Chronic hepatitis B baseline viral load and on-treatment liver cancer risk: A multinational cohort study of HBeAg-positive patients.

BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.

Orthopoxvirus-Specific T-Cell Responses in Convalescent Mpox Patients.

Orthopoxvirus-specific T-cell responses were analyzed in 10 patients who had recovered from Mpox including 7 people with human immunodeficiency virus (PWH). Eight participants had detectable virus-specific T-cell responses, including a PWH who was not on antiretroviral therapy and a PWH on immunosuppressive therapy. These 2 participants had robust polyfunctional CD4+ T-cell responses to peptides from the 121L vaccinia virus (VACV) protein. T-cells from 4 of 5 HLA-A2-positive participants targeted at least 1 previously described HLA-A2-restricted VACV epitope, including an epitope targeted in 2 participants. These results advance our understanding of immunity in convalescent Mpox patients.

Staphylococcal Periscope proteins Aap, SasG, and Pls project noncanonical legume-like lectin adhesin domains from the bacterial surface.

Staphylococcus aureus and Staphylococcus epidermidis are frequently associated with medical device infections that involve establishment of a bacterial biofilm on the device surface. Staphylococcal surface proteins Aap, SasG, and Pls are members of the Periscope Protein class and have been implicated in biofilm formation and host colonization; they comprise a repetitive region ("B region") and an N-terminal host colonization domain within the "A region," predicted to be a lectin domain. Repetitive E-G5 domains (as found in Aap, SasG, and Pls) form elongated "stalks" that would vary in length with repeat number, resulting in projection of the N-terminal A domain variable distances from the bacterial cell surface. Here, we present the structures of the lectin domains within A regions of SasG, Aap, and Pls and a structure of the Aap lectin domain attached to contiguous E-G5 repeats, suggesting the lectin domains will sit at the tip of the variable length rod. We demonstrate that these isolated domains (Aap, SasG) are sufficient to bind to human host desquamated nasal epithelial cells. Previously, proteolytic cleavage or a deletion within the A domain had been reported to induce biofilm formation; the structures suggest a potential link between these observations. Intriguingly, while the Aap, SasG, and Pls lectin domains bind a metal ion, they lack the nonproline cis peptide bond thought to be key for carbohydrate binding by the lectin fold. This suggestion of noncanonical ligand binding should be a key consideration when investigating the host cell interactions of these bacterial surface proteins.

Translational molecular imaging: Thrombosis imaging with positron emission tomography.

A key focus of cardiovascular medicine is the detection, treatment, and prevention of disease, with a move towards more personalized and patient-centred treatments. To achieve this goal, novel imaging approaches that allow for early and accurate detection of disease and risk stratification are needed. At present, the diagnosis, monitoring, and prognostication of thrombotic cardiovascular diseases are based on imaging techniques that measure changes in structural anatomy and biological function. Molecular imaging is emerging as a new tool for the non-invasive detection of biological processes, such as thrombosis, that can improve identification of these events above and beyond current imaging modalities. At the forefront of these evolving techniques is the use of high-sensitivity radiotracers in conjunction with positron emission tomography imaging that could revolutionise current diagnostic paradigms by improving our understanding of the role and origin of thrombosis in a range of cardiovascular diseases.

Do recruitment SWAT interventions have an impact on participant retention in randomised controlled trials? A systematic review.

BACKGROUND: Evidence-based methods for randomised controlled trial recruitment and retention are extremely valuable. Despite increased testing of these through studies within a trial, there remains limited high-certainty evidence for effective strategies. In addition, there has been little consideration as to whether recruitment interventions also have an impact on participant retention. METHODS: A systematic review was conducted. Studies were eligible if they were randomised controlled trials using a recruitment intervention and which also assessed the impact of this on retention at any time point. Searches were conducted through MEDLINE, EMBASE, Cochrane Library, and the Northern Ireland Hub for Trials Methodology Research SWAT Repository. Two independent reviewers screened the search results and extracted data for eligible studies using a piloted extraction form. RESULTS: A total of 7815 records were identified, resulting in 10 studies being included in the review. Most studies (n = 6, 60%) focussed on the information given to participants (n = 6, 60%), with two (20%) focussing on incentives, and two focussing on trial design and recruiter interventions. Due to intervention heterogeneity, none of the interventions could be meta-analysed. Only one study found any statistically significant effect of letters including a photograph (odds ratio: 5.40, 95% CI 1.12-26.15, p = 0.04). CONCLUSION: Assessment of the impacts of recruitment strategies, evaluated in a SWAT, on retention of participants in the host trial remains limited. Assessment of the impact of recruitment interventions on retention is recommended to minimise future research costs and waste.

Conditional sanctioning in a legume-Rhizobium mutualism.

Legumes are high in protein and form a valuable part of human diets due to their interaction with symbiotic nitrogen-fixing bacteria known as rhizobia. Plants house rhizobia in specialized root nodules and provide the rhizobia with carbon in return for nitrogen. However, plants usually house multiple rhizobial strains that vary in their fixation ability, so the plant faces an investment dilemma. Plants are known to sanction strains that do not fix nitrogen, but nonfixers are rare in field settings, while intermediate fixers are common. Here, we modeled how plants should respond to an intermediate fixer that was otherwise isogenic and tested model predictions using pea plants. Intermediate fixers were only tolerated when a better strain was not available. In agreement with model predictions, nodules containing the intermediate-fixing strain were large and healthy when the only alternative was a nonfixer, but nodules of the intermediate-fixing strain were small and white when the plant was coinoculated with a more effective strain. The reduction in nodule size was preceded by a lower carbon supply to the nodule even before differences in nodule size could be observed. Sanctioned nodules had reduced rates of nitrogen fixation, and in later developmental stages, sanctioned nodules contained fewer viable bacteria than nonsanctioned nodules. This indicates that legumes can make conditional decisions, most likely by comparing a local nodule-dependent cue of nitrogen output with a global cue, giving them remarkable control over their symbiotic partners.

Solution Combustion Synthesis and Characterization of Magnesium Copper Vanadates.

Magnesium vanadate (MgV2O6) and its alloys with copper vanadate were synthesized via the solution combustion technique. Phase purity and solid solution formation were confirmed by a variety of experimental techniques, supported by electronic structure simulations based on density functional theory (DFT). Powder X-ray diffraction combined with Rietveld refinement, laser Raman spectroscopy, diffuse reflectance spectroscopy, and high-resolution transmission electron microscopy showed single-phase alloy formation despite the MgV2O6 and CuV2O6 end members exhibiting monoclinic and triclinic crystal systems, respectively. DFT-calculated optical band gaps showed close agreement in the computed optical bandgaps with experimentally derived values. Surface photovoltage spectroscopy, ambient-pressure photoemission spectroscopy, and Kelvin probe contact potential difference (work function) measurements confirmed a systematic variation in the optical bandgap modification and band alignment as a function of stoichiometry in the alloy composition. These data indicated n-type semiconductor behavior for all the samples which was confirmed by photoelectrochemical measurements.

The Impact of Vaccination on Incidence and Outcomes of SARS-CoV-2 Infection in Patients with Kidney Failure in Scotland.

BACKGROUND: Patients with kidney failure requiring KRT are at high risk of complications and death following SARS-CoV-2 infection, with variable antibody responses to vaccination reported. We investigated the effects of COVID-19 vaccination on the incidence of infection, hospitalization, and death from COVID-19 infection. METHODS: The study design was an observational data linkage cohort study. Multiple health care datasets were linked to ascertain all SARS-CoV-2 testing, vaccination, hospitalization, and mortality data for all patients treated with KRT in Scotland from the start of the pandemic over a period of 20 months. Descriptive statistics, survival analyses, and vaccine effectiveness were calculated. RESULTS: As of September 19, 2021, 93% (n=5281) of the established KRT population in Scotland had received two doses of an approved SARS-CoV-2 vaccine. Over the study period, there were 814 cases of SARS-CoV-2 infection (15.1% of the KRT population). Vaccine effectiveness rates against infection and hospitalization were 33% (95% CI, 0 to 52) and 38% (95% CI, 0 to 57), respectively. Within 28 days of a SARS-CoV-2-positive PCR test, 9.2% of fully vaccinated individuals died (7% patients on dialysis and 10% kidney transplant recipients). This compares to <0.1% of the vaccinated general Scottish population admitted to the hospital or dying due to COVID-19 during that period. CONCLUSIONS: These data demonstrate that a primary vaccine course of two doses has limited effect on COVID-19 infection and its complications in patients with KRT. Adjunctive strategies to reduce risk of both COVID-19 infection and its complications in this population are urgently required.

Nutrition-Related Information Shared by Latine Influencers: A YouTube Content Analysis.

Latines are the fastest growing populace in the United States. Latine is a new, inclusive term for Hispanic and Latino populations regardless of gender identity. When compared with non-Latine counterparts, Latines have higher prevalence rates of obesity, diabetes, chronic liver disease, and kidney disease, which are associated with poor dietary behaviors. More research is warranted into the factors behind Latines' understanding of nutrition and potential sources of health information that influence dietary behaviors. This study describes the nutrition-related health information shared through YouTube by English-speaking Latine individuals between the ages of 18 and 49. For this content analysis, a cross-sectional study design was used. A four-step search strategy identified eligible YouTube channels and their corresponding video blogs (vlogs): discovery, screening, eligibility, and included. NVivo 1.0 was used to qualitatively code the nutrition-related information. A total of 68 vlogs were identified and reviewed. Five main themes emerged from the data (what vloggers discussed): Nutrition Philosophies, Inaccurate Information, Product Promotion, Recommendations based on the 2020-2025 Dietary Guidelines for Americans (DGA), and Recommendations not based on the 2020-2025 DGA. Although some of the nutrition-related information shared followed the 2020-2025 DGA, not all information were in line with these guidelines. Misinformation can undermine the scientific work done by health professionals and can threaten the health and lives of the citizenry by creating barriers for accessing, understanding, and utilizing evidenced-informed guidance in making health decisions. This study revealed that more research is warranted into specific aspects of social media and how they influence health behavior.

Healthcare provider and service user perspectives on STI risk reduction interventions for young people and MSM in the UK.

OBJECTIVE: Behavioural interventions have been shown to reduce sexual behaviours associated with increased risk of sexually transmitted infections in young people (<25 years) and men who have sex with men (MSM) internationally, but evidence from England is limited. We aimed to explore service provider and user experiences and perspectives on behavioural interventions to reduce sexual behaviour risks, and the use of automated methods to triage individuals to these services. METHODS: We conducted a sequential mixed methods study with sexual health service providers and users in 2015/2016. Qualitative interviews with providers and service users (heterosexual young people and MSM) in London and Brighton allowed us to explore a range of experiences and expectations. A subsequent national web-survey of service providers measured the feasibility of delivery within existing resources and preferences for intervention attributes. RESULTS: We conducted 35 service user (15 heterosexual young people; 20 MSM) and 26 provider interviews and had 100 web-survey responses. We found considerable heterogeneity in prevention services offered. Service users and providers were broadly supportive of tailoring interventions offered, but service users raised concerns about automated, data-driven triage, particularly around equity and fairness of service delivery. Digital technologies, including social media or apps, were appealing to providers, being less resource intensive. However, one-to-one talking interventions remained popular with both service users and providers, being familiar, trustworthy and personal. Key tensions between desirability of interventions and availability of resources to deliver them were acknowledged/recognised by providers and users. CONCLUSION: Overall, behavioural interventions to reduce sexual behaviour risks were viewed favourably by service providers and users, with key considerations including: privacy, personalisation and convenience. However, introducing desirable targeted interventions within heterogeneous sexual health settings will require resources to adapt interventions and research to fully understand the barriers and facilitators to use within routine services.

Examining the Relationship Between Vancomycin Area Under the Concentration Time Curve and Serum Trough Levels in Adults With Presumed or Documented Staphylococcal Infections.

BACKGROUND: Investigations of the relationship between vancomycin trough concentrations and area under the concentration time curve (AUC) are growing, but still limited. The authors sought to determine vancomycin exposure among hospitalized adults with presumed or confirmed invasive staphylococcal infections using 2-level pharmacokinetic monitoring to inform changes to an institutional vancomycin dosing protocol. METHODS: This was a retrospective observational study performed in 2 acute care hospitals. Adults prescribed vancomycin (therapeutic trough 15-20 mg/L) for a presumed or documented invasive staphylococcal infection were evaluated. Two steady-state serum vancomycin levels were used to determine each patient's 24-hour AUC to minimum inhibitory concentration ratio (AUC/MIC) using a non-Bayesian, equation-based approach. Patient demographics and crude clinical outcomes were also collected. RESULTS: Thirty-four patients were included in the study, with 2 patients having vancomycin levels drawn twice (36 sets of levels). Most patients were located in an intensive care unit (91.2%), and 85.3% of patients were prescribed vancomycin for bacteremia, pneumonia, or endocarditis. The mean ± SD vancomycin Cmin was 16.6 ± 6.1 mg/L, and the mean AUC/MIC was 588 ± 156 mg/L × hour. The rate of 24-hour vancomycin AUC/MIC target attainment was 91.2% (n = 31/34). Of the patients with a Cmin > 9 mg/L, 100% (n = 33) achieved AUC/MIC values >400 mg/L × hour and 93.9% were >500 mg/L × hour. There was a strong correlation between vancomycin Cmin and AUC24 hr (R = 0.731; P < 0.001). CONCLUSIONS: Targeting a vancomycin trough between 15 and 20 mg/L frequently resulted in an AUC/MIC greater than that thought to be necessary for efficacy optimization. Considering these findings alongside the practical challenges associated with wide-scale implementation of AUC monitoring, reducing the target trough as a means to prevent vancomycin overexposure warrants clinical consideration and further evaluation.

Caenorhabditis microbiota: worm guts get populated.

Until recently, almost nothing has been known about the natural microbiota of the model nematode Caenorhabditis elegans. Reporting their research in BMC Biology, Dirksen and colleagues describe the first sequencing effort to characterize the gut microbiota of environmentally isolated C. elegans and the related taxa Caenorhabditis briggsae and Caenorhabditis remanei In contrast to the monoxenic, microbiota-free cultures that are studied in hundreds of laboratories, it appears that natural populations of Caenorhabditis harbor distinct microbiotas.

Caenorhabditis elegans star formation and negative chemotaxis induced by infection with corynebacteria.

Caenorhabditis elegans is one of the major model systems in biology based on advantageous properties such as short life span, transparency, genetic tractability and ease of culture using an Escherichia coli diet. In its natural habitat, compost and rotting plant material, this nematode lives on bacteria. However, C. elegans is a predator of bacteria, but can also be infected by nematopathogenic coryneform bacteria such Microbacterium and Leucobacter species, which display intriguing and diverse modes of pathogenicity. Depending on the nematode pathogen, aggregates of worms, termed worm-stars, can be formed, or severe rectal swelling, so-called Dar formation, can be induced. Using the human and animal pathogens Corynebacterium diphtheriae and Corynebacterium ulcerans as well as the non-pathogenic species Corynebacterium glutamicum, we show that these coryneform bacteria can also induce star formation slowly in worms, as well as a severe tail-swelling phenotype. While C. glutamicum had a significant, but minor influence on survival of C. elegans, nematodes were killed after infection with C. diphtheriae and C. ulcerans. The two pathogenic species were avoided by the nematodes and induced aversive learning in C. elegans.

Commensals, probiotics and pathogens in the Caenorhabditis elegans model.

Caenorhabditis elegans is a useful model host for a wide variety of microorganisms that have implications for human health. Recent surveys of mammalian and metazoan microbiota demonstrate the often profound effects of gut commensal bacteria on host lifespan, health and development. Work using C. elegans has revealed the surprising extent to which bacterial metabolism can interact with host pathways with examples from Escherichia coli folate metabolism and Bacillus subtilis nitric oxide synthesis. The C. elegans model has also shed light on the mechanisms by which probiotic bacteria influence lifespan.

Leucobacter musarum subsp. musarum sp. nov., subsp. nov., Leucobacter musarum subsp. japonicus subsp. nov., and Leucobacter celer subsp. astrifaciens subsp. nov., three nematopathogenic bacteria isolated from Caenorhabditis, with an emended description of Leucobacter celer.

Three Gram-stain-positive, irregular-rod-shaped, non-motile, non-spore-forming bacteria were isolated from nematodes collected from Santa Antao, Cabo Verde (CBX151T, CBX152T) and Kakegawa, Japan (CBX130T). Based on 16S rRNA gene sequence similarity, strains CBX130T, CBX151T and CBX152T were shown to belong to the genus Leucobacter. This affiliation was supported by chemotaxonomic data (2,4-diaminobutyric acid in the cell wall; major respiratory quinones MK-10 and MK-11; major polar lipids phosphatidylglycerol and diphosphatidylglycerol; major fatty acids anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0). Strains CBX130T and CBX152T were found to share salient characteristics. Based on morphological, physiological, chemotaxonomic and biochemical analysis, strain CBX152T represents a novel species of the genus Leucobacter, for which the name Leucobacter musarum sp. nov. (type strain CBX152T = DSM 27160T = CIP 110721T) is proposed. Two subspecies of Leucobacter musarum sp. nov. are proposed: Leucobacter musarum sp. nov. subsp. musarum subsp. nov. (type strain CBX152T = DSM 27160T = CIP 110721T) and Leucobacter musarum sp. nov. subsp. japonicus subsp. nov. (type strain CBX130T = DSM 27158T = CIP 110719T). The third novel strain, CBX151T, showed genetic similarities with Leucobacter celer NAL101T indicating that these strains belong to the same species. Based on morphological, physiological, chemotaxonomic and biochemical differences it is proposed to split the species Leucobacter celer into two novel subspecies, Leucobacter celer subsp. celer subsp. nov. (type strain NAL101T = KACC 14220T = JCM 16465T) and Leucobacter celer subsp. astrifaciens subsp. nov. (type strain CBX151T = DSM 27159T = CIP 110720T), and to emend the description of Leucobacter celerShin et al. 2011.

Acute Pain Medicine in the United States: A Status Report.

BACKGROUND: Consensus indicates that a comprehensive,multimodal, holistic approach is foundational to the practice of acute pain medicine (APM),but lack of uniform, evidence-based clinical pathways leads to undesirable variability throughout U. S. healthcare systems. Acute pain studies are inconsistently synthesized to guide educational programs. Advanced practice techniques involving regional anesthesia assume the presence of a physician-led, multidisciplinary acute pain service,which is often unavailable or inconsistently applied.This heterogeneity of educational and organizational standards may result in unnecessary patient pain and escalation of healthcare costs. METHODS: A multidisciplinary panel was nominated through the APM Shared Interest Group of the American Academy of Pain Medicine. The panel met in Chicago, IL, in July 2014, to identify gaps and set priorities in APM research and education. RESULTS: The panel identified three areas of critical need: 1) an open-source acute pain data registry and clinical support tool to inform clinical decision making and resource allocation and to enhance research efforts; 2) a strong professional APM identity as an accredited subspecialty; and 3) educational goals targeted toward third-party payers,hospital administrators, and other key stake holders to convey the importance of APM. CONCLUSION: This report is the first step in a 3-year initiative aimed at creating conditions and incentives for the optimal provision of APM services to facilitate and enhance the quality of patient recovery after surgery, illness, or trauma. The ultimate goal is to reduce the conversion of acute pain to the debilitating disease of chronic pain.

A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.

Recent studies suggest that thousands of genes may contribute to breast cancer pathophysiologies when deregulated by genomic or epigenomic events. Here, we describe a model "system" to appraise the functional contributions of these genes to breast cancer subsets. In general, the recurrent genomic and transcriptional characteristics of 51 breast cancer cell lines mirror those of 145 primary breast tumors, although some significant differences are documented. The cell lines that comprise the system also exhibit the substantial genomic, transcriptional, and biological heterogeneity found in primary tumors. We show, using Trastuzumab (Herceptin) monotherapy as an example, that the system can be used to identify molecular features that predict or indicate response to targeted therapies or other physiological perturbations.

The frequency of cardiac arrests in patients with congenital heart disease undergoing cardiac catheterization.

BACKGROUND: Cardiac catheterization for patients with congenital heart disease has shifted from diagnostic to predominantly interventional procedures because of advances in catheter-based technologies. Children undergoing therapeutic catheterization may be at higher risk of adverse events, and the purpose of our study was to determine the incidence of cardiac arrest (CA) in patients with congenital heart disease undergoing cardiac catheterization at a large pediatric tertiary referral center. METHODS: All CAs from January 2004 through December 2009 occurring in the cardiac catheterization laboratory were reviewed. A CA was defined as an event in which cessation of circulation required chest compressions. Procedure, patient, practitioner, and system-related factors were examined. RESULTS: Over the study period, during 7289 catheterization procedures, 70 procedures were associated with a CA (0.96 [99% confidence interval, 0.7-1.3] per 100 procedures); 48 events (69%) were successfully resuscitated to a perfusing rhythm, 18 events (26%) resulted in need for extracorporeal membrane oxygenation, and 4 events (6%) resulted in unsuccessful resuscitation. Sudden onset of cardiac arrhythmia led to CA during 38 events (54%). The duration of resuscitation after CA was ≤11 minutes in 71%. Occurrence of CA was associated with interventional procedures (P < 0.001) and younger age (P < 0.001). A change in systems for scheduling and communication of cases was associated with a significant reduction in the incidence of CA (1.5% vs 0.7%; P = 0.002). CONCLUSIONS: The incidence of CA in children undergoing cardiac catheterization is high compared with pediatric noncardiac surgery. Procedural and system factors were associated with occurrence of CA in this cohort. These issues highlight the need for close communication, anticipation, and preparation.

Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials: lessons learnt from the PROMETHEUS research programme.

Background: Randomised controlled trials ('trials') are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Objectives: PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial. Design: A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously. Setting: Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible. Participants: Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom. Interventions: Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial. Main outcome measures: Number of host trials funded. Results: Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials. Limitations: The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (n = 2) or prematurely terminated (n = 3). Conclusions: PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial. Future work: Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice. Study registration: All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.

A Study Within A Trial is a research study nested inside a larger 'host trial', promoting the use of Studies Within A Trial aimed to do Study Within A Trial routine practice in clinical trial units by funding and supporting at least 25 Studies Within A Trial. The best way to test health and social care treatments is to do a randomised controlled trial ('trial'), where some patients get the treatment being tested and some do not. The results of different groups are compared to see if the treatment improves care. Recruiting patients and keeping them involved in trials is often very difficult. Research teams often do not know how best to recruit and keep patients engaged as the methods have not been tested to see if they work. The best way to test these methods is by doing a Study Within A Trial. We test a programme of Studies Within A Trial for recruiting and keeping patients engaged in trials. Trial teams were able to apply for funding of up to £5000 and receive support from Promoting the use of Study Within A Trial team to do Studies Within A Trial. We used our experience of doing Studies Within A Trial to outline lessons learnt for doing Studies Within A Trial. We funded 42 Studies Within A Trial and gave teams necessary advice to do them. We significantly increased the knowledge for both recruitment and retention strategies, and found 'pre-notifying' before sending questionnaires, sending pens and personalised text messages were all effective for increasing responses by participants. We tested Studies Within A Trial across several different trials at the same time to find out more quickly whether their methods worked. We highlight key lessons learnt to guide others doing Studies Within A Trial, including involving patient partners; picking the right strategy to test; getting ethical approvals; how to do and report Studies Within A Trial. Promoting the use of studies within a trial was successful and supported more Studies Within A Trial than planned. We hope our experience will support those doing Studies Within A Trial in the future.