOS after abdominal surgery (MD - 0.60 days, 95% CI - 1.99 to 0.79) but not after spinal fusion (MD 0.10 days, 95% CI - 0.29 to 0.50; p for interaction = 0.0362). The benefits of postoperative chewing gum in children remain uncertain, with potential surgery-specific differences in LOS warranting investigation.

Humans↗

PubMed2026

Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.

Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.

Humans↗

PubMed2026

Diagnostic accuracy of bronchoalveolar lavage fluid-based testing for pulmonary cryptococcosis: A systematic review and meta-analysis.

BACKGROUND: Pulmonary cryptococcosis(PC) presents diagnostic challenges because of its non-specific clinical and radiological manifestations. Bronchoalveolar lavage fluid (BALF)-based testing, which includes latex agglutination (LA) and lateral flow assay (LFA), offers a minimally invasive diagnostic method, yet its pooled diagnostic accuracy remains unclear. METHODS: We systematically searched PubMed, Embase, Cochrane Library, and Scopus from inception to May 2026. Studies evaluating BALF-based testing for PC with extractable 2 × 2 data were included. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. Pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratio (DOR) were estimated using a bivariate random-effects model. Subgroup analyses were performed by testing method and reference standard type. Heterogeneity was evaluated through paired forest plots, HSROC visualization, and exploratory bivariate meta-regression. RESULTS: The pooled sensitivity was 0.87 (95% CI: 0.81-0.91), and the specificity was 0.99 (95% CI: 0.982 - 0.995). The pooled positive likelihood ratio (PLR) was 88.00 (95% CI: 47.39 - 163.42), the negative likelihood ratio (NLR) was 0.13 (95% CI: 0.09 -0.20), and the DOR was 658.50 (95% CI: 285.36-1519.55). No significant threshold effect or publication bias was detected. Exploratory meta-regression suggested a possible assay-method effect in the joint model (P = 0.03), mainly driven by specificity (P = 0.01). CONCLUSIONS: The study demonstrates the high accuracy of CrAg in BALF for the diagnosis of pulmonary cryptococcosis, supporting its role as an important adjunctive diagnostic tool, particularly when tissue biopsy is not feasible or rapid results are needed. Larger prospective studies with standardized protocols are needed to validate these estimates.

Humans↗

PubMed2026

Revisiting somatosensory evoked potentials in motor neuron diseases: neurophysiological insights from a large cohort.

OBJECTIVE: To systematically investigate Somatosensory Evoked Potential (SEP) abnormalities in a large cohort of patients with Motor Neuron Disease (MND), and to explore their relationship with Motor Evoked Potentials (MEPs) and clinical phenotypes. METHODS: We retrospectively analyzed 267 patients with confirmed MND who underwent standardized SEPs and transcranial magnetic stimulation. Patients were divided into pure/predominant Upper Motor Neuron (UMN) and pure/predominant Lower Motor Neuron/Amyotrophic Lateral Sclerosis (LMN/ALS) groups. SEP abnormalities were assessed using internal normative data, including prolonged latencies, reduced amplitudes, and increased N20-P25 amplitudes. MEPs were classified semi-quantitatively as normal or abnormal by independent raters. RESULTS: At least one SEP abnormality was detected in 75 % of patients, with no significant differences between the UMN and LMN/ALS groups. Increased N20-P25 amplitudes were observed in both phenotypes, suggesting widespread sensory cortical hyperexcitability across the MND spectrum. In contrast, abnormal MEPs were significantly more frequent in UMN patients (p < 0.001). No significant association was found between SEP abnormalities and MEP findings. Upper- and lower-limb SEP latencies were strongly correlated (all p < 0.001), whereas increased SEP amplitudes did not correlate with latency abnormalities. CONCLUSIONS: SEP abnormalities are highly prevalent in MND and appear largely independent from corticospinal dysfunction. Increased SEP amplitudes likely reflect primary cortical sensory hyperexcitability rather than impaired sensory conduction. SIGNIFICANCE: These findings support the concept of MND as a multisystem network disorder that involves sensory cortical circuits and highlight the role of SEPs in the diagnostic workup.

Humans↗

PubMed2026

Chronic neurological diseases with acute respiratory failure in a real-life cohort: insights into ICU and long-term survival-A retrospective study.

BACKGROUND: Patients with chronic neurological diseases (CND) are at increased risk of pulmonary complications that often require ICU admission. This study aimed to identify clinical factors associated with ICU mortality and long-term survival in patients with CND who developed acute respiratory failure (ARF). METHODS: This retrospective cohort study was conducted in a level III respiratory ICU. Patients with pre-existing CND admitted to the ICU with ARF were included. ICU mortality was analyzed using multivariable logistic regression. Long-term survival after ICU discharge was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. Mortality timing was further characterized using hazard function analysis. RESULTS: A total of 220 patients were included; the most common neurological diagnoses were dementia (37.3%), stroke (22.7%), and amyotrophic lateral sclerosis (14.1%). ICU mortality was 33.6%. Higher APACHE II scores were independently associated with increased ICU mortality (OR 1.076 per point increase; 95% CI 1.029-1.126; p < 0.001). Long-term survival differed significantly by post-discharge respiratory support strategy, with Kaplan-Meier analysis demonstrating more favorable survival patterns among patients receiving home non-invasive mechanical ventilation (NIMV) (p = 0.003). In Cox regression analysis, age, home NIMV, and feeding modality at discharge were independently associated with long-term outcomes. Survival analyses revealed an early clustering of deaths within the first months after ICU discharge, particularly among patients with dementia. CONCLUSIONS: In patients with CND, acute physiological severity was the main determinant of ICU mortality, whereas long-term survival after ICU discharge was poor, with deaths clustering within the first months thereafter. Post-discharge respiratory support and nutritional management should be individualized according to the expected clinical trajectory and patient values.

Humans↗

PubMed2026

Contemporary surgical decision-making for hallux valgus and hallux rigidus in Switzerland: A national cross-sectional survey using standardized clinical scenarios.

BACKGROUND: Surgical management of hallux valgus and hallux rigidus is influenced by deformity severity, surgeon training, and evolving techniques. Previous surveys in Australia (2012), Switzerland (2015), and Israel (2023) using identical hypothetical cases demonstrated marked regional differences and a recent rise in minimally invasive Chevron-Akin (MICA). Whether these advances have altered contemporary Swiss practice remains unclear. METHODS: An electronic survey replicating the original questionnaire was distributed to members of the Swiss Foot and Ankle Society. Three standardized clinical cases were presented: mild hallux valgus, severe hallux valgus, and hallux valgus et rigidus. Respondents selected nonoperative versus operative management and specified procedures and fixation methods. Demographics, subspecialty training, and surgical volume were recorded. Current results were compared with prior Swiss data to assess temporal change. RESULTS: Eighty surgeons completed the survey (94% foot and ankle specialists). For mild hallux valgus, 87.7% recommended surgery; Scarf osteotomy remained most common (49.4%), followed by Chevron (21.0%) and Minimally Invasive Hallux Valgus correction (14.8%). Minimally Invasive adopters were predominantly mid-career (83% aged 41-50), high-volume surgeons. For severe hallux valgus, 95.1% favoured surgery; MTPJ arthrodesis was preferred (50.6% isolated; 11.1% with Lapidus), while Minimally Invasive Hallux Valgus correction was rarely chosen (2.5%). In hallux valgus et rigidus, 96% selected MTPJ fusion, most commonly plate-and-screw fixation (45.1%). Compared with 2015, fixation strategies evolved, yet procedure selection remained largely unchanged. CONCLUSION: Despite global expansion of minimally invasive bunion surgery, Swiss surgeons continue to favour established open techniques, particularly Scarf osteotomy and fusion-based strategies. Adoption of MIS remains limited and concentrated among high-volume, mid-career specialists, indicating a cautious national diffusion pattern. LEVEL OF EVIDENCE: IV, survey study.

Hallux Valgus↗

PubMed2026

Granger connectivity and graph-theoretical analysis of scalp EEG across the preictal to ictal transition for presurgical evaluation.

OBJECTIVE: To assess the feasibility of estimating lateralization and localization of the epileptogenic zone (EZ) in temporal and extratemporal lobe epilepsy by combining Electric Source Imaging (ESI) with functional connectivity analysis of high-density EEG from the preictal to the ictal phase. METHODS: Adults with drug-resistant focal epilepsy and at least one recorded seizure during 40- or 64 channels EEG monitoring were retrospectively included. Granger causality and hubness centrality were computed over the 10-s preictal interval and the first 5 s of the ictal period, with ictal onset defined as the first EEG change identified by experienced epileptologists. The reference standard for EZ localization was based on resective surgical outcome or stereo-EEG findings. RESULTS: Thirteen patients (7 females; median age 35 years) were included. Connectivity analyses showed higher concordance with clinical findings during the preictal phase than during the ictal phase for both lateralization (91% vs 46%) and localization (73% vs 27%). Performance was highest in temporal (7/7 lateralization; 6/7 localization) and frontal lobe epilepsy (2/2 for both), and lower in parieto-occipital epilepsy (1/2 and 0/2, respectively). In two cases with poor surgical outcome or no surgical indication, connectivity findings were discordant with clinical estimates. CONCLUSIONS: Connectivity analysis across the preictal to ictal transition provides relevant lateralizing and localizing information, particularly in temporal and frontal lobe epilepsy, and may reveal clinically meaningful discordance. SIGNIFICANCE: Integrating high-density EEG, ESI, and functional connectivity during the phase preceding the first EEG change may support non-invasive presurgical evaluation.

Humans↗

PubMed2026

Nondominant Hand Training in Laparoscopy for Surgical Interns: Feasibility and Impact.

OBJECTIVE: Laparoscopy requires bimanual proficiency, yet early trainees demonstrate underdeveloped nondominant hand (NDH) performance. Although deliberate practice of NDH skill contributes to overall performance, NDH training is rarely incorporated into residency simulation curricula and has not been formally evaluated in surgical trainees. We assessed feasibility and impact of integrating structured NDH training with established laparoscopic curriculum for surgery interns. DESIGN: Prospective, single-institution randomized pilot study. Interns were assigned the standard 4-week curriculum of laparoscopic dominant hand and bimanual tasks (Control) or completed assigned NDH tasks in addition to the standard curriculum (Intervention). Feasibility was determined by assigned task completion, daily standard and NDH-specific self-reported practice time, and improvement in bimanual task performance. Performance was video recorded weekly and assessed by blinded evaluators using MISTELS and GOALS scoring. Cognitive workload during laparoscopic tasks was measured via NASA-TLX. Exploratory analyses were conducted within a Bayesian framework. SETTING: A single academic institution with a surgical simulation training program. PARTICIPANTS: General surgery interns on their 4-week simulation rotation. RESULTS: Eleven general surgery interns (6 intervention, 5 controls; all right-hand dominant) completed the study with 100% task completion and practice log compliance. Both groups improved in bimanual performance and perceived cognitive load. Reduction in cognitive workload during bimanual task performance was greater in the NDH group. Time spent on NDH practice over 4 weeks was associated with improved bimanual performance, independent of time spent on standard curriculum tasks. CONCLUSIONS: Structured NDH training is feasible to implement within an existing curriculum and reduces perceived cognitive workload during bimanual laparoscopic tasks. NDH practice demonstrates a beneficial dose-response relationship with performance, supporting its integration into early laparoscopic training.

Laparoscopy↗

PubMed2026

A STORM-based protocol for nanoscale imaging and quantitative analysis of protein-associated and phospholipid-associated structures in natural rubber.

Stochastic Optical Reconstruction Microscopy (STORM) enables nanoscale mapping of molecular components beyond the diffraction limit; however, its reproducible implementation in hydrophobic polymer matrices remains challenging because fluorescence-labeling specificity, fluorophore photoswitching, three-dimensional localization, chromatic registration, and quantitative image analysis must be carefully controlled. This protocol presents a standardized experimental workflow for dual-color labeling, astigmatism-based three-dimensional STORM acquisition, and quantitative analysis of protein-associated and phospholipid-associated structures in natural rubber (NR). The workflow covers sample pretreatment, Cy5 NHS ester labeling of protein-associated primary amines, DiI labeling of phospholipid-rich domains, STORM imaging-buffer preparation, three-dimensional single-molecule localization, dual-channel registration, generation of standardized xy projections, aggregate-size analysis, and projected lateral spatial correlation assessment. Reproducibility is supported by defined acquisition and localization criteria, three independent sample preparations with at least five fields of view analyzed per condition, and unlabeled, single-color, dye-only matrix, and processing-associated Cy5 controls. Mean lateral localization precisions of 11.8 ± 2.3 nm for Cy5 and 13.5 ± 2.9 nm for DiI were obtained, while two-dimensional Fourier ring correlation analysis of the xy projections yielded effective lateral image resolutions of approximately 25 and 28 nm, respectively. Image-based particle segmentation and localization-coordinate-based density-based spatial clustering of applications with noise (DBSCAN) were applied to standardized xy projections as complementary quantitative approaches. Application of the protocol to untreated, centrifuged, and protease-treated NR samples demonstrated treatment-associated changes in the detected abundance and projected size distributions of protein- and phospholipid-associated aggregates, together with a non-monotonic change in their projected lateral spatial correlation. These observations describe alterations in nanoscale organization but do not, by themselves, establish stable protein-phospholipid complex formation. Unlike previous studies that primarily demonstrated the feasibility of STORM imaging in rubber materials, the principal contribution of this work is an end-to-end, step-by-step protocol incorporating defined controls, three-dimensional localization, image-quality metrics, chromatic-registration procedures, and complementary quantitative-analysis pipelines for non-expert users. The workflow may be adaptable to other hydrophobic polymers and soft-material systems after appropriate optimization and validation.

Rubber↗

PubMed2026

Efficacy and safety of rib-guided percutaneous thoracic sympathetic radiofrequency thermocoagulation at two different targets for primary palmar hyperhidrosis: a randomized controlled trial.

OBJECTIVES: To compare the efficacy and safety of computed tomography-guided percutaneous thoracic sympathetic radiofrequency thermocoagulation (RFT) targeting the upper versus lateral margin of the fourth rib head for severe primary palmar hyperhidrosis (PPH). METHODS: Patients with severe PPH were randomly divided into Group U (upper margin target) and Group L (lateral margin target). Outcome measures included 1-year recurrence rate, Hyperhidrosis Disease Severity Scale (HDSS), Dermatology Life Quality Index (DLQI), palm skin temperature, finger perfusion index (PI), compensatory hyperhidrosis and patient satisfaction. RESULTS: Both groups (n = 55 each, 110 sides) successfully underwent RFT. No preprocedural PI differences were found (p > 0.05). Immediately post-RFT, PI in Group L was significantly higher than in Group U (left p = 0.025, right p = 0.013). No significant differences in HDSS grades were observed between groups before and at 1 day, 2 weeks, 1 month and 3 months post-procedure. However, at 6 and 12 months, Group L showed significantly lower HDSS grades (left p = 0.033 and 0.016; right p = 0.039 and 0.025) and lower DLQI scores (p = 0.037 and 0.024) than Group U. Patient satisfaction did not differ within 6 months, but Group L had significantly higher satisfaction at 12 months (p = 0.036). CONCLUSIONS: Targeting the lateral margin of the fourth rib head for RFT achieved greater efficacy, better quality of life and higher patient satisfaction compared to the upper margin target.

Humans↗

PubMed2026

Longitudinal associations between family factors and the neurodevelopmental and psychosocial outcomes of children with congenital heart disease: A systematic review.

Family factors have been gaining increased attention in understanding adverse neurodevelopmental and psychosocial outcomes for children with congenital heart disease (CHD). To clarify relevance, we undertook a systematic review of only longitudinal studies which assessed such associations. Comparisons with the contribution of disease/surgical factors were also made where included studies considered such. We included longitudinal studies which assessed dynamic family factors (e.g. parent mental health, attachment, family functioning) and later child outcomes. Searches were conducted across CINAHL, Medline-Pubmed, PsychInfo and SCOPUS Web of Science. The NIH Quality Assessment Tool was used to evaluate study quality and risk of bias. Eighteen studies, utilizing data from 11 study samples and 2109 participants, met inclusion criteria. These studies included samples from infancy, with follow-up periods stretching into young adulthood, and with various degrees of CHD severity. The quality of studies was "good" to "fair", with key limitations of attrition and limited sociocultural diversity in samples. Findings suggested that family factors predicted later child psychosocial outcomes and more consistently than severity of disease indicators. This contrasted with a much smaller number of studies examining family factors and child neurodevelopmental outcomes, where no reliable conclusions could be reached. Findings highlight the importance of screening and family focused interventions for this population.

Child↗

PubMed2026

Peptide molecular lock-engineered nanobodies enable an oriented dual-modal immunoassay for reliable detection of Cronobacter sakazakii.

Conventional nanobody ELISAs for trace Cronobacter sakazakii in powdered infant formula suffer from random orientation and low signal output. We developed an oriented dual-modal immunoassay that combines site-specific biotinylation via a C-terminal AviTag and a peptide molecular lock, enabling controlled surface orientation while preserving nanobody structural integrity. This strategy was further integrated with phage-displayed nanobodies for multivalent amplification and both fluorescent and colorimetric readouts. The assay exhibited a broad linear range of 103-106 CFU/mL, with limits of detection (LODs) of 6.70 × 102 CFU/mL for fluorescence and 1.55 × 103 CFU/mL for colorimetry, showing improved sensitivity compared with the conventional passive adsorption-based Nb-ELISA evaluated in this study. XGBoost-based multimodal fusion improved quantitative accuracy, and SHAP analysis elucidated modality contributions. In spiked powdered infant formula samples, recoveries ranged from 92.1% to 118% with coefficients of variation below 5.98%, confirming acceptable matrix tolerance and analytical reliability.

Cronobacter sakazakii↗

PubMed2026

Ensemble DNA methylation clock demonstrates Immune-metabolic aging signatures associated with mortality.

Aging is a multifactorial process that is best described in terms of the progressive acquisition of multiple layers of phenotypic changes, such as epigenetic modifications, inflammation, and metabolic dysregulation. DNA methylation clocks have been extensively used to construct epigenetic clocks based on the DNAm profiles that can be used to estimate biological age and predict age-associated outcomes. Nevertheless, the vast majority of clocks constructed so far have been based on linear models, which are unlikely to fully account for the heterogeneity and non-linearity of survival-related DNAm signatures. In this work, we constructed a heterogeneous stacked ensemble survival model based on DNAm data obtained from the Framingham Heart Study. We first identified 190 CpG loci using elastic net Cox regression and subsequently constructed a survival prediction model based on the fusion of five complementary survival models by means of a neural network meta-learner. The prediction power of the survival model was evaluated in an external validation cohort, where we observed strong performance for predicting all-cause mortality that significantly exceeded PhenoAge and was statistically comparable to GrimAge. These performance estimates were derived in cohorts of European ancestry and externally validated in postmenopausal women aged 50-79 years, and should therefore be interpreted as applicable only to demographically similar populations.

Humans↗

PubMed2026

Comparative Bioavailability of Trimodal (CTx-1301) Versus Bimodal Dexmethylphenidate Modified-Release Formulations in Adults with Attention-Deficit/Hyperactivity Disorder: A Randomized, Single-Dose, Crossover Study.

BACKGROUND AND OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder that often requires sustained symptom control throughout the day. Although bimodal extended-release dexmethylphenidate (d-MPH XR) formulations provide initial and intermediate drug release, they may not consistently maintain therapeutic exposure into the late afternoon and evening. Trimodal formulations with an additional delayed release component may extend drug exposure later in the day, although this remains to be established. To explore differences in pharmacokinetic (PK) profiles between trimodal (CTx-1301) and bimodal delivery of d-MPH XR, a comparative bioavailability study was conducted at the highest and lowest doses for both formulations. METHODS: In this randomized, 4-period, crossover study, adults with ADHD received single doses of CTx-1301 (50 mg and 6.25 mg) and d-MPH XR (40 mg and 5 mg). Comparative bioavailability was assessed through adjusted geometric mean ratios for exposure parameters (maximum observed plasma concentration [Cmax], area under plasma concentration-time curve to last measurable concentration [AUClast] and extrapolated to infinity [AUC0-inf]), with a prespecified bioequivalence range of 0.80 to 1.25. Secondary endpoints included partial AUCs and safety assessments. RESULTS: The study population (N = 45) was predominantly male (88.9%) and White (55.6%), with mean age of 29.6 ± 8.01 years. Adjusted geometric mean ratios comparing the primary exposure parameters (Cmax, AUClast, and AUC0-inf) for CTx-1301 versus d-MPH XR were within the bioequivalence range (0.80-1.25) at both the high and low doses. The CTx-1301-to-d-MPH XR partial AUC ratios were within the bioequivalence range from 0 to 9 hours post-dose. At later intervals (AUC9-12 and AUC12-16), adjusted geometric mean ratios exceeded the upper bioequivalence threshold, consistent with the expected contribution of the third medication release component. Dose proportionality was observed between the two CTx-1301 doses and two d-MPH XR formulations. CTx-1301 was generally well tolerated. The most commonly reported adverse events included tachycardia, insomnia, headache, nausea, and euphoric mood. The incidence of treatment-emergent adverse events was numerically lower with CTx-1301 than with d-MPH XR; however, no statistical analysis was performed. CONCLUSIONS: Key exposure parameters including Cmax, AUClast, and AUC0-inf for trimodal CTx-1301 were statistically bioequivalent to bimodal d-MPH XR. Interval‑specific PK analyses demonstrated higher exposure with CTx‑1301 during later post-dose intervals (9-16 h), consistent with the formulation's third release component. However, the clinical relevance of these PK differences requires further evaluation. CTx-1301 demonstrated dose proportionality and was well tolerated at high and low doses. REGISTRATION: ClinicalTrials.gov, NCT04138498; 19 September 2019.

Humans↗

PubMed2026

Early radiographic loss of intermetatarsal angle correction after single first TMT arthrodesis (Modified Lapidus) versus three-corner TMT arthrodesis.

INTRODUCTION: The Lapidus procedure treats hallux valgus with first-ray hypermobility. It can be performed as a single first tarsometatarsal (TMT) arthrodesis or a three-corner TMT construct with additional intermetatarsal fusion. Early loss of correction remains a concern. This study compared early radiographic stability between techniques. METHODS: Fifty patients (15 three-corner TMT arthrodesis, 35 single first TMT arthrodesis) treated between 2014 and 2023 were retrospectively reviewed. Hallux valgus angle (HVA), intermetatarsal angle (IMA), Méary's angle, and tibial sesamoid position were measured on weight-bearing radiographs at 6 weeks and 6 months postoperatively. RESULTS: Both techniques achieved significant correction. The three-corner TMT arthrodesis group showed greater initial IMA correction at 6 weeks (p = 0.020) and maintained a lower IMA at 6 months (p = 0.001). Early IMA loss was greater after single first TMT arthrodesis (1.5°±1.7° vs 0.6°±0.8°, p = 0.013). CONCLUSION: Three-corner TMT arthrodesis was associated with greater early intermetatarsal stability than single first TMT arthrodesis.

Humans↗

PubMed2026

Matched targeted therapy use after broad genomic profiling in advanced Non-Small cell lung cancer.

INTRODUCTION: While broad genomic profiling is increasingly used in advanced NSCLC (aNSCLC), the impact of test results on subsequent guideline-concordant targeted therapy selection remains incompletely understood. METHODS: Using a merged dataset of two large, nationwide, patient-level databases, we identified patients who were diagnosed with aNSCLC 2017-2023, had potentially actionable genomic profiling findings, and initiated systemic therapy. Patients were categorized into actionability subgroups based on contemporaneous regulatory approvals and NCCN guideline recommendations. Within each subgroup, we assessed receipt of guideline-concordant targeted therapy within 24 months, including potential underuse (non-receipt of recommended treatment) and overuse (receipt of non-recommended treatment). RESULTS: Among 6620 patients (67.4% ≥65 years, 54.6% female, 68.9% White), guideline-concordant targeted therapy use varied substantially by actionability category: 2313 (89.6%) of 2582 patients with available 1st-line on-label options received them (10.4% underuse), while 212 (67.3%) of 315 patients with available later-line on-label options received them after 1st-line (32.7% underuse). Among 441 patients with available guideline-concordant off-label options, only 122 (27.7%) received them (72.3% underuse). Conversely, 238 (8.6%) of 3282 patients received matched but guideline-discordant off-label options, representing overuse of ineffective or unestablished therapies. Smoking history, squamous histology, and high PD-L1 expression were associated with lower targeted therapy receipt. CONCLUSIONS: In this cohort study of aNSCLC care, the guideline concordance of targeted therapy use varied by clinical actionability of molecular testing results. Underuse was more common in patients with later-line and off-label targeted therapy options. Patients with classical smoking-related risk profiles were substantially less likely to receive targeted therapy even when actionable alterations were identified.

Journal Article↗

PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗

PubMed2026

Mortality of Individuals With PRNP Variants Associated With Prion Disease in the United States, 1998-2024.

BACKGROUND AND OBJECTIVES: To characterize the survival of individuals with pathogenic PRNP variants-including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. METHODS: In this single-center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center (NPDPSC), including both diagnostic tests in symptomatic individuals, and predictive tests in asymptomatic individuals. Genetic test and autopsy results were queried from the NPDPSC database, and public record searches were conducted using online tools. RESULTS: Four hundred four individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated 92.6% sensitivity. We evaluated the age-dependent penetrance of the reportedly highly penetrance variants D178N and E200K and the reportedly low-penetrance variant V210I. Among 99 initially asymptomatic individuals with the pathogenic E200K variant, more than 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. For the pathogenic D178N variant, the median age at death was 57, which was numerically later, but not significantly different from, that seen in retrospective data. For V210I, just 2 deaths occurred, both after age 90, consistent with minimal penetrance. DISCUSSION: Our data support high penetrance of PRNP D178N and E200K variants and low penetrance of V210I. For E200K, the age at onset distribution appears to be shifted slightly later, and lifetime risk slightly lower, than previously reported. Autopsy data and public death records in combination were sensitive and concordant for determining long-term outcomes, but additional prospective data should be gathered to support future preventive trials.

Journal Article↗