Examining service utilisation and impact among consumers of a national mental health stepped care programme in Australia: a protocol using linked administrative data.

INTRODUCTION: Mental well-being is a global public health priority with increasing mental health conditions having substantial burden on individuals, health systems and society. 'Stepped care', where services are provided at an intensity to meet the changing needs of the consumer, is the chosen approach to mental health service delivery in primary healthcare in Australia for its efficiencies and patient outcomes; yet limited evidence exists on how the programme is being rolled out and its impact in practice. This protocol outlines a data linkage project to characterise and quantify healthcare service utilisation and impacts among a cohort of consumers of a national mental health stepped care programme in one region of Australia. METHODS AND ANALYSIS: Data linkage will be used to establish a retrospective cohort of consumers of mental health stepped care services between 1 July 2020 and 31 December 2021 in one primary healthcare region in Australia (n=approx. 12 710). These data will be linked with records from other healthcare service data sets (eg, hospitalisations, emergency department presentations, community-based state government-delivered mental healthcare, hospital costs). Four areas for analysis will include: (1) characterising the nature of mental health stepped care service use; (2) describing the cohort's sociodemographic and health characteristics; (3) quantifying broader service utilisation and associated economic costs; and (4) assessing the impact of mental health stepped care service utilisation on health and service outcomes. ETHICS AND DISSEMINATION: Approval from the Darling Downs Health Human Research Ethics Committee (HREA/2020/QTDD/65518) has been granted. All data will be non-identifiable, and research findings will be disseminated through peer-reviewed journals, conference presentations and industry meetings.

Structural basis and dynamics of Chikungunya alphavirus RNA capping by nsP1 capping pores.

Alphaviruses are emerging positive-stranded RNA viruses which replicate and transcribe their genomes in membranous organelles formed in the cell cytoplasm. The nonstructural protein 1 (nsP1) is responsible for viral RNA capping and gates the replication organelles by assembling into monotopic membrane-associated dodecameric pores. The capping pathway is unique to Alphaviruses; beginning with the N7 methylation of a guanosine triphosphate (GTP) molecule, followed by the covalent linkage of an m7GMP group to a conserved histidine in nsP1 and the transfer of this cap structure to a diphosphate RNA. Here, we provide structural snapshots of different stages of the reaction pathway showing how nsP1 pores recognize the substrates of the methyl-transfer reaction, GTP and S-adenosyl methionine (SAM), how the enzyme reaches a metastable postmethylation state with SAH and m7GTP in the active site, and the subsequent covalent transfer of m7GMP to nsP1 triggered by the presence of RNA and postdecapping reaction conformational changes inducing the opening of the pore. In addition, we biochemically characterize the capping reaction, demonstrating specificity for the RNA substrate and the reversibility of the cap transfer resulting in decapping activity and the release of reaction intermediates. Our data identify the molecular determinants allowing each pathway transition, providing an explanation for the need for the SAM methyl donor all along the pathway and clues about the conformational rearrangements associated to the enzymatic activity of nsP1. Together, our results set ground for the structural and functional understanding of alphavirus RNA-capping and the design of antivirals.

Challenges in implementing GP clusters in Scotland: a qualitative study comparing the views of senior primary care stakeholders in 2016 with those in 2021.

BACKGROUND: Formation of GP clusters began in Scotland in April 2016 as part of a new Scottish GP contract. They aim to improve the care quality for local populations (intrinsic role) and the integration of health and social care (extrinsic role). AIM: To compare predicted challenges of cluster implementation in 2016 with reported challenges in 2021. DESIGN & SETTING: Qualitative study of senior national stakeholders in primary care in Scotland. METHOD: Qualitative analysis of semi-structured interviews with 12 senior primary care national stakeholders in 2016 (n = 6) and 2021 (n = 6). RESULTS: Predicted challenges in 2016 included balancing intrinsic and extrinsic roles, providing sufficient support, maintaining motivation and direction, and avoiding variation between clusters. Progress of clusters in 2021 was perceived as suboptimal and was reported to vary significantly across the country, reflecting differences in local infrastructure. Practical facilitation (data, administrative support, training, project improvement support, and funded time) and strategic guidance from the Scottish Government was felt to be lacking. GP engagement with clusters was felt to be hindered by the significant time and workforce pressures facing primary care. These barriers were considered as collectively contributing to cluster lead 'burnout' and loss of momentum, exacerbated by inadequate opportunities for shared learning between clusters across Scotland. Such barriers preceded, but were perpetuated by, the impact of the COVID-19 pandemic. CONCLUSION: Apart from the COVID-19 pandemic, many of the challenges reported by stakeholders in 2021 were predicted in 2016. Accelerating progress in cluster working will require renewed investment and support applied consistently across the country.

Evaluating the cost of managing patients with cellulitis in Wales, UK: A 20-year population-scale study.

This study aimed to estimate costs associated with managing patients with cellulitis from the UK National Health Service (NHS) perspective. The analysis was undertaken through the Secure Anonymised Information Linkage Databank, which brings together population-scale, individual-level anonymised linked data from a wide range of sources, including 80% of primary care general practices within Wales (population coverage ~3.2 million). The data covered a 20-year period from 1999 to 2019. All patients linked to the relevant codes were tracked through primary care settings, recording the number of general practice visits (number of days with an event recorded) and number of in-patient stays. Resources were valued in monetary terms (£ sterling), with costs determined from national published sources of unit costs. These resources were then extrapolated out to reflect UK NHS costs. This is the first attempt to estimate the financial burden of cellulitis using routine data sources on a national scale. The estimated direct annual costs to the Welsh NHS (£28 554 338) are considerable. In-Patient events and length of stay costs are the main cost drivers, with annual Welsh NHS estimates of £19 664 126 with primary care events costing £8 890 212. Initiatives to support patients and healthcare professionals in identifying early signs/risks of cellulitis, improve the accuracy of initial diagnosis, prevent cellulitis recurrence, and improve evidence-based treatment pathways would result in major financial savings, to both the Welsh and UK NHS. In light of these findings, Wales has developed the innovative National Lymphoedema cellulitis Improvement Programme to address these burdens; providing a proactive model of cellulitis care.

A spotlight on lymphoedema Did Not Attends: Demographics and workforce costs.

This unique evaluation aimed to estimate, the financial impact of non-attendance on a nation-wide hospital lymphoedema service. Along with gaining some understanding of patient characteristics of those who Did Not Attend (DNA) and were subsequently discharged. The evaluation design interrogated existing performance data from 2012 to 2022. This information was used to estimate the costs incurred based on national published sources and pay scales. Staffing costs of over £1.1 m in one decade related to the financial impact of over 23 000 unattended lymphoedema appointments. The characteristics of 870 patients from 2019/2020 were also evaluated suggesting that those with a wound alongside complex lymphoedema were less likely to DNA appointments. Two-thirds of patients were managing two or more comorbidities-obesity, cardiac conditions and diabetes being the most common. It seems likely that some DNAs are avoidable by adapting appointment administrative processes and greater understanding of patients' perception of value. However, the reasons for DNA are likely to be varied and nuanced so potentially a small proportion are unavoidable. Modernising appointment processes and identifying patient value may help minimise DNA costs in the future.

The Lymphatic System, Lymphoedema, and Medical Curricula-Survey of Australian Medical Graduates.

The aim of this study was to survey the perceptions of recent (i.e., within the past 12 months) Australian medical graduates regarding (i) their understanding of the lymphatic system and lymphoedema, and (ii) the extent to which the lymphatic system and lymphoedema were covered as part of their medical degree. Medical graduates were invited to participate in a 17-item online survey that asked respondents to rate their level of agreement (using a 5-point Likert scale; higher scores = higher agreement) to statements that explored their understanding and comprehensiveness of their medical degree. Responses to each item were described using n (%). Subscale scores for understanding and medical degree were computed by summing scores of individual items, described using means (SD) and compared by participant characteristics. Medical graduates (n = 230) perceived their understanding of the lymphatic system and lymphoedema to be low, and comprehensiveness of medical curricula specific to the lymphatic system and lymphoedema to be lacking. Subscale scores did not differ by participant characteristics. Improvement of medical graduates understanding of lymphoedema may facilitate greater awareness of lymphoedema, thus optimizing the timeliness of diagnosis and access to treatment.

The Winchcombe meteorite, a unique and pristine witness from the outer solar system.

Direct links between carbonaceous chondrites and their parent bodies in the solar system are rare. The Winchcombe meteorite is the most accurately recorded carbonaceous chondrite fall. Its pre-atmospheric orbit and cosmic-ray exposure age confirm that it arrived on Earth shortly after ejection from a primitive asteroid. Recovered only hours after falling, the composition of the Winchcombe meteorite is largely unmodified by the terrestrial environment. It contains abundant hydrated silicates formed during fluid-rock reactions, and carbon- and nitrogen-bearing organic matter including soluble protein amino acids. The near-pristine hydrogen isotopic composition of the Winchcombe meteorite is comparable to the terrestrial hydrosphere, providing further evidence that volatile-rich carbonaceous asteroids played an important role in the origin of Earth's water.

Children and young people with lymphoedema: a project to assess the education needs of healthcare professionals.

Healthcare professionals need adequate preparatory education to treat children and young people with lymphoedema confidently and competently. This collaborative international project, based on existing literature and expert focus groups, seeks to identify the nature of that education need and in what format it could be addressed.

The education needs of health professionals conservatively managing genital oedema: UK survey findings.

BACKGROUND: Adults and children report genital oedema but prevalence is unknown. Pre-registration nurse training rarely includes genital oedema and postgraduate training opportunities are rare. AIM: To identify the education needs of health professionals regarding management of genital oedema. METHOD: An electronic survey was cascaded to health professionals through relevant professional groups and social media. FINDINGS: Of 149 UK respondents, most manage patients with genital oedema but only 2% felt current training was sufficient. Of 138 responding regarding supplemental training, only a half had completed genital oedema specific education, usually of 1-4 hours' duration. Confidence in knowledge was up to 22.5% higher in those with genital oedema education, even accounting for years of experience. The most common top three individual needs were compression, contemporary surgical and medical management and patient assessment. Educational resources are needed and both offline and online formats were suggested; collaborative events with urology/pelvic health are essential. CONCLUSION: Health professionals working in lymphoedema care have (unmet) specific education needs regarding genital oedema management. The desire for both offline and online resources reflects the necessity of accessing learning at a distance and on an 'as needed' basis.

A long intergenic non-coding RNA regulates nuclear localization of DNA methyl transferase-1.

DNA methyl transferase-1 or DNMT1 maintains DNA methylation in the genome and is important for regulating gene expression in cells. Aberrant changes in DNMT1 activity and DNA methylation are commonly observed in cancers and many other diseases. Recently, a number of long intergenic non-protein-coding RNAs or lincRNAs have been shown to play a role in regulating DNMT1 activity. CCDC26 is a nuclear lincRNA that is frequently mutated in cancers and is a hotbed for disease-associated single nucleotide changes. However, the functional mechanism of CCDC26 is not understood. Here, we show that this lincRNA is concentrated on the nuclear periphery. Strikingly, in the absence of CCDC26 lincRNA, DNMT1 is mis-located in the cytoplasm, and the genomic DNA is significantly hypomethylated. This is accompanied by double-stranded DNA breaks and increased cell death. These results point to a previously unrecognized mechanism of lincRNA-mediated subcellular localization of DNMT1 and regulation of DNA methylation.

Structural Insights into the Mechanisms of Action of Functionally Distinct Classes of Chikungunya Virus Nonstructural Protein 1 Inhibitors.

Chikungunya virus (CHIKV) nonstructural protein 1 (nsP1) harbors the methyltransferase (MTase) and guanylyltransferase (GTase) activities needed for viral RNA capping and represents a promising antiviral drug target. We compared the antiviral efficacies of nsP1 inhibitors belonging to the MADTP, CHVB, and FHNA series (6'-fluoro-homoneplanocin A [FHNA], its 3'-keto form, and 6'-ß-fluoro-homoaristeromycin). Cell-based phenotypic cross-resistance assays revealed that the CHVB and MADTP series had similar modes of action that differed from that of the FHNA series. In biochemical assays with purified Semliki Forest virus and CHIKV nsP1, CHVB compounds strongly inhibited MTase and GTase activities, while MADTP-372 had a moderate inhibitory effect. FHNA did not directly inhibit the enzymatic activity of CHIKV nsP1. The first-of-their-kind molecular-docking studies with the cryo-electron microscopy (cryo-EM) structure of CHIKV nsP1, which is assembled into a dodecameric ring, revealed that the MADTP and CHVB series bind at the S-adenosylmethionine (SAM)-binding site in the capping domain, where they would function as competitive or noncompetitive inhibitors. The FHNA series was predicted to bind at the secondary binding pocket in the ring-aperture membrane-binding and oligomerization (RAMBO) domain, potentially interfering with the membrane binding and oligomerization of nsP1. Our cell-based and enzymatic assays, in combination with molecular docking and mapping of compound resistance mutations to the nsP1 structure, allowed us to group nsP1 inhibitors into functionally distinct classes. This study identified druggable pockets in the nsP1 dodecameric structure and provides a basis for the rational design, optimization, and combination of inhibitors of this unique and promising antiviral drug target.

Guidelines for managing people with lymphoedema remotely: a post-COVID-19 response document.

During the COVID-19 pandemic it was initially not possible to see people with lymphoedema face-to-face at lymphoedema services, due to the potential risks of the virus, because they were shielding, because of redeployment of rooms or staff, and due to sporadic restrictions of movement. The pandemic therefore accelerated adjustments in lymphoedema service delivery, while ensuring effective and efficient care was paramount. This document presents a pragmatic guide for lymphoedema services. Although clinical and non-clinical staff need to comply with guidance from their own organisations/commissioners, this document aims to provide specific guidance and share good practice in relation to lymphoedema management. These guidelines are based on analysis of the national response of Lymphoedema Network Wales during the first few months of the COVID-19 pandemic and incorporate supporting contemporary advice. They have been used throughout NHS Wales, providing a standardised approach in supporting care for people with lymphoedema. In light of the enduring nature of COVID-19, it is imperative that lymphoedema services have a means to provide suitable care for patients. Although face-to-face appointments are sometimes deemed necessary, many patients can be suitably supported via telehealth consultations. These guidelines may help lymphoedema services restore and reset in a safe and acceptable manner.

Challenges and opportunities identified for lymphoedema services in Wales during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, lymphoedema staff adapted services, providing care remotely, and worked in other NHS sectors. The impact on services and staff must be understood in order to safeguard patient care and foster workforce resilience. AIMS: To evaluate the experiences of clinical and non-clinical lymphoedema staff in Wales during the COVID-19 pandemic. METHODS: An anonymous online survey, based on scoping work, was sent out via the Welsh lymphoedema services mailing list. FINDINGS: 71% (68/96) of eligible lymphoedema staff completed the survey. More than half supported lymphoedema services (40/68) with the remaining staff deployed elsewhere. Overall, staff and services felt prepared for new ways of working. Concerns about others and the future burden on services when life returned to normal were reported. Opportunities identified included education initiatives and virtual services. CONCLUSION: Lymphoedema services were well prepared to deliver virtually, enable effective care and share knowledge. Co-ordinated efforts to uphold patient advocacy will support virtual services to meet their needs.

Capping pores of alphavirus nsP1 gate membranous viral replication factories.

Positive-sense single-stranded RNA viruses, such as coronaviruses, flaviviruses and alphaviruses, carry out transcription and replication inside virus-induced membranous organelles within host cells1-7. The remodelling of the host-cell membranes for the formation of these organelles is coupled to the membrane association of viral replication complexes and to RNA synthesis. These viral niches allow for the concentration of metabolites and proteins for the synthesis of viral RNA, and prevent the detection of this RNA by the cellular innate immune system8. Here we present the cryo-electron microscopy structure of non-structural protein 1 (nsP1) of the alphavirus chikungunya virus, which is responsible for RNA capping and membrane binding of the viral replication machinery. The structure shows the enzyme in its active form, assembled in a monotopic membrane-associated dodecameric ring. The structure reveals the structural basis of the coupling between membrane binding, oligomerization and allosteric activation of the capping enzyme. The stoichiometry-with 12 active sites in a single complex-redefines viral replication complexes as RNA synthesis reactors. The ring shape of the complex implies it has a role in controlling access to the viral organelle and ensuring the exit of properly capped viral RNA. Our results provide high-resolution information about the membrane association of the replication machinery of positive-sense single-stranded RNA viruses, and open up avenues for the further characterization of viral replication on cell membranes and the generation of antiviral agents.

Mode of Action of the Catalytic Site in the N-Terminal Ribosome-Inactivating Domain of JIP60.

Jasmonate-induced protein 60 (JIP60) is a ribosome-inactivating protein (RIP) from barley (Hordeum vulgare) and is involved in the plant immune response dependent on jasmonate hormones. Here, we demonstrate in Nicotiana benthamiana that transient expression of the N-terminal domain of JIP60, from which the inhibitor domain (amino acids 163-185) is removed, initiates cell death, leading to extensive necrosis of leaf tissues. We used structure prediction of JIP60 to identify potential catalytic amino acids in the active site and tested these by mutagenesis and in planta assays of necrosis induction by expression in N. benthamiana, as well as through an in vitro translation-inactivation assay. We found that Tyr 96, Glu 201, Arg 204, and Trp 234 in the presumptive active site of JIP60 are conserved in 815 plant RIPs in the Pfam database that were identified by HUMMR as containing a RIP domain. When these amino acid residues are individually mutated, the necrosis-inducing activity is completely abolished. We therefore propose that the role of these amino acids in JIP60 activity is to depurinate adenosine in ribosomes. This study provides insight into the catalytic mechanism of JIP60.

Exploring the impact of lymphoedema on individuals and if lymphatic venous anastomosis surgery effects perceptions on quality of life: A qualitative study.

PURPOSE: Lymphoedema is a chronic condition, a cancer consequence and causes physical, psychological, and social implications. A new super-micro surgical treatment Lymphatic Venous Anastomosis (LVA) may improve the symptoms of lymphoedema. This study aims to explore the impact of lymphoedema on individuals and if LVA Surgery changes perceptions on quality of life. METHOD: Semi-structured interviews were conducted with sixteen individual's pre-LVA surgery and repeated six months later post-LVA with ten of the participants. Transcripts were analysed using thematic analysis. RESULTS: Themes identified pre-LVA included: Impact of Living with Lymphoedema, Being Different, and Future Hopes and Emotions. Participants reported making significant changes to 'normal' life due to living with lymphoedema. Changes included alteration in shopping, cleaning, hobbies, familial roles, employment and sexual intimacy. The wearing of compression garments engendered feelings of being unattractive. Themes found post-LVA were: I am one of the Lucky Ones and Returning to Former Self. Post-LVA, participants described how life had become more normalised with fear and apprehension of developing cellulitis reduced. Positive changes had enabled usual activities of daily living to recommence. Some participants had decreased pain, aching, heaviness, stiffness and were wearing their compression garments less. CONCLUSION: The findings suggest that the real impact of living with lymphoedema is much more challenging than previously identified. The findings suggest that LVA can give a future of greater choice for some of its recipients, but further research should explore longer-term benefits. LVA could offer hope to some people with lymphoedema, but a realistic expectation is essential.

Structure and function of the Toscana virus cap-snatching endonuclease.

Toscana virus (TOSV) is an arthropod-borne human pathogen responsible for seasonal outbreaks of fever and meningoencephalitis in the Mediterranean basin. TOSV is a segmented negative-strand RNA virus (sNSV) that belongs to the genus phlebovirus (family Phenuiviridae, order Bunyavirales), encompassing other important human pathogens such as Rift Valley fever virus (RVFV). Here, we carried out a structural and functional characterization of the TOSV cap-snatching endonuclease, an N terminal domain of the viral polymerase (L protein) that provides capped 3'OH primers for transcription. We report TOSV endonuclease crystal structures in the apo form, in complex with a di-ketoacid inhibitor (DPBA) and in an intermediate state of inhibitor release, showing details on substrate binding and active site dynamics. The structure reveals substantial folding rearrangements absent in previously reported cap-snatching endonucleases. These include the relocation of the N terminus and the appearance of new structural motifs important for transcription and replication. The enzyme shows high activity rates comparable to other His+ cap-snatching endonucleases. Moreover, the activity is dependent on conserved residues involved in metal ion and substrate binding. Altogether, these results bring new light on the structure and function of cap-snatching endonucleases and pave the way for the development of specific and broad-spectrum antivirals.

Are you handling genital oedema confidently?

Men, women or children can suffer from oedema (swelling) of the genitalia. When differential diagnosis has excluded acute trauma or pathology and swelling remains, the condition may be diagnosed as genital lymphoedema, a chronic condition that increases the relative risk of cellulitis. Diagnosis of genital oedema is often delayed due to problems with patient and health professional behaviour, in terms of embarrassment, lack of confidence or lack of knowledge. Awareness of this condition and knowledge on how to manage it will go a long way in helping both patients and clinicians overcome the challenges of addressing genital oedema. This article describes the authors' experiences in managing genital oedema. It also briefly discusses a new international project that seeks to identify the knowledge and training that health professionals need to manage this condition more confidently.

A left-sided cerebrospinal fluid hydrothorax and a right ventricular-peritoneal shunt: a unique clinical case study.

We describe the case of a 84-year-old woman with a right ventricular-peritoneal shunt and a left-sided pleural effusion, the analysis of which was positive for cerebrospinal fluid. We consider the potential causative mechanisms. Our patient was managed conservatively due to her frailty, the effusion being asymptomatic and her preference not to pursue further invasive diagnostic testing. This case report is unique due to the contralateral nature of the effusion to the shunt, which has not been described before in the literature.