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Circadian clocks present throughout the brain and body coordinate diverse physiological processes to support daily homeostasis and respond to changing environmental conditions. The local dependencies within the mammalian clock network are not well defined. We previously demonstrated that the skeletal muscle clock controls transcript oscillations of genes involved in fatty acid metabolism in the liver, yet whether the liver clock also regulates the muscle was unknown. Here, we use hepatocyte-specific Bmal1 KO mice (Bmal1 hep-/- ) and reveal that approximately one third of transcriptional rhythms in skeletal muscle are regulated by the liver clock vivo. Treatment of myotubes with serum harvested from Bmal1 hep-/- mice inhibited expression of genes involved in metabolic pathways, including oxidative phosphorylation. Overall, the transcriptional changes induced by liver clock-driven endocrine-communication revealed from our in vitro system were small in magnitude, leading us to surmise that the liver clock acts to fine-tune metabolic gene expression in muscle. Strikingly, treatment of myotubes with serum from Bmal1 hep-/- mice inhibited mitochondrial ATP production compared to WT and this effect was only observed with serum harvested during the active phase. Overall, our results reveal communication between the liver clock and skeletal muscle-uncovering a bidirectional endocrine communication pathway dependent on clocks in these two key metabolic tissues. Targeting liver and muscle circadian clocks may represent a potential avenue for exploration for diseases associated with dysregulation of metabolism in these tissues.

Marine protected areas (MPAs) are widely implemented tools for long-term ocean conservation and resource management. Assessments of MPA performance have largely focused on specific ecosystems individually and have rarely evaluated performance across multiple ecosystems either in an individual MPA or across an MPA network. We evaluated the conservation performance of 59 MPAs in California's large MPA network, which encompasses 4 primary ecosystems (surf zone, kelp forest, shallow reef, deep reef) and 4 bioregions, and identified MPA attributes that best explain performance. Using a meta-analytic framework, we evaluated the ability of MPAs to conserve fish biomass, richness, and diversity. At the scale of the network and for 3 of 4 regions, the biomass of species targeted by fishing was positively associated with the level of regulatory protection and was greater inside no-take MPAs, whereas species not targeted by fishing had similar biomass in MPAs and areas open to fishing. In contrast, species richness and diversity were not as strongly enhanced by MPA protection. The key features of conservation effectiveness included MPA age, preimplementation fisheries pressure, and habitat diversity. Important drivers of MPA effectiveness for single MPAs were consistent across MPAs in the network, spanning regions and ecosystems. With international targets aimed at protecting 30% of the world's oceans by 2030, MPA design and assessment frameworks should consider conservation performance at multiple ecologically relevant scales, from individual MPAs to MPA networks., (Conservation BiologyConservation Biology© 2024 The Author(s). Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Objective: Meat intake is suggested to affect gut microbiome composition and the risk of chronic diseases. We aimed to identify meat-associated gut microbiome features and their association with host factors., Design: Gut microbiota species were profiled by deep shotgun metagenomics sequencing in 9669 individuals. Intake of white meat, unprocessed red meat, and processed red meat was assessed using a food frequency questionnaire. The associations of meat intake with alpha-diversity and relative abundance of gut microbiota species were tested using linear regression models with adjustment for dietary fiber intake, body mass index, and other potential confounders. Meat-associated species were further assessed for association with enrichment of microbial gene function, meat-associated plasma metabolites, and clinical biomarkers., Results: Higher intake of processed red meat was associated with reduced alpha microbial diversity. White meat, unprocessed, and processed red meat intakes were associated with 36, 14, and 322 microbiota species, respectively. Species associated with processed red meat were enriched for bacterial pathways like amino acid degradation, while those negatively linked were enriched for pathways like homoacetogenesis. Furthermore, species positively associated with processed red meat were to a large extent associated with reduced trimethylamine N-oxide and glutamine levels but increased creatine and carnitine metabolites, fasting insulin and glucose, C-reactive protein, apolipoprotein A1, and triglyceride levels and higher blood pressure., Conclusion: This largest to date population-based study on meat and gut microbiota suggests that meat intake, particularly processed red meat, may modify the gut microbiota composition, functional capacity, and health-related biomarkers., Competing Interests: Conflict of interest HBN and JBH are employees of Clinical Microbiomics. JS reports direct or indirect stock ownership in companies (Anagram kommunikation AB, Sence Research AB, Symptoms Europe AB, MinForskning AB) providing services to companies and authorities in the health sector including Amgen, AstraZeneca, Bayer, Boehringer, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, WeMindstock ownership in Anagram kommunikation AB and Symptoms Europe AB, unrelated to the present study. JÄ has served on advisory boards for Astella, AstraZeneca, and Boehringer Ingelheim, and has received lecturing fees from AstraZeneca and Novartis, all of which are unrelated to the present work. The remaining authors declare no competing interests., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Maintaining homeostasis is essential for continued health, and the progressive decay of homeostatic processes is a hallmark of ageing. Daily environmental rhythms threaten homeostasis, and circadian clocks have evolved to execute physiological processes in a manner that anticipates, and thus mitigates, their effects on the organism. Clocks are active in almost all cell types; their rhythmicity and functional output are determined by a combination of tissue-intrinsic and systemic inputs. Numerous inputs for a specific tissue are produced by the activity of circadian clocks of other tissues or cell types, generating a form of crosstalk known as clock communication. In mammals, the central clock in the hypothalamus integrates signals from external light-dark cycles to align peripheral clocks elsewhere in the body. This regulation is complemented by a tissue-specific milieu of external, systemic and niche inputs that modulate and cooperate with the cellular circadian clock machinery of a tissue to tailor its functional output. These mechanisms of clock communication decay during ageing, and growing evidence suggests that this decline might drive ageing-related morbidities. Dietary, behavioural and pharmacological interventions may offer the possibility to overcome these changes and in turn improve healthspan., Competing Interests: Competing interests: S.A.B. is a cofounder and scientific adviser of ONA Therapeutics. P.M.-C. is an employee of Altos Labs. T.M. and J.G.S. declare no competing interests., (© 2025. Springer Nature Limited.)

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r g  = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias., Competing Interests: Competing interests: S.A.L. is employed by Novartis as of July 2022. S.A.L. received sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, IBM, Medtronic and Premier and consulted for Bristol Myers Squibb/Pfizer, Bayer AG, Blackstone Life Sciences and Invitae. C.R. is a full-time employee at GSK as of July 2024. P.T.E. has received sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG and MyoKardia. S.M.D. receives research support from RenalytixAI and Novo Nordisk, outside the scope of the current research. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb (and Celgene and Celgene International II Sàrl), Genentech, Merck Sharp & Dohme, Pfizer, GlaxoSmithKline Intellectual Property Development, Sanofi US Services, Maze Therapeutics, Janssen Biotech, Novartis AG and Boehringer Ingelheim International GmbH. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Background: Patients in hospitals that serve disproportionately patients of Black race have worse outcomes than patients in other hospitals, but the modifiable nursing factors that may contribute to such disparities have not been explored., Objective: The study objective was to examine whether nurse staffing differs in hospitals that serve predominantly patients of Black race (Black-serving hospitals) as compared to other hospitals., Methods: A cross-sectional correlational design using a nurse survey in a national hospital sample was used to fulfill the study objective. Nurse staffing was measured as the maximum number of patients cared for on the last shift from the 2015 annual registered nurse survey conducted in National Database of Nursing Quality Indicators hospitals. Hospitals were classified into subgroups of low, medium, and high percentages of patients of Black race using the 2019 Medicare Provider Analysis and Review database., Results: In survey data from 179,336 registered nurses in 574 hospitals, nurse staffing was significantly worse in high-Black-serving hospitals as compared to medium- and low-Black-serving hospitals. In Poisson regression models that adjusted for nursing unit type and hospital characteristics, nurses in high-Black-serving hospitals and medium-Black-serving hospitals had more patients-per-nurse than did nurses in low-Black-serving hospitals., Discussion: Small, statistically significant differences in nurse staffing that are worse in hospitals where Black patients disproportionately access their care were found using nurse survey data accounting for nursing unit type. The poorer nurse staffing in Black-serving hospitals may compromise the care and outcomes of the seven in 10 hospitalized Black older adults who receive care in Black-serving hospitals. The consequences for patient outcome disparities of poorer nurse staffing in Black-serving hospitals deserve investigation. Policies to increase nurse staffing in hospitals serving a higher proportion of patients of Black race are needed to contribute to efforts to reduce health disparities., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Due to the importance of post-translational modification (PTM) in cellular function, viruses have evolved to both take advantage of and be susceptible to such modification. Adenovirus encodes a multifunctional protein called protein VII, which is packaged with the viral genome in the core of virions and disrupts host chromatin during infection. Protein VII has several PTMs whose addition contributes to the subnuclear localization of protein VII. Here, we used mutant viruses that abrogate or mimic these PTMs on protein VII to interrogate their impact on protein VII function during adenovirus infection. We discovered that acetylation of the lysine in positions 2 or 3 (K2 or K3) is deleterious during early infection as mutation to alanine led to greater intake of protein VII and viral DNA to the nucleus and enhanced early gene expression. Furthermore, we determined that protein VII is acetylated at alternative residues late during infection which may compensate for the mutated sites. Lastly, due to the role of the early viral protein E1A in viral gene activation, we investigated the interaction between protein VII and E1A and demonstrated that protein VII interacts with E1A through a chromatin-mediated interaction. Together, these results emphasize that the complexity of virus-host interactions is intimately tied to post-translational modification., Importance: Adenoviruses are ubiquitous human pathogens that cause a variety of diseases, such as respiratory infections, gastroenteritis, and conjunctivitis. While often viewed as a self-limiting infection in healthy individuals, adenoviruses are particularly harmful to immunocompromised patients. Here, we investigate the functional role of post-translational modifications (PTMs) on an essential adenovirus core protein, protein VII, describing how they regulate its function during the early and late stages of infection. Our study focuses on how specific PTMs on protein VII influence transcription, localization, and interactions with other proteins, highlighting how PTMs are employed by viruses to alter protein function.

Background & Aims: Epidemiological evidence on ultra-processed food (UPF) and cause-specific mortality remains limited and mixed. Molecular mechanisms underlying UPF intake and mortality remain unexplored. This study aimed to evaluate the associations between UPF consumption, metabolic signatures, and all-cause, premature, and cause-specific mortality., Methods: This study included 27670 participants (mean age 58.1 years) from the Malmö Diet and Cancer (MDC) cohort study. Consumption of UPF was assessed using a food frequency questionnaire and a 7-day food diary. In a subset of the MDC (n = 879), the associations of UPF with 991 plasma metabolites were investigated. An elastic net regression model was used to establish the metabolic signature of UPF. Cox proportional hazards regression model was used to determine the association between UPF intake, metabolic signature, and mortality risk., Results: During a median follow-up of 23.3 years, a total of 11333 participants died. UPF intake showed a nonlinear positive association with all-cause mortality, with more pronounced associations found in females (P interaction  = 0.044); in females, UPF was linked to a higher mortality risk in a linear manner, while the association was J-shaped in males. Each standard deviation (SD) increment in UPF intake was associated with an increased risk of premature mortality (HR, 1.06; 95 % CI, 1.03-1.09), cardiovascular disease (CVD) mortality (HR, 1.05; 95 % CI, 1.01-1.08) or respiratory disease mortality (HR, 1.08; 95 % CI, 1.01-1.15), but not cancer mortality. The metabolic signature for UPF consumption (with 93 metabolites) was positively associated with all-cause mortality risk (HR per 1 SD, 1.23; 95 % CI, 1.06-1.42)., Conclusions: Our results suggest that higher UPF intake is associated with increased risk of all-cause, premature, CVD, and respiratory disease mortality, with the association varying across sex for all-cause mortality. The plasma metabolic signature of UPF showed a positive association with all-cause mortality., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics., Competing Interests: Competing interests: S.L.Z. has acted as a consultant for Health Lumen. A.H. and R.T.L. have received funding from Pfizer Inc. R.T.L. has performed paid consultancy for Health Lumen and Fitfile Ltd. J.S.W. has acted as a consultant for MyoKardia, Pfizer, Foresite Labs and Health Lumen and received institutional support from Bristol Myers Squibb and Pfizer Inc. P.C. has received personal fees for consultancies, outside the present work, for Amicus, Pfizer Inc., Owkin and Bristol Myers Squibb. M.-P.D. declares holding equity in Dalcor Pharmaceuticals, unrelated to this work. The authors who are affiliated with deCODE genetics/Amgen Inc. and Regeneron Pharmaceuticals declare competing financial interests as employees. The other authors declare no competing interests., (© 2024. The Author(s).)

Certain species D human adenoviruses (HAdV-D19, -D37, and -D64) are causative agents of epidemic keratoconjunctivitis. HAdV-D37 has previously been shown to bind CD46 (membrane cofactor protein) and sialic acid as adhesion receptors. HAdV-D64 is genetically highly similar to HAdV-D37, with an identical fiber protein sequence, but differs substantially in its penton base and hexon proteins, two other major capsid components, due to genetic recombination. Here, we demonstrate that, like HAdV-D37, HAdV-D64 virions bind directly to CD46 and that CD46 and sialic acid also function as receptors for HAdV-D64 on multiple cell types. Expression of CD46 on CD46-negative cells conferred susceptibility to HAdV-D64 entry. Specifically blocking HAdV-D64 binding to CD46 on the host cell surface strongly inhibits viral entry and gene delivery into multiple cell lines that represent target tissues. We show that CD46 is expressed on human conjunctival epithelial cells and directly binds to the HAdV-D64 virion. Our results suggest that HAdV-D64 may be used to deliver genes to target conjunctival cells and that interrupting HAdV-D64 entry through its interaction with CD46 may prevent or lessen adenovirus-associated ocular disease.

We develop a method for the extraction of the surface impedance tensor of a generic reflective metasurface using an analytic relation between the tensorial surface impedance and the four polarisation-dependent reflection coefficients. We apply this technique to experimental data obtained from a metasurface with a rhomboidal unit cell in the 16-26 GHz range, but note that it could be applied to reflective metasurfaces in any frequency regime. The extraction method can also be applied to model data to facilitate the design process of spatially graded tensorial metasurfaces that allow for full control of the form of the scattered field., (© 2024. The Author(s).)

Background: The pandemic profoundly stressed practicing nurses and could have thereby affected trends in nursing-sensitive quality indicators (NSIs), measures that detect changes in patient health status directly affected by nursing care., Objectives: The aim of the study was to determine if NSIs have worsened in response to the pandemic and then returned to prepandemic levels using data from 2019 through 2022., Methods: We conducted a cross-sectional descriptive study of annual trends, examining unit data from the National Database of Nursing Quality Indicators (NDNQI) from 2019 through 2022 for five indicators: rates of falls, central line-associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), hospital-acquired pressure injuries (HAPI), and ventilator-associated events (VAE). The NDNQI is the largest repository of nursing quality indicators, which are derived from patient-level events, reported at the nursing unit level, and submitted quarterly by over 2,000 member hospitals. Adult medical-surgical or critical care inpatient nursing units with complete data for the 4 years were included, with samples ranging from 456 to 5,818 nursing units in 2,346 hospitals. Analysis of variance was conducted by comparing the 2019 rates to each subsequent year., Results: In decreasing order of prevalence, the mean prepandemic rates were 6.58 VAE per 1,000 ventilator days (critical care only), 2.41 HAPI per 1,000 device days, 2.20 falls per 1,000 patient days, 0.96 CAUTI per 1,000 catheter days, and 0.68 CLABSI per 1,000 central line days for medical-surgical and critical care units combined. The rates for all five nurse-sensitive indicators increased significantly beginning in 2020 and have begun to decline but have not returned to baseline by 2022. The maximum rate was observed in 2020 for falls and 2021 for the remaining indicators. These increases to the maximum ranged from a 12% increase in CAUTI to 49% for CLABSI., Discussion: NSIs increased during the pandemic and are now returning to baseline. The pandemic underscored the importance of nursing practice. The pandemic's enduring negative effects on the nursing workforce must be addressed to preserve patient safety., Competing Interests: Drs. Pascal and Warshawsky are employed by Press Ganey but did not receive any special incentives for this project. The remaining authors have no conflicts of interest to report., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Young people from racialised backgrounds are overrepresented in justice services. This study explored differences in community support offered to young people from racialised groups referred to a forensic child and adolescent mental health service., Method: We compared support offered to 427 young people, according to five ethnic groups., Results: Over 20% of young people referred were Black (compared with 14% of the local population) and 15.8% were Dual White and Black Heritage (compared with 4% of the local population). Odds ratios showed that Black and Dual Heritage groups were more frequently involved with youth offending services (Black: 2.59, Dual Heritage: 2.88), gangs services (Black: 4.31, Dual Heritage: 7.13) and have a national referral mechanism (Black: 3.61, Dual Heritage: 4.01) than their White peers, but were less often in mainstream education compared with their Asian peers (Black: 0.26, Dual Heritage: 0.29). Black (odds ratio 0.35) and Dual Heritage (odds ratio 0.40) young people were less frequently diagnosed with a neurodevelopmental disorder than their White peers., Conclusions: Those from Black and Dual Heritage backgrounds were disproportionately disadvantaged.

Aim(s): The aim of this systematic literature review was to determine the extent and quality of quantitative evidence regarding associations between hospital organizational features, person-centred care (PCC) and nursing-sensitive outcomes among persons with dementia in the acute care setting., Design: Systematic review., Methods: Key terms were utilized to guide searches in four databases. The two reviewers deduplicated articles and came to a consensus for the final sample using inclusion and exclusion criteria., Data Sources: MEDLINE/OVID, CINHAL, COCHRANE and WEB OF SCIENCE., Results: There were 10 studies included. PCC was associated with better outcomes for persons with dementia (i.e. decreased restraint use, decreased length of stay, increased involvement with families and the patient, and increased nurse confidence and competence in caring for this population). Of the studies, none explicitly identified an association between nursing-sensitive outcomes, PCC and hospital organizational features in the acute care setting among persons with dementia., Conclusion: This review highlights a clinically significant gap in knowledge regarding associations between hospital organizational features, PCC and nursing sensitive outcomes. The impact of face-to-face dementia competency training as a standard practice among acute care facilities, the importance of leadership engagement, support and involvement to improve nurse confidence and competence in caring for persons with dementia needs to be explored., Impact Statement: These findings support future research to understand the relationship between organization features and patient-centred care and how these collectively impact nursing-sensitive outcomes, specifically in persons with dementia in acute care settings., (© 2024 John Wiley & Sons Ltd.)

Growing nursing workforce maldistributions impede rural healthcare access globally. In-depth exploration of underlying philosophical ideas about rural health in nursing curricular could support recruitment and retention of nurses who are well positioned to support and advocated for health care and services relevant to their communities. Through a lens of positionality, the purpose of this paper is to explore rural health and nursing within the United States and Australia from the perspective of undergraduate students. Recognizing that both countries have 'first world' health services, issues of access to services associated with systemic and structural biases were significant features identified by participants. Their perceptions were supported by discussion with attendees of the 26th International Nursing Philosophy Conference from several countries, during a presentation titled 'What is different about rural health nursing: A philosophical exploration.' This international consistency suggests that systemic and structural biases are global phenomena. While exposure to rural health and rural nursing may be beneficial for recruitment, preparing nurses for rural practice requires more than educating students to complete clinical tasks. Uncovering collaboration, advocacy and policy development opportunities for nurses in rural communities could move the dial from recruiting rural nurses to fulfill immediate needs to retention of well-educated and highly skilled nurses. Building a stronger philosophical base for rural healthcare inclusive of all people, honouring their distinguishing characteristics such as age, gender, ethnicity, is long overdue. Positionality can inform how nurses across the globe relate to other countries' governments, cultures, norms, values, expectations, etc., which can influence the advancement of the profession and address social inequities among rural populations., (© 2024 John Wiley & Sons Ltd.)

Antiviral immunity compromises the efficacy of adeno-associated virus (AAV) vectors used for gene therapy. This is well understood for the adaptive immune response. However, innate immune effectors like alpha-defensin antimicrobial peptides also block AAV infection, although their mechanisms of action are unknown. To address this gap in knowledge, we investigated AAV2 neutralization by human neutrophil peptide 1 (HNP1), a myeloid alpha-defensin, and human defensin 5 (HD5), an enteric alpha-defensin. We found that both defensins bind to AAV2 and inhibit infection at low micromolar concentrations. While HD5 prevents AAV2 from binding to cells, HNP1 does not. However, AAV2 exposed to HD5 after binding to cells is still neutralized, indicating an additional block to infection. Accordingly, both HD5 and HNP1 inhibit externalization of the VP1 unique domain, which contains a phospholipase A 2 enzyme required for endosome escape and nuclear localization signals required for nuclear entry. Consequently, both defensins prevent AAV2 from reaching the nucleus. Disruption of intracellular trafficking of the viral genome to the nucleus is reminiscent of how alpha-defensins neutralize other non-enveloped viruses, suggesting a common mechanism of inhibition. These results will inform the development of vectors capable of overcoming these hurdles to improve the efficiency of gene therapy., Author Summary: AAVs are commonly used as gene therapy vectors due to their broad tropism and lack of disease association; however, host innate immune factors, such as human alpha-defensin antimicrobial peptides, can hinder gene delivery. Although it is becoming increasingly evident that human alpha-defensins can block infection by a wide range of nonenveloped viruses, including AAVs, their mechanism of action remains poorly understood. In this study, we describe for the first time how two types of abundant human alpha-defensins neutralize a specific AAV serotype, AAV2. We found that one defensin prevents AAV2 from binding to cells, the first step in infection, while both defensins block a critical later step in AAV2 entry. Our findings support the emerging idea that defensins use a common strategy to block infection by DNA viruses that replicate in the nucleus. Through understanding how innate immune effectors interact with and impede AAV infection, vectors can be developed to bypass these interventions and allow more efficient gene delivery.

Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been shown to synergize in vitro with proteasome inhibitors (PIs) in reducing the viability of cells derived from B cell malignancies, but the mechanism is not known. We report here that an off-target effect of ibrutinib causes synergy because not all BTK inhibitors exhibited the synergistic effect, and those that synergized did so even in cells that do not express BTK. The allosteric BTK inhibitor CGI-1746 showed the strongest synergy. Co-treatment of cells with CGI-1746 increased PI-induced accumulation of ubiquitin conjugates and expression of heat shock proteins and NOXA and decreased a ratio of reduced to oxidized glutathione. CGI-1746, but not other BTK inhibitors, inhibited ATPase activity and all three peptidase activities of the 26S proteasome. The effect demonstrates a conceptually novel mode of proteasome inhibition that may aid the development of more potent PIs., Competing Interests: A.F.K. is a founder and Chief Scientific Officer of InhiProt, LLC., (© 2024 The Author(s).)

Separating individual lanthanide (Ln) elements in aqueous mixtures is challenging. Ion-selective capture by porous materials, such as metal-organic frameworks (MOFs), is a promising approach. To design ion-selective MOFs, molecular details of the Ln adsorption complexes within the MOFs must be understood. We determine the local coordination environment of lanthanides Nd(III), Gd(III), and Lu(III) adsorbed onto Cr(III)-based terephthalate MOF (Cr-MIL-101) and Zr(IV)-based Universitet in Oslo MOFs (UiO-66 and UiO-68) and their derivatives. In the Cr(III)- and Zr(IV)-based MOFs, Ln adsorb as inner-sphere complexes at the metal oxo clusters, regardless of whether the organic linkers are decorated with amino groups. Missing linkers result in favorable Ln binding sites at oxo clusters; however, Ln can coordinate to metal sites even with linkers in place. MOF functionalization with phosphonate groups led to Ln chemisorption onto these groups, which out-compete metal cluster sites. Ln form monodentate and bidentate and mononuclear and binuclear surface complexes. We conclude that MOFs for ion-selective Ln capture can be designed by a combination of (1) maximizing metal-lanthanide interactions via shared O atoms at the metal oxo cluster sites, where mixed oxo clusters can lead to ion-selective Ln adsorption, and (2) functionalizing MOFs with Ln-selective groups capable of out-completing the metal oxo cluster sites.

Aims: To synthesize literature examining (1) rural hospital or obstetric unit closures as a social determinant of maternal/infant health outcomes and (2) closures as a social determinant of racial/ethnic disparities in maternal/infant health outcomes., Design: Scoping review., Data Sources: MEDLINE, OVID/Embase and CINAHL were searched systematically to identify sources from 31 July 2003 to 31 July 2023. The Arksey and O'Malley methodology for scoping reviews was used., Results: Four studies from the United States and Australia documented the impact of rural hospital or obstetric unit closures on maternal/infant health outcomes, such as increased births in hospitals without obstetric units, out-of-hospital births or babies born before arrival, preterm birth, infant mortality and sociocultural risks that contribute to clinical risk. No eligible studies investigated hospital or obstetric unit closure as a social determinant of racial disparities in rural maternal/infant health outcomes., Conclusion: Despite significant racial and ethnic rural maternal health disparities, associations between rural closures and maternal health outcomes for racial and ethnic minorities are understudied. More research is needed to understand the extent to which rural closures, a social determinant of health, could disproportionately, negatively affect the health of racially and ethnically minoritized women., Implications for the Profession and Patient Care: Rural women have a greater risk of maternal and infant mortality and morbidity compared with urban women, and the impact of rural closures on racial and ethnic maternal health disparities is not well documented. Research about the impact of rural closures on maternal health disparities could inform policy to assure essential obstetric care is available for rural populations globally., Impact: Findings provide a call to action for research to understand relationships between rural closures and racial and ethnic maternal health disparities, which is especially important for serving rural Non-Hispanic Black and American Indian/Alaska Native women., Patient or Public Contribution: No patient or public contribution., (© 2023 John Wiley & Sons Ltd.)

Background: Poorer leadership communication during COVID-19 may have contributed to the moral distress of nurses in hospitals where Black patients predominantly access their care (BSH)., Purpose: To compare nurse moral distress and leadership communication during the COVID-19 pandemic in hospitals that serve disproportionately many or few patients of Black race., Methods: In a national hospital sample (n = 90), nurse survey data were collected (March 2021). Nurse moral distress was analyzed in linear regression models. The key covariates were BSH category (Medicare Black patient percentage) and leadership communication., Discussion: Nurses in high-BSH had significantly greater moral distress and more difficulty accessing personal protective equipment than nurses in low-BSH. The percentage of nurses in high-BSHs with high moral distress was double that of nurses in low-BSHs. Poorer leadership communication in BSHs accounted for the nurses' greater moral distress., Conclusion: Policies should improve leadership communication, mitigate distress, and support nurses in under-resourced settings., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies., Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors., Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years., Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein., Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses., Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people., Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

In mammals, the circadian clock network drives daily rhythms of tissue-specific homeostasis. To dissect daily inter-tissue communication, we constructed a mouse minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By transcriptomic and functional characterization of this isolated connection, we identified a gatekeeping function of the peripheral tissue clock with respect to systemic inputs. The epidermal clock concurrently integrates and subverts brain signals to ensure timely execution of epidermal daily physiology. Timely cell-cycle termination in the epidermal stem cell compartment depends upon incorporation of clock-driven signals originating from the brain. In contrast, the epidermal clock corrects or outcompetes potentially disruptive feeding-related signals to ensure the optimal timing of DNA replication. Together, we present an approach for cataloging the systemic dependencies of daily temporal organization in a tissue and identify an essential gate-keeping function of peripheral circadian clocks that guarantees tissue homeostasis., Competing Interests: Declaration of interests S.A.B. is a cofounder and scientific advisor of ONA Therapeutics. P.M.-C. is an employee of Altos Laboratories., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pain is the prominent feature of sickle cell disease (SCD) and negatively affects quality of life. Delivery of pain management programmes (PMPs) has been suggested in clinical guidelines for pain management in SCD; however, further evidence of the feasibility and effectiveness of PMPs in this population is needed. This study explored the feasibility of delivering a sickle cell pain management programme (SCPMP) for adults within a haemoglobinopathies service., Methods: A single arm, repeated-measures observational design was used to determine feasibility of delivering the SCPMP at one study site. Primary feasibility outcomes were recruitment, completion of treatment and outcome measures, satisfaction, credibility and acceptability to participants. Secondary feasibility outcomes were treatment outcomes and processes, frequency of vaso-occlusive crisis (VOC) and healthcare utilisation., Results: Four of five feasibility criteria were met. Annual recruitment of eight participants to a SCPMP was not achieved. Twenty-nine people began a SCPMP during the study period. Twenty-five (86.2%) participants attended ≥5/8 sessions and 21(84%) programme completers provided all end of programme questionnaires. Mean scores of >7 on ten-point scales were seen across satisfaction and credibility questions. At least moderate (Hedges g >0.5) effect sizes were seen in pre-post SCPMP measures of pain interference, anxiety, depression, self-efficacy, pain-related worry and acceptance. A small (Hedges g 0.4) effect size was seen in HRQoL. Following SCPMP attendance, mean frequency of self-reported VOC and hospital admissions reduced., Conclusions: This study suggests that, given an adequate source of referrals, a SCPMP is feasible to deliver and appears acceptable and credible to participants. Exploration of influences on recruitment, such as barriers to group interventions, would be illuminating, prior to investigating feasibility of an adequately powered randomised-controlled trial., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

A molecular clock network is crucial for daily physiology and maintaining organismal health. We examined the interactions and importance of intratissue clock networks in muscle tissue maintenance. In arrhythmic mice showing premature aging, we created a basic clock module involving a central and a peripheral (muscle) clock. Reconstituting the brain-muscle clock network is sufficient to preserve fundamental daily homeostatic functions and prevent premature muscle aging. However, achieving whole muscle physiology requires contributions from other peripheral clocks. Mechanistically, the muscle peripheral clock acts as a gatekeeper, selectively suppressing detrimental signals from the central clock while integrating important muscle homeostatic functions. Our research reveals the interplay between the central and peripheral clocks in daily muscle function and underscores the impact of eating patterns on these interactions.

Plasma metabolomics holds potential for precision medicine, but limited information is available to compare the performance of such methods across multiple cohorts. We compared plasma metabolite profiles after an overnight fast in 11,309 participants of five population-based Swedish cohorts (50-80 years, 52% women). Metabolite profiles were uniformly generated at a core laboratory (Metabolon Inc.) with untargeted liquid chromatography mass spectrometry and a comprehensive reference library. Analysis of a second sample obtained one year later was conducted in a subset. Of 1629 detected metabolites, 1074 (66%) were detected in all cohorts while only 10% were unique to one cohort, most of which were xenobiotics or uncharacterized. The major classes were lipids (28%), xenobiotics (22%), amino acids (14%), and uncharacterized (19%). The most abundant plasma metabolome components were the major dietary fatty acids and amino acids, glucose, lactate and creatinine. Most metabolites displayed a log-normal distribution. Temporal variability was generally similar to clinical chemistry analytes but more pronounced for xenobiotics. Extensive metabolite-metabolite correlations were observed but mainly restricted to within each class. Metabolites were broadly associated with clinical factors, particularly body mass index, sex and renal function. Collectively, our findings inform the conduct and interpretation of metabolite association and precision medicine studies., (© 2024. The Author(s).)

Many factors influence cognitive performance in dogs, including breed, temperament, rearing history, and training. Studies in working dog populations have demonstrated age-related improvements in cognitive task performance across the first years of development. However, the effect of certain factors, such as age, sex, and temperament, on cognitive performance in puppies has yet to be evaluated in a more diverse population of companion dogs. In this study, companion dogs under 12 months of age were tested once on two tasks purported to measure aspects of executive function: the delayed-search task (DST) and the detour reversal task (DRT). Owners also filled out the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) to evaluate how temperament influenced task performance. Contrary to prior research, performance did not improve with age on either task. However, the lack of age effects was likely the result of small sample sizes and individual differences across other factors influencing performance. Specifically, temperament differences as measured by the C-BARQ subscales for nonsocial fear and excitability predicted task performance on the DST, but the effect of temperament on task performance differed between males and females. Excitability also predicted performance on the DRT, but the effect depended on the age of the dog. In addition, no correlations were observed between task measures, indicating a lack of construct validity. Overall, these findings provide a preliminary analysis of factors that appear to influence cognitive task performance in young companion dogs and highlight suggestions for future research evaluating the impact of individual differences on cognitive performance., (© 2024. The Author(s).)

Memory has been identified as the least heritable cognitive trait in canines, suggesting a significant influence of non-genetic factors. We observed a trend that overall memory scores (OMS) improve with age in a cohort of 27 young dogs, but considerable plasticity exists. Employing linear discriminant analysis of gut microbiome data from dogs exhibiting low and high OMS, a single bacterial species, Bifidobacterium pseudolongum , was identified and confirmed to be correlated with elevated OMS. Subsequent analysis using a random forest regression model revealed that sex, litter, and breed identity had minimal predictive importance. Age had some predictive value but failed to achieve statistical significance in this dataset. In sharp contrast, the abundance of 17 bacterial taxa in the microbiome showed a stronger predictive capacity for memory performance. Our findings provide insights into microbiome underpinnings of mammalian cognitive functions and suggest avenues for developing psychobiotics to enhance canine memory and learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (© 2024 The Author(s).)

Background: Obtaining accurate information is critical for youth's sexual and reproductive health (SRH). Youth not in foster care often learn about SRH from their biological parents. Separated from their biological parents, youth in care depend on healthcare providers and caregivers for SRH information. However, they often receive insufficient information and feel unsupported in meeting their needs for SRH information., Purpose: This study explored female African American adolescents in foster care's perspectives on effective SRH communication with caregivers to help them avoid sexual risks., Methods: A qualitative study was conducted using semi-structured interviews. We used purposive sampling to recruit 16 adolescents aged 18 to 20 years old with a history of foster care placement. The transcribed interviews underwent inductive thematic analysis. The Positive Youth Development theory underpinned this research., Results: Two prominent themes emerged: establishing a relationship and preferred communication approach. Youth reported that for caregivers to engage in effective SRH communication, they must first establish a relationship by being aware of the youth's childhood trauma, building trust, having patience, and being vulnerable. Youth also appreciated caregivers who ensured comfortability and were honest and straightforward., Discussion: Caregivers should be trained on adverse childhood experiences, trauma-informed approaches, SRH knowledge, and communication., Implications to Practice: Healthcare providers should make use of the time spent with youth and discuss SRH topics during clinical encounters. This time spent with youth may be their only chance to obtain accurate SRH information. Youth's perspectives regarding communication about SRH should be implemented in future SRH communication interventions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome-wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix-loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that increased strain of primary human myocardial fibroblasts results in increased TSLP expression and that the TSLP receptor is expressed in myocardial mast cells in human single nuclei RNA sequence data. Finally, we show that TSLP overexpression induces increased transforming growth factor β expression in myocardial mast cells and tissue fibrosis. Collectively, our findings based on follow-up of a human genetic finding implicate a novel pathway in myocardial tissue homeostasis and remodeling., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Introduction: Pharmacists provide a spectrum of services and comprehensive medication management for patients with substance use disorders (SUDs) with many providing timely and increased access to care for patients. Prior studies have evaluated other healthcare professionals' attitudes, knowledge and practice in regard to SUD treatment and harm reduction services. However, no reviews to date summarise the available literature on the attitudes, knowledge and practice in regard to SUD treatment and harm reduction services from the pharmacist perspective. This scoping review aims to systematically map the extent, range and nature of available evidence and identify and describe gaps in knowledge, practice and attitudes towards SUD treatment among pharmacists with the goal of providing information for meaningful integration of pharmacists into SUD care., Methods and Analysis: We will use the framework proposed by Arksey and O'Malley (2005) updated with recommendations by Levac et al (2010) and the Joanna Briggs Institute (2020). The protocol is registered via Open Science Framework (https://osf.io/92dek). We will search for peer-reviewed literature containing empirical evidence investigating SUD treatment or harm reduction with outcomes pertaining to the knowledge, practice or attitudes of pharmacists. Findings will be guided and assessed by research objectives and summarised using descriptive statistics and thematically for quantitative and qualitative findings, respectively. This review will be conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews., Ethics and Dissemination: Our findings will provide crucial information and support for future interventions and programmes which aim to meaningfully integrate pharmacists into SUD care. We will disseminate findings at conferences and publish in a peer-reviewed journal. In addition, we will integrate feedback on search strategy, data extraction and our dissemination approach from multidisciplinary collaborators including those within our team's institution and outside experts with clinical or administrative knowledge in SUD care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ecological communities can be stable over multiple generations, or rapidly shift into structurally and functionally different configurations. In kelp forest ecosystems, overgrazing by sea urchins can abruptly shift forests into alternative states that are void of macroalgae and primarily dominated by actively grazing sea urchins. Beginning in 2014, a sea urchin outbreak along the central coast of California resulted in a patchy mosaic of remnant forests interspersed with sea urchin barrens. In this study, we used a 14-year subtidal monitoring dataset of invertebrates, algae, and fishes to explore changes in community structure associated with the loss of forests. We found that the spatial mosaic of barrens and forests resulted in a region-wide shift in community structure. However, the magnitude of kelp forest loss and taxonomic-level consequences were spatially heterogeneous. Taxonomic diversity declined across the region, but there were no declines in richness for any group, suggesting compositional redistribution. Baseline ecological and environmental conditions, and sea urchin behaviour, explained the persistence of forests through multiple stressors. These results indicate that spatial heterogeneity in preexisting ecological and environmental conditions can explain patterns of community change.

The direct observation of a solid-state chemical reaction can reveal otherwise hidden mechanisms that control the reaction kinetics. However, probing the chemical bond breaking and formation at the molecular level remains challenging because of the insufficient spatial-temporal resolution and composition analysis of available characterization methods. Using atomic-resolution differential phase-contrast imaging in scanning transmission electron microscopy, we have visualized the decomposition chemistry of K 2 PtCl 4 to identify its transient intermediate phases and their interfaces that characterize the chemical reduction process. The crystalline structure of K 2 PtCl 4 is found to undergo a disproportionation reaction to form K 2 PtCl 6 , followed by gradual reduction to crystalline Pt metal and KCl. By directly imaging different Pt─Cl bond configurations and comparing them to models predicted via density functional theory calculations, a causal connection between the initial and final states of a chemical reaction is established, showcasing new opportunities to resolve reaction pathways through atomistic experimental visualization.

Background: Previous population-based studies investigating the relationship between physical activity and the gut microbiota have relied on self-reported activity, prone to reporting bias. Here, we investigated the associations of accelerometer-based sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity with the gut microbiota using cross-sectional data from the Swedish CArdioPulmonary bioImage Study., Methods: In 8416 participants aged 50-65, time in SED, MPA, and VPA were estimated with hip-worn accelerometer. Gut microbiota was profiled using shotgun metagenomics of faecal samples. We applied multivariable regression models, adjusting for sociodemographic, lifestyle, and technical covariates, and accounted for multiple testing., Findings: Overall, associations between time in SED and microbiota species abundance were in opposite direction to those for MPA or VPA. For example, MPA was associated with lower, while SED with higher abundance of Escherichia coli. MPA and VPA were associated with higher abundance of the butyrate-producers Faecalibacterium prausnitzii and Roseburia spp. We observed discrepancies between specific VPA and MPA associations, such as a positive association between MPA and Prevotella copri, while no association was detected for VPA. Additionally, SED, MPA and VPA were associated with the functional potential of the microbiome. For instance, MPA was associated with higher capacity for acetate synthesis and SED with lower carbohydrate degradation capacity., Interpretation: Our findings suggest that sedentary and physical activity are associated with a similar set of gut microbiota species but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain gut microbiota species., Funding: European Research Council, Swedish Heart-Lung Foundation, Swedish Research Council, Knut and Alice Wallenberg Foundation., Competing Interests: Declaration of interests JÄ has served on the advisory boards for Astella, AstraZeneca and Boehringer Ingelheim and has received lecturing fees from AstraZeneca and Novartis, all unrelated to the present work. Remaining authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: P-wave indices reflect atrial abnormalities contributing to atrial fibrillation (AF). We aimed to assess a comprehensive set of P-wave characteristics for prediction of incident AF in a population-based setting., Methods: Malmö Preventative Project (MPP) participants were reexamined in 2002-2006 with electrocardiographic (ECG) and echocardiographic examinations and followed for 5 years. AF-free subjects (n = 983, age 70 ± 5 years, 38% females) with sinus rhythm ECGs were included in the study. ECGs were digitally processed using the Glasgow algorithm. P-wave duration, axis, dispersion, P-terminal force in lead V1 and interatrial block (IAB) were evaluated. ECG risk score combining the morphology, voltage and length of P-wave (MVP score) was calculated. New-onset diagnoses of AF were obtained from nation-wide registers., Results: During follow up, 66 patients (7%) developed AF. After adjustment for age and gender, the independent predictors of AF were abnormal P-wave axis > 75° (HR 1.63 CI95% 1.95-11.03) and MVP score 4 (HR 6.17 CI 95% 1.76-21.64), both correlated with LA area: Person r - 0.146, p < 0.001 and 0.192, p < 0.001 respectively. Advanced IAB (aIAB) with biphasic P-wave morphology in leads III and aVF was the most prevalent variant of aIAB and predicted AF in a univariate model (HR 2.59 CI 95% 1.02-6.58)., Conclusion: P-wave frontal axis and MVP score are ECG-based AF predictors in the population-based cohort. Our study provides estimates for prevalence and prognostic importance of different variants of aIAB, providing a support to use biphasic P-wave morphology in lead aVF as the basis for aIAB definition., (Copyright © 2023 Elsevier Inc. All rights reserved.)