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Objectives: Demographic and presentation profile of patients using an innovative mobile outreach clinic compared with mainstream practice. Design: Retrospective cohort study. Setting: Primary care mobile street health clinic and mainstream practice in Western Australia. Participants: 2587 street health and 4583 mainstream patients. Main outcome measures: Prevalence and patterns of chronic diseases in anatomical domains across the entire age spectrum of patients and disease severity burden using Cumulative Illness Rating Scale (CIRS). Results: Multimorbidity (2+ CIRS domains) prevalence was significantly higher in the street health cohort (46.3%, 1199/2587) than age-sex-adjusted mainstream estimate (43.1%, 2000/4583), p=0.011. Multimorbidity prevalence was significantly higher in street health patients <45 years (37.7%, 615/1649) compared with age-sex-adjusted mainstream patients (33%, 977/2961), p=0.003 but significantly lower if 65+ years (62%, 114/184 vs 90.7%, 322/355, p<0.001). Controlling for age and gender, the mean CIRS Severity Index score for street health (M=1.4, SD=0.91) was significantly higher than for mainstream patients (M=1.1, SD=0.80), p<0.001. Furthermore, 44.2% (530/1199) of street health patients had at least one level 3 or 4 score across domains compared with 18.3% (420/2294) for mainstream patients, p<0.001. Street health population comprised 29.6% (766/2587) Aboriginal patients with 50.4% (386/766) having multimorbidity compared with 44.6% (813/1821) for non-Aboriginals, p=0.007. There were no comprehensive data on Indigenous status in the mainstream cohort available for comparison. Musculoskeletal, respiratory and psychiatric domains were most commonly affected with multimorbidity significantly associated with male gender, increasing age and Indigenous status. Conclusions: Age-sex-adjusted multimorbidity prevalence and disease severity is higher in the street health cohort. Earlier onset (23-34 years) multimorbidity is found in the street health cohort but prevalence is lower in 65+ years than in mainstream patients. Multimorbidity prevalence is higher for Aboriginal patients of all ages. [ABSTRACT FROM AUTHOR]

PURPOSE Multiple chronic conditions in a single patient can be a challenging health burden. We aimed to examine patterns and prevalence of multimorbidity among patients attending 2 large Australian primary care practices and to estimate disease severity burden using the Cumulative Illness Rating Scale (CIRS). METHODS Using published CIRS guidelines and a disease severity index calculated for each individual, we extracted data from the medical records of all 7,247 patients (58.5% female) seen over 6 months in 2008 who were rated for chronic conditions across 14 anatomical domains. RESULTS Fifty-two percent of patients had multimorbidity in 2 or more CIRS domains, ranging from 20.6% if younger than 25 years, 43.7% if aged 25 to 44 years, 75.5% if aged 45 to 64 years, 87.5% if aged 65 to 74 years, and 97.1% if aged 75 years and older. Using a cutoff of 3 or more CIRS domains, 34.5% had multimorbidity ranging from 4.8% if younger than 25 years, 22.3% if aged 25 to 44 years, 56.1% if aged 45 to 64 years, 74.6% if aged 65 to 74 years, and 92.0% if aged 75 years and older. Musculoskeletal, singularly or in combination with others, was the commonest morbidity domain. The moderate severity index category increased with increasing age. CONCLUSIONS Multimorbidity is a significant problem in men and women across all age-groups, and the moderate severity index increases with age. The musculoskeletal domain was most commonly affected. Mild and moderate severity index categories may underrepresent disease burden. Severity burden assessment in the primary care setting needs to take into account the severity index, as well as levels of domain severity within the index categories. [ABSTRACT FROM AUTHOR]

Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis.

A letter and a response to the editor are presented regarding the randomized trial of absolute cardiovascular risk reduction.

This article offers update on the 2006 Intensive Programme (IP) in Great Britain. The programme was hosted and coordinated by Fontys Sporthogeschool in Tillburg, the Netherlands and was funded by the European Union Commission. The participants of the program were segregated into multicultural focus groups to represent participating countries, like Great Britain, Hungary, Romania, Norway, Denmark, U.S., Lithuania and the Netherlands. A significant element of the IP were the social activities that encouraged maximal group integration and communication.

Clinical isolates of Yersinia, Klebsiella, and Escherichia coli frequently secrete the small molecule metallophore yersiniabactin (Ybt), which passivates and scavenges transition metals during human infections. YbtT is encoded within the Ybt biosynthetic operon and is critical for full Ybt production in bacteria. However, its biosynthetic function has been unclear because it is not essential for Ybt production by the in vitro reconstituted nonribosomal peptide synthetase/polyketide synthase (NRPS/ PKS) pathway. Here, we report the structural and biochemical characterization of YbtT. YbtT structures at 1.4 -1.9 A resolution possess a serine hydrolase catalytic triad and an associated substrate chamber with features similar to those previously reported for low-specificity type II thioesterases (TEIIs). We found that YbtT interacts with the two major Ybt biosynthetic proteins, HMWP1 (high-molecular-weight protein 1) and HMWP2 (high-molecular-weight protein 2), and hydrolyzes a variety of aromatic and acyl groups from their phosphopantetheinylated carrier protein domains. In vivo YbtT titration in uro-pathogenic E. coli revealed a distinct optimum for Ybt production consistent with a tradeoff between clearing both stalled inhibitory intermediates and productive Ybt precursors from HMWP1 and HMWP2. These results are consistent with a removing nonproductive, inhibitory thioesters that form aberrantly at multiple sites on HMWP1 and HMWP2. [ABSTRACT FROM AUTHOR]

The Triggering Receptor Expressed on Myeloid Cells-2 (TREM2), a pivotal innate immune receptor, orchestrates functions such as inflammatory responses, phagocytosis, cell survival, and neuroprotection. TREM2 variants R47H and R62H have been associated with Alzheimer's disease, yet the underlying mechanisms remain elusive. Our previous research established that TREM2 binds to heparan sulfate (HS) and variants R47H and R62H exhibit reduced affinity for HS. Building upon this groundwork, our current study delves into the interplay between TREM2 and HS and its impact on microglial function. We confirm TREM2's binding to cell surface HS and demonstrate that TREM2 interacts with HS, forming HS-TREM2 binary complexes on microglia cell surfaces. Employing various biochemical techniques, including Surface Plasmon Resonance, low molecular weight HS microarray screening, and serial HS mutant cell surface binding assays, we demonstrate TREM2's robust affinity for HS, and the effective binding requires a minimum HS size of approximately 10 saccharide units. Notably, TREM2 selectively binds specific HS structures, with 6-O-sulfation and, to a lesser extent, the iduronic acid residue playing crucial roles. N-sulfation and 2-O-sulfation are dispensable for this interaction. Furthermore, we reveal that 6-O-sulfation is essential for HS-TREM2 ternary complex formation on the microglial cell surface, and HS and its 6-O-sulfation are necessary for TREM2-mediated ApoE3 uptake in microglia. By delineating the interaction between HS and TREM2 on the microglial cell surface and demonstrating its role in facilitating TREM2-mediated ApoE uptake by microglia, our findings provide valuable insights that can inform targeted interventions for modulating microglial functions in Alzheimer's disease., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The Ca 2+ -activated Cl - channel regulator CLCA1 potentiates the activity of the Ca 2+ -activated Cl - channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca 2+ -dependent Cl - current (I CaCC ) density. We now present evidence of functional pairing between two other CLCA and TMEM16 protein family members, namely CLCA4 and the CaCC TMEM16B. Similar to CLCA1, (i) CLCA4 is a self-cleaving metalloprotease, and the N-terminal portion (N-CLCA4) is secreted; (ii) the von Willebrand factor type A (VWA) domain in N-CLCA4 is sufficient to potentiate I CaCC in HEK293T cells; and (iii) this is mediated by the metal ion-dependent adhesion site motif within VWA. The results indicate that, despite the conserved regulatory mechanism and homology between CLCA1 and CLCA4, CLCA4-dependent I CaCC are carried by TMEM16B, rather than TMEM16A. Our findings show specificity in CLCA/TMEM16 interactions and suggest broad physiological and pathophysiological links between these two protein families., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Institutions are established patterns of recurrent social relationships playing a fundamental part in all our lives. The family is the best-known institution, but other 'total' institutions serve as organisations directly affecting the lives of many individuals in the healthcare sector., Objective: This paper examines the sociological theory of institutionalisation as applied to individuals admitted to aged-care facilities, where the complete life-rounds of inmates occur within clearly defined limits. The study provides a framework to enable general practitioners, nurses and healthcare professionals to better appreciate the processes involved as individuals adapt to their new environment., Discussion: Sociology provides valuable insights for healthcare providers in understanding how individuals adapt to their loss of independent living and find themselves subjected to intimate regulation in the total institution. The biopsychosocial model of healthcare delivery is better understood when we as health professionals have greater insights to appreciate the competing processes at work.

Background: Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature cardiovascular morbidity and mortality. High-level evidence and clinical practice guidelines support preventative care for people with FH. However, it is estimated that less than 10% of people at risk of FH have been detected using any approach across Australian health settings. The aim of this study was to identify the implementation barriers to and facilitators of the detection of FH in Australia., Methods: Four, 2-hour virtual focus groups were facilitated by implementation scientists and a clinicians as part of the 2021 Australasian FH Summit. Template analysis was used to identify themes., Results: There were 28 workshop attendees across four groups (n=6-8 each), yielding 13 barriers and 10 facilitators across three themes: (1) patient related, (2) provider related, and (3) system related. A "lack of care pathways" and "upskilling clinicians in identifying and diagnosing FH" were the most interconnected barriers and facilitators for the detection of FH., Conclusions: The relationships between barriers and facilitators across the patient, provider, and system themes indicates that a comprehensive implementation strategy is needed to address these different levels. Future research is underway to develop a model for implementing the Australian FH guidelines into practice., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: General practitioners (GPs) are ideally placed to have a much larger role in detection and management of familial hypercholesterolaemia (FH) among their patients. The aim of this study was to seek the reflections of practice staff and newly diagnosed patients with FH on the implementation of an FH model of care in the general practice setting., Method: Qualitative descriptive methodology was used. Interviews were conducted with 36 practice staff and 51 patients from 15 practices participating in the study., Results: Data were analysed thematically and coded into themes - efficacy of GP training, screening for FH, model of care, patient awareness and cascade testing., Discussion: Findings reflect the real-world clinical experience of Australian general practice and the acceptability of the model of care for both patients with FH and practice staff. Patient health literacy is a barrier to both management of FH and cascade testing. A systematic approach to cascade testing is required.

Background and Objectives: Familial hypercholesterolaemia (FH) can be effectively detected and managed in primary care, but the health economic evidence for this is scarce. The aim of this study was to examine management pathways and cost implications of FH screening and management in Australian general practice., Method: Cost-effectiveness outcomes were projected using a life table model. Data was used from 133 patients in 15 Australian general practice clinics from an earlier screening and management study. Costing and mortality data were sourced from governmental sources and published literature., Results: Most patients had a regular general practice consultation at baseline (82%), though the proportion seen under a chronic disease management item at follow-up increased to 23%. The median cost of management was $275 per annum in the first year of management. Managing patients with statins up to the age of 60 years yielded an increase of 248,954 life-years at a cost of $759 million, representing a cost per life-year gained of $3047., Discussion: Screening and management of FH in general practice has the potential for substantial health benefits while requiring relatively modest investments from the health system.

Background: Familial hypercholesterolaemia (FH) is a monogenic lipid disorder that may be overlooked in the diagnostic process., Objective: The aim of this article is to review the key areas for identification and management of FH that affect Australian general practitioners (GPs)., Discussion: Recent consensus advice on the care of patients with FH in Australia provides an opportunity for GPs to increase their awareness and skills in diagnosing and managing FH. New Medicare Benefits Schedule items for genetic testing and Pharmaceutical Benefits Scheme listing for the use of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors offer GPs additional supports to improve the care of patients with FH. A shared-care approach between GPs and non-GP specialists with expertise in multiple disciplines offers the best option to facilitate genetic testing and management of index cases and affected family relatives. Implementation of this guidance in the primary care setting remains an ongoing challenge and needs to be embraced as a high priority.

Background and Objectives: A lack of public and health professional awareness about familial hypercholesterolaemia (FH) leads to an estimated 90,000 Australians remaining undiagnosed. The aim of this study was to establish the level of knowledge and awareness of FH in Australian general practices., Method: A qualitative descriptive methodology was used to explore baseline knowledge and perceptions of practice staff about diagnosing and managing FH. Overall, 63 interviews were conducted with general practice staff at 15 practices taking part in a National Health and Medical Research Council partnership grant study (GNT1142883)., Results: Data were analysed thematically and coded into themes - knowledge/awareness/recall, management, use of guidelines/referrals, and contacting family members. Most general practitioners treated the high cholesterol component as their primary focus. Guidelines and referrals were rarely used., Discussion: This research reflected a lack of knowledge, awareness and use of guidelines similar to that shown in other published studies. Improved primary care infrastructure, knowledge and awareness of FH need to be addressed.

Background: Guidelines on lipid disorders are constantly evolving. General practitioners regularly face critical decisions about the best treatment strategies for individual patients. Cardiovascular disease (CVD) is common, with most morbidity and mortality due to atherosclerosis. Raised low-density lipoprotein cholesterol (LDL-C) is the most atherogenic component - lowering it lowers the risk of future cardiovascular events., Objective: The aim of this article is to provide an evidence-informed summary of national guidelines and recent research to help clinicians reduce the risk of atherosclerotic CVD and improve health service delivery through improved lipid management strategies., Discussion: Elevated plasma lipids, especially LDL-C, increase the likelihood of a CVD event over time. Knowledge of family and personal histories plus other risk factors for CVD should alert clinicians to the need for treatment. The greater the overall burden of combined risk factors, the greater the lifetime risk. This update provides new information that informs future approaches for improving lipid management in Australian general practice.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder of low-density lipoprotein (LDL) catabolism, which if untreated causes lifelong elevated LDL-cholesterol (LDL-c), accelerated atherosclerosis and premature cardiovascular disease. Recent evidence suggests the prevalence of heterozygous FH is ∼1:220, making FH the most common autosomal dominant condition. Lowering LDL-c with statin and lifestyle therapy reduces the risk of cardiovascular events. Furthermore, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower LDL-c in addition to statin therapy, and early outcome data suggest improved vascular outcomes with these agents in FH patients in addition to statins. However, the vast majority of people with FH still remain undiagnosed. The onus is on clinicians to identify kindreds with FH, as PCSK9 inhibitors, although expensive, are funded for patients with FH in Australia. Multiple strategies for detecting FH have been proposed. The detection of index cases can be achieved through applying electronic screening tools to general practice databases, universal screening of children during immunisation, and targeted screening of patients with premature cardiovascular disease. Advances in genomic technology have decreased costs of genetic testing, improved the understanding of the pathogenesis of FH and facilitated cascade screening. However, awareness of FH amongst clinicians and the general public still requires optimisation. This review outlines recent advances in FH detection, including emerging strategies and challenges for the next decade., (Copyright © 2018 Royal College of Pathologists of Australasia. All rights reserved.)

Fifty per cent of first-degree relatives of index cases with familial hypercholesterolemia (FH) inherit the disorder. Despite cascade screening being the most cost-effective method for detecting new cases, only a minority of individuals with FH are currently identified. Primary care is a key target area to increase identification of new index cases and initiate cascade screening, thereby finding close relatives of all probands. Increasing public and health professional awareness about FH is essential. In the United Kingdom and in Australia, most of the population are reviewed by a General Practitioner (GP) at least once over a three-year period, offering opportunities to check for FH as part of routine clinical consultations. Such opportunistic approaches can be supplemented by systematically searching electronic health records with information technology tools that identify high risk patients. GPs can help investigate and implement results of this data retrieval. Current evidence suggests that early detection of FH and cascade testing meet most of the criteria for a worthwhile screening program. Among heterozygous patients the long latent period before the expected onset of coronary artery disease provides an opportunity for initiating effective drug and lifestyle changes. The greatest challenge for primary care is to implement an efficacious model of care that incorporates sustainable identification and management pathways., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objectives: Street-based clinics provide general practice services to marginalised and homeless persons. The objective of this study was to examine prevalence, patterns and severity of multimorbidity in patients attending one such service., Method: A retrospective cohort study (2006–15), comprising medical record review of patients (n = 4285), was undertaken. A Cumulative Illness Rating Scale (CIRS) was used to assess multimorbidity., Results: Average age of patients was 38.2 ± 17.9 years. Of 31.5% Aboriginal patients, 50.8% were female (37.6% in non Aboriginal patients). Of all patients, 53% had multimorbidity. Aboriginal patients had higher rates of multimorbidity than non-Aboriginal patients (58.0% vs 50.6%, P <0.001). Psychiatric, musculoskeletal (especially skin) and respiratory conditions were most common. Disease severity was mild to moderate, with 26.8% having at least one severe or extremely severe condition. Multimorbidity and disease severity increased between 2006–11 and 2012–15. Aboriginality was the strongest predictor of multimorbidity (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.8–2.4; P <0.001)., Discussion: Street-based general practice services are critical to facilitate easy access to primary and secondary management of chronic multimorbid conditions in marginalised (especially Aboriginal) patients.

Discussion: People who are homeless or marginalised have poor engagement with mainstream healthcare services. The aim of this study was to explore patient and staff perspectives of a street-based, primary health service, to help identify factors influencing patient access and management. A qualitative study was undertaken from April to September 2016. Interviews (n = 27) explored patients’ experiences of accessing healthcare services. Interviews with allied service staff (n = 5) explored referral pathways and patients’ access to healthcare.  Factors influencing patients’ willingness to access primary healthcare through the street health service were identified as doctor–patient empathy, better understanding of patient circumstances, fostering of social capital, facilitating referral pathways and supporting the transition to mainstream general practice as circumstances improve. Hospital discharge planning and follow-up management were identified as gaps in the continuity of service. Ease of access provided by a street-based health service facilitates access to the healthcare system for homeless and marginalised patients.&nbsp;

Medical student numbers in Australia have increased significantly in recent years. A resulting increase in medical graduates is inevitable and desirable. Western Australian medical graduates will double by 2012 and treble shortly afterward. Insufficient training positions in hospitals will likely require additional training opportunities to be provided by general practices. This article reviews innovative general practice training schemes for new medical graduates in Australia and overseas. It examines whether Australian general practice can play a role in training the rising numbers of new doctors.

Heartwatch is a national program in Irish general practice for the secondary prevention of cardiovascular disease. The program--a joint initiative of the Irish Department of Health and Children, the Irish College of General Practitioners, and the Irish Heart Foundation--has a number of key components, many of which may be suitable for adapting to Australian primary care.