Physiological blood-brain transport is impaired with age by a shift in transcytosis.

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

Bronchiectasis among Indigenous adults in the Top End of the Northern Territory, 2011-2020: a retrospective cohort study.

OBJECTIVES: To assess the prevalence of bronchiectasis among Aboriginal and Torres Strait Islander (Indigenous) adults in the Top End of the Northern Territory, and mortality among Indigenous adults with bronchiectasis. STUDY DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS: Aboriginal and Torres Strait Islander adults (18 years or older) living in the Top End Health Service region of the NT in whom bronchiectasis was confirmed by chest computed tomography (CT) during 1 January 2011 - 31 December 2020. MAIN OUTCOME MEASURES: Prevalence of bronchiectasis, and all-cause mortality among Indigenous adults with CT-confirmed bronchiectasis - overall, by sex, and by health district - based on 2011 population numbers (census data). RESULTS: A total of 23 722 Indigenous adults lived in the Top End Health Service region in 2011; during 2011-2020, 459 people received chest CT-confirmed diagnoses of bronchiectasis. Their median age was 47.5 years (interquartile range [IQR], 39.9-56.8 years), 254 were women (55.3%), and 425 lived in areas classified as remote (93.0%). The estimated prevalence of bronchiectasis was 19.4 per 1000 residents (20.6 per 1000 women; 18.0 per 1000 men). The age-adjusted prevalence of bronchiectasis was 5.0 (95% CI, 1.4-8.5) cases per 1000 people in the Darwin Urban health area, and 18-36 cases per 1000 people in the three non-urban health areas. By 30 April 2023, 195 people with bronchiectasis had died (42.5%), at a median age of 60.3 years (IQR, 50.3-68.9 years). CONCLUSION: The prevalence of bronchiectasis burden among Indigenous adults in the Top End of the NT is high, but differed by health district, as is all-cause mortality among adults with bronchiectasis. The socio-demographic and other factors that contribute to the high prevalence of bronchiectasis among Indigenous Australians should be investigated so that interventions for reducing its burden can be developed.

Costs and healthcare use of patients with chronic kidney disease in the Northern Territory, Australia.

BACKGROUND: The burden of chronic kidney disease (CKD) is high in the Northern Territory (NT), Australia. This study aims to describe the healthcare use and associated costs of people at risk of CKD (e.g. acute kidney injury, diabetes, hypertension, and cardiovascular disease) or living with CKD in the NT, from a healthcare funder perspective. METHODS: We included a retrospective cohort of patients at risk of, or living with CKD, on 1 January 2017. Patients on kidney replacement therapy were excluded from the study. Data from the Territory Kidney Care database, encompassing patients from public hospitals and primary health care services across the NT was used to conduct costing. Annual healthcare costs, including hospital, primary health care, medication, and investigation costs were described over a one-year follow-up period. Factors associated with high total annual healthcare costs were identified with a cost prediction model. RESULTS: Among 37,398 patients included in this study, 23,419 had a risk factor for CKD while 13,979 had CKD (stages 1 to 5, not on kidney replacement therapy). The overall mean (± SD) age was 45 years (± 17), and a large proportion of the study cohort were First Nations people (68%). Common comorbidities in the overall cohort included diabetes (36%), hypertension (32%), and coronary artery disease (11%). Annual healthcare cost was lowest in those at risk of CKD (AUD$7,958 per person) and highest in those with CKD stage 5 (AUD$67,117 per person). Inpatient care contributed to the majority (76%) of all healthcare costs. Predictors of increased total annual healthcare cost included more advanced stages of CKD, and the presence of comorbidities. In CKD stage 5, the additional cost per person per year was + $53,634 (95%CI 32,769 to 89,482, p < 0.001) compared to people in the at risk group without CKD. CONCLUSION: The total healthcare costs in advanced stages of CKD is high, even when patients are not on dialysis. There remains a need for effective primary prevention and early intervention strategies targeting CKD and related chronic conditions.

Developing an integrated clinical decision support system for the early identification and management of kidney disease-building cross-sectoral partnerships.

BACKGROUND: The burden of chronic conditions is growing in Australia with people in remote areas experiencing high rates of disease, especially kidney disease. Health care in remote areas of the Northern Territory (NT) is complicated by a mobile population, high staff turnover, poor communication between health services and complex comorbid health conditions requiring multidisciplinary care. AIM: This paper aims to describe the collaborative process between research, government and non-government health services to develop an integrated clinical decision support system to improve patient care. METHODS: Building on established partnerships in the government and Aboriginal Community-Controlled Health Service (ACCHS) sectors, we developed a novel digital clinical decision support system for people at risk of developing kidney disease (due to hypertension, diabetes, cardiovascular disease) or with kidney disease. A cross-organisational and multidisciplinary Steering Committee has overseen the design, development and implementation stages. Further, the system's design and functionality were strongly informed by experts (Clinical Reference Group and Technical Working Group), health service providers, and end-user feedback through a formative evaluation. RESULTS: We established data sharing agreements with 11 ACCHS to link patient level data with 56 government primary health services and six hospitals. Electronic Health Record (EHR) data, based on agreed criteria, is automatically and securely transferred from 15 existing EHR platforms. Through clinician-determined algorithms, the system assists clinicians to diagnose, monitor and provide guideline-based care for individuals, as well as service-level risk stratification and alerts for clinically significant events. CONCLUSION: Disconnected health services and separate EHRs result in information gaps and a health and safety risk, particularly for patients who access multiple health services. However, barriers to clinical data sharing between health services still exist. In this first phase, we report how robust partnerships and effective governance processes can overcome these barriers to support clinical decision making and contribute to holistic care.

Development and validation of algorithms to identify patients with chronic kidney disease and related chronic diseases across the Northern Territory, Australia.

BACKGROUND: Electronic health records can be used for population-wide identification and monitoring of disease. The Territory Kidney Care project developed algorithms to identify individuals with chronic kidney disease (CKD) and several commonly comorbid chronic diseases. This study aims to describe the development and validation of our algorithms for CKD, diabetes, hypertension, and cardiovascular disease. A secondary aim of the study was to describe data completeness of the Territory Kidney Care database. METHODS: The Territory Kidney Care database consolidates electronic health records from multiple health services including public hospitals (n = 6) and primary care health services (> 60) across the Northern Territory, Australia. Using the database (n = 48,569) we selected a stratified random sample of patients (n = 288), which included individuals with mild to end-stage CKD. Diagnostic accuracy of the algorithms was tested against blinded manual chart reviews. Data completeness of the database was also described. RESULTS: For CKD defined as CKD stage 1 or higher (eGFR of any level with albuminuria or persistent eGFR < 60 ml/min/1.732, including renal replacement therapy) overall algorithm sensitivity was 93% (95%CI 89 to 96%) and specificity was 73% (95%CI 64 to 82%). For CKD defined as CKD stage 3a or higher (eGFR < 60 ml/min/1.732) algorithm sensitivity and specificity were 93% and 97% respectively. Among the CKD 1 to 5 staging algorithms, the CKD stage 5 algorithm was most accurate with > 99% sensitivity and specificity. For related comorbidities - algorithm sensitivity and specificity results were 75% and 97% for diabetes; 85% and 88% for hypertension; and 79% and 96% for cardiovascular disease. CONCLUSIONS: We developed and validated algorithms to identify CKD and related chronic diseases within electronic health records. Validation results showed that CKD algorithms have a high degree of diagnostic accuracy compared to traditional administrative codes. Our highly accurate algorithms present new opportunities in early kidney disease detection, monitoring, and epidemiological research.

The relationship between citations, downloads and alternative metrics in rheumatology publications: a bibliometric study.

OBJECTIVE: Scientific journals and authors are frequently judged on 'impact'. Commonly used traditional metrics are the Impact Factor and H-index. However, both take several years to formulate and have many limitations. Recently, Altmetric-a metric that measures impact in a non-traditional way-has gained popularity. This project aims to describe the relationships between subject matter, citations, downloads and Altmetric within rheumatology. METHODS: Data from publications in Rheumatology were used. Articles published from 2010 to 2015 were reviewed. Data were analysed using Stata 14.2 (StataCorp, College Station, TX, USA). Correlation between citations, downloads and Altmetric were quantified using linear regression, comparing across disease topics. Relationship between downloads and months since publications were described using negative binomial regression, clustering on individual articles. RESULTS: A total of 1460 Basic Science and Clinical Science articles were identified, with the number of citations, downloads and Altmetric scores. There were no correlations between disease topic and downloads (R2 = 0.016, P = 0.03), citations (R2 = 0.011, P = 0.29) or Altmetric (R2 = 0.025, P = 0.02). A statistically significant positive association was seen between the number of citations and downloads (R2 = 0.29, P < 0.001). No correlations were seen between Altmetric and downloads (R2 = 0.028, P < 0.001) or citations (R2 = 0.004, P = 0.445). CONCLUSION: Disease area did not correlate with any of the metrics compared. Correlations were apparent with clear links between downloads and citations. Altmetric identified different articles as high impact compared with citation or download metrics. In conclusion: tweeting about your research does not appear to influence citations.

Men at risk of gonococcal urethritis: a case-control study in a Darwin sexual health clinic.

BACKGROUND: Male urethritis is primary sexually transmitted. Northern Territory (NT) has the highest rates of gonococcal infection in Australia and local guidelines recommend empiric treatment with azithromycin and ceftriaxone for all men presenting with urethritis. As gonococcal drug resistance is a growing concern, this study aims to improve empiric use of ceftriaxone through examining local patterns of male urethritis, comparing cases of gonococcal urethritis (GU) to controls with non-gonococcal urethritis (NGU). METHODS: A retrospective study was undertaken of all men with symptomatic urethritis presenting to Darwin sexual health clinic from July 2015 to July 2016 and aetiology of urethritis in this population was described. Demographic, risk profile, and clinical features of GU cases were compared to NGU controls. RESULTS: Among n = 145 men, the most common organisms identified were Chlamydia trachomatis (23.4%, SE 3.5%) and Neisseria gonorrhoeae (17.2%, SE 3.1%). The main predictors of GU were any abnormalities on genital examination (aOR 10.4, 95% CI 2.1 to 50.8) and a history of urethral discharge (aOR 5.7, 95% CI 1.4 to 22.6). Aboriginal patients (aOR 3.0, 95% CI 0.9 to 9.6) and those over 30 years of age (aOR 1.4, 95% CI 0.3 to 7.0) were more likely to have GU in the unadjusted analysis, but not in the adjusted model. CONCLUSION: This is the first study looking at patterns of male urethritis in urban NT and the results support a move towards adopting national guidelines to use ceftriaxone for empiric management of syndromic urethritis only in high-risk patients. In addition to traditional demographic risk factors, clinical features remain an important component of risk stratification.

A systematic review of chronic disease management interventions in primary care.

BACKGROUND: Primary and community care are key settings for the effective management of long term conditions. We aimed to evaluate the pattern of health outcomes in chronic disease management interventions for adults with physical health problems implemented in primary or community care settings. METHODS: The methods were based on our previous review published in 2006. We performed database searches for articles published from 2006 to 2014 and conducted a systematic review with narrative synthesis using the Cochrane Effective Practice and Organisation of Care taxonomy to classify interventions and outcomes. The interventions were mapped to Chronic Care Model elements. The pattern of outcomes related to interventions was summarized by frequency of statistically significant improvements in health care provision and patient outcomes. RESULTS: A total of 9589 journal articles were retrieved from database searches and snowballing. After screening and verification, 165 articles that detailed 157 studies were included. There were few studies with Health Care Organization (1.9% of studies) or Community Resources (0.6% of studies) as the primary intervention element. Self-Management Support interventions (45.8% of studies) most frequently resulted in improvements in patient-level outcomes. Delivery System Design interventions (22.6% of studies) showed benefits in both professional and patient-level outcomes for a narrow range of conditions. Decision Support interventions (21.3% of studies) had impact limited to professional-level outcomes, in particular use of medications. The small number of studies of Clinical Information System interventions (8.9%) showed benefits for both professional- and patient-level outcomes. CONCLUSIONS: The published literature has expanded substantially since 2006. This review confirms that Self-Management Support is the most frequent Chronic Care Model intervention that is associated with statistically significant improvements, predominately for diabetes and hypertension.

Design, effectiveness, and economic outcomes of contemporary chronic disease clinical decision support systems: a systematic review and meta-analysis.

OBJECTIVES: Electronic health record-based clinical decision support (CDS) has the potential to improve health outcomes. This systematic review investigates the design, effectiveness, and economic outcomes of CDS targeting several common chronic diseases. MATERIAL AND METHODS: We conducted a search in PubMed (Medline), EBSCOHOST (CINAHL, APA PsychInfo, EconLit), and Web of Science. We limited the search to studies from 2011 to 2021. Studies were included if the CDS was electronic health record-based and targeted one or more of the following chronic diseases: cardiovascular disease, diabetes, chronic kidney disease, hypertension, and hypercholesterolemia. Studies with effectiveness or economic outcomes were considered for inclusion, and a meta-analysis was conducted. RESULTS: The review included 76 studies with effectiveness outcomes and 9 with economic outcomes. Of the effectiveness studies, 63% described a positive outcome that favored the CDS intervention group. However, meta-analysis demonstrated that effect sizes were heterogenous and small, with limited clinical and statistical significance. Of the economic studies, most full economic evaluations (n = 5) used a modeled analysis approach. Cost-effectiveness of CDS varied widely between studies, with an estimated incremental cost-effectiveness ratio ranging between USD$2192 to USD$151 955 per QALY. CONCLUSION: We summarize contemporary chronic disease CDS designs and evaluation results. The effectiveness and cost-effectiveness results for CDS interventions are highly heterogeneous, likely due to differences in implementation context and evaluation methodology. Improved quality of reporting, particularly from modeled economic evaluations, would assist decision makers to better interpret and utilize results from these primary research studies. REGISTRATION: PROSPERO (CRD42020203716).

Risk Factors for Dental Caries Experience in Children and Adolescents with Cerebral Palsy-A Scoping Review.

Cerebral palsy is a developmental motor disorder which has far-reaching impacts on oral health. This scoping review examined the extent of research undertaken regarding the risk factors affecting dental caries experience in children and adolescents with cerebral palsy. Data were obtained from the electronic databases Web of Science and PubMed, using 10 search strings, for studies published between 1983 and 2018. Eligible studies were required to have investigated caries in children under 18 with cerebral palsy, as well as be written in English. 30 papers published were identified for inclusion in the review. These included 23 cross-sectional, 6 case-control, and 1 longitudinal study. Studies were categorized into six domains of risk factors: socioeconomic status (SE); cerebral palsy subtype (CPS); demographics (D); condition of oral cavity (OC); dental habits (DH); nutrition and diet (ND). This review was conducted and reported in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. The most significant risk factors were caregiver-related education levels, oral health literacy, and sugar intake; this underlines the important role of special education and dental awareness in reducing dental caries incidence in CP children. Other factors showed divergent findings, highlighting the need for standardization and culturally specific studies in future literature.

Barriers and enablers to implementing and using clinical decision support systems for chronic diseases: a qualitative systematic review and meta-aggregation.

BACKGROUND: Clinical decision support (CDS) is increasingly used to facilitate chronic disease care. Despite increased availability of electronic health records and the ongoing development of new CDS technologies, uptake of CDS into routine clinical settings is inconsistent. This qualitative systematic review seeks to synthesise healthcare provider experiences of CDS-exploring the barriers and enablers to implementing, using, evaluating, and sustaining chronic disease CDS systems. METHODS: A search was conducted in Medline, CINAHL, APA PsychInfo, EconLit, and Web of Science from 2011 to 2021. Primary research studies incorporating qualitative findings were included if they targeted healthcare providers and studied a relevant chronic disease CDS intervention. Relevant CDS interventions were electronic health record-based and addressed one or more of the following chronic diseases: cardiovascular disease, diabetes, chronic kidney disease, hypertension, and hypercholesterolaemia. Qualitative findings were synthesised using a meta-aggregative approach. RESULTS: Thirty-three primary research articles were included in this qualitative systematic review. Meta-aggregation of qualitative data revealed 177 findings and 29 categories, which were aggregated into 8 synthesised findings. The synthesised findings related to clinical context, user, external context, and technical factors affecting CDS uptake. Key barriers to uptake included CDS systems that were simplistic, had limited clinical applicability in multimorbidity, and integrated poorly into existing workflows. Enablers to successful CDS interventions included perceived usefulness in providing relevant clinical knowledge and structured chronic disease care; user confidence gained through training and post training follow-up; external contexts comprised of strong clinical champions, allocated personnel, and technical support; and CDS technical features that are both highly functional, and attractive. CONCLUSION: This systematic review explored healthcare provider experiences, focussing on barriers and enablers to CDS use for chronic diseases. The results provide an evidence-base for designing, implementing, and sustaining future CDS systems. Based on the findings from this review, we highlight actionable steps for practice and future research. TRIAL REGISTRATION: PROSPERO CRD42020203716.

The association between gravidity, parity and the risk of developing rheumatoid arthritis: A systematic review and meta-analysis.

OBJECTIVE: To establish if gravidity and parity associate with the development of rheumatoid arthritis (RA), and to establish if this effect is influenced by the time elapsed since pregnancy/childbirth, the number of pregnancies/childbirths, and serological status, through systematically reviewing the literature and undertaking a meta-analysis. METHODS: We searched Medline/EMBASE (from 1946 to 2018) using the terms "rheumatoid arthritis.mp" or "arthritis, rheumatoid/" and "pregnancy.mp" or "pregnancy/" or "parity.mp" or "parity/" or "gravidity.mp" or "gravidity/" (observational study filter applied). Case-control/cohort studies that examined the relationship between parity/gravidity and the risk of RA in women were included. Studies reporting effect size data for RA in ever vs. never parous/gravid women as ORs/RRs with 95% confidence intervals were included in a meta-analysis. Other relationships (i.e. risk by pregnancy/childbirth numbers) were analysed descriptively. RESULTS: Twenty studies (from 626 articles) met our inclusion criteria, comprising 14 case-control (4799 cases; 11,941 controls) and 6 cohort studies (8575 cases; 2,368,439 individuals). No significant association was observed in the meta-analysis of studies reporting the risk of RA in ever vs. never parous women (OR 0.91; 95% CI 0.80-1.04) and ever vs. never gravid women (OR 0.86; 95% CI 0.46-1.62). No consistent evidence of a relationship between the number of pregnancies/childbirths and RA risk was seen. No significant association was observed between being pregnant, or in the immediate post-partum period, and the risk of developing RA. CONCLUSION: Our systematic review does not support the concept that gravidity and parity are associated with the risk of RA development.

Brain Endothelial Cells Are Exquisite Sensors of Age-Related Circulatory Cues.

Brain endothelial cells (BECs) are key constituents of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Yet, because circulatory proteins have prominent age-related effects on adult neurogenesis, neuroinflammation, and cognitive function in mice, we wondered whether BECs receive and potentially relay signals between the blood and brain. Using single-cell RNA sequencing of hippocampal BECs, we discover that capillary BECs-compared with arterial and venous BECs-undergo the greatest transcriptional changes in normal aging, upregulating innate immunity and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulate key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice exert rejuvenation effects on the capillary transcriptome. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.