BACKGROUND: Heart failure (HF) is a chronic and common condition with a rising prevalence, especially in the elderly. Morbidity and mortality rates in people with HF are similar to those with common forms of cancer. Clinical guidelines highlight the need for more detailed prognostic information to optimise treatment and care planning for people with HF. Besides proven prognostic biomarkers and numerous newly developed prognostic models for HF clinical outcomes, no risk stratification models have been adequately established. Through a number of linked systematic reviews, we aim to assess the quality of the existing models with biomarkers in HF and summarise the evidence they present. METHODS: We will search MEDLINE, EMBASE, Web of Science Core Collection, and the prognostic studies database maintained by the Cochrane Prognosis Methods Group combining sensitive published search filters, with no language restriction, from 1990 onwards. Independent pairs of reviewers will screen and extract data. Eligible studies will be those developing, validating, or updating any prognostic model with biomarkers for clinical outcomes in adults with any type of HF. Data will be extracted using a piloted form that combines published good practice guidelines for critical appraisal, data extraction, and risk of bias assessment of prediction modelling studies. Missing information on predictive performance measures will be sought by contacting authors or estimated from available information when possible. If sufficient high quality and homogeneous data are available, we will meta-analyse the predictive performance of identified models. Sources of between-study heterogeneity will be explored through meta-regression using pre-defined study-level covariates. Results will be reported narratively if study quality is deemed to be low or if the between-study heterogeneity is high. Sensitivity analyses for risk of bias impact will be performed. DISCUSSION: This project aims to appraise and summarise the methodological conduct and predictive performance of existing clinically homogeneous HF prognostic models in separate systematic reviews.Registration: PROSPERO registration number CRD42019086990.
\n \n\n \n \nBackground: To date, signals of adverse reactions to herbal medicines have not been systematically reviewed, limiting pharmacovigilance of herbal medicines because of a lack of data. Objectives: We sought to analyse the available evidence on signals involving herbal medicines and to determine to what extent they had been documented at the European Union (EU) level and in the USA. Methods: We used the results of a published scoping review of interventional and non-interventional studies that reported signals of adverse reactions to drugs. We assigned Anatomical Therapeutic Chemical classification to all drugs, and identified herbal medicines when they fell under the Anatomical Therapeutic Chemical V90. We ascertained the presence of the adverse reaction, or related adverse reactions, for each signal in reference documents for healthcare professionals: the US Botanical Safety Handbook and the EU monographs and US Dietary Supplement Fact Sheets; and in those for consumers: the US Dietary Supplement Label Database. We summarised the data descriptively, treating US documents as one and comparing harms across pairs of US and EU documents by signal. Documents were deemed concordant if they both included the same or related adverse reactions, or if neither did. We also compared adverse reactions across US documents for healthcare professionals with those for consumers. Results: Of the 10,861 signals covered by the scoping review, 53 (0.49%) concerned herbal medicines, all based on case reports. Reference documents from both the US and EU were available for 37 signals. Most of the documents were concordant (73%), and ten (27%) were discordant: six adverse reactions were mentioned only in US documents, three only in EU monographs, and one was warned against in US documents but not in EU documents. Twenty-one signals could be followed up in the Botanical Safety Handbook and Dietary Supplement Fact Sheets. Most (68%) US documents for healthcare professionals were concordant. When the Botanical Safety Handbook and Dietary Supplement Fact Sheets did not include an adverse reaction, neither did the Dietary Supplement Label Database. However, when they did, only 20% of the labels for consumers did too. The proportion of labels mentioning adverse reactions otherwise available in documents intended for healthcare professionals ranged widely, reflecting differences across multiple labels for the same products. Conclusions: Very few signals of adverse reactions from the wider scoping review concerned herbal medicines, and were all based on case reports. Information was mostly concordant across documents in the EU and USA. As manufacturers are solely responsible for the contents of the Dietary Supplement Label Database, regulatory oversight may be required to ensure that consistent and comprehensive information on the harms of herbal medicines is made available to consumers in the USA.
\n \n\n \n \nBackground: About 30% of patients with depression treated with antidepressant medication do not respond sufficiently to the first agents used. Pramipexole might usefully augment antidepressant medication in such cases of treatment-resistant depression, but data on its effects and tolerability are scarce. We aimed to assess the efficacy and tolerability of pramipexole augmentation of ongoing antidepressant treatment, over 48 weeks, in patients with treatment-resistant depression. Methods: We did a multicentre, double-blind, placebo-controlled randomised trial in which adults with resistant major depressive disorder were randomly assigned (1:1; using an online randomisation system) to 48 weeks of pramipexole (titrated to 2\u00b75 mg) or placebo added to their ongoing antidepressant medication. The study was conducted in nine National Health Service Trusts in England. Participants, investigators, and researchers involved in recruitment and assessment were masked to group allocation, and the central pharmacy team dispensing the medication was not masked. The primary outcome was change from baseline to week 12 in the total score of the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR16). The primary analysis was performed on the intention-to-treat population that included all eligible, randomly assigned participants. People with lived experience were involved in the design, oversight, and interpretation of the study. The trial was registered with ISCTRN (ISRCTN84666271) and EudraCT (2019-001023-13) and is complete. Findings: Between Feb 16 and May 29, 2024, 217 participants attended a screening visit, of whom 66 were excluded due to ineligibility. 151 participants were randomly assigned (75 to the pramipexole group and 75 to the placebo group, after one participant was found to be ineligible after randomisation). 84 (56%) participants were female and 66 (44%) were male and the mean age of participants was 44\u00b79 years (SD 14\u00b70). Ethnicity data were not available. The mean QIDS-SR16 total score at baseline was 16\u00b74 (SD 3\u00b74) in the pramipexole group and 16\u00b72 (3\u00b75) in the placebo group. The mean dose of pramipexole received at week 12 was 2\u00b73 mg (SD 0\u00b745). Adjusted mean decrease from baseline to week 12 of the QIDS-SR16 total score was 6\u00b74 (SD 4\u00b79) for the pramipexole group and 2\u00b74 (4\u00b70) for the placebo group; the mean difference between groups was \u22123\u00b791 (95% CI \u22125\u00b737 to \u22122\u00b745; p<0\u00b70001). Termination of trial treatment due to adverse events was more frequent in the pramipexole group (15 participants [20%]) than in the placebo group (four participants [5%]), with reported adverse events consistent with known side-effects of pramipexole, in particular nausea, headache, and sleep disturbance or somnolence. Interpretation: In this trial involving participants with treatment-resistant depression, pramipexole augmentation of antidepressant treatment, at a target dose of 2\u00b75 mg, demonstrated a reduction in symptoms relative to placebo at 12 weeks but was associated with some adverse effects. These results suggest that pramipexole is a clinically effective option for reducing symptoms in patients with treatment-resistant depression. Future trials directly comparing pramipexole with existing treatments for this disorder are needed. Funding: National Institute of Health and Care Research, Efficacy and Mechanism Evaluation Programme.
\n \n\n \n \nIntroduction: Lower limb open fractures are severe injuries that can lead to long-term sequelae. Clinical guidelines for managing these patients are associated with expedited treatment and better outcomes. However, few countries have implemented guidelines for open lower limb fractures. The aim of this study was to develop and validate a framework for the introduction of clinical guidelines in settings that do not have one at present. Methods: Using the qualitative analysis for the Limitations to the Implementation of Open Trauma Guidelines (LINEAGE) study, a framework proposal was designed. This included 4 clusters of inter-related concepts, including clinician, team, health and cultural factors. To validate this framework a modified Delphi study was devised. The elements of the framework were translated into 12 statements that were compiled in a Delphi questionnaire. A panel of orthopaedic and plastic surgeons was assembled to obtain structured feedback and assess the degree of consensus regarding the framework proposal. Results: Using purposive sampling, 43 clinicians enrolled in an international expert panel, including 20 orthopaedic and 23 plastic surgeons based in countries with no guidelines at present. Following three Delphi rounds, 11 out of the 12 assessed statements achieved the threshold for validation. The single statement that did not reach consensus status was then removed from the framework. Discussion: Frameworks are a well-described aid in implementation science, being able to describe complexity and propose strategies for improvement. We present the first validated framework for the development and implementation of open fracture guidelines.
\n \n\n \n \nBackground: In 2022, WHO\u2019s World Health Assembly adopted resolution WHA75.8, emphasizing the critical role of clinical trials in generating high-quality evidence and promoting equitable access to health interventions globally. In response, rapid landscape reviews were conducted to assess global clinical trial regulations, capacities, and funding distribution. Methods The analysis synthesized regulatory frameworks from 94 countries, institutional capacity data from the WHO International Clinical Trial Registry Platform (ICTRP), and funding data from World RePORT for trials registered between 2018-2022. Gaps in data availability and quality were assessed. Results Most countries reference international ethical guidelines, with universal requirements for ethics approval and informed consent. However, only 66% mandate public trial registration, and 40% require results reporting, with stark disparities between high- and low-income countries. High-income countries host over half of global trials; low-income countries contribute less than 1% despite high disease burden. Clinical trials sponsored by non-commercial entities are particularly scarce in low- and middle-income countries. Funding remains concentrated in the Americas and European regions, primarily driven by major funders such as the National Institutes of Health in the United States of America and European Commission. Significant data accessibility challenges persist due to incomplete registry records, inconsistent standards, lack of harmonized identifiers, and limited bulk data access. Recommendations Urgent actions include reinforcing international standards for trial registries, harmonizing data fields, improving registry interoperability, leveraging unique identifiers, enhancing multilingual accessibility, auditing data quality, pooling analytical resources, promoting open data policies, and investing in registry infrastructure and trained personnel. Conclusion Addressing data gaps and inequities in clinical trial ecosystems requires concerted action by global stakeholders. Improved data transparency and interoperability are essential to guide equitable research investments, foster coordination, and strengthen clinical trial capacity worldwide.
\n \n\n \n \nBackground: SARS-CoV-2 transmission has been reported to be associated with close contact with infected individuals. However, the mechanistic pathway for transmission in close contact settings is unclear. Our objective was to identify, appraise and summarise the evidence from studies assessing the role of close contact in SARS-CoV-2 transmission.\u00a0 Methods: : This review is part of an Open Evidence Review on Transmission Dynamics of SARS-CoV-2. We conduct ongoing searches using WHO Covid-19 Database, LitCovid, medRxiv, PubMed and Google Scholar; assess study quality based on the QUADAS-2 criteria and report important findings on an ongoing basis. Results: : \u00a0We included 278 studies: 258 primary studies and 20 systematic reviews. The settings for primary studies were predominantly in home/quarantine facilities (39.5%) and acute care hospitals (12%). The overall reporting quality of the studies was low-to-moderate. There was significant heterogeneity in design and methodology. The frequency of attack rates (PCR testing) varied between 2.1-75%; attack rates were highest in prison and wedding venues, and in households. The frequency of secondary attack rates was 0.3-100% with rates highest in home/quarantine settings. Three studies showed no transmission if the index case was a recurrent infection. Viral culture was performed in four studies of which three found replication-competent virus; culture results were negative where index cases had recurrent infections. Eighteen studies performed genomic sequencing with phylogenetic analysis \u2013 the completeness of genomic similarity ranged from 77-100%. Findings from systematic reviews showed that children were significantly less likely to transmit SARS-CoV-2 and household contact was associated with a significantly increased risk of infection. Conclusions: The evidence from published studies demonstrates that SARS-CoV-2 can be transmitted in close contact settings. The risk of transmission is greater in household contacts. There was a wide variation in methodology. Standardized guidelines for reporting transmission in close contact settings should be developed.
\n \n\n \n \nBackground: Solid organ and haematopoietic stem cell transplant recipients are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) than non-transplant recipients due to immunosuppression, and may pose a continued transmission risk, especially within hospital settings. Detailed case reports including symptoms, viral load and infectiousness, defined by the presence of replication-competent viruses in culture, provide an opportunity to examine the relationship between clinical course, burden and contagiousness, and provide guidance on release from isolation. Objectives: To investigate the relationship between serial SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) value or cycle of quantification value, or other measures of viral burden and the likelihood and duration of the presence of infectious virus based on viral culture, including the influence of age, sex, underlying pathologies, degree of immunosuppression, and/or vaccination on this relationship, in transplant recipients. Methods: LitCovid, medRxiv, Google Scholar and the World Health Organization COVID-19 database were searched from 1st November 2019 to 26th October 2022. Studies reporting relevant data (results from serial RT-PCR testing and viral culture data from the same respiratory samples) for transplant recipients with SARS-CoV-2 infection were included in this systematic review: Methodological quality was assessed using five criteria, and the data were synthesized narratively and graphically. Results: Thirteen case reports and case series reporting on 41 transplant recipients (22 renal, five cardiac, one bone marrow, two liver, one bilateral lung and 10 blood stem cell) were included in this review. A relationship was observed between proxies of viral burden and likelihood of shedding replication-competent SARS-CoV-2. Three individuals shed replication-competent viruses for >100 days after symptom onset. Lack of standardization of testing and reporting platforms precludes establishing a definitive viral burden cut-off. However, the majority of transplant recipients stopped shedding replication-competent viruses when the Ct value was >30 despite differences across platforms. Conclusions: Viral burden is a reasonable proxy for infectivity when considered within the context of the clinical status of each patient. Standardized study design and reporting are essential to standardize guidance based on an increasing evidence base.
\n \n\n \n \nBACKGROUND: Blood tests used to identify patients at increased risk of undiagnosed cancer are commonly used in isolation, primarily by monitoring whether results fall outside the normal range. Some prediction models incorporate changes over repeated blood tests (or trends) to improve individualized cancer risk identification, as relevant trends may be confined within the normal range. OBJECTIVE: Our aim was to critically appraise existing diagnostic prediction models incorporating blood test trends for the risk of cancer. METHODS: MEDLINE and EMBASE were searched until April 3, 2025 for diagnostic prediction model studies using blood test trends for cancer risk. Screening was performed by 4 reviewers. Data extraction for each article was performed by 2 reviewers independently. To critically appraise models, we narratively synthesized studies, including model building and validation strategies, model reporting, and the added value of blood test trends. We also reviewed the performance measures of each model, including discrimination and calibration. We performed a random-effects meta-analysis of the c-statistic for a trends-based prediction model if there were at least 3 studies validating the model. The risk of bias was assessed using the PROBAST (prediction model risk of bias assessment tool). RESULTS: We included 16 articles, with a total of 7 models developed and 14 external validation studies. In the 7 models derived, full blood count (FBC) trends were most commonly used (86%, n=7 models). Cancers modeled were colorectal (43%, n=3), gastro-intestinal (29%, n=2), nonsmall cell lung (14%, n=1), and pancreatic (14%, n=1). In total, 2 models used statistical logistic regression, 2 used joint modeling, and 1 each used XGBoost, decision trees, and random forests. The number of blood test trends included in the models ranged from 1 to 26. A total of 2 of 4 models were reported with the full set of coefficients needed to predict risk, with the remaining excluding at least one coefficient from their article or were not publicly accessible. The c-statistic ranged 0.69-0.87 among validation studies. The ColonFlag model using trends in the FBC was commonly externally validated, with a pooled c-statistic=0.81 (95% CI 0.77-0.85; n=4 studies) for 6-month colorectal cancer risk. Models were often inadequately tested, with only one external validation study assessing model calibration. All 16 studies scored a low risk of bias regarding predictor and outcome details. All but one study scored a high risk of bias in the analysis domain, with most studies often removing patients with missing data from analysis or not adjusting the derived model for overfitting. CONCLUSIONS: Our review highlights that blood test trends may inform further investigation for cancer. However, models were not available for most cancer sites, were rarely externally validated, and rarely assessed calibration when they were externally validated.
\n \n\n \n \nBACKGROUND: Social prescribing link workers have become part of primary health care in recent years. They help patients to recognise non-medical factors affecting their health and identify sources of support, often in the voluntary, community and social enterprise sector. They form part of wider work to strengthen person-centred care, which actively seeks to engage individuals in decision-making about their health, taking into account their medical, social, psychological, financial and spiritual circumstances. OBJECTIVE: To understand how buy-in to social prescribing and the link worker role is established for a patient, and how this relates to person-centred care. DESIGN: A realist evaluation. SETTING: Patients engaging with link workers in seven different parts of England were involved. METHODS: As part of data collection, we observed link workers interacting with 35 patients. We also interviewed 61 patients and re-interviewed 41 of them 9-12 months later. Data were coded and developed into context-mechanism-outcome configurations, which were used to produce a programme theory. RESULTS: Data highlighted how patients might be uncertain about the link worker role but agree to a referral as they sought assistance with their non-medical issues. Patients talked about experiencing a sense of hope through the trust they developed in a link worker. This trust was established through the communication skills and knowledge demonstrated by a link worker, and by their ability to act as an anchor point when required - a reliable, consistent source of support to whom patients could offload. The link worker role also involved connecting patients to external support, which called for sensitivity around how ready someone was to move forward; this was shaped by a patient's motivation but also their capacity to make changes given other demands in their life. Connecting patients to external support could be affected by structural factors outside the link workers' control (e.g. housing options or employment opportunities). LIMITATIONS: We did not interview patients who had rejected the offer of social prescribing, and most had a positive view of meeting with a link worker. CONCLUSIONS: Person-centred care is engendered by link workers through their skills, knowledge and ability to respond to the individual readiness of patients to engage with external support. It can be curtailed by structural factors outside link workers' sphere of control, such as access to housing or caring responsibilities of patients. This can hinder patients' ability to 'connect to', leaving link workers to continue 'connecting with' patients as they act as an anchor point. FUTURE WORK: Exploration is required of factors affecting patients who interact with a link worker but do not access external support. Longitudinal work with a cohort of patients, speaking to them on a regular basis, may provide further understanding in this respect. FUNDING: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme as award number NIHR130247.
\n \n\n \n \nINTRODUCTION: Secure Extended Care Units (SECU) offer low-secure, long-term inpatient rehabilitation for patients with severe mental illnesses. Limited research is available about the profile of patients referred to such units. OBJECTIVE: This study aimed to explore the sociodemographic and clinical characteristics of patients referred to Austin Health SECU over a 5-year period in Australia. METHODS: A retrospective study design was used to investigate 121 consecutive referrals. The 98 first-time patient referrals were included in the primary analysis. Descriptive statistics were used with non-parametric comparisons (Chi-square and Fisher's exact test where appropriate). RESULTS: Most of the total sample were single males of European ancestry, between 25 and 34\u2009years old, with 10\u2009years or less of education and receiving disability benefits. Schizophrenia was the predominant diagnosis, with 50% having a comorbid personality trait/disorder; substance use was high (82.6%). More than three-fourths had a history of trauma. Physical comorbidity was high (80%), with hepatitis C positivity at 20%. Treatments like Clozapine and Electroconvulsive therapy (ECT) were low. The Median Health of Nations Outcome Scale (HoNOS) was 20 (IQR: 14, 23) and the Life Skills Profile (LSP) was 22.5 (IQR: 16.25, 27). CONCLUSIONS: Referrals showed a high level of psychosocial-physical complexity, with a range of patient needs, service goals, and high psychiatric and interpersonal risk before the referral. The study discusses the need for medium and high-secure beds and a new model of care that integrates Community Care Units (CCU). A trauma-informed approach that creates holistic treatment plans and includes patients and families is indicated. The study makes a case for Universal screening of patients for Bloodborne Hepatitis and treatment for this cohort in an inpatient setting.
\n \n\n \n \nBackground\u00a0The integration of diagnostic services presents a critical opportunity to improve health outcomes in low- and middle-income countries (LMICs), potentially averting up to 1 million premature deaths annually. Antenatal care provides a critical platform for diagnosing multiple diseases in an integrated manner.Aim\u00a0This study explored the experiences of healthcare providers and pregnant women using integrated diagnostic services at a primary care facility in Zimbabwe.Setting\u00a0A qualitative case study was conducted at Mabvuku Polyclinic in Harare, Zimbabwe.Methods\u00a0Using purposive sampling, 14 healthcare workers and 22 pregnant women participated in interviews. Observations and semi-structured interviews were recorded, transcribed and analysed using NVivo software. Thematic analysis was applied to identify key themes related to access, patient-provider interactions and systemic barriers.Results\u00a0According to the interviewees' reports, challenges such as limited resources, medical equipment and staff hinder efforts to integrate diagnostic services. The women strongly preferred integrated diagnosis, even if it meant enduring long waiting times, and valued the convenience of receiving all necessary services in a single visit. The study highlighted the hidden socio-economic barriers to 'free' healthcare and underscored the importance of addressing systemic inefficiencies.Conclusion\u00a0The insights gained from this study are transferable and contribute to the understanding of integrated diagnostic services in maternal healthcare contexts.Contribution:\u00a0They offer practical recommendations for improving service delivery and health outcomes in similar settings.
\n \n\n \n \n