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MIS-TLIF Versus Open TLIF in Combined Lumbar Stenosis and Low-Grade Spondylolisthesis : Of Discharge Timing and Treatment Pricing.

STUDY DESIGN: An open-label, randomized, noninferiority clinical trial. OBJECTIVE: To determine the effectiveness of the MIS-TLIF over the O-TLIF in patients with symptomatic lumbar stenosis combined with low-grade spondylolisthesis by comparing the clinical efficacy and safety. SUMMARY OF BACKGROUND DATA: In patients with combined lumbar spinal stenosis and spondylolisthesis, it remains uncertain whether minimally invasive fusion surgery is noninferior to the open approach. MATERIALS AND METHODS: We conducted an open-label, noninferiority trial involving patients with symptomatic lumbar stenosis combined with low-grade spondylolisthesis. Patients were randomly assigned in a 1:1 ratio to undergo either MIS-TLIF or open TLIF surgery. The primary endpoint was the reduction in the Oswestry disability index (ODI) score from baseline to three months postsurgery, with a noninferiority margin of 12 points. Secondary outcomes included three-month changes from baseline in back and leg pain, neuropathic pain, satisfaction with treatment, intraoperative data, and cost-effectiveness. RESULTS: In the modified intention-to-treat population, the mean difference was 0.4, with the corresponding 90% CI of -5.7 to 6.5, having a lower bound below the noninferiority margin of 12. Similar results were obtained by analysis of the per-protocol population. 82.8% of patients achieved the MCID for the ODI. Results for secondary outcomes (clinical scales, complications) showed no significant differences between the treatment groups (all P >0.05). Although the open TLIF group had a hospital stay that was 1.5 days longer ( P =0.005) and required additional analgesia more frequently ( P =0.026), direct costs were 10.5% higher in the MIS-TLIF group ( P <0.001). CONCLUSIONS: This is the first high-quality study comparing open TLIF and MIS-TLIF with a validated primary endpoint. Among patients with combined lumbar degenerative stenosis and degenerative spondylolisthesis, MIS-TLIF resulted in clinical outcomes at three months that were noninferior to those with open TLIF.

Humans

Simultaneous quantitative detection of multiple low-frequency variants by high-dynamic-range capillary electrophoresis.

Sensitive and quantitative detection of low-frequency variants across multiple loci is critical for nucleic acid-based diagnostics, yet clinical implementation requires a balance among sensitivity, multiplexing capacity, cost, and operational simplicity. We previously developed a high-dynamic-range capillary electrophoresis system capable of detecting variants at allele frequencies below 1%; however, its application was limited to single-locus analysis. Here, we expanded this platform to multiplex detection by incorporating mobility-shift strategies into the assay design. This approach enabled simultaneous analysis of 15 hotspot variants across three clinically relevant loci: KRAS codons 12 and 13 and GNAS codon 201. Validation using synthetic oligonucleotides, formalin-fixed paraffin-embedded tissue, and liquid specimens demonstrated high quantitative accuracy over clinically relevant variant allele frequency ranges, with measured values closely matching expected values (R2 > 0.97). The assay showed high concordance with targeted amplicon sequencing and digital polymerase chain reaction for all variants at variant allele frequencies &#x2265;1%, while also detecting selected variants below this threshold. Collectively, these results establish a multiplexed high-dynamic-range capillary electrophoresis assay for simultaneous, quantitative detection of low-frequency variants, offering a scalable and cost-effective approach for disease-focused gene panels in clinical laboratory settings.

HiDy

Integrating GWAS and Transcriptome Analysis Identifies Candidate Genes for Kernel Starch Quality Traits in Maize.

Maize (Zea mays L.) starch quality is a complex trait with significant implications for grain processing and industrial applications. However, the genetic basis underlying starch quality, particularly for gelatinization and thermodynamic properties, remains poorly understood. In this study, we evaluated 12 starch quality traits, including seven gelatinization characteristics, four thermodynamic traits, and kernel starch content (KSC) in a diverse panel of 335 maize inbred lines. Considerable phenotypic variation was observed for all traits. A total of 228 quantitative trait loci (QTLs) were significantly associated with 12 starch quality traits through genome-wide association studies (GWAS). By integrating a dynamic transcriptome analysis of two maize inbred lines with contrasting starch quality, we identified 60 candidate genes. One gene, waxy1, encoding a starch synthase, was found to be associated with enthalpy of gelatinization (&#x394;Hgel) and pasting temperature (Ptemp). Six variants in waxy1 contributed to natural variation in &#x394;Hgel and Ptemp, and a cost-effective InDel and two PARMS-based molecular markers were developed and validated in 144 maize inbred lines, enabling efficient marker-assisted selection. Our findings provide key genes and molecular markers for high-quality maize breeding with improved starch properties.

Zea mays

Quantitative RNA modification mapping by mass spectrometry with isobaric tags and nucleobase fragment analysis.

RNA modifications regulate RNA stability, translation, stress responses, and disease processes, yet their function remains poorly understood due to technical limitations in sequence analysis. Here, we present an RNA-specific isobaric tandem mass tagging (RMT) platform for omic-scale quantitative mapping of RNA modifications. The platform combines RNA-specific tags adapted from proteomics with an end-to-end workflow spanning sample preparation through data processing. Validation using synthetic oligonucleotides and total tRNA from Pseudomonas aeruginosa yielded reproducible quantification, with coefficients of variation below 5%. Together with nucleobase fragment analysis, we identified and quantified 24 RNA modifications in PA14 tRNAs, including previously undescribed m2A38 and Gm/Cm39, and assigned their corresponding writer enzymes. Further analyses of tRNAs from writer knockout strains and stressed cells revealed dynamic modification patterns, modification interdependencies, and their potential roles in stress adaptation. This method provides a robust, cost-effective platform for quantitative RNA modification mapping, enabling deeper biological insights.

RNA, Transfer

Single-nucleotide transcription start sites profiling via Nascent Strand-Specific RNA sequencing uncovers IFN-&#x3b3;-induced promoter dynamics.

Transcriptional regulation is a highly dynamic process in which nascent RNAs provide the most immediate readout of transcriptional activity. Precise mapping of transcription start sites (TSSs) is therefore critical for understanding promoter architecture and gene regulation, yet remains technically challenging. Here, we introduce Nascent Strand-Specific RNA sequencing (NSS-seq), a robust and streamlined method for genome-wide profiling of the capped 5' ends of nascent RNAs. By directly capturing transcription initiation events, NSS-seq overcomes the temporal delay inherent to conventional RNA-seq and enables time-resolved interrogation of transcriptional dynamics. Applied to interferon-&#x3b3; (IFN-&#x3b3;)-stimulation, NSS-seq uncovers previously unrecognized IFN-&#x3b3;-responsive genes and transient transcription factor activation patterns underlying interferon-mediated tumor-suppressive functions. Together, NSS-seq provides a cost-effective and technically accessible platform for dissecting promoter-level regulatory dynamics during cellular responses.

Promoter Regions, Genetic

A hybrid and cost-efficient barcoding strategy for full-length 16S rRNA gene nanopore sequencing of environmental samples.

BACKGROUND: Accurate species-level identification of bacteria in complex environmental samples is essential for applications in biotechnology, ecological monitoring, and clinical diagnostics. Short-read platforms such as Illumina frequently truncate the 16S rRNA gene, limiting taxonomic resolution. In this work, we applied Oxford Nanopore Technology (ONT) long-read sequencing to full-length 16S rRNA amplicon in samples from natural soil amended with lignocellulosic biomass and a simplified microbial community derived from cultures grown on selective and differential carboxymethyl cellulose (CMC)-based substrates, with the aim to evaluate the difference in performance between a real, complex community and a less complex system. To reduce consumable costs, we substituted the standard ONT Barcoding kits with an in-house hybrid barcoding workflow. Specifically, PacBio PCR-based barcoding protocol was used for sample indexing, followed by library preparation using the ONT Ligation Sequencing Kit. This simplified approach retained compatibility with MinION and Flongle flow cells and supported accurate downstream demultiplexing while lowering barcode costs substantially. Additionally, a new bioinformatic workflow tailored to ONT data was implemented. RESULTS: Overall, the hybrid protocol significantly reduced per-sample barcoding costs while preserving high sequencing quality and throughput. The sequencing run yielded over 5 Gb of quality-filtered data (Q-score &#x2265; 10). Furthermore, the new bioinformatic workflow allowed taxonomic assignment at the species level for 49.38% of annotated taxa, compared to just 4.59% using Illumina NovaSeq sequencing of the V3-V4 region. ONT also recovered 2.3 times more genera and 1.3 times more families. Although 16S rRNA gene sequencing often cannot distinguish between closely related species, particularly within taxonomically complex groups, in this work, full-length reads substantially improved both taxonomic resolution and database matching. CONCLUSIONS: These results show that full-length 16S rRNA sequencing with ONT, paired with a low-cost barcoding strategy, enhanced taxonomic resolution compared to short-read workflows. This approach also offers a scalable and cost-effective option for high-resolution microbiome profiling in research and applied settings.

RNA, Ribosomal, 16S

Health Service Delivery Outcomes From Nursing in Genomics: A Scoping Review of the Literature (2012-2025).

AIM: This study aimed to summarize the current state of the science for "health service delivery-oriented outcomes" from nursing in genomics (2012-2025). BACKGROUND: Nurses can play a vital role in increasing access to genomic healthcare and improving outcomes for patients, families, and communities. METHODS: We conducted a scoping review of the literature in four databases (2012-2025). Articles were categorized using the Cochrane Collaboration outcome domains and sub-domains to identify salient topics and synthesize findings. RESULTS: Of 11,646 retrieved articles, 66 publications reporting "health service delivery-oriented outcomes" were included for analysis. Identified articles spanned three sub-domains: "service delivery level," "related to research," and "societal or governmental." Within sub-domains, articles were further categorized into dimensions, the most prominent being "service utilization" under the "service delivery level" sub-domain. Studies were primarily from anglophone countries and near-evenly split into interventional and noninterventional studies. Studies reported that nurses working in multidisciplinary and/or interprofessional teams are a cost-effective means to increase access to genomic healthcare and reduce burden on genetic specialists. Nurses are incorporating genomics in various settings, including oncology, pharmacogenomics, genetic counseling, rare genetic diseases, and symptom science. CONCLUSION: Despite evidence of nurses contributing to health system delivery-oriented outcomes, evidence suggests that nurses are underutilized and underprepared in genomic healthcare. IMPLICATIONS FOR NURSING: A significant barrier to integrating genomics into nursing practice is a lack of foundational knowledge and genomic competency across nursing education, clinical practice, and nursing policymakers. IMPLICATIONS FOR NURSING POLICY: Nursing leadership spanning education, research, practice, and policy domains will be critical for integrating genomics in nursing practice and improving health system delivery-oriented outcomes.

Humans

An Application of Iterative Health Economic Evaluation: An Update on the Early Cost Effectiveness of Whole-Genome Sequencing in Advanced Non-small-Cell Lung Cancer.

OBJECTIVE: Whole genome sequencing (WGS) can identify more druggable targets than the standard of care (SoC) panels, however, its health effects and costs are highly uncertain. Given the rapidly evolving treatment landscape and pricing, an iterative approach is crucial to continuously reassess evidence and adapt economic models. Our objective was to update a previously developed economic model for WGS. METHODS: We used a structured approach to identify and report model elements requiring updates, based on established tools and methodological guidance, and applied it to the probabilistic decision model by Simons et al.(2021), which compared SoC, WGS, and SoC followed by WGS in patients with inoperable stage IIIB, C/IV NSCLC in the Dutch setting. RESULTS: Updates included a new treatment (sotorasib), revised drug and diagnostic costs, and adherence to the latest guidelines. Drug and WGS diagnostics costs fell by 8% and 26%, respectively. SoC diagnostic prices increased by 17%. We explored the impact of the prevalence of druggable targets, effectiveness of off-label treatments, (academic-specific) diagnostic costs, and price negotiations. The ICER of WGS versus SoC decreased from &#x20ac;737,197 to &#x20ac;419,053/QALY. WGS would become cost-effective if diagnostic costs descended from &#x20ac;2,180 to &#x20ac;1,246 or if additional druggable targets were identified in &#x2265;3.3% of patients. CONCLUSION: Our structured approach effectively identified items in the original analysis requiring updates and provides a foundation for further developing a checklist to guide iterative HTA. Continued monitoring and assessment of new treatment options, the dynamic diagnostics and costs throughout the life-cycle remain necessary to determine when WGS can be considered cost-effective.

NSCLC

Efficacy and safety of thulium fiber laser versus conventional holmium:YAG laser in anatomical endoscopic enucleation of the prostate: a systematic review and pairwise meta-analysis.

PURPOSE: Anatomical endoscopic enucleation is an established treatment for benign prostatic obstruction. Whether thulium fiber laser enucleation (ThuFLEP) improves outcomes over conventional holmium:YAG laser enucleation (HoLEP) remains uncertain. We compared the efficacy and safety of ThuFLEP versus non-MOSES-modulated HoLEP. METHODS: We performed a PRISMA-compliant systematic review and pairwise meta-analysis of randomised and comparative cohort studies comparing ThuFLEP and conventional HoLEP in adult men. Six databases were searched. Outcomes included International Prostate Symptom Score (IPSS), IPSS quality-of-life score, maximum urinary flow rate (Qmax), post-void residual volume, hospital stay, and complications. Risk of bias and certainty of evidence were assessed with RoB 2/ROBINS-I and GRADE. RESULTS: Seven non-overlapping comparative populations in eight publications included 3,509 patients. ThuFLEP was associated with a small statistically significant reduction in IPSS at 3&#xa0;months (mean difference [MD] -1.04 points, 95% confidence interval [CI] -1.81 to -0.28) of uncertain clinical relevance. Qmax differences were small and directionally inconsistent across follow-up (favouring HoLEP at 3&#xa0;months and ThuFLEP at 6 and 12&#xa0;months) and derived mainly from retrospective cohorts, with neutral randomised subgroups. Stress and urge urinary incontinence were less frequent overall (RR 0.75, 95% CI 0.58 to 0.96, and RR 0.39, 95% CI 0.22 to 0.68), but both estimates depended on one large registry cohort and were not robust to its exclusion. Most other complications and hospital stay showed no clear between-group difference. Limitations include few studies per outcome, heterogeneity, sparse safety events, inconsistent prostate-specific antigen reporting, and mostly low/very low certainty evidence. CONCLUSION: ThuFLEP and conventional HoLEP are clinically comparable with no definitive superiority of either laser. Platform selection should be individualised according to surgeon expertise, institutional resources, and patient characteristics. Future trials should standardise cost-effectiveness outcomes and investigate whether the distinct laser-tissue interactions impact adenoma clearance, PSA reduction, enucleation completeness, and long-term durability.

Humans

An economic evaluation of functional genomic testing for individuals with undiagnosed rare disorders.

PURPOSE: Functional genomics (FG) approaches, such as RNA-seq and proteomics, offer a complementary diagnostic modality for individuals whose cases remain unsolved after genomic sequencing. This study evaluates the cost-effectiveness and cost-benefit of FG for individuals with suspected monogenic disorders relative to manual reanalysis of genomic data at 18 months. METHODS: A decision tree model compared the costs and outcomes of FG and 18-month reanalysis using data from two Australian Undiagnosed Disease Programs. Deterministic and probability sensitivity analysis were performed. RESULTS: With a diagnostic yield of 13%, FG enabled 4 additional diagnoses per 100 individuals tested at an additional cost of $390 (US $240), resulting in an incremental cost-effectiveness ratio of $8,550 ($5,313) and an 85% probability of being cost-effective. CONCLUSION: Functional genomics enables timely diagnosis for individuals with suspected monogenic disorders by evaluating the functional impact of variants of uncertain significance, offering an advantage over reanalyzing genomic data at 18 months. Integration into the Australian healthcare system, supported by collaborative networks and secure data-sharing infrastructure, coupled with addressing barriers to accessing funded genomic testing, could lead to an annual net benefit of up to $1.1 million ($0.7 M).

Functional genomics

Three-dimensional porous nano-hydroxyapatite@gelatin composite as efficient adsorbent for uranyl ion removal from low-level radioactive wastewater.

The contamination of water resources by uranyl (UO22+) ions poses significant environmental and health risks, requiring the development of efficient and sustainable remediation strategies. Adsorption-based techniques have emerged as promising approaches in the field of UO22+ removal, but the design of cost-effective, high-capacity, and environmentally friendly adsorbents remains challenging. In this study, a three-dimensional porous nano-hydroxyapatite@gelatin (nHAP@Ge) composite was synthesized through glutaraldehyde cross-linking, combining the structural stability of Ge with the high uranium affinity of nHAP. The optimized nHAP@Ge, with a nHAP:Ge mass ratio of 1:0.5, exhibited exceptional UO22+ removal efficiency (97 %), along with high adsorption capacity (364.03 mg/g). Systematic characterizations using scanning electron microscopy (SEM), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, and X-ray photoelectron spectroscopy (XPS) methods revealed that the porous structure and surface functional groups (-OH, Ca2+, and PO43-) of the material synergistically contributed to binding UO22+ species. Furthermore, the incorporation of nHAP into the Ge framework resulted in enhanced thermal stability while significantly improving the UO22+ adsorption performance. This work presents a scalable, eco-friendly, and recyclable strategy for the effective treatment of uranium-contaminated water, with potential applications in nuclear wastewater treatment and environmental remediation.

Adsorption

Zebrafish as a versatile model in biomedical research, from disease modeling to regenerative medicine: a review.

Zebrafish are an effective animal model widely utilized in biomedical research. They are known for their rapid reproduction and substantial genetic similarity to humans. Their transparent embryos directly enable the visualization of developmental processes and disease progression. This makes zebrafish invaluable for studying a broad range of human diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Compared with other vertebrate models, zebrafish offer several advantages, including ease of genome editing, cost-effective maintenance, and suitability for high-throughput drug screening. Recent advancements have expanded the use of zebrafish in disease modeling and regenerative medicine, providing deeper insights into the genetic and cellular mechanisms underlying human pathologies. Zebrafish provide a robust platform for evaluating the safety, efficacy, and regenerative potential of both natural and synthetic biomaterials, including hydroxyapatite, bioactive glass nanoparticles, and bioceramics. This capability facilitates the creation of artificial tissues that closely resemble native structures. Additionally, integrating artificial intelligence technologies has improved automated data analysis and phenotyping in zebrafish studies, enhancing both accuracy and throughput. This review highlights current applications of zebrafish in disease modeling, drug discovery, regenerative medicine, and biomaterial assessment, emphasizing their evolving role as a versatile preclinical platform supported by advanced genetic and computational tools.

Animals

Holmium laser enucleation of the prostate for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia.

RATIONALE: A range of surgical options is available for the treatment of benign prostatic hyperplasia (BPH), including holmium laser enucleation of the prostate (HoLEP). The evidence is unclear regarding differences in functional, perioperative, and morbidity outcomes between these modalities. OBJECTIVES: To assess the effects of holmium laser enucleation of the prostate compared with other surgical treatments for lower urinary tract symptoms in men with benign prostatic hyperplasia. SEARCH METHODS: We searched multiple databases (including MEDLINE, Embase, CENTRAL, Web of Science, LILACS, and the International HTA database), trial registries, and conference abstracts through April 08, 2026. ELIGIBILITY CRITERIA: We only included randomized trials of men over 40 years of age with a prostate volume of at least 20 mL (assessed by digital rectal examination, ultrasound, or conventional imaging) who exhibited lower urinary tract symptoms (LUTS) defined by an International Prostate Symptom Score (IPSS) of eight or greater undergoing surgical interventions for BPH. OUTCOMES: The critical outcomes measured were the urologic symptoms score, the quality-of-life score, and major adverse events. The important outcomes measured were: re-treatment, erectile function, ejaculatory function, transfusions, acute urinary retention, indwelling urinary catheter duration, and hospital stay duration. RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 1) to assess for potential sources of bias on a study and outcome level basis. SYNTHESIS METHODS: We pooled outcome data using the random-effects model and performed meta-analyses using the Mantel-Haenszel method. We assessed statistical heterogeneity in the pooled data by visually inspecting forest plots and using the I2 statistic to quantify it. We used the GRADE framework to assess the certainty of evidence. INCLUDED STUDIES: We included 52 trials that included 6242 participants that compared HoLEP to other surgical interventions for benign prostatic hyperplasia. The median age of participants across the studies ranged from 65 to 74 years. The baseline prostate volume ranged from 30 cc to 142 cc. Baseline IPSS scores ranged from 19.6 to 28.6 (range 0-35). SYNTHESIS OF RESULTS: We prioritized comparing HoLEP with transurethral resection of the prostate (TURP) at short-term follow-up (up to 12 months), because TURP is the long-standing reference standard and the predominant comparator in randomized surgical trials. Findings for the four remaining comparisons (laser ablation, alternative energy source enucleation, other minimally invasive therapies, and simple prostatectomy), for long-term follow-up, and for all remaining outcomes are reported in full in the review. Compared to TURP, at short-term follow-up: Critical outcomes - HoLEP may result in little to no difference in short-term urologic symptom scores measured using the IPSS (range 0 to 35; lower values reflect fewer symptoms) (MD -0.67, 95% CI -1.20 to -0.14; I&#xb2; = 93%; 14 studies, 1666 participants, low-certainty evidence). - HoLEP may result in little to no difference in short-term quality of life (range 0 to 6; lower values reflect better quality of life) (MD -0.04, 95% CI -0.23 to 0.15; I&#xb2; = 73%; 6 studies, 876 participants, low-certainty evidence). - HoLEP may result in little to no difference in short-term major adverse events (RR 0.75, 95% CI 0.35 to 1.58; I&#xb2; = 0%; 10 studies, 1147 participants, low-certainty evidence). Important outcomes - HoLEP likely results in little to no difference in re-treatment (RR 0.45, 95% CI 0.14 to 1.50; I&#xb2; = 0%; 8 studies, 813 participants, moderate-certainty evidence). - HoLEP likely results in little to no difference in erectile function (MD -0.03, 95% CI -0.47 to 0.42; I&#xb2; = 0%; 3 studies, 518 participants, moderate-certainty evidence). - Ejaculatory function: we did not find any data for this outcome. - HoLEP likely reduces the need for blood transfusion (RR 0.19, 95% CI 0.09 to 0.42; I&#xb2; = 0%; 15 studies, 1755 participants, moderate-certainty evidence). AUTHORS' CONCLUSIONS: Compared with TURP, HoLEP may achieve similar relief of urologic symptoms, similar quality of life, and similar rates of major adverse events in the first 12 months after surgery, and probably similar re-treatment rates and erectile function. HoLEP likely reduces the need for blood transfusion; this is the only advantage of HoLEP that the randomized evidence, as summarized here, supports as clinically important. There was insufficient evidence to assess outcomes in the subset of individuals with larger prostates or on anticoagulation. Future research should prioritize long-term trials reporting sexual function and urinary incontinence outcomes, recruit men with very large prostates (&#x2265; 150 cc) or on anticoagulation therapy, and evaluate cost-effectiveness and training requirements. FUNDING: No external funding was received for this review. REGISTRATION: The protocol for this review was published in the Cochrane Database 2019 (https://doi.org/10.1002/14651858.CD013291).

Humans

Effectiveness of psychologically informed physical therapy, tendon-specific exercise program and routine physical therapy in prolonged unilateral shoulder pain and symptom correlations with imaging: a single-center, randomized, parallel-group, three-arm study (RESPECT).

BACKGROUND: Shoulder complaints are one of the most common musculoskeletal ailments. Patient-specific characteristics such as obesity, depression and physical labor are established risk factors, whereas imaging findings are common and associations between specific imaging findings and symptomatology is limited. General exercises are considered useful in treatment whereas evidence for specific tendon exercises is lacking. Biopsychosocial model is also recommended, but has not been extensively studied concerning shoulder symptoms. This article describes the study protocol designed to evaluate the effectiveness and the cost-effectiveness of routine and specific physical therapy (PT) interventions. Imaging is performed for descriptive, longitudinal and imaging-symptom correlation studies. METHODS: The Rehabilitation of Shoulder Pain: Evaluation and Clinical Trial (RESPECT) is a randomized three-arm parallel-group study involving 300 participants aged 20 to 60&#xa0;years with prolonged unilateral shoulder pain. Participants will receive either routine PT, physiotherapist-guided tendon-specific exercise program or psychologically informed PT. Bilateral shoulder radiographs, ultrasound and magnetic resonance imaging will be done at the baseline and at 12 and 36&#xa0;months. Electronic surveys will be completed at the baseline and at 3, 6, 12 and 36&#xa0;months. The primary outcome will be patient-specific functional scale (PSFS) at 12&#xa0;months, analyzed using analysis of covariance (ANCOVA), adjusted for baseline PSFS. DISCUSSION: RESPECT will provide systematic and controlled data regarding different PT interventions in prolonged shoulder symptoms, which is currently limited. Being one of the most common sources of musculoskeletal pain, improved management could reduce symptom-related burden and prolonged functional impairment at individual and population level. CLINICALTRIALS: gov; Registration number NCT07235969; Registered November 18th, 2025; Version: 1.0.

Humans

Nurse-led titration models of care for heart failure reduced ejection fraction: a systematic narrative review of characteristics, patient outcomes, and healthcare resource utilization.

AIMS: Nurse-led titration (NLT) models of care assist with delivery of guideline directed medical therapy for patients with heart failure with reduced ejection fraction (HFrEF). Effectiveness of NLT is established but there is limited information of characteristics of models, patient outcomes and healthcare resource utilization. To build upon the existing evidence by providing a systematic narrative review of the literature of NLT of medications for patients with HFrEF. This review syntheses characteristics of NLT models of care, patient outcomes and healthcare resource utilization. METHODS AND RESULTS: A systematic narrative literature review with systematic search strategy, identification of results, thematic analysis and narrative synthesis. A search was conducted from 2012 to 2025 in Medline, Cinahl complete, Embase and Cochrane. Sixteen studies of NLT models of care were identified from 1944 screened records. Characteristics of models of care were participation of nurses, multidisciplinary teams, follow-up and common features of service delivery. Patient outcomes of mortality were favourable for those that received NLT. There is some evidence of changes in healthcare resource utilization; studies in which the NLT groups received more HF nurse visits and greater HF medication use also reported reduced rehospitalizations. CONCLUSION: Findings reinforce the published benefits of NLT. Additional studies examining adverse events and quality-of-life outcomes are needed to strengthen the evidence base. Several studies suggest a shift in resource use with NLT, highlighting the need for an economic evaluation to inform a cost-effective model of care.

Humans

Seqwin: ultrafast identification of signature sequences in microbial genomes.

MOTIVATION: Polymerase chain reaction (PCR) enables rapid, cost-effective diagnostics but requires prior identification of genomic regions that allow sensitive and specific detection of target microbial groups, herein referred to as microbial signature sequences. We introduce Seqwin, an open-source framework designed to automate microbial genome signature discovery. Tens of thousands of microbial genomes are now available for a single species, limiting the application of existing manual and automated approaches for identifying signatures. Modern approaches that are capable of leveraging all available microbial genomes will ensure sensitive and accurate DNA signature identification and enable robust pathogen detection for clinical, environmental, and public health applications. RESULTS: Seqwin builds weighted pan-genome minimizer graphs and uses a traversal algorithm to identify signature sequences that occur frequently in target genomes but remain rare in non-targets. Unlike earlier tools that depend on strict presence or absence of sequences, Seqwin accommodates natural sequence variation and scales to very large genome collections. When applied to genomes from C. difficile, M. tuberculosis, and S. enterica, Seqwin recovered more high-quality signatures than alternative methods with lower computational burden. Seqwin's analysis of nearly 15&#x2009;000 S. enterica genomes yielded over 200 candidate signatures in three minutes. Seqwin provides an open-source solution for the long-standing need for scalable microbial signature discovery and diagnostic assay design. AVAILABILITY AND IMPLEMENTATION: Seqwin is available on GitHub (https://github.com/treangenlab/Seqwin) and can be installed via Bioconda (https://bioconda.github.io/recipes/seqwin/README.html). Benchmarking datasets, outputs, and scripts are available on Zenodo (https://doi.org/10.5281/zenodo.19874011).

Software

Machine learning for population-level risk prediction of future cholangiocarcinoma.

BACKGROUND: The poor prognosis of cholangiocarcinoma (CCA) is largely driven by rapid, asymptomatic disease progression, which usually results in a late diagnosis in the absence of established screening strategies. An early, cost-effective, and universally applicable risk assessment strategy would therefore be valuable. METHODS: We developed machine learning (ML) models on prospective, multimodal data from 487,495 UK Biobank (UKB) participants, of whom 649 developed CCA during follow-up. Data from England (80%) were utilised for ML development via five-fold cross-validation, and then all models were tested on withheld data from Scotland, Wales, and Newcastle (20%). Iterative ablation studies reduced inputs from >150 features across demographic data, lifestyle, health records, blood parameters, genomics, and metabolomics to models built on five and ten routinely available clinical parameters. These were externally validated in the Penn Medicine Biobank (PMBB; n = 2638; 28 CCA), All of Us Research Program (AOU; n = 330,433; 362 CCA), Japan Medical Data Centre Claims Database (JMDC; n = 8,425,522; 723 CCA) and TriNetX (n = 728,886; 1592 CCA). FINDINGS: We show that ML models integrating biliary-disease associated health records and Gamma glutamyltransferase can stratify risk of future CCA. Evaluation on the UKB test set as well as three independent cohorts revealed robust performance and generalisability across ethnicities. We achieved AUROCs of 0.71 [95% CI: 0.703-0.711], 0.77 [95% CI: 0.764-0.778 ], 0.796 [95% CI: 0.795-0.798] and 0.8 [95% CI: 0.794-0.805] for UKB, PMBB, AOU, and JMDC respectively, with respective AUPRCs of 0.014 [95% CI: 0.009-0.018], 0.042 [95% CI: 0.037-0.048], 0.038 [95% CI: 0.033-0.042] and 0.001 [95% CI: 0.001-0.001]. In AOU, application of the Youden J-optimised threshold yielded a number needed to screen of 79. Separate models for intra- and extrahepatic CCA did not improve performance. In line with the pathophysiology, performance declined for longer intervals between assessment and event. A group-level analysis in the TriNetX cohort revealed hazard ratios of up to 82.5 [95% CI: 26.4-257.96]. We provide extensive interpretability results and release all source codes used to develop the presented models. INTERPRETATION: We provide a comprehensive framework for early CCA risk stratification in the general population, identifying key predictors, and demonstrating the potential of data-driven models in personalised screening for hepatobiliary cancer. FUNDING: German Cancer Aid (grant #70115730), Junior Principal Investigator Fellowship programme of RWTH Aachen Excellence strategy.

Humans

Evaluation of one-step amplicon-based targeted enrichment for SARS-CoV-2 whole-genome sequencing using the Midnight amplicon scheme.

Genomic surveillance proved invaluable during the COVID-19 pandemic for tracking SARS-CoV-2 variants and guiding outbreak responses, underscoring the ongoing need to reduce whole-genome sequencing (WGS) costs and improve workflow efficiency to ensure accessibility in resource limited settings. Here, we evaluated a one-step reverse transcription polymerase chain reaction (RT-PCR) approach using the Midnight V2 primer scheme for targeted amplification of the SARS-CoV-2 genome, assessed its compatibility with Illumina sequencing, and compared its performance to a well-established two-step method. Initially, we determined optimal RT-PCR reaction conditions using the Midnight V2 primer panel for the one-step RT-PCR kit and scaled reaction volumes for both RT-PCR and library preparation. Clinical specimens (n&#x202f;=&#x202f;53) that had undergone routine WGS for surveillance purposes using the established two-step RT-PCR method were compared using the one-step RT-PCR assay. For samples with genome completeness greater than 70%, both methods gave comparable results with similar sequence coverage and 100% concordance for lineage assignment. Further investigation revealed a higher percentage of reads aligning to the SARS-CoV-2 genome with a greater depth of coverage using the one-step method compared to the two-step method. Finally, analysis of scaled one-step and library reaction volumes revealed significant cost savings for samples undergoing WGS. Overall, the results presented here verify the accuracy and reproducibility of one-step targeted amplification and offer an efficient and cost-effective workflow for routine SARS-CoV-2 genomic surveillance.

Humans