Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial.

BACKGROUND: Cholestatic pruritus and fatigue are debilitating conditions associated with primary biliary cholangitis (PBC) and can significantly impact patients' quality of life. Pruritus in PBC often worsens at night and patients frequently report sleep disturbance, which contributes to cognitive symptoms and fatigue. Linerixibat is an ileal bile acid transporter inhibitor in clinical development for the treatment of pruritus associated with PBC and was recently assessed versus placebo in the Phase 2b GLIMMER trial. This post-hoc analysis assesses the relationship between pruritus severity and sleep disturbance in participants of GLIMMER regardless of treatment group. METHODS: GLIMMER (NCT02966834), a multicenter, double-blind, randomized, placebo-controlled trial, recruited 147 patients with PBC and moderate-to-severe pruritus. Following 4 weeks single-blind placebo, patients (randomized 3:1) received linerixibat or placebo for 12 weeks (to Week 16). Participants graded their itch (twice daily) and its interference with sleep (once daily) in an electronic diary using a 0-10 numerical rating scale (NRS). Weekly and monthly itch scores were calculated as the mean of the worst daily itch score over the respective time period. At study visits, participants completed the 5-D itch scale and the PBC-40 quality of life questionnaire, both of which contain an item specific to itch-related sleep disturbance. The impact of pruritus on sleep was assessed post hoc through correlations between the changes in NRS, 5-D itch, and PBC-40. RESULTS: Strong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) at the end of treatment (Week 16), as well as in monthly itch and sleep NRS scores (r = 0.84 [95% CI: 0.80; 0.87]). Patients with improved weekly pruritus score severity category demonstrated reduced perceived sleep interference on average. Itch responders (≥2-point improvement in weekly itch score from baseline) displayed larger improvements in weekly sleep NRS score, 5-D itch, and PBC-40 sleep items, than itch non-responders (<2-point improvement). CONCLUSIONS: A strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep.

A secreted proteomic footprint for stem cell pluripotency.

With a view to developing a much-needed non-invasive method for monitoring the healthy pluripotent state of human stem cells in culture, we undertook proteomic analysis of the waste medium from cultured embryonic (Man-13) and induced (Rebl.PAT) human pluripotent stem cells (hPSCs). Cells were grown in E8 medium to maintain pluripotency, and then transferred to FGF2 and TGFß deficient E6 media for 48 hours to replicate an early, undirected dissolution of pluripotency. We identified a distinct proteomic footprint associated with early loss of pluripotency in both hPSC lines, and a strong correlation with changes in the transcriptome. We demonstrate that multiplexing of four E8- against four E6- enriched secretome biomarkers provides a robust, diagnostic metric for the pluripotent state. These biomarkers were further confirmed by Western blotting which demonstrated consistent correlation with the pluripotent state across cell lines, and in response to a recovery assay.

Identifying primary care clinicians' preferences for, barriers to, and facilitators of information-seeking in clinical practice in Singapore: a qualitative study.

BACKGROUND: The growth of medical knowledge and patient care complexity calls for improved clinician access to evidence-based resources. This study aimed to explore the primary care clinicians' preferences for, barriers to, and facilitators of information-seeking in clinical practice in Singapore. METHODS: A convenience sample of ten doctors and ten nurses was recruited. We conducted semi-structured face-to-face in-depth interviews. The interviews were recorded, transcribed verbatim, and analysed using thematic content analysis. RESULTS: Of the 20 participants, eight doctors and ten nurses worked at government-funded polyclinics and two doctors worked in private practice. Most clinicians sought clinical information daily at the point-of-care. The most searched-for information by clinicians in practice was less common conditions. Clinicians preferred evidence-based resources such as clinical practice guidelines and UpToDate®. Clinical practice guidelines were mostly used when they were updated or based on memory. Clinicians also commonly sought answers from their peers. Furthermore, clinicians frequently use smartphones to access the Google search engine and UpToDate® app. The barriers to accessing clinical information included the lack of time, internet surfing separation of work computers, limited search functions in the organisation's server, and limited access to medical literature databases. The facilitators of accessing clinical information included convenience, easy access, and trustworthiness of information sources. CONCLUSION: Most primary care clinicians in our study sought clinical information at the point-of-care daily and reported increasing use of smartphones for information-seeking. Future research focusing on interventions to improve access to credible clinical information for primary care clinicians at the point-of-care is recommended. TRIAL REGISTRATION: This study has been reviewed by NHG Domain Specific Review Board (NHG DSRB) (the central ethics committee) for ethics approval. NHG DSRB Reference Number: 2018/01355 (31/07/2019).

A glucan-particle based tularemia subunit vaccine induces T-cell immunity and affords partial protection in an inhalation rat infection model.

Tularemia is a zoonotic disease caused by the facultative intracellular gram-negative bacterium Francisella tularensis. F. tularensis has a very low infection dose by the aerosol route which can result in an acute, and potentially lethal, infection in humans. Consequently, it is classified as a Category A bioterrorism agent by the US Centers for Disease Control (CDC) and is a pathogen of concern for the International Biodefence community. There are currently no licenced tularemia vaccines. In this study we report on the continued assessment of a tularemia subunit vaccine utilising ß-glucan particles (GPs) as a vaccine delivery platform for immunogenic F. tularensis antigens. Using a Fischer 344 rat infection model, we demonstrate that a GP based vaccine comprising the F. tularensis lipopolysaccharide antigen together with the protein antigen FTT0814 provided partial protection of F344 rats against an aerosol challenge with a high virulence strain of F. tularensis, SCHU S4. Inclusion of imiquimod as an adjuvant failed to enhance protective efficacy. Moreover, the level of protection afforded was dependant on the challenge dose. Immunological characterisation of this vaccine demonstrated that it induced strong antibody immunoglobulin responses to both polysaccharide and protein antigens. Furthermore, we demonstrate that the FTT0814 component of the GP vaccine primed CD4+ and CD8+ T-cells from immunised F344 rats to express interferon-γ, and CD4+ cells to express interleukin-17, in an antigen specific manner. These data demonstrate the development potential of this tularemia subunit vaccine and builds on a body of work highlighting GPs as a promising vaccine platform for difficult to treat pathogens including those of concern to the bio-defence community.

Information-seeking behaviour of primary care clinicians in Singapore at the point-of-care: A qualitative study.

BACKGROUND: Clinicians' information-seeking behaviours impact patient care quality. Earlier studies indicated that barriers to accessing information deter clinicians from seeking answers to clinical questions. OBJECTIVES: To explore primary care clinicians' information-seeking behaviour at point-of-care, focusing on when and how they seek answers to clinical questions. METHODS: Semi-structured interviews were conducted with 45 clinicians after clinical sessions to investigate their information-seeking habits. Follow-up interviews were conducted after a week for those intending to address unanswered queries. RESULTS: Two thirds of clinicians encountered questions during care, with nearly three quarters resolving them during the session. Colleagues, guidelines and online platforms were common information sources, with smartphones being used to access Google, WhatsApp or UpToDate®. Facilitators included reliable sources and the drive to confirm knowledge, while barriers included ineffective search methods and high workload. Despite challenges, most clinicians expressed satisfaction with their information-seeking process. DISCUSSION: The findings underscore the increasing use of smartphones for accessing clinical information among Singaporean primary care clinicians and suggest the need for tailored training programmes and guidelines to optimise information-seeking practices. CONCLUSION: Insights from this study can inform the development of training programmes and guidelines aimed at improving information-seeking practices among primary care clinicians, potentially enhancing patient care quality.

Pruritus in primary biliary cholangitis is under-recorded in patient medical records.

OBJECTIVE: Cholestatic pruritus in primary biliary cholangitis (PBC) reduces patients' health-related quality of life (HRQoL). Despite this, existing research suggests that pruritus is under-recorded in patients' health records. This study assessed the extent to which pruritus was recorded in medical records of patients with PBC as compared with patient-reported pruritus, and whether patients reporting mild itch were less likely to have pruritus recorded. We also evaluated clinico-demographic characteristics and HRQoL of patients with medical record-documented and patient-reported pruritus. DESIGN: This cross-sectional study used clinical information abstracted from medical records, together with patient-reported (PBC-40) data from patients with PBC in the USA enrolled in the PicnicHealth cohort. Medical record-documented pruritus was classified as 'recent' (at, or within 12 months prior to, enrolment) or 'ever' (at, or any point prior to, enrolment). Patient-reported pruritus (4-week recall) was assessed using the first PBC-40 questionnaire completed on/after enrolment; pruritus severity was classified by itch domain score (any severity: ≥1; clinically significant itch: ≥7). Patient clinico-demographic characteristics and PBC-40 domain scores were described in patients with medical record-documented and patient-reported pruritus; overlap between groups was evaluated. Descriptive statistics were reported. RESULTS: Pruritus of any severity was self-reported by 200/225 (88.9%) patients enrolled; however, only 88/225 (39.1%) had recent medical record-documented pruritus. Clinically significant pruritus was self-reported by 120/225 (53.3%) patients; of these, 64/120 (53.3%) had recent medical record-documented pruritus. Patients reporting clinically significant pruritus appeared to have higher mean scores across PBC-40 domains (indicating reduced HRQoL), versus patients with no/mild patient-reported pruritus or medical-record documented pruritus. CONCLUSION: Compared with patient-reported measures, pruritus in PBC is under-recorded in medical records and is associated with lower HRQoL. Research based only on medical records underestimates the true burden of pruritus, meaning physicians may be unaware of the extent and impact of pruritus, leading to potential undertreatment.

Licensing Requirements for Poultry Veterinary Biologics in the United States.

The use of veterinary biologicals is an integral component of poultry health programs. All veterinary biologicals are licensed and sold by manufacturing firms under strict regulation by the U.S. Department of Agriculture to ensure purity, potency, efficacy, and safety of the product. The licensing process for a new vaccine is a complex process involving a defined set of studies for each type of vaccine that are performed by the biologics firm, according to approved protocols, with results submitted to the Center for Veterinary Biologics for review. There are 10 classifications of veterinary biologicals and four types of licenses. Manufacturing and testing procedures are also defined within the licensing process. Licensing requirements were initially codified into law. In addition, guidance documents in the form of memoranda and notices have been published to address licensing for additional classes of vaccines and disease agents. This overview of vaccine licensure in the United States is offered to provide a better understanding of the process, the participants, and the factors that influence the time required to produce a commercial product.

Estudio recapitulativo- Requisitos de licencia para productos biológicos veterinarios avícolas en los Estados Unidos. El uso de productos biológicos veterinarios es un componente integral de los programas de salud avícola. Todos los productos biológicos veterinarios están autorizados y son vendidos por empresas fabricantes bajo estricta regulación del Departamento de Agricultura de los Estados Unidos para garantizar la pureza, potencia, eficacia y seguridad del producto. El proceso de concesión de licencia para una nueva vacuna es un proceso complejo que implica un conjunto definido de estudios para cada tipo de vacuna que son llevados a cabo por la empresa productora de biológicos, según protocolos aprobados y los resultados se envían al Centro de Productos Biológicos Veterinarios para su revisión. Existen 10 clasificaciones de biológicos veterinarios y cuatro tipos de licencias. Los procedimientos de fabricación y de prueba también se definen dentro del proceso de concesión de licencias. Los requisitos para la concesión de licencias se codificaron inicialmente como ley. Además, se han publicado documentos de orientación en forma de memorandos y avisos que han sido publicados para abordar la concesión de licencias para clases adicionales de vacunas y agentes patógenos. Esta revisión de los procesos de licencia de vacunas en los Estados Unidos se ofrece para brindar una mejor comprensión del proceso, los participantes y los factores que influyen en el tiempo necesario para producir un producto comercial.

Integrating international policy standards in the implementation of postnatal care: a rapid review.

INTRODUCTION: International legal and political documents can assist policy-makers and programme managers in countries to create an enabling environment to promote maternal and newborn health. This review aimed to map and summarise international legal and political documents relevant to the implementation of the WHO recommendations on maternal and newborn care for a positive postnatal experience. METHODS: Rapid review of relevant international legal and political documents, including legal and political commitments (declarations, resolutions and treaties) and interpretations (general comments, recommendations from United Nations human rights treaty bodies, joint United Nations statements). Documents were mapped to the domains presented in the WHO postnatal care (PNC) recommendations; relating to maternal care, newborn care, and health systems and health promotion interventions, and by type of human right implied and/or stated in the documents. RESULTS: Twenty-nine documents describing international legal and political commitments and interpretations were mapped, out of 45 documents captured. These 29 documents, published or entered into force between 1944 and 2020, contained content relevant to most of the domains of the PNC recommendations, most prominently the domains of breastfeeding and health systems interventions and service delivery arrangements. The most frequently mapped human rights were the right to health and the right to social security. CONCLUSION: Existing international legal and political documents can inform and encourage policy and programme development at the country level, to create an enabling environment during the postnatal period and thereby support the provision and uptake of PNC and improve health outcomes for women, newborns, children and families. Governments and civil society organisations should be aware of these documents to support efforts to protect and promote maternal and newborn health.

Layering vaccination with antibiotic therapy results in protection and clearance of Burkholderia pseudomallei in Balb/c mice.

Melioidosis is a disease that is difficult to treat due to the causative organism, Burkholderia pseudomallei being inherently antibiotic resistant and it having the ability to invade, survive, and replicate in an intracellular environment. Combination therapy approaches are routinely being evaluated in animal models with the aim of improving the level of protection and clearance of colonizing bacteria detected. In this study, a subunit vaccine layered with the antibiotic finafloxacin was evaluated in vivo against an inhalational infection with B. pseudomallei in Balb/c mice. Groups of mice vaccinated, infected, and euthanized at antibiotic initiation had a reduced bacterial load compared to those that had not been immunized. In addition, the subunit vaccine provided a synergistic effect when it was delivered with a CpG ODN and finafloxacin was initiated at 48 h post-challenge. Vaccination was also shown to improve the outcome, in a composite measure of survival and clearance. In summary, layering a subunit vaccine with the antibiotic finafloxacin is a promising therapeutic alternative for use in the treatment of B. pseudomallei infections.

Exploring the impact of a co-designed shared book reading environment for families in a community hub.

BACKGROUND: Evidence supports the effectiveness of shared book reading for promoting language and literacy development, but it is known that families experiencing vulnerability may have reduced access to books and are less likely to share books regularly at home. Community hubs often provide support to families experiencing vulnerability and may provide an opportunity to create environments that support families to engage in shared book reading, especially if families are invited into the creation of these environments through co-design. However, there is currently little evidence regarding the impact of co-designing shared book reading environments with families in community settings. AIMS: The current study is part of a broader project which used co-design to develop a shared book reading environment in collaboration with stakeholders in a community hub. This small-scale study aimed to provide a preliminary evaluation of the impact of this co-designed shared book reading environment at the community hub on (1) the frequency of shared book reading at the hub; (2) participants' confidence and enjoyment of reading with children at the hub; and (3) participants' experiences of shared book reading at the hub. METHOD & PROCEDURES: The co-design project was carried out in four phases with families, staff and community partners at the community hub. A convergent mixed-methods approach was used to collect and analyse quantitative and qualitative data in the first and last phase of the project to evaluate project outcomes. Quantitative data (environmental observations of reading at the hub and participant ratings of confidence and enjoyment of reading with children at the hub) were analysed using descriptive statistics and nonparametric statistical tests. Qualitative data (participants' responses regarding their experiences of changes implemented in the community hub) were analysed using inductive content analysis. OUTCOME & RESULTS: An increased frequency of shared book reading was observed within the community hub after changes were implemented, and positive changes in enjoyment of book reading were recorded. Qualitative responses from participants following conclusion of the project were organised into three main categories, which showed that (1) children and families were reading more and enjoying reading activities that were happening; (2) children and families were borrowing more books; and (3) families had changed the way they were reading at home with their children. CONCLUSIONS & IMPLICATIONS: A co-designed shared book reading environment within a community hub had a positive impact on shared book reading experiences for families in areas with high levels of vulnerability. WHAT THIS PAPER ADDS: What is already known on this subject Community hubs provide a unique opportunity to support early language and literacy development in partnership with families in areas of vulnerability; however, there is limited literature investigating the impacts of these supports. A previous study utilised co-design to develop a shared book reading environment with stakeholders at a community hub in an area where a high proportion of children are considered to be 'vulnerable' in terms of language and literacy development. It was found that co-design enabled the development of collaborative changes to support shared book reading that were valued and owned by families, staff and community partners at the community hub. What this study adds The current study focused on evaluating the impact of a co-design project on the frequency of shared book reading at the hub and participants' experiences, confidence and enjoyment of reading with children at the hub. Analysis of pre- and post-data provide preliminary evidence that a co-designed shared book reading environment in a community hub can have a positive impact on increasing families' awareness and engagement with book borrowing, engagement in shared book reading activities in the community and at home, and participants' confidence and enjoyment of reading with children. What are the clinical implications of this work? Speech pathologists have an important role to play in prevention and promotion. This study has shown that collaboration with families experiencing vulnerability can support the implementation of strategies to promote shared reading in a community hub and demonstrate increased quality and frequency of shared book reading. The utilisation of a community hub also highlights the opportunities for the speech pathology profession to deliver community-based promotion and prevention initiatives as a strategy to address equitable language outcomes.

Diabetes knowledge, self-efficacy and dietary, psychological and physical health barriers: Comparing young and usual-onset type 2 diabetes.

AIMS: Young-onset (21-39 years old) type 2 diabetes (YOD) is associated with high complication rates and glycaemic levels, and poor self-management plays a significant role. Knowledge, skills and barriers influence self-management behaviours considerably. Therefore, this study assessed diabetes knowledge, self-efficacy and barriers (situational dietary barriers, physical health, mental health and diabetes-related distress) between participants with young and usual-onset (40-59 years old) (UOD) diabetes. METHODOLOGY: A cross-sectional survey was conducted. Differences between YOD and UOD were analysed using bivariate analysis and effect sizes were estimated with Cohen's d. Differences were further adjusted by demographic factors (gender, ethnicity, marital status, educational level, income level) and diabetes duration. RESULTS: A total of 409 (97 YOD, 312 UOD) participants were recruited. Participants with YOD had lower self-efficacy levels (adjusted B = -0.19, CI -0.35 to -0.03) and higher dietary barriers (adjusted B = 3.6, CI 2.1-5.1), lower mental health scores (adjusted B = -3.5, CI -5.7 to -1.4) and higher diabetes-related distress levels (adjusted B = 0.2, CI 0.2-0.4). CONCLUSIONS: Our study found that participants with YOD faced more challenges with adapting to life with diabetes when compared with UOD. More effective self-management programmes are needed to support the multifaceted needs of adults with YOD.

Artificial intelligence in clinical decision-making: Rethinking personal moral responsibility.

Artificially intelligent systems (AISs) are being created by software developing companies (SDCs) to influence clinical decision-making. Historically, clinicians have led healthcare decision-making, and the introduction of AISs makes SDCs novel actors in the clinical decision-making space. Although these AISs are intended to influence a clinician's decision-making, SDCs have been clear that clinicians are in fact the final decision-makers in clinical care, and that AISs can only inform their decisions. As such, the default position is that clinicians should hold responsibility for the outcomes of the use of AISs. This is not the case when an AIS has influenced a clinician's judgement and their subsequent decision. In this paper, we argue that this is an imbalanced and unjust position, and that careful thought needs to go into how personal moral responsibility for the use of AISs in clinical decision-making should be attributed. This paper employs and examines the difference between prospective and retrospective responsibility and considers foreseeability as key in determining how personal moral responsibility can be justly attributed. This leads us to the view that moral responsibility for the outcomes of using AISs in healthcare ought to be shared by the clinical users and SDCs.

A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

Identifying barriers and facilitators to self care in young adults with type 2 diabetes.

AIMS: There is a rising trend of young-onset type 2 diabetes (YOD) occurring before the age of 40 years. Lower adherence to self care behaviours (diet, physical activity and taking medication) contributed to poorer glycaemic control and higher risk of complications. Young adults with YOD face unique challenges, and our study aimed to identify the main barriers and facilitators of self care behaviours in this population. METHODOLOGY: A qualitative study was conducted in the National Healthcare Group Polyclinics, Singapore, using in-depth semi-structured interviews. Maximal variation sampling was employed to include participants with YOD of varied age, ethnicity, educational levels and marital status. Thematic analysis was conducted, and barriers and facilitators were identified and mapped to domains of the theoretical domains framework. RESULTS: Twenty-one participants aged 22-39 years were interviewed. We found patterns of intentions, self care behaviours and mindsets that were associated with different barriers and facilitators. Four patterns were identified and were named according to mindsets: avoidant, indifferent, striving and activated. In addition, experience of stigma and self-blame from having type 2 diabetes in young adulthood was common across all mindsets, contributing to poorer self care behaviours and increased psychological burden. CONCLUSION: Our study identified key barriers and facilitators of diet, physical activity and medication adherence in young adults with type 2 diabetes. Understanding barriers and facilitators, as related to mindsets, intentions and behaviours, will support a more individualised care approach.

Correction: The hallmarks of childhood abuse and neglect: A systematic review.

[This corrects the article DOI: 10.1371/journal.pone.0243639.].

Several confirmed and probable zoonotic cases of toxigenic Corynebacterium ulcerans, Queensland, Australia.

Background: Toxigenic Corynebacterium ulcerans is an emerging zoonosis globally, causing both cutaneous and respiratory diphtheria-like illness. In Queensland, human infection with toxigenic C. ulcerans is rare, with only three cases reported before October 2015. This case series describes five subsequent cases of toxigenic C. ulcerans in Queensland with links to companion animals. Methods: All data were collected as part of routine public health response, and strains were whole genome sequenced for further characterisation. Household contacts were screened, treated with appropriate antibiotics, and received a diphtheria toxoid-containing vaccine if more than five years had elapsed since their last dose. Findings: No epidemiological or genomic links could be established between any of the five patients, including between the two cases notified from the same locality within eight days of each other. The C. ulcerans strains from Cases Two, Four and Five were closely related to the strains isolated from their respective pets by whole genome sequencing. Domestic dogs were identified as the most likely mode of transmission for Cases One and Three; however, this was unable to be laboratory confirmed, since Case One's dog was treated with antibiotics before it could be tested, and Case Three's dog was euthanised and cremated prior to case notification. Interpretation: These are the first reported Australian cases of this emerging zoonosis with links to companion animals. These cases demonstrate the likely transmission route between companion animals and humans, with no evidence of human-to-human transmission. The existing requirement in the Queensland Health Public Health Management Guidelines, of restrictions on cases and some contacts while awaiting swab results, is currently under review.

General practitioners' perceptions of the roles of community pharmacists and their willingness to collaborate with pharmacists in primary care.

BACKGROUND: Community pharmacists (CPs) have the capacity to contribute to patient care given their expertise in medication and accessibility to residents in the community. However, multidisciplinary patient care programmes where CPs collaborate with general practitioners (GPs) in patient care is rare in Singapore despite increasing healthcare demand. OBJECTIVES: This study explores GPs' perceptions of CPs' current roles and GPs' ideas for and attitudes towards interprofessional collaboration. METHODS: Semi-structured qualitative interviews were conducted with 20 private GPs from August to December 2020 via an online video-chat platform. GPs were recruited from the Primacy Care Research Network (pcRn), primary care networks, and using snowballing strategies. All interviews were recorded, transcribed and coded thematically. RESULTS: Current working relationships between GPs and CPs appeared amicable but limited. GPs appreciate the existing roles of CPs: dispensing drugs not stocked in their practices and clarifying prescription details. Still, GPs appeared to rarely consider collaborative working. GPs acknowledged that CPs could enhance patient care with initiatives including medication reconciliation and advising on using medical devices. It was suggested that CPs could coordinate the purchase of drugs for primary care networks to improve GPs' inventory management, but less enthusiasm was expressed for clinical collaborations with CPs. Major concerns about GP-CP clinical collaborations included direct competition with GPs' own business interests, perceived low acceptability of pharmacy-led services by patients (citing extra time and cost), threat to continuity of care and the absence of a shared patient electronic health record system. Current funding mechanisms do not enable reimbursement of clinical services provided by CPs. Adoption of telemedicine technologies and governmental financial support were identified as possible enablers of GP-CP collaboration. CONCLUSIONS: GPs saw potential in CPs' increased involvement in patient care, but perceived multiple barriers. Strategies focusing on overcoming these barriers could enable GP-CP collaboration to enhance patient care.

Molecular basis for short-chain thioester hydrolysis by acyl hydrolase domains in trans -acyltransferase polyketide synthases.

Polyketide synthases (PKSs) are multi-domain enzymatic assembly lines that biosynthesise a wide selection of bioactive natural products from simple building blocks. In contrast to their cis -acyltransferase (AT) counterparts, trans -AT PKSs rely on stand-alone AT domains to load extender units onto acyl carrier protein (ACP) domains embedded in the core PKS machinery. Trans -AT PKS gene clusters also encode acyl hydrolase (AH) domains, which are predicted to share the overall fold of AT domains, but hydrolyse aberrant acyl chains from ACP domains, thus ensuring efficient polyketide biosynthesis. How such domains specifically target short acyl chains, in particular acetyl groups, tethered as thioesters to the substrate-shuttling ACP domains, with hydrolytic rather than acyl transfer activity, has remained unclear. To answer these questions, we solved the first structure of an AH domain and performed structure-guided activity assays on active site variants. Our results offer key insights into chain length control and selection against coenzyme A-tethered substrates, and clarify how the interaction interface between AH and ACP domains contributes to recognition of cognate and non-cognate ACP domains. Combining our experimental findings with molecular dynamics simulations allowed for the production of a data-driven model of an AH:ACP domain complex. Our results advance the currently incomplete understanding of polyketide biosynthesis by trans -AT PKSs, and provide foundations for future bioengineering efforts.

Promoting Activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED): randomised controlled trial.

OBJECTIVE: To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care. DESIGN: Randomised controlled trial. SETTING: Participants' homes and communities at five sites in the United Kingdom. PARTICIPANTS: 365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers. INTERVENTION: The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic. MAIN OUTCOME MEASURES: The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15. RESULTS: 365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference -1.3, 95% confidence interval -5.2 to 2.6; Cohen's d effect size -0.06, 95% confidence interval -0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3). CONCLUSION: The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15320670.