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Robust high spatiotemporal resolution daily PM2.5 exposure estimates are limited in Australia. Estimates of daily PM2.5 and the PM2.5 component from extreme pollution events (e.g., bushfires and dust storms) are needed for epidemiological studies and health burden assessments attributable to these events. We sought to: (1) estimate daily PM2.5 at a 5 km × 5 km spatial resolution across the Australian continent between 1 January 2001 and 30 June 2020 using a Random Forest (RF) algorithm, and (2) implement a seasonal-trend decomposition using loess (STL) methodology combined with selected statistical flags to identify extreme events and estimate the extreme pollution PM2.5 component. We developed an RF model that achieved an out-of-bag R-squared of 71.5% and a root-mean-square error (RMSE) of 4.5 µg/m3. We predicted daily PM2.5 across Australia, adequately capturing spatial and temporal variations. We showed how the STL method in combination with statistical flags can identify and quantify PM2.5 attributable to extreme pollution events in different locations across the country.

Robust high spatiotemporal resolution daily PM[sub.2.5] exposure estimates are limited in Australia. Estimates of daily PM[sub.2.5] and the PM[sub.2.5] component from extreme pollution events (e.g., bushfires and dust storms) are needed for epidemiological studies and health burden assessments attributable to these events. We sought to: (1) estimate daily PM[sub.2.5] at a 5 km × 5 km spatial resolution across the Australian continent between 1 January 2001 and 30 June 2020 using a Random Forest (RF) algorithm, and (2) implement a seasonal-trend decomposition using loess (STL) methodology combined with selected statistical flags to identify extreme events and estimate the extreme pollution PM[sub.2.5] component. We developed an RF model that achieved an out-of-bag R-squared of 71.5% and a root-mean-square error (RMSE) of 4.5 µg/m[sup.3] . We predicted daily PM[sub.2.5] across Australia, adequately capturing spatial and temporal variations. We showed how the STL method in combination with statistical flags can identify and quantify PM[sub.2.5] attributable to extreme pollution events in different locations across the country.

Fibrotic diseases account for nearly half of all deaths in the developed world. Despite its importance, the pathogenesis of fibrosis remains poorly understood. Recently, the two mechanosensitive transcription cofactors YAP and TAZ have emerged as important profibrotic regulators in multiple murine tissues. Despite this growing recognition, a number of important questions remain unanswered, including which cell types require YAP/TAZ activation for fibrosis to occur and the time course of this activation. Here, we present a detailed analysis of the role that myofibroblast YAP and TAZ play in organ fibrosis and the kinetics of their activation. Using analyses of cells, as well as multiple murine and human tissues, we demonstrated that myofibroblast YAP and TAZ were activated early after organ injury and that this activation was sustained. We further demonstrated the critical importance of myofibroblast YAP/TAZ in driving progressive scarring in the kidney, lung, and liver, using multiple transgenic models in which YAP and TAZ were either deleted or hyperactivated. Taken together, these data establish the importance of early injury-induced myofibroblast YAP and TAZ activation as a key event driving fibrosis in multiple organs. This information should help guide the development of new antifibrotic YAP/TAZ inhibition strategies.

Adherence to therapy for pulmonary arterial hypertension is essential to optimize patient outcomes, but data on real-world adherence to different pulmonary arterial hypertension drug classes are limited. This retrospective database analysis evaluated relationships between adherence, hospitalization, and healthcare costs in pulmonary arterial hypertension patients treated with endothelin receptor antagonists or phosphodiesterase type-5 inhibitors. From the IQVIA Adjudicated Health Plan Database, patients with pulmonary arterial hypertension were identified based on diagnostic codes and prescriptions for endothelin receptor antagonists (ambrisentan, bosentan, macitentan) or phosphodiesterase type-5 inhibitors (sildenafil, tadalafil) approved for pulmonary arterial hypertension. Patients were assigned to the class of their most recently initiated (index) pulmonary arterial hypertension therapy between 1 January 2009 and 30 June 2015. Medication adherence was measured by proportion of days covered; patients with proportion of days covered ≥80% were considered adherent. The proportion of adherent patients was higher for endothelin receptor antagonists (571/755; 75.6%) than for phosphodiesterase type-5 inhibitors (970/1578; 61.5%; P < 0.0001). In both groups, hospitalizations declined as proportion of days covered increased. Among adherent patients, those on endothelin receptor antagonists had a significantly lower hospitalization rate than those on phosphodiesterase type-5 inhibitors (23.1% versus 28.5%, P = 0. 0218), fewer hospitalizations (mean (standard deviation) 0.4 (0.8) versus 0.5 (0.9); P = 0.02), and mean hospitalization costs during the six-month post-index ($9510 versus $15,726, P = 0.0318). Increasing adherence reduced hospitalization risk more for endothelin receptor antagonists than for phosphodiesterase type-5 inhibitors (hazard ratio 0.176 versus 0.549, P = 0.001). Rates and numbers of rehospitalizations within 30 days post-discharge were similar between groups. Mean total costs were higher with endothelin receptor antagonists than phosphodiesterase type-5 inhibitors in all patients ($91,328 versus $72,401, P = 0.0003) and in adherent patients ($88,867 versus $56,300, P < 0.0001), driven by higher drug costs.

Abstract Background Almost 40% of individuals at ultra-high risk (UHR) for psychosis experience persistent attenuated psychotic symptoms (APS) yet it is unclear (1) whether they share overlapping clinical and functional outcomes compared to individuals who transition to psychosis, (2) when symptom and functioning trajectories begin to diverge between UHR individuals with different clinical outcomes, and (3) whether non-remission (persistent APS or transition) can be predicted using baseline and/or longitudinal data. Study Design Participants were drawn from 2 randomized clinical trials: Neurapro (n = 220; discovery sample) and STEP (n = 180; external validation sample). First, 12–24 month symptoms and functioning were compared between UHR individuals with persistent APS, sustained remission, or transition to psychosis. Next, short-term changes in symptoms and functioning were compared between groups to determine timepoints at which trajectories began to diverge. Finally, we used support vector machines to predict non-remission (persistent APS or transition) vs sustained remission using data from baseline, 6-month follow-up, and combined baseline and 6-month follow-up. Results Individuals with persistent APS had substantially poorer outcomes compared to those who remitted, and more closely resembled individuals who later transitioned to psychosis. Despite few baseline differences between groups, clinical and functional trajectories of the persistent APS and transition groups rapidly diverged from those who remitted. Prediction of non-remission was poor using baseline data but improved substantially when using 6-month follow-up or combined baseline-6-month data. Conclusions Ultra-high-risk individuals with persistent APS display similar clinical and functional trajectories to transitioned cases, suggesting that more intensive and sustained intervention is required for this subgroup. However, prospective identification of individuals with poor clinical outcomes (ie, persistence or deterioration of attenuated psychotic symptoms) may require longitudinal monitoring of symptom and functioning trajectories for several months.

Since the late 1990s, there has been a worldwide surge of scientific interest in the pre-psychotic phase, resulting in the introduction of several clinical tools for early detection. The predictive accuracy of these tools has been limited, motivating the need for methodological and perspectival improvements. The EASE manual supports systematic assessment of anomalous self-experience, and proposes an overall model of understanding how most psychotic experiences may be initially generated on the basis of a unifying, fundamental, pre-reflective distortion of subjectivity. The EASE is time-consuming, so in order to spread the use of this essential perspective of psychosis risk we selected prototypical and frequent phenomena from the EASE, combining them into SQuEASE-11. To investigate this instrument for clinical relevance, basic psychometric properties, factor structure, and relationships with gold standard instruments and the full EASE, it was administered as an interview in the STEP intervention trial (Melbourne, Australia), with 328 clinical high-risk for psychosis (CHR-P) patients. The SQuEASE-11 had moderate internal consistency and revealed two correlated factors. Significant relationships were observed between the SQuEASE-11 and the widely used and validated instruments CAARMS, BPRS, SANS, MADRS, DACOBS, and SOFAS. The correlation with the full EASE was very strong. These 11 items do not necessarily relate specifically to ipseity disturbance, but the SQuEASE-11 seems to be a clinically relevant and brief supplementary first-line interview in CHR-P subjects. It may give a qualified indication of the need for a complete EASE interview, and it may also, importantly, inform treatment planning.

Through Community Health and Information Fairs (CHIFs) held in equity-deserving neighbourhoods in North York, Canada, health and social care partners provide low-barrier access to services and information, including for those who do not have health insurance or a primary care provider. Certain neighbourhoods disproportionately experience health inequities due to challenges such as low health system literacy, transportation difficulties, limited resources, and gaps in health and community support services including for sexual health.  North York Toronto Health Partners (NYTHP) Ontario Health Team has worked to address these gaps through an innovative model of integrated care—CHIFs in high-needs neighbourhoods.  NYTHP is a coordinated network of over 50 organizations including a primary care clinic, community hospital, newcomer settlement agency, and mental health organizations.  Co-designed with our Patient and Caregiver Health Council members and community ambassadors, CHIFs provide hyper-local, low-barrier access to services and information, even to individuals without health insurance or a primary care provider.  To select neighbourhoods and tailor the themed services, we consider local health data and community ambassador input.  Community ambassadors are essential team members for designing, implementing, and monitoring CHIFs: they advise on CHIF locations, provide community knowledge, promote CHIFs in-person and online, and participate in meetings.  As trusted community members working within a peer education framework, our trained ambassadors provide system navigation support, trauma-informed peer engagement, and primary care connection in a culturally sensitive manner. We have held 40 CHIFs since May 2022.  In April 2024, we began providing sexual health services at the CHIF through a newly established partnership with the Immigrant Women’s Health Centre.  This CHIF also welcomed individuals without health insurance who would not be able to access the services otherwise.  Over the course of one afternoon, we provided 33 tests for sexually transmitted infections, 32 cervical cancer screenings, and 13 requisitions for additional tests including pelvic exams and intrauterine device follow-up.  Attendees reported a 27% increase in their understanding of local community health information and services.  Other survey results were that attendees were female (100%), aged 25-39 (65%), preferred speaking a non-English language (93%), and did not have a consistent primary care provider (96%).  Community ambassadors were key to this successful CHIF by providing the initial community feedback that sexual health services are a gap in that neighbourhood; they also advised on a suitable location near a transit hub, outreach strategy, and timing in consideration of cultural holidays.  CHIFs are an example of co-designing care approaches and leveraging partnerships to improve community well-being with a hyper-local focus.  The CHIF perspective acknowledges the social determinants of health and seeks to address the needs of individuals that are not met by traditional service models.  We illustrate how community ambassadors are crucial to the success of CHIFs and how this integrated care model can be improved to reduce inequities in high-needs neighbourhoods.  Next steps are to expand CHIFs to more equity-deserving neighbourhoods, forge new and strengthen existing local partnerships, and continue collaborating with community ambassadors to identify and address service gaps in a culturally informed manner.

Background: North York, Toronto faces unique healthcare challenges, with 70% of its population identifying a primary language other than English. This language barrier, combined with an aging demographic and high prevalence of chronic conditions, limits access to healthcare and complicates system navigation. These challenges particularly affect the prevention and management of Congestive Heart Failure (CHF), Chronic Obstructive Pulmonary Disease (COPD), and diabetes. Underlying mental health concerns have emerged due to difficulties in navigating the healthcare system, exacerbated by inconsistent access to primary care services. The overall rate of unattachment to primary care for North York Toronto Health Partners (NYTHP) is around 13%, with \"\"uncertain attachment\"\" in some neighbourhoods ranging from 15% to 23%. In response, NYTHP, an Ontario Health Team (OHT), developed an Integrated Chronic Disease Prevention and Management (ICDPM) Hub in November 2024 to address these systemic issues through low-barrier, community-centered care. Methods: NYTHP launched the ICDPM Hub, based on best practices from the Diabetes Prevention Program, Diabetes Education Program, and Community Health Information Fairs (CHIFs). The initiative engaged all 22 OHT core partners, including primary care organizations, hospitals, service providers, community agencies, and equity-deserving communities with lived experiences. The ICDPM Steering Committee guided the transition from planning to implementation. The model embedded social determinants of health (SDOH) supports throughout client journeys and gathered health equity data to inform services. It relied on Community Health Ambassadors (CHAs), trusted local change agents trained in peer education, to provide multilingual engagement, education, and navigation support. Interprofessional care teams included CHAs, community health workers, care navigators, nurse practitioners, pharmacists, and physicians. Mobile care models enhanced access for underserved populations. The system integrated data sharing and consent frameworks, enabling coordinated care and holistic supports backed by evidence-based decision tools. Results: By spring 2025, the ICDPM model aims to enroll at least 100 patients and clients to receive integrated prevention and management services. It will establish care pathways with 10 key partners and include co-creation and ongoing evaluation with five providers and community health ambassadors. Four pilot ICDPM Hub Clinics featuring CHIF events focused on CHF, COPD, and diabetes will be implemented. The team expects to identify 30 individuals for access to the ICDPM Hub through referrals, with 15 participants enrolled in prevention and management education programs and 10 receiving direct point-of-care services. A survey of 200 community members projects a 10% increase in system knowledge and service usage. Digital engagement is anticipated to reach 1,000 website visits through 10 partner organizations. The ICDPM model will use a learning health system framework to iterate improvements, with outcome data available by spring 2025. Conclusions: This community-co-designed Integrated Chronic Disease Prevention and Management (ICDPM) model addresses the urgent needs of equity-deserving populations by providing culturally relevant, language-specific care tailored to diverse urban communities. Integrating Community Health Ambassadors (CHAs) within clinical pathways shifts away from disease-specific approaches, offering holistic support for equity-deserving groups. Key insights emphasize the value of co-design, collective impact, and integrated care across the continuum to improve health outcomes for those facing systemic barriers.

Huntington disease (HD) is an autosomal dominant neurological disorder that is caused by a CAG repeat expansion, translated into polyglutamine, in the huntingtin (HTT) gene. Although the length of this repeat polymorphism is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. Genomic studies have provided evidence for the involvement of DNA repair in modifying this trait, potentially through somatic repeat instability. We therefore assessed genetic variants within the 12bp interrupting sequence between the pathogenic CAG repeat and the polymorphic proline (CCG) tract in the HTT gene and identified variants that result in complete loss of interruption (LOI) between the adjacent CAG/CCG repeats. Analysis of multiple HD pedigrees showed that this variant is associated with dramatically earlier AOO and is particularly relevant to HD patients with reduced penetrance alleles. On average AOO of HD is hastened by an average of 25 years in LOI carriers. This finding indicates that the number of uninterrupted CAG repeats is the most significant contributor to AOO of HD and is more impactful than polyglutamine length, which is not altered in these patients. We show that the LOI variant is associated with increases in both somatic and germline repeat instability, demonstrating a potential mechanism for this effect. Screening individuals from the general population (n=2,674 alleles) suggests that the variant occurs only in expanded CAG repeat alleles. Identification of this modifier has important clinical implications for disease management of HD families, especially for those in the reduced penetrance ranges.

The fungi kingdom is composed of eukaryotic heterotrophs, which are responsible for balancing the ecosystem and play a major role as decomposers. They also produce a vast diversity of secondary metabolites, which have antibiotic or pharmacological properties. However, our lack of knowledge of gene function in fungi precludes us from tailoring them to our needs and tapping into their metabolic diversity. To remedy this, we gathered genomic and gene expression data of 19 most widely-researched fungi to build a database, fungi.guru, which contains tools for cross-species identification of conserved pathways, functional gene modules, and gene families. We exemplify how our database can elucidate the molecular function, biological process and cellular component of genes involved in various biological processes, by identifying a secondary metabolite pathway producing gliotoxin in Aspergillus fumigatus, the catabolic pathway of cellulose in Coprinopsis cinerea and the conserved DNA replication pathway in Fusarium graminearum and Pyricularia oryzae. The database is available at www.fungi.guru. Competing Interest Statement The authors have declared no competing interest. Footnotes * http://www.fungi.guru/