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The COVID-19 pandemic demonstrated the potential role of digital health tools in enhancing pandemic preparedness and response. These tools became essential, supporting not only health care delivery but also decision-making, communication, case identification, contact tracing, surveillance, vaccination rollout, and intervention evaluation. The interest in applying digital health tools to pandemic preparedness and response motivated conversations about digital epidemiology-a field of study that aims to provide insight into health and disease determinants by leveraging diverse digital data sources. In a globalized world, effective preparedness and response to pandemics require coordinated global action. This study investigates experts' opinions on strategies for improving global health security through the effective use of digital epidemiology, considering the current landscape of digital determinants of health. Epidemiologists, public health specialists, data scientists, and professionals with expertise in various components of digital health were recruited through convenience and snowball sampling methods. Their opinions were elicited using an electronic questionnaire developed by the authors in Research Electronic Data Capture (REDCap; Vanderbilt University). To ensure a global perspective, participants were recruited from Africa, North America, Oceania, and Europe. Thematic analysis and the strengths, weaknesses, opportunities, and threats (SWOT) analysis framework were used to analyze participants' responses. Most participants were familiar with the concept of digital epidemiology and expressed positive sentiments about its potential in strengthening global health security. Privacy and security, along with ethical and legal considerations, were ranked by most experts as high priority areas that decision-makers and implementers must consider to ensure sustainable integration of digital epidemiology tools in future pandemic preparedness and response. A SWOT analysis of participants' views on the promise of digital epidemiology revealed fewer strengths and more weaknesses compared to other components of the analysis framework. This study highlights the growing recognition of digital epidemiology as a critical tool for enhancing global health security, particularly using nontraditional data sources and emerging technologies, including artificial intelligence. The study affirms the need for a globally coordinated approach to governance, regulation, and investment in digital health infrastructure to ensure the responsible and effective application of digital innovations in epidemiological practice.

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a standard treatment for relapsed or refractory B-cell non-Hodgkin lymphomas. Long-term results and curative potential remain uncertain. We evaluated long-term outcomes in 38 patients with relapsed or refractory B-cell non-Hodgkin lymphomas (24 patients with large B-cell lymphoma and 14 with follicular lymphoma) who had been treated with CTL019 (now called tisagenlecleucel) - autologous T cells expressing CD19-directed, 4-1BB-costimulated chimeric receptors. Lymphoma-free survival was defined as the time from the tisagenlecleucel infusion to relapse or lymphoma-related death. The incidence of non-relapse-related death and second primary cancer was estimated with the Aalen-Johansen method. The data-cutoff date was October 1, 2025. At a median follow-up of 10.1 years (range, 7.9 to 11.5), no relapses had occurred beyond 5.4 years. The 10-year lymphoma-free survival was 32% (95% confidence interval [CI], 14 to 51) among patients with large B-cell lymphoma and 47% (95% CI, 20 to 71) among those with follicular lymphoma. In an analysis that included deaths from any cause, the 10-year progression-free survival was 17% (95% CI, 5 to 34) among patients with large B-cell lymphoma and 29% (95% CI, 9 to 52) among those with follicular lymphoma; the 10-year overall survival was 17% (95% CI, 5 to 34) and 50% (95% CI, 23 to 72), respectively. Persistent grade 2 or 3 neutropenia occurred in 2 patients (5%); no late anemia or thrombocytopenia was observed. A second primary cancer developed in 9 patients (10-year cumulative incidence, 21%). The 10-year non-relapse-related mortality was 18% (14% when deaths related to coronavirus disease 2019 were excluded). Higher CAR-transgene persistence appeared to be associated with long-term response. B-cell aplasia persisted in 44% of patients with a long-term response. Among patients with heavily pretreated B-cell non-Hodgkin lymphoma, a single infusion of tisagenlecleucel led to decade-long remissions (lymphoma-free survival) in approximately one third of the patients with large B-cell lymphomas and in nearly one half of those with follicular lymphoma. (Funded by the Richard Berman Family Innovations Center in CLL and Lymphomas and others; ClinicalTrials.gov number, NCT02030834.).

Access to geriatric mental health (GMH) care is limited in rural areas. To meet this need, the Veterans Health Administration provides specialty tele-GMH care for aging rural veterans via regional telehealth hubs. This study aims to create a roadmap describing key phases and determinants underlying the implementation and sustainment of tele-GMH services as part of a qualitative longitudinal evaluation of tele-GMH teams. Semistructured interviews were conducted with clinicians from all 8 tele-GMH teams (n=25) at 3 time points across a 3-year period (October 2021-September 2024). Interview (n=46) data were summarized into key domains using a templated rapid qualitative approach, guided by the Consolidated Framework for Implementation Research (CFIR) 2.0. Further thematic analysis and team discussion elucidated the findings. We identified key activities and determinants of success in three phases: (1) preimplementation (engaging leaders, securing funding/hiring, and defining services); (2) implementation scale-up and expansion (advertising, addressing challenges, seeking feedback, refining, and growth); and (3) sustainment (maintenance). Activities within each phase were cyclical and iterative (ie, nonlinear). Barriers to implementation included unfamiliarity with local aging resources; facilitators included tailoring strategies and engaging referring clinicians. Similar processes emerged across regions in the development and sustainment of tele-GMH services, allowing for the creation of a unified roadmap. Limitations including sampling bias are discussed. Further work could apply and evaluate the utility of the roadmap to guide creation of tele-GMH services in new regions to enhance access to specialty care for aging rural veterans.

To report updated patient-reported (PRO) health-related quality of life (HRQOL) findings and evaluate the effect of disease progression on HRQOL using data from the final analysis of the PRIMA/ENGOT-OV26/GOG-3012 trial. Patients were randomized 2:1 to niraparib first-line maintenance or placebo. Longitudinal HRQOL was a prespecified secondary endpoint assessed via European Organisation for Research and Treatment of Cancer QOL-Core Questionnaire (EORTC QLQ-C30) and -Ovarian Cancer module (EORTC QLQ-OV28), Functional Assessment of Cancer Therapy Ovarian Cancer Symptom Index (FOSI), and EuroQol 5-dimension 5-level questionnaire with visual analog scale (EQ-VAS). Post hoc analyses evaluated least-squares mean change from baseline or last on-treatment visit before disease progression (clinical cutoff: April 8, 2024). Questionnaire completion rates exceeded 89% through cycle 24 and were 80% at end of treatment. Early differences in gastrointestinal symptom scores between arms resolved over time, and no differences in overall HRQOL were observed. Disease progression reduced overall HRQOL across arms, with marked reductions in EORTC QLQ-C30 overall HRQOL, FOSI, and EQ-VAS scores that never recovered to pre-progression levels. Progression also resulted in sustained deterioration across all EORTC QLQ-C30 and QLQ-OV28 functional scales and worsening symptom scores, particularly for fatigue, dyspnea, pain, and appetite loss. Similar results were observed when patients were evaluated by homologous recombination deficiency status. In the final PRIMA PRO analysis, results confirmed that niraparib first-line maintenance did not negatively affect HRQOL versus placebo. Disease progression caused sustained HRQOL deterioration across arms, emphasizing the clinical importance of extending progression-free survival to preserve patient HRQOL. NCT02655016.

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. Patients are unable to convert the amino acid phenylalanine (Phe) into tyrosine (Tyr), leading to neurotoxic Phe accumulation. Chronically elevated Phe results in intellectual disability, psychiatric disorders, motor impairments, and epilepsy in affected children. Although there are interventions that focus on reducing plasma Phe levels, no curative therapies exist for PKU. Utilizing an adenine base editor (ABE), we demonstrate efficient in vivo corrective editing of hepatocytes in humanized PKU mice homozygous for the common P281L (c.842C>T) variant of PAH. Delivery of the ABE via lipid nanoparticles (LNPs) at four weeks of age resulted in significant reductions in Phe levels in plasma and cortex, as well as increases in cerebral amino acid and neurotransmitter concentrations. Behavioral assessment post-treatment revealed improvements in abnormal motor phenotypes. These data provide increased support for the viability of ABE-based therapeutics as a durable treatment for patients with monogenic metabolic disorders.

RNA covalent modifications (RCMs) influence RNA stability and translation efficiency, and thus play critical roles in eukaryotic growth and development. However, their role in regulating plant performance under abiotic stress remains largely unexplored. Here, we integrated multi-omics data in six Sorghum bicolor accessions under water-limiting conditions in the field to explore the relationship between RCMs and drought response. Within a stress and photosynthesis-associated gene co-expression module, we identified SbDUS2, a member of a family of enzymes conserved across eukaryotes, that catalyzes the reduction of uracil to dihydrouridine (DHU) on RNA molecules. DHU-modified transcripts in this module were enriched for photosynthetic functions and showed strong correlation with photosynthetic traits. To elucidate the function of this RCM, we characterized loss of function dus2 mutants in Arabidopsis thaliana. Under control conditions, these DHU-deficient mutants exhibited impaired germination and delayed development. Furthermore, under heat or water-limiting conditions, these mutants showed significantly reduced net CO2 assimilation and survival. Using multiple transcriptome-wide RNA stability assays, we demonstrated that transcripts associated with lower DHU levels in a dus2 background generally exhibited increased stability compared to Col-0 controls. Particularly, lack of DUS2 led to the hyperstability of photosynthesis-related transcripts, impeding their turnover and likely preventing proper photosynthetic acclimation during stress. We propose a model where DHU acts as a critical post-transcriptional regulator marking mRNAs for rapid turnover under stress, highlighting an overlooked regulatory layer contributing to plant resilience.

The third in a series of Paediatric Therapeutic Development Workshops focused on rhabdomyosarcoma. Rhabdomyosarcoma is the most common soft tissue sarcoma in children, with 90% survival for those with the lowest risk disease, but just 20-30% in children with metastatic disease. An urgent unmet need exists to develop targeted therapeutics for high-risk disease and to reduce the toxicity of treatment. The results of trials of CAR T-cells and ADCs against FGFR4 are awaited with great interest, and developing a FGFR4 degrader is a priority. Directly targeting PAX3::FOXO1 and PAX7::FOXO1 fusion proteins is a high priority. An in vivo study of a MYOD1 degrader approach is required prior to clinical development. Degraders of P300/CBP should be evaluated preclinically with a view to clinical investigation. ROR2 is an interesting target for the L122R mutant MYOD1 rhabdomyosarcoma. Development of a TEAD degrader is a high priority, and this should be evaluated in combination with a Notch inhibitor. Considering targets with existing clinical agents, antibody-drug conjugates targeting cell-surface antigen B7-H3/CD276 are showing preclinical promise in other paediatric cancers and are also deemed a high priority for evaluation in rhabdomyosarcoma. Based on currently available evidence, MEK inhibitors should be evaluated, potentially with BRAF or PI3K inhibitors, in combination with chemotherapy in the maintenance setting. Understanding the mechanism of action underpinning drug combinations, gaining access to therapeutics and optimising clinical trial design will be essential to enable combinatorial testing in patients.

Concerns persist within the surgical community that completion of an accredited surgical residency no longer consistently ensures that trainees are ready for independent practice. In response, the Independent Committee for Graduate Surgical Education (ICGSE) was established in January 2025 to address the unique requirements of surgical training. The committee's mandate was to recommend program standards that would potentially optimize education and training for surgical residents, with the goal of improving patient care. The ICGSE, consisting of 71 surgeons across 16 specialties, reviewed the history of surgical accreditation and relevant literature. Workgroup-led discussions identified strategies for improving trainee readiness and modernization of program accreditation standards. A literature review showed a "readiness gap" affecting 20%-30% of surgical trainees across multiple specialties. Key areas for improvement include:1. Designing curricula that increase clinical exposure, promote progressive autonomy, and facilitate transition to independent practice.2. Aligning training with the realities of surgical practice.3. Balancing accreditation requirements with efforts to reduce administrative burden and enhance faculty development.4. Emphasizing program evaluation beyond board passage rates and surveys to include real-time and longitudinal tracking of skill and clinical judgment acquisition.5. Supporting faculty education in teaching and assessment.6. Providing clear developmental roadmaps for lifelong learning. 1. Modernize accreditation through application of continuous quality improvement processes.2. Implement an outcomes-focused curriculum adaptable to each specialty that encourages innovation.3. Supplement case logs with an evidence-based framework for assuring procedural competency.4. Require standardized nontechnical skills training and assessment.5. Establish a longitudinal, competency-based assessment system.6. Mandate verifiable faculty development with institutional support. The ICGSE recommends that the graduate surgery education community, in collaboration with oversight organizations and professional associations, work to develop common surgery-focused accreditation standards that would drive the excellence required in surgical care.

Efficient priming of B cell precursors is a rate-limiting step in the induction of V2 apex broadly neutralizing antibodies (bNAbs)1,2. Here, we describe a novel germline-targeted HIV-1 Env (CAP256.OPT4) that increases the efficiency of V2 apex bNAb precursor priming by 30-400 fold compared with wild-type HIV-1 Envs and induces - in >90% of macaques - neutralization breadth that includes N130-containing viruses. Using three different delivery platforms - persistently replicating simian human immunodeficiency viruses (SHIVs), protein nanoparticles, and mRNA - we show bNAb priming as early as 4 weeks post-infection or immunization, and neutralization breadth in plasma by 12 weeks. In 14 SHIV-infected macaques, neutralization breadth reached as high as 90% on a 21-virus panel with potency as great as 1:20,000 (50% inhibitory dilution, ID50). Monoclonal bNAbs isolated from these animals were similarly broad and potent, with cryo-EM structures representing three distinct lineages revealing canonical needle-like HCDR3 binding. Env-Ab coevolution and structural analyses identified five key residues and loop features under positive selection and temporally associated with neutralization breadth. Importantly, prime-boost immunogens designed to capture these features induced broad and potent neutralization of globally diverse viruses including those containing N130 glycan. Further, rhesus bNAbs were not restricted to IGHD3-15*01 heavy chain alleles. These results expand the utility of the rhesus model for HIV-1 vaccine design and provide a molecular blueprint for inducing V2 apex bNAbs in rhesus and humans.

As integral members of pulmonary nodule (PN) programs, advanced practice providers (APPs) routinely evaluate PN cancer risk and make management recommendations. It is unknown whether an artificial intelligence (AI) tool impacts APP PN assessment and decision-making. What is the theoretical effect of APP use of a commercially available AI radiomics-based computer-aided diagnosis tool on PN diagnostic accuracy and management decision-making? In this retrospective multi-reader multi-case study performed from May 2024 to June 2024, 6 APP "readers" (4 in pulmonology, 2 in thoracic surgery) independently evaluated 300 chest CT scan "cases", each with an indeterminate PN 5-30 mm in maximal diameter (50% cancer prevalence). Using solely CT imaging data, APPs provided an estimate of cancer risk and management recommendation for each case without and then with AI tool assistance. The effect of the AI tool on readers' diagnostic performance and management decisions was assessed using descriptive statistics, area under the receiver operating characteristic curve (AUC), and reclassification plots and tables. With AI tool assistance, APP readers' average PN diagnostic accuracy increased by 9 percentage points (AUC: 0.79 vs 0.88; P<0.001). A higher proportion of malignant PNs were classified as high (>65%) risk (63% vs 46%; P<0.001) and recommended for a lung biopsy or surgical resection (72% vs 55%; P<0.001) with AI tool assistance. While benign PNs were more often classified as low (<5%) risk (39% vs 34%; P<0.001) with AI tool assistance, there was no statistically significant difference in the proportion recommended for an invasive procedure (18% vs 17%; P=0.3). APP use of a commercially available AI radiomics-based tool for PN evaluation was associated with increased diagnostic accuracy and invasive diagnostic procedure recommendation for malignant PNs. Future prospective, randomized clinical trials are required to assess its use in routine clinical practice.

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Primary hyperparathyroidism (PHPT) affects 1% of adults, but fewer than one-third of screen-eligible patients are tested. We developed and evaluated two new non-interruptive, clinician-facing alerts to increase appropriate PHPT screening. We designed process changes to facilitate guideline-informed patient identification via electronic phenotyping, laboratory test ordering, result interpretation, and follow-up. The computable phenotype was retrospectively validated. Clinician-facing alerts were built atop existing workflows for health maintenance (HM) and pended orders (PO) and evaluated in separate primary care clinics. Screening laboratory orders were more frequent in PO (81%; n = 30/37; p < 0.001) and HM (57%; n = 51/90; p < 0.001) than in control (19%; n = 373/1945) clinics. Increased screening appeared to yield higher detection of likely PHPT in PO (43%; 16/37; p < 0.001) and HM (8%; 7/90; p = 0.01) than in control (2%; 48/1945) clinics. Non-interruptive alerts demonstrate potential to substantially increase PHPT screening among appropriate patients.

Antimicrobial-resistant bacterial and fungal pathogens constitute a severe threat to public health. The pace at which new antimicrobials are being released is far slower than the pace of resistance emergence. Over the last decade, however, the genomics big data revolution has catalyzed major advances in antimicrobial discovery. Here, we briefly review how different human and other microbiomes have been mined to accurately extract biosynthetic gene clusters and antimicrobial peptides and proteins, with a focus on the latter groups. In addition to classical methods, artificial intelligence-enabled computational methods and innovative experimental strategies are increasingly used to prioritize candidates, identify novel small molecules and proteins active against priority pathogens, and reveal new modes of action. We highlight the urgent need to expand antifungal discovery, given the limited number of therapeutic classes and the slow pace of pipeline replenishment.

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The ability to inactivate gene function in an adult organism is essential for studies of biological processes such as regeneration and behavior. This is best achieved by engineering an allele that could be conditionally inactivated using drug-inducible Cre recombinase. Several recent studies clearly demonstrate the feasibility of engineering such conditional alleles in zebrafish. Meanwhile, achieving a sufficient degree of recombination to induce complete loss of function has remained a major limitation. Herein, we address this limitation by engineering a recombinant ubiquitin promoter ubbR consisting of the zebrafish ubiquitin promoter supplemented with an intronic enhancer from the carp beta-actin2 gene. Using phiC31-mediated targeted integration, we demonstrate that ubbR outperforms both parental promoters at all embryonic stages tested. Furthermore, the ubbR:CreERT2 driver line we generated ensures a high-level recombination of floxed alleles in adult zebrafish tissues. Finally, we demonstrate that our ubbR promoter-driven construct retains high activity when integrated at other genomic loci, making this promoter a promising new tool for robust expression of transgenes at all stages of zebrafish ontogenesis.

Most bacterial phyla have few or no pure cultures, including Atribacterota, comprised of ubiquitous anaerobes. Here, we report genome-guided enrichment and isolation of two Atribacterota species representing a new family, Caldatribacterium saccharofermentans from a hot spring, and Caldatribacterium inferamans from a deep aquifer. Both were co-enriched with sulfate-reducing bacteria and initially resisted isolation, which we link to inadvertent removal of precipitated folic acid by filter-sterilization of unbuffered Wolin's vitamin solution. We then predict folate auxotrophy across the Atribacterota and ~29% of all bacteria, with extensive auxotrophy in 27% of phyla. Since &#x2265;604 of 791 (&#x2009;&#x2265;&#x2009;76%) media with folic acid additions in the MediaDive database use unbuffered vitamin solutions in which folic acid is likely removed during filter-sterilization, we propose that folate auxotrophy limits culturability in defined media en masse. We also uncover unusual features of Caldatribacterium, including three lipid membrane-like layers (LMLs), with the inner LML surrounding the nucleoid, and a high percentage of secreted proteins, supporting a unique cell biology of Atribacterota.

There is urgent need for effective medication to treat cocaine use disorder (CUD). Clavulanic acid (CLAV) is a clinical stage medication that has potential for treating CUD. Sixty-four participants with CUD were randomized and received either 500mg/day CLAV or matched placebo in a 12-week outpatient study, with dose escalation to 750mg/day in week 5 with continued use. There was no statistically significant improvement in the CLAV treatment group compared to the placebo group. However, women taking CLAV reduced use. Starting at week 4, women reported significantly more days without cocaine use relative to baseline than women taking placebo. During the last 3 weeks of the study, women taking CLAV had a median of 4.0 more days without cocaine per week relative to baseline compared to 0.6 days in the placebo group. CLAV treatment also reduced cocaine withdrawal symptoms in women relative to baseline compared to the placebo over the first 3 weeks of the study. No such trends were identifiable in men. At the 500-750mg/day dose there is a signal that CLAV is associated with a reduction in the number of days of cocaine use in women with CUD. Men with CUD did not benefit from CLAV treatment at these doses. CLAV for 12 weeks was safe and reasonably well tolerated in people with CUD. Future studies should refine a therapeutic dose for men with CUD and further elucidate the effect of CLAV on the observed effects in women.

Poetry condenses language into minimal forms, evoking emotion, imagery, and aesthetic judgment, yet the neural basis of such evaluations remains poorly understood. We investigated how the brain evaluates two structurally matched but thematically distinct poetic forms: nature-themed Haiku and emotion-themed Senryu. Participants read poems and rated them across five dimensions-aesthetic appeal, vivid imagery, being moved, originality, and creativity-while EEG was recorded. Using multiclass gradient-boosted tree models with SHapley Additive exPlanations, we predicted evaluative ratings from oscillatory neural features across temporal windows and scalp regions. Models outperformed linear baselines and showed limited cross-theme generalization, indicating content-specific neural encoding. Distinct processing patterns emerged: Senryu showed stronger beta-band contributions, whereas Haiku engaged more distributed multifrequency dynamics. Temporal profiles also differed, with Haiku showing sustained engagement across reading and contemplation phases and Senryu showing earlier evaluative resolution during reading. Prestimulus neural activity contributed to prediction of subsequent evaluations, suggesting a role for anticipatory brain states in aesthetic evaluation. Across poems, evaluative dimensions converged on a dominant shared axis that was reliably predicted from neural features. Together, these findings suggest that aesthetic evaluation of poetry reflects an interaction between anticipatory neural states, content-specific oscillatory dynamics, and dimension-specific processes organized around a shared evaluative axis. This work establishes poetry as a tractable model system for studying how the brain constructs meaning and value from minimal linguistic input.

Estimating the number of insect species on Earth is a daunting challenge. The current consensus estimate-about six million species-is likely far too low, as we will show. Our estimate of the global number of insect species rests on a sample of more than 1,600,000 DNA-barcoded insect specimens representing 53,945 species from 15 "core" Malaise traps deployed in dry forest, cloud forest, and rainforest ecosystems of the &#xc1;rea de Conservaci&#xf3;n Guanacaste (ACG) in Costa Rica. Even this massive sample fails to reveal the full extent of ACG insect species richness. To estimate total ACG insect richness, we adjust the observed count of insect species by an "undersampling ratio," computed for a hyperdiverse subfamily of parasitoid wasps (Braconidae: Microgastrinae). The ratio compares microgastrine richness from the core Malaise traps to a lower-bound estimate of true microgastrine richness-including undetected species-based on 21,669 specimens from three sources: the 15 core Malaise traps, 15 "peripheral" Malaise traps spanning all three ecosystems, and 11,373 DNA-barcoded specimens reared from some 1,500 species of microgastrine-parasitized caterpillars (Lepidoptera). To estimate global insect richness, we apply Earth/ACG ratios for tree species and several animal taxa to upscale our estimate of ACG insect richness (nearly 333,000 species). Adopting conservative assumptions, we reach an estimate of 14 to 20 million insect species on Earth, depending on the upscaling group-two to three times the current consensus estimates. Upscaling instead from a point estimate of ACG richness with a wide CI, global estimates reach nearly 30 million species.