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.

Identifying studies examining the validity of instruments for use as outcome measures in child and adolescent forensic mental health services: a systematic review.

BACKGROUND: Outcome measurement in child and adolescent forensic mental health services can support service improvement, research, and patient progress evaluation. This systematic review aimed to identify studies which validate structured instruments available for use as outcome measures in the child and adolescent forensic mental health service cohort and assess the quality of these studies. METHODS: A systematic review was conducted following PRISMA guidelines. Studies were identified by searching six online databases in November 2023. The quality and risk of bias of each study meeting inclusion criteria was independently assessed by two authors using the Crowe Critical Appraisal Tool. Results were synthesised narratively. RESULTS: A total of eight studies were identified which met inclusion criteria. These looked at six instruments which primarily focused on outcome measures in the areas of treatment motivation, level of functioning, psychiatric symptoms, care needs and response to social situations. Papers scored between 17/40 and 30/40 on the Crowe Critical Appraisal Tool. Studies were rated as low (n = 1), moderate (n = 6), high (n = 1) or very high quality (n = 0). CONCLUSIONS: Despite the large number of structured instruments potentially available, evidence for their use as outcome measures in child and adolescent forensic mental health services is limited. Future research should aim to validate current structured instruments for use in the forensic child and adolescent setting, with consideration of whether new instruments should be developed specifically for this group. Such instruments should be developed with both young people as service users and professionals who will be utilising the instrument in mind.

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.

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.

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.

Survey on barriers to psychiatrists' use of clozapine for young people in Scotland and suggestions for reducing these.

INTRODUCTION: The Mental Welfare Commission for Scotland published a report into the death of a young person, with recommendations for the Royal College of Psychiatry in Scotland Child and Adolescent Faculty; to explore if there were barriers to the use of Clozapine in young people in Scotland. METHODS: A mixed-methods study was performed using a cross-sectional survey of clinicians working in child and adolescent psychiatry across Scotland, to determine attitudes towards clozapine use and the perceived barriers and facilitators to clozapine treatment. RESULTS: Results suggest that there may be a lack of clearly defined pathways within and between services, as well as a lack of resources provided for the necessary monitoring of a young person started on clozapine. Multiple respondents felt unskilled in clozapine initiation and had not accessed formal training. The most frequently mentioned themes for improving facilitation of clozapine prescription were that of increased resources and training. DISCUSSION: National policymakers including the Mental Welfare Commission, NHS Education for Scotland, and NHS Scotland should consider these findings to address the potential underutilisation of clozapine for people aged under 18 in services across Scotland. A review of current service provision should take place, with consideration of whether the facilitators to clozapine prescription which our study has highlighted could be implemented more effectively. This may help reduce identified barriers and increase clozapine prescription to those who would benefit from it, potentially improving outcomes for young people with treatment-resistant psychosis.

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).

Demographic diversity of participants in clinical trials conducted in Singapore.

Introduction: The under-representativeness of participants in clinical trials limits the generalisability of results. This review evaluates the representative-ness within pharmaceutical randomised controlled trials (RCTs) in Singapore. Method: Four bibliographic databases were searched for papers on pharmaceutical RCTs which included Singapore adults (≥18 years old), published between 2017 and 2022. The demographic characteristics of study participants were compared against the population in the 2020 Singapore census. Recruitment strategies and authors' comments on the generalisa-bility of their findings were reviewed. Results: Thirty-three publications were included (19 Singapore-only studies and 14 multiregional trials which included Singapore). Where data were available, we found that females and Indians were under-represented compared to the census (41.3% versus [vs] 51.1%, P<0.05; 7.3% vs 9.0%, P<0.05). Ethnic diversity varied between individual studies, and almost half (46.2%) of Singapore-only studies achieved census levels. However, more than one-third of the trials provided no data (31.6%) or partial data (5.3%) on ethnicity. Half of the multiregional publications stated the number of participants recruited from Singapore, but only 1 reported any detail beyond Asian participants. Recruitment strategies were mentioned in fewer than half (42.4%), and less than a quarter (24.2%) commented on sample representative-ness or the external validity of the evidence generated. Conclusion: There is room for improvement regarding the recruitment of RCT participants in Singapore, with particular attention to female gender and Indian ethnicity. Demographic data should also be presented in full. RCTs should be designed and reported such that clinicians can ascertain the generalisability to the Singapore population and the potential benefits from the studied interventions in clinical practice.

Understanding the preferences of young adults with type 2 diabetes mellitus with regard to diabetes self-management education: a qualitative study.

AIM: Young-onset type 2 diabetes (YOD) is associated with poorer clinical outcomes. To support the development of more effective diabetes self-management education (DSME) programmes, this study aimed to understand the preferences of young adults with YOD in relation to the modality, content and qualities of DSME. METHODS: Maximal variation sampling was employed to recruit participants of varied age, ethnicity and marital status. In-depth interviews using a semistructured questionnaire were conducted. Subsequently, thematic analysis with coding and conceptualisation of data was applied to identify the main themes regarding DSME. RESULTS: 21 young adult participants aged 22-39 years were interviewed from three polyclinics in Singapore. The most used modalities for DSME included education from healthcare providers, information and support from family and friends and information from internet sources. Participants were most interested in information regarding diet, age-specific diabetes-related conditions and medication effects. Additionally, participants valued DSME that was credible, accessible, individualised and empathetic. Conversely, absence of the above qualities and stigma hindered participants from receiving DSME. CONCLUSION: Our study explored the preferences of young adults with YOD with regard to DSME, identifying the most used modalities, preferred content and qualities that were valued by young adults. Our findings will help inform the development of DSME programmes that can better meet the needs and preferences of young adults with YOD.

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.

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.

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.

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 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.

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

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