Networks underlie the generation and interpretation of many biological datasets: gene networks shed light on the regulatory structure of the genome, and cell networks can capture structure of the tumor micro-environment. However, most methods that learn such networks make the faulty 'independence assumption'; to learn the gene network, they assume that no cell network exists. 'Multi-axis' methods, which do not make this assumption, fail to scale beyond a few thousand cells or genes. This limits their applicability to only the smallest datasets. We develop a multi-axis method, which learns conditional dependency networks, capable of processing million-cell datasets within minutes. This was previously impossible, and unlocks the use of such methods on modern scRNA-seq datasets, as well as more complex datasets. We apply the method to a new scRNA-seq dataset for neuronal cell development, and compare the result to an existing state of the art method, hdWGCNA. We demonstrate that the new method yields gene networks that have a more focused biological interpretation and that the simultaneously learned cell network has advantages over a conventional kNN-based clustering. Further, our method yields novel biological insights by identifying long non-coding RNAs that potentially have a role in neuronal development. Our methodology is available as a Python package GmGM on PyPI (https://pypi.org/project/GmGM/0.5.3/). The code for all experiments performed in this paper is available on GitHub (https://github.com/BaileyAndrew/GmGM-Bioinformatics) and Zenodo (10.5281/zenodo.20384566). Contains our proofs and some additional experiments.
For many guideline-developing organisations, expert opinion remains essential when evidence is scarce. However, its unstandardised use remains a significant gap in guideline methodology. This article presents the development of the Semmelweis Framework, a methodological tool for structuring expert opinion in clinical practice guidelines when evidence is limited, indirect, or absent. The Semmelweis Framework was developed through a stepwise methodological process. First, a meta-epidemiological study mapped expert opinion use across 2,296 recommendations from 136 organisations. Second, a methodological review of 98 guideline manuals synthesised the functional definition of expert opinion that informed the Framework. Building on this definition, the Framework was refined through independent multi-reviewer application to 30 published recommendations, with calibration meetings, qualitative comparison of classifications, and parallel development of a Preconditions Checklist. The Semmelweis Framework offers an approach for structuring the role of expert opinion in clinical guidelines by classifying recommendations in four classes according to their evidentiary foundation. These classes form a continuum: from recommendations based on direct comparative evidence to those relying entirely on expert opinion when no relevant group-level evidence exists. Class I is grounded in direct comparative evidence. Class II addresses indirect evidence and requires explicit labelling of indirectness while using expert opinion to support applicability. Class III relies on non-comparative evidence and is heavily influenced by expert opinion, whereas Class IV is based entirely on expert opinion, operationalised as structured expert judgement, when no group-level evidence exists. Across all classes, fixed verbs and notations are proposed to standardise communication. A core component of the Framework is the specifically developed Preconditions Checklist, designed to ensure integrity and transparency when recommendations rely substantially on expert opinion. Under the Semmelweis Framework, "expert opinion" should not be used as a generic recommendation label; instead, its roles are redistributed across recommendation classes, each with explicit foundations and labelling. The Semmelweis Framework reframes the role of expert opinion and offers an approach for structuring its use in clinical guidelines. By introducing safeguards and new recommendation classes according to their evidentiary foundations, the Framework addresses a long-standing methodological gap.
BackgroundEvidence is lacking on whether support and education programs, facilitated by mobile technology, benefit people with stroke.Aims:The primary aim was to determine the effectiveness of a co-designed, eHealth self-management intervention for reducing unplanned hospital presentations.MethodsProspective, multicentre randomised trial with blinded outcome assessment and intention-to-treat analysis. Randomisation (1:1, stratified by age and level of disability at baseline) within 2 weeks of hospital discharge. Participants aged ≥18 years with modified Rankin score (mRS) 0-4 were recruited from 11 Australian hospitals. To maintain blinding, all participants co-developed 3-5 self-management goals with a trained clinician-researcher, using a standardised approach. Following randomisation, participants were allocated to receive personalised, goal-centred electronic messages (intervention) or administrative messages (active control) over 12 weeks via text or email. The groups were not informed about the number of messages they would receive and were unaware that only the intervention group had their messages tailored to their goals. The primary outcome was unplanned hospital presentations (emergency/admission) within 90 days post-randomisation. Secondary outcomes included goal attainment, self-efficacy, and various health outcomes. We used generalised mixed effects regression model with a logistic link for categorical outcomes and Cohen's d (0.2 considered small effect, 0.5 moderate-1.0 large) to assess within-group change.ResultsThe trial was impacted by COVID-19 and terminated with 556/890 planned participants; 465 were randomised (n=234 control, n=231 experimental) a median of 10 days post-discharge (median age 67.2 years, 67.1% male; median 3 goals/participant). Primary outcome assessments for 222 control and 218 experimental participants showed no between-group differences for unplanned hospital presentations (OR: 1.32; 95% CI: 0.52, 3.34). Compared to controls at 90 days, a larger proportion of the experimental group had ≥3 unmet needs and slight to severe disability (both <6% difference).. Both groups showed non-significant improvements in goal attainment at 90 days post-randomisation; overall attainment was stronger among intervention participants (within group change Cohen's d intervention 0.76 vs. 0.61).ConclusionWe found no evidence that tailored, electronic messaging over 12 weeks, in addition to structured goal setting reduced unplanned hospital presentations. Future research is needed to understand the role of disability and unmet needs, and factors that influence goal attainment.Trial registration:ACTRN12618001468213, U1111-1206-7237.
Tropical forests can recover diversity, structure, and function rapidly after disturbance. However, plant compositional recovery remains incomplete even after many decades, and the reasons for this lag are poorly understood. We investigated the roles of source, dispersal, and establishment limitation in affecting compositional recovery in Costa Rican forests using long-term data on species composition of trees, seeds, seedlings, and saplings, along with measurements of herbivory and leaf pathogen damage in seedlings and saplings from old-growth (OG) and second-growth (SG) forest plots. We classified tree species into successional groups, including: generalist (similar relative abundance in OG and SG), old-growth specialist (higher relative abundance in OG), old-growth exclusive (detected only in OG), and too rare to classify conclusively. Infrequent species drove community dissimilarity between old-growth and second-growth plots, and 40% of species in old-growth plots were absent as trees in second-growth forests up to 55 y old. Old-growth exclusive species (as trees and seedlings and saplings in OG plots and as seeds in seed traps in OG and SG) have extremely low abundance (11 trees/ha; 1 seedling or sapling/ha; 8 seeds/ha), indicating strong source limitation. Old-growth exclusive species shared seed dispersal traits with old-growth specialists established in SG, providing no evidence of dispersal limitation. Old-growth specialist seedlings and saplings had higher survival in SG than in OG, providing no evidence of establishment limitation. These findings suggest source limitation as the primary driver of delayed compositional recovery in mid-to-late stages of forest succession and underscore the potential for targeted enrichment plantings to accelerate full compositional recovery.
Zn-substituted Na0.75Mn0.68Ni0.25Zn0.07O2 has been synthesized in P3, P2, and composite P2/P3 structures and compared with unsubstituted Na0.7Mn0.75Ni0.25O2 analogues as positive electrodes for sodium-ion batteries. The synthesis temperature was shown to provide a means of controlling the phase ratio of P2 and P3 phases. Powder diffraction measurements, high-resolution transmission electron microscopy (TEM), and selected area electron diffraction (SAED) revealed that Zn substitution enhanced the ordering of the transition metal (TM) layers. Electrochemical studies combined with XAS measurements showed that after Zn substitution, Ni activity was enhanced, while the irreversible activity of O and Mn was suppressed. Structural transformations were suppressed, and the reversibility of Zn-substituted samples on cycling was improved. Among the Zn-substituted samples, Zn-P2/P3 delivers the best electrochemical performance with an initial capacity of 121 mAh g-1 at a rate of 25 mA g-1 and 90% capacity retention after 100 cycles in half-cells. This work reveals the intrinsic correlation among cation doping, synthesis conditions, and crystal phase compositions but also provides a reliable strategy for designing high-stability composite layered cathode materials for sodium-ion batteries.
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In this study, Salmonella Typhimurium (ST) vaccine diluent effects on caecal tonsils gene regulation in layer chicks were investigated. A live attenuated ST vaccine was reconstituted in Marek's and/or water diluents, chicks vaccinated and caecal tonsils were assessed for global gene expression at days 7 and 14 post-vaccination. Differentially expressed genes (DEGs) involved in the activation of the intestinal immune network for IgA production were upregulated earlier (e.g. day 7 post-vaccination) in the water diluent group, while in the Marek's diluent group, this pathway was enriched by the upregulated DEGs at day 14 post-vaccination. The commonly upregulated biological pathways between the two diluents were cytokine-cytokine receptor interaction, toll-like receptor signaling pathway and cytosolic DNA-sensing pathway. At day 7 post-vaccination, 28.5% and 40.2% of the significantly upregulated genes were unique to Marek's and water diluents, respectively, whereas 31.3% were common between the Marek's and water diluent groups, showing the role of the diluent in priming the vaccine for host immune system modulation. At day 14 post-vaccination, 52.7% and 15.4% of the upregulated DEGs were unique to Marek's and water diluents, respectively. Overall, the data showed that the live attenuated ST vaccine reconstituted in Marek's diluent affected the regulation of immune system-related genes in the caecal tonsils of chicks, with a difference in pattern when water was used as a diluent.
Prostate interventions are increasingly employed in management of benign prostatic hyperplasia (BPH) and prostate cancer. Routinely performed procedures include a widening array of surgical therapies for BPH, prostate needle biopsy, focal therapies, radical prostatectomy, and radiation therapy. While generally safe, these interventions are associated with various complications, broadly categorized as vascular, infectious, urinary, radiation related, and miscellaneous. CT is the first-line modality for detection of early complications, such as active hemorrhage and postoperative fluid collections. Fluoroscopic studies such as voiding cystourethrography and conventional cystography assist in evaluation of urinary leaks, fistulas, and strictures. MRI is particularly useful for characterization of late complications, such as complex urinary fistulas and pubic osteomyelitis, as well as detection of local recurrence alongside prostate-specific membrane antigen (PSMA) PET/CT or PET/MRI. Familiarity with expected and unexpected postinterventional imaging findings is essential to avoid delayed diagnosis and guide appropriate management. The authors highlight key complications through illustrative cases across multiple imaging modalities. ©RSNA, 2026 Supplemental material is available for this article.
Depression and anxiety commonly emerge during adolescence and are associated with substantial personal, social, and economic burden. Parenting practices are well-established modifiable risk and protective factors for adolescent affective disorders, yet many parents lack access to evidence-based guidance. Digital parenting interventions offer a potentially scalable approach, but evidence for their effectiveness in high-risk adolescent populations remains limited. The PIPA Trial was a school-based, UK-wide, two-arm randomised controlled trial evaluating a personalised online parenting programme compared with a standard educational parenting package. Parent-adolescent dyads were eligible if adolescents aged 11-15 years scored ≥7 on the Short Mood and Feelings Questionnaire (SMFQ). The primary outcome was change in parent-reported adolescent depressive symptoms (SMFQ) from baseline to 15 months. Secondary outcomes included parenting practices, parent-child attachment, adolescent anxiety, wellbeing, and parent wellbeing. A total of 512 dyads were randomised, with 510 included in intention-to-treat analyses. Adolescents presented with elevated baseline depressive symptoms and substantial prior mental health difficulties. Depressive symptoms declined over time in both trial arms, with no significant between-group difference at 15 months (adjusted difference - 0.12 SMFQ points, 95% CI -1.23 to 0.98). In contrast, parents allocated to the personalised programme showed greater improvements in guideline-concordant parenting practices and parent-child attachment. Engagement was modest, and over 40% of adolescents triggered duty-of-care procedures due to elevated risk during the trial. In this high-risk UK sample, a personalised digital parenting programme improved parenting practices but did not reduce adolescent depressive symptoms beyond an active educational control. These findings highlight the importance of matching intervention intensity to baseline symptom severity and support the role of digital parenting programmes as part of stepped prevention and early intervention frameworks. ISRCTN63358736.
Global investments in digital health are accelerating progress toward universal health coverage, yet low- and middle-income countries face persistent challenges: fragmented data and limited interoperability inhibit systematic transformation. The World Health Organization's SMART (Standards-based, Machine-readable, Adaptive, Requirements-based, and Testable) guidelines and Digital Adaptation Kits (DAKs) offer a standardized, evidence-based framework that enables countries to localize digital content and reinforce the uptake of standards at the point of care. Lessons from early adopters, including Cameroon, Ethiopia, Ghana, and Zambia, demonstrate that structured DAK localization strengthens alignment with national digital strategies and the potential to harmonize information systems. Effective adoption is driven by early user engagement, strong government leadership, and multisectorial collaboration. Mainstreaming the SMART Guidelines approach highlights the importance of robust governance and contextual adaptation in sustaining and scaling digital solutions that align with global standards.
The tiny Allomerus ants utilise antibiotic producing bacteria to maintain the fungal monoculture that they grow to camouflage and reinforce the galleries that they build for the capture of insect prey. Until now, filipin complex was the only identified antifungal used in the trap ant system. Here we chemically identify the presence of the unusual and potent antifungal vD844. We identify the biosynthetic gene cluster responsible for its assembly and demonstrate its heterologous expression. With the full set of genes encoding vD844 in hand, we reveal further insight into the biosynthesis of this unusual compound.
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Hypertension is a modifiable risk factor for dementia, yet the comparative effectiveness of angiotensin receptor blockers (ARBs) versus angiotensin converting enzyme inhibitors (ACEIs) on dementia risk remains uncertain. To compare the risk of dementia and dementia-free death of ARB versus ACEI initiation among US Veterans with incident hypertension. We conducted a retrospective target trial emulation using a new-user, active-comparator design among Veterans with incident hypertension. We analyzed longitudinal electronic health records from 2,577,000 individuals who initiated ARBs or ACEIs between 1/1/2000-12/31/2017, with up to five years of follow-up. The exposure was initiation of an ARB-based versus ACEI-based antihypertensive regimen. Co-primary outcomes were dementia, identified using natural language processing of clinical notes, and dementia-free death. We used inverse probability of treatment weights based on 66 pretreatment covariates to estimate the cumulative incidence of the outcomes for each treatment group. Weighted risk ratios and absolute risk differences through five years were computed with bootstrapped 95% CIs. Secondary outcomes included all-cause death and a composite of dementia or death, evaluated using a weighted Kaplan-Meier approach. Among 2,577,000 Veterans (mean age, 63 years; 4.5% female; 65% White; 15% Black), 10% initiated ARBs and 90% initiated ACEIs. Over five years of follow up, 6% developed dementia, 12% died without dementia, and 13% died overall. ARB initiation yielded consistently lower risk of dementia (risk ratio, 0.88; 95% CI, 0.83-0.93 at 6 months to 0.92; 95% CI, 0.90-0.94 at 5 years) and dementia-free death (risk ratio, 0.90; 95% CI, 0.86-0.96 at 6 months to 1.00; 95% CI, 0.98-1.01 at 5 years) than ACEI initiation. Effects on secondary outcomes were similar to those for primary outcomes. Greater protective dementia effects were observed in older and male Veterans and non-statin users, with similar effects on dementia-free death. Among US Veterans with incident treated hypertension, initiation of ARB versus ACEI antihypertensive regimen conveyed a modestly lower risk of dementia. Given the high prevalence of hypertension, these modest effects may confer meaningful population-level benefits on brain health. Future research estimating per-protocol effects using a more generalizable population is needed to confirm our findings. antihypertensive medication, dementia, natural language processing, target trial emulation, Veteran.
To examine whether adolescents' friends' depressed mood in-school is longitudinally associated with their own mental health from adolescence into adulthood. We used data from Waves I-V of the National Longitudinal Study of Adolescent to Adult Health. Participants included 10,769 individuals (Mage = 15.6 [SD = 1.7] years at Wave I, 37.6 years [SD = 1.8] at Wave V; 52% girls; 56% Non-Hispanic White). At Wave I, adolescents nominated friends within their school and reported depressed mood frequency. Friends' depressed mood was the average depressed mood score across adolescents' friends. Using mixed effects logistic regression we examined the association between friends' depressed mood and time-varying outcomes (ego depressed mood, suicidal ideation, suicide attempts) alongside outcomes of lifetime diagnoses of depression and anxiety. We also examined whether associations differed by gender. Adolescents' friends' depressed mood was longitudinally associated with small increases in the odds of their own depressed mood, suicidal ideation, and suicide attempts up to one year later, during adolescence. There was weak evidence this pattern persisted into adulthood or that it was associated with self-reported diagnoses of depression or anxiety. Gender moderated one association: friends' depressed mood was associated with a small increase in the odds of suicidal ideation in boys but not girls. Depressogenic friendship networks in adolescence may increase short, but not long-term, risk of depressed mood and suicidality. Findings have important implications for risk assessment, and targeted school-based interventions.
Intestinal failure-associated liver disease (IFALD) is a recognized complication of long-term parenteral nutrition (PN), with reported prevalence ranging from 25-85%, reflecting heterogeneity in patient populations, diagnostic criteria, and PN practices. We aimed to estimate the prevalence of IFALD in Australian adults receiving long-term home-PN (HPN), describe its biochemical and elastographic features, and identify predictors of IFALD. This was a single-centre, cross-sectional observational study in an Australian tertiary centre. Adults currently receiving long-term HPN (>12 weeks) or had received HPN within the previous decade were included. Patients with malignancy or pre-existing liver disease were excluded. IFALD was defined as persistent, unexplained elevation of liver function tests after exclusion of alternative causes of liver injury. Vibration controlled transient elastography (VCTE) was performed in all patients. Univariate logistic regression was used to evaluate associations between IFALD, nutritional, and biochemical variables. 24 patients were included. The median (inter-quartile range) duration of HPN was 42.5months (15.8-62.3); and weekly calories were 6647 kilocalories (3476.3-8471.3). 15 (62.5%) patients had IFALD. Cholestasis was the predominant biochemical pattern (80%). VCTE demonstrated significant fibrosis (≥ 8 kPa) in 20% and significant steatosis in 40% of IFALD patients. Ongoing HPN was the only variable significantly associated with IFALD on univariate analysis (OR=8, p=0.03). IFALD was highly prevalent and manifested as cholestatic liver injury, with a subset demonstrating elastographic evidence of fibrosis. Ongoing HPN was the main predictor, suggesting potential reversibility with PN cessation. Larger, multicentre studies are needed to identify any clinical predictors of IFALD.
We present a study of gypsum-mediated proteinoid formation and the electrochemical properties of the resulting mineral-organic composites. Proteinoid-gypsum composites were synthesized by thermal condensation of glutamate, phenylalanine, and aspartate with calcium sulfate dihydrate. These composites exhibited spontaneous electrical oscillations that lasted more than 70 h without external energy input. Electrochemical impedance spectroscopy showed a 20-fold drop in impedance compared to pure proteinoids. Cyclic voltammetry revealed asymmetric redox behavior, highlighting a preference for oxidation processes. Power spectral density analysis revealed clear scaling regimes. At ultra-low frequencies, α=2.96. At intermediate frequencies, α=1.64. These values are consistent with multiscale electrochemical dynamics spanning diffusive and capacitive processes. The mean firing rate was 2.31×10-4Hz. The average inter-spike interval was 72minutes. These values make these oscillations some of the slowest known spontaneous electrochemical oscillators. These findings suggest that prebiotic mineral-organic systems may have exhibited organized electrochemical dynamics prior to the emergence of cellular life, supporting the possibility that minerals participated in the organization of early electrochemical processes.
Prevalence and incidence are fundamental metrics with numerous applications in epidemiology. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline lacks specific items for reporting studies of disease prevalence or incidence. To address this gap, the STROBE Enhanced Prevalence and Incidence Criteria (STROBE EPIC) extension was developed in accordance with established methods for reporting guideline development. The authors generated an initial list of reporting items, conducted a modified Delphi process, and convened a face-to-face consensus meeting to confirm the need for a STROBE extension and to generate an early version of the checklist. They conducted 2 further Delphi surveys, first extending from typhoid and other invasive salmonelloses to all infectious diseases, and then to noncommunicable diseases and injuries. Finally, experts piloted the checklist on relevant manuscripts to critically assess if it was clear, concise, complete, and free of errors. An executive group curated the checklist after every survey round. The STROBE EPIC checklist comprises 47 items in the domains of title (1 item), abstract (2 items), introduction (1 item), methods (25 items), results (6 items), discussion (7 items), and other information (5 items). STROBE EPIC items address reporting of study design, adjustment factors for underreporting and underdiagnosis, denominator population estimation, case ascertainment methods, factors producing artefactual changes to observed disease prevalence or incidence, limitations of incomplete surveillance coverage, generalizability of short-duration studies, and data availability. The authors anticipate that the STROBE EPIC extension will be used by researchers, authors, modelers, burden-of-disease researchers, peer reviewers, and journal editors to optimize the presentation of epidemiologic evidence to support diverse health policy decisions.
We report the complete genome sequence of four Microbacterium phages, Pharky, Phedro, Phractured, and StagePhright, isolated using the bacterial host Microbacterium foliorum from soil samples collected in Philadelphia. All four phages are genetically very similar and contain a gene of unknown function, which is uncommon in the EK2 cluster.
With this status report, we aim to provide a timely snapshot of the protein engineering field as a broad and rapidly advancing discipline that integrates computational, molecular biology, structure-guided, evolutionary, and synthetic approaches to create new and improved proteins with tailored structures and useful functions. The report is organized into eight thematic areas spanning core methodologies and major application domains, including enzymes, therapeutics, detection, synthetic biology, and materials. Contributions from experts across these areas highlight both the historical foundations and recent advances in their respective fields, with particular emphasis on the growing influence of machine learning and artificial intelligence-based methods. Emerging from this broad overview is a central message: protein engineering appears to be entering a golden age, defined by a rapidly accelerating pace of progress, even as significant challenges in design, screening, and real-world application remain. Looking ahead, the continued integration of computational and experimental strategies is poised to further accelerate the impact of protein engineering across an expanding range of economically and societally important sectors, from therapeutics and molecular imaging to diagnostics, plastic recycling, and industrial chemistry.