PROTOCOL: Methods used in the development, production and updating of evidence and gap maps: A scoping review.

Evidence and gap maps (EGMs) are an increasinly popular approach used in evidence synthesis. As an approach they address broad research questions, describing the existing evidence base, highlighting evidence gaps and providing an interactive visual tool for knowledge users. The purpose of this methodological study is to explore the the processes used in the development of EGM's and how they are reported. The aim is to better understand current practice and identify where clearer guidance is needed to support their production.

Long-term assessment of the NHS hybrid closed-loop real-world study on glycaemic outcomes, time-in-range, and quality of life in children and young people with type 1 diabetes.

Hybrid closed-loop (HCL) systems seamlessly interface continuous glucose monitoring (CGM) with insulin pumps, employing specialised algorithms and user-initiated automated insulin delivery. This study aimed to assess the efficacy of HCLs at 12 months post-initiation on glycated haemoglobin (HbA1c), time-in-range (TIR), hypoglycaemia frequency, and quality of life measures among children and young people (CYP) with type 1 diabetes mellitus (T1DM) and their caregivers in a real-world setting. Conducted between August 1, 2021, and December 10, 2022, the prospective recruitment took place in eight paediatric diabetes centres across England under the National Health Service England's (NHSE) HCL pilot real-world study. A cohort of 251 CYP (58% males, mean age 12.3 years) with T1DM participated (89% white, 3% Asian, 4% black, 3% mixed ethnicity, and 1% other). The study utilised three HCL systems: (1) Tandem Control-IQ AP system, which uses the Tandem t:slim X2 insulin pump (Tandem Diabetes Care, San Diego, CA, USA) with the Dexcom G6® CGM (Dexcom, San Diego, CA, USA) sensor; (2) Medtronic MiniMed™ 780G with the Guardian 4 sensor (Medtronic, Northridge, CA, USA); and (3) the CamAPS FX (CamDiab, Cambridge, UK) with the Ypsomed insulin pump (Ypsomed Ltd, Escrick, UK) and Dexcom G6® CGM.All systems were fully funded by the NHS. Results demonstrated significant improvements in HbA1c (average reduction at 12 months 7 mmol/mol; P < 0.001), time-in-range (TIR) (average increase 13.4%; P < 0.001), hypoglycaemia frequency (50% reduction), hypoglycaemia fear, and quality of sleep (P < 0.001) among CYP over a 12-month period of HCL usage. Additionally, parents and carers experienced improvements in hypoglycaemia fear and quality of sleep after 6 and 12 months of use. In addition to the improvements in glycaemic management, these findings underscore the positive impact of HCL systems on both the well-being of CYP with T1DM and the individuals caring for them.

Cost-Effectiveness of Closed-Loop Automated Insulin Delivery Using the Cambridge Hybrid Algorithm in Children and Adolescents with Type 1 Diabetes: Results from a Multicenter 6-Month Randomized Trial.

BACKGROUND/OBJECTIVE: The main objective of this study is to evaluate the incremental cost-effectiveness (ICER) of the Cambridge hybrid closed-loop automated insulin delivery (AID) algorithm versus usual care for children and adolescents with type 1 diabetes (T1D). METHODS: This multicenter, binational, parallel-controlled trial randomized 133 insulin pump using participants aged 6 to 18 years to either AID (n = 65) or usual care (n = 68) for 6 months. Both within-trial and lifetime cost-effectiveness were analyzed. Analysis focused on the treatment subgroup (n = 21) who received the much more reliable CamAPS FX hardware iteration and their contemporaneous control group (n = 24). Lifetime complications and costs were simulated via an updated Sheffield T1D policy model. RESULTS: Within-trial, both groups had indistinguishable and statistically unchanged health-related quality of life, and statistically similar hypoglycemia, severe hypoglycemia, and diabetic ketoacidosis (DKA) event rates. Total health care utilization was higher in the treatment group. Both the overall treatment group and CamAPS FX subgroup exhibited improved HbA1C (-0.32%, 95% CI: -0.59 to -0.04; P = .02, and -1.05%, 95% CI: -1.43 to -0.67; P < .001, respectively). Modeling projected increased expected lifespan of 5.36 years and discounted quality-adjusted life years (QALYs) of 1.16 (U.K. tariffs) and 1.52 (U.S. tariffs) in the CamAPS FX subgroup. Estimated ICERs for the subgroup were £19 324/QALY (United Kingdom) and -$3917/QALY (United States). For subgroup patients already using continuous glucose monitors (CGM), ICERs were £10 096/QALY (United Kingdom) and -$33 616/QALY (United States). Probabilistic sensitivity analysis generated mean ICERs of £19 342/QALY (95% CI: £15 903/QALY to £22 929/QALY) (United Kingdom) and -$28 283/QALY (95% CI: -$59 607/QALY to $1858/QALY) (United States). CONCLUSIONS: For children and adolescents with T1D on insulin pump therapy, AID using the Cambridge algorithm appears cost-effective below a £20 000/QALY threshold (United Kingdom) and cost saving (United States).

The aetiology of fracture and nonunion in the hook of the hamate.

Fractures of the hook of the hamate are traditionally thought to be caused by direct trauma. A review of the anatomy and function of the hamate hook suggests that fracture is more likely as a result of a fatigue response that develops in the hook from repetitive load applied by the adjacent deep flexor tendons. Additional vascular compromise, from direct pressure of the tendons on critical local vessels, reduces blood flow leading to both mechanical and vascular effects that create pathological osseous change and weakening. These changes are likely to predispose to stress fracture and nonunion in repetitive gripping activities and are consistent with radiological findings.

Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Glycemic Outcomes with Closed-Loop Insulin Delivery.

The presence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) is associated with higher glycated hemoglobin levels over time. We evaluated whether hybrid-closed loop (HCL) therapy from onset of T1D could prevent the adverse impact of DKA at diagnosis on long-term glycemic outcomes. This was a posthoc analysis from 51 adolescents using HCL from diagnosis of T1D as part of the CLOuD trial (NCT02871089). We compared glycemic and insulin metrics between adolescents with (n = 17) and without (n = 34) DKA at diagnosis. Participants with and without DKA at diagnosis had similar time in target glucose range 3.9-10.0 mmol/L (70-180 mg/dL), time below range (<3.9 mmol/L, <70 mg/dL) and HbA1c at 6, 12, and 24 months. While insulin requirements at 6 months were higher in those with DKA at diagnosis, this was not statistically significant after adjusting for bodyweight. Residual C-peptide secretion was similar between groups. We conclude that HCL therapy may mitigate against the negative glycemic effects of DKA at T1D diagnosis.

Rapid reviews methods series: guidance on rapid qualitative evidence synthesis.

This paper forms part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group and addresses rapid qualitative evidence syntheses (QESs), which use modified systematic, transparent and reproducible methodsu to accelerate the synthesis of qualitative evidence when faced with resource constraints. This guidance covers the review process as it relates to synthesis of qualitative research. 'Rapid' or 'resource-constrained' QES require use of templates and targeted knowledge user involvement. Clear definition of perspectives and decisions on indirect evidence, sampling and use of existing QES help in targeting eligibility criteria. Involvement of an information specialist, especially in prioritising databases, targeting grey literature and planning supplemental searches, can prove invaluable. Use of templates and frameworks in study selection and data extraction can be accompanied by quality assurance procedures targeting areas of likely weakness. Current Cochrane guidance informs selection of tools for quality assessment and of synthesis method. Thematic and framework synthesis facilitate efficient synthesis of large numbers of studies or plentiful data. Finally, judicious use of Grading of Recommendations Assessment, Development and Evaluation approach for assessing the Confidence of Evidence from Reviews of Qualitative research assessments and of software as appropriate help to achieve a timely and useful review product.

Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.

Advancing the methodology of mapping reviews: A scoping review.

This scoping review aims to identify and systematically review published mapping reviews to assess their commonality and heterogeneity and determine whether additional efforts should be made to standardise methodology and reporting. The following databases were searched; Ovid MEDLINE, Embase, CINAHL, PsycINFO, Campbell collaboration database, Social Science Abstracts, Library and Information Science Abstracts (LISA). Following a pilot-test on a random sample of 20 citations included within title and abstracts, two team members independently completed all screening. Ten articles were piloted at full-text screening, and then each citation was reviewed independently by two team members. Discrepancies at both stages were resolved through discussion. Following a pilot-test on a random sample of five relevant full-text articles, one team member abstracted all the relevant data. Uncertainties in the data abstraction were resolved by another team member. A total of 335 articles were eligible for this scoping review and subsequently included. There was an increasing growth in the number of published mapping reviews over the years from 5 in 2010 to 73 in 2021. Moreover, there was a significant variability in reporting the included mapping reviews including their research question, priori protocol, methodology, data synthesis and reporting. This work has further highlighted the gaps in evidence synthesis methodologies. Further guidance developed by evidence synthesis organisations, such as JBI and Campbell, has the potential to clarify challenges experienced by researchers, given the magnitude of mapping reviews published every year.

Streamlining search methods to update evidence and gap maps: A case study using intergenerational interventions.

Background: Evidence and Gap Maps (EGMs) should be regularly updated. Running update searches to find new studies for EGMs can be a time-consuming process. Search Summary Tables (SSTs) can help streamline searches by identifying which resources were most lucrative for identifying relevant articles, and which were redundant. The aim of this study was to use an SST to streamline search methods for an EGM of studies about intergenerational activities. Methods: To produce the EGM, 15 databases were searched. 8638 records were screened and 500 studies were included in the final EGM. Using an SST, we determined which databases and search methods were the most efficient in terms of sensitivity and specificity for finding the included studies. We also investigated whether any database performed particularly well for returning particular study types. For the best performing databases we analysed the search terms used to streamline the strategies. Results: No single database returned all of the studies included in the EGM. Out of 500 studies PsycINFO returned 40% (n = 202), CINAHL 39% (n = 194), Ageline 25% (n = 174), MEDLINE 23% (n = 117), ERIC 20% (n = 100) and Embase 19% (n = 98). HMIC database and Conference Proceedings Citation Index-Science via Web of Science returned no studies that were included in the EGM. ProQuest Dissertations & Theses (PQDT) returned the highest number of unique studies (n = 42), followed by ERIC (n = 33) and Ageline (n = 29). Ageline returned the most randomised controlled trials (42%) followed by CINAHL (34%), MEDLINE (29%) and CENTRAL (29%). CINAHL, Ageline, MEDLINE and PsycINFO performed the best for locating systematic reviews. (62%, 46% and 42% respectively). CINAHL, PsycINFO and Ageline performed best for qualitative studies (41%, 40% and 34%). The Journal of Intergenerational Relationships returned more included studies than any other journal (16%). No combinations of search terms were found to be better in terms of balancing specificity and sensitivity than the original search strategies. However, strategies could be reduced considerably in terms of length without losing key, unique studies. Conclusion: Using SSTs we have developed a method for streamlining update searches for an EGM about intergenerational activities. For future updates we recommend that MEDLINE, PsycINFO, ERIC, Ageline, CINAHL and PQDT are searched. These searches should be supplemented by hand-searching the Journal of Intergenerational Relationships and carrying out backwards citation chasing on new systematic reviews. Using SSTs to analyse database efficiency could be a useful method to help streamline search updates for other EGMs.

A New Hierarchy of Research Evidence for Tumor Pathology: A Delphi Study to Define Levels of Evidence in Tumor Pathology.

The hierarchy of evidence is a fundamental concept in evidence-based medicine, but existing models can be challenging to apply in laboratory-based health care disciplines, such as pathology, where the types of evidence and contexts are significantly different from interventional medicine. This project aimed to define a comprehensive and complementary framework of new levels of evidence for evaluating research in tumor pathology-introducing a novel Hierarchy of Research Evidence for Tumor Pathology collaboratively designed by pathologists with help from epidemiologists, public health professionals, oncologists, and scientists, specifically tailored for use by pathologists-and to aid in the production of the World Health Organization Classification of Tumors (WCT) evidence gap maps. To achieve this, we adopted a modified Delphi approach, encompassing iterative online surveys, expert oversight, and external peer review, to establish the criteria for evidence in tumor pathology, determine the optimal structure for the new hierarchy, and ascertain the levels of confidence for each type of evidence. Over a span of 4 months and 3 survey rounds, we collected 1104 survey responses, culminating in a 3-day hybrid meeting in 2023, where a new hierarchy was unanimously agreed upon. The hierarchy is organized into 5 research theme groupings closely aligned with the subheadings of the WCT, and it consists of 5 levels of evidence-level P1 representing evidence types that merit the greatest level of confidence and level P5 reflecting the greatest risk of bias. For the first time, an international collaboration of pathology experts, supported by the International Agency for Research on Cancer, has successfully united to establish a standardized approach for evaluating evidence in tumor pathology. We intend to implement this novel Hierarchy of Research Evidence for Tumor Pathology to map the available evidence, thereby enriching and informing the WCT effectively.

Revision of Failed Nonanatomic Extensor Retinacular Stabilization of the Unstable ECU Tendon: Surgical Technique and Case Series.

Nonanatomic surgical stabilization of the unstable extensor carpi ulnaris (ECU) tendon (where the subluxing tendon is re-routed away from the bony groove in the distal ulna) utilizes a flap of extensor retinaculum to create a new retaining sheath that will stabilize the tendon during forearm rotation movements. When this surgery fails, the extensor retinaculum tissue does not regenerate with sufficient structural strength to be used again. Previously, a different approach has then been needed for revision surgery, often using more complex surgical techniques with a substantially greater impact on recovery. We describe a highly reliable yet simple method of using local soft tissue to adequately restabilize the subluxing ECU tendon in cases where an extensor retinacular flap has already been used. We report the results of this technique in 4 patients, all of whom returned to jobs/hobbies where ECU instability was a considerable functional risk.

Association between stress, depression or anxiety and cancer: Rapid review of reviews.

Background: Several studies have suggested links between psychological stress, depression or anxiety, and cancer incidence or outcomes. Existing systematic reviews have addressed this question, with differing results. Aims: This rapid systematic umbrella review summarises existing reviews assessing the association between psychological stress, depression or anxiety and cancer incidence or cancer outcomes. Methods: Systematic reviews assessing stress, depression or anxiety and cancer were identified via searches of MEDLINE, PsycInfo and Cochrane Database of Systematic Reviews from 2010 to November 2020. Results: Twelve systematic reviews were included, summarising cohort and case-control studies, most of which adjusted for confounders. Regarding cancer incidence, one large meta-analysis reported a significant association between depression/anxiety and cancer incidence, while another showed a non-significant trend. Two further meta-analyses reported significant associations between stressful life events and cancer incidence. Conversely, two meta-analyses of work stress showed no significant association with cancer incidence. Regarding outcomes among cancer patients, three meta-analyses reported significant associations between depression/anxiety and cancer mortality, while another reported a non-significant trend for depression and cancer recurrence. One meta-analysis reported a significant association between partner bereavement and cancer mortality, while another showed no significant association between work stress and cancer mortality. Conclusions: There is consistent evidence for an association between psychological stress, depression or anxiety and cancer incidence in general populations, and some evidence for an association with mortality in cancer populations. Future research may focus on confirmation of these findings, as well as the role of social support and stress-reducing interventions in buffering against these effects.

What is the effect of intergenerational activities on the wellbeing and mental health of older people?: A systematic review.

Background: Opportunities for social connection between generations have diminished over the last few decades around the world as a result of changes in the way that we live and work. The COVID-19 pandemic has exacerbated loneliness for many with young and old being kept apart for safety. The Public Health England prevention concordat for better mental health (Office for Health Improvement and Disparities) aims to bring a prevention-focused approach to improving public mental health. The concordat promotes evidence-based planning and commissioning to increase the impact on reducing health inequalities using sustainable and cost-effective interventions that impact on the wider determinants of mental health and wellbeing for children and young people and older people. Intergenerational activities could provide an opportunity to support both populations. In 2023, we produced an evidence and gap map to illustrate the amount and variety of research on intergenerational interventions and the gaps in research that still exist in this area. The review conducted here is based on the evidence in that map. Objectives: This systematic review examines the impact of intergenerational interventions on the wellbeing and mental health of older people and identifies areas for future research as well as key messages for service commissioners. Search Methods: We searched an evidence and gap map published in 2022 (comprehensive searches conducted July 2021 and updated June 2023) to identify randomised controlled trials of intergenerational interventions that report mental health and wellbeing outcomes for older people. Selection Criteria: Randomised controlled trials of intergenerational interventions that involved unrelated younger and older people with at least one skipped generation between them and reported mental health or wellbeing outcomes for older people were included in this review. Data Collection and Analysis: We used standard methodological procedures expected by The Campbell Collaboration. We conducted data extraction and Cochrane risk of bias assessments in EPPI reviewer. Where data allowed meta-analyses were conducted in STATA. Main Results: This review includes 14 trials from six different countries. The trials had some important methodological weaknesses. Interventions were mainly delivered in-person and often in groups. They included visiting programmes, school volunteering programmes, music-based interventions and task-oriented interventions such as activities set in a multigenerational park, reminiscing activities, aggression management programmes, learning a language, making local environmental changes and in-school project work. Intergenerational interventions showed a small positive trend towards improving self-esteem (effect size [ES]: 0.33, 95% confidence interval [CI]: -0.35, 1.01) and depression (ES: 0.19, 95% CI: -0.23, 0.60) for older people participating. However, due to the small study sizes and low number of studies available, we cannot be confident about any effects. The results for other mental health and wellbeing outcomes are reported but due to little overlap in similar assessments across the studies, we could not combine them to assess the strength of evidence. There were no data about social isolation, spiritual health or sense of community. There are no long-term studies and no data on equity. We still know very little about what works and how or why. Whilst some interventions do use theories and logic to inform their development others do not. More exploration of this is needed. Authors' Conclusions: Commissioners and intervention developers should ensure interventions provide sufficient theoretical evidence for the logic behind the proposed intervention and should improve their consideration of equity within the interventions Research on intergenerational interventions need more consistent and agreed measures for reporting outcomes including community outcomes (core outcome sets). More understanding is needed on how best to measure 'community' outcomes. Research on intergenerational interventions should measure outcomes for BOTH the older and younger population engaged in the intervention-these may or may not be the same outcomes reflected in both populations. Further research is needed on the long-term impact of interventions on outcomes (whether participants need to keep being involved in an 'intervention' to continue to benefit) and sustainability of interventions beyond the initial funding of the research project. Supporting this our stakeholders highlighted that interventions that are initiated for research and then end (usually within a year) are not helpful.

Strategies for reducing pain at dressing change in chronic wounds: protocol for a mapping review.

INTRODUCTION: Although pain experienced at dressing change has been reported as the worst aspect of living with chronic wounds, UK guidance for their management is primarily tailored to wound healing and only attends to pain as a secondary consideration. Consequently, there is little up-to-date guidance that specifically addresses how patients, carers and healthcare professionals should manage wound-related pain at dressing change. This mapping review will identify, describe and appraise the existing research evidence for strategies used to assess pain intensity and prevent or alleviate pain at dressing change in chronic wounds. In addition, it will highlight areas for future research and inform the development of up-to-date guidance for healthcare professionals. METHODS AND ANALYSIS: We will search MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily (via Ovid SP), Embase (via Ovid SP), Cochrane Central Register of Controlled Trials (via Wiley Cochrane Library), Cumulative Index of Nursing and Allied Health Literature (via EBSCO) and the Web of Science Citation Index Expanded and Social Sciences Citation Index (via Clarivate Analytics). Screening will be undertaken independently by two reviewers, with any disagreements resolved through discussion. Included studies will be subject to coding, using a tested data extraction tool, by two reviewers working independently. The methodological quality of the studies included will be reviewed using quality assessment instruments appropriate for each study design (Cochrane Risk of Bias tool (RoB 2); Risk of Bias in Non-randomised Studies of interventions tool; Critical Appraisal Skills Programme tool). Data will be described narratively and also presented visually in an interactive web-based evidence and gap map. ETHICS AND DISSEMINATION: As this mapping review does not collect original data, ethical approval is not applicable. Findings will be disseminated via a written report, an interactive online mapping tool and in peer-reviewed journals and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42021260130.

Weight Management Interventions for Adults With Idiopathic Intracranial Hypertension: A Systematic Review and Practice Recommendations.

BACKGROUND AND OBJECTIVES: Idiopathic intracranial hypertension (IIH) is associated with obesity; however, there is a lack of clinical consensus on how to manage weight in IIH. The aim of this systematic review was to evaluate weight loss interventions in people with IIH to determine which intervention is superior in terms of weight loss, reduction in intracranial pressure (ICP), benefit to visual and headache outcomes, quality of life, and mental health. METHODS: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered with PROSPERO (CRD42023339569). MEDLINE and CINAHL were searched for relevant literature published from inception until December 15, 2022. Screening and quality appraisal was conducted by 2 independent reviewers. Recommendations were graded using Scottish Intercollegiate Guidelines Network methodology. RESULTS: A total of 17 studies were included. Bariatric surgery resulted in 27.2-27.8 kg weight loss at 24 months (Level 1- to 1++). Lifestyle weight management interventions resulted in between 1.4 and 15.7 kg weight loss (Level 2+ to 1++). Bariatric surgery resulted in the greatest mean reduction in ICP (-11.9 cm H2O) at 24 months (Level 1++), followed by multicomponent lifestyle intervention + acetazolamide (-11.2 cm H2O) at 6 months (Level 1+) and then a very low-energy diet intervention (-8.0 cm H2O) at 3 months (Level 2++). The least ICP reduction was shown at 24 months after completing a 12-month multicomponent lifestyle intervention (-3.5 cm H2O) (Level 1++). Reduction in body weight was shown to be highly correlated with reduction in ICP (Level 2++ to 1++). DISCUSSION: Bariatric surgery should be considered for women with IIH and a body mass index (BMI) ≥35 kg/m2 since this had the most robust evidence for sustained weight management (grade A). A multicomponent lifestyle intervention (diet + physical activity + behavior) had the most robust evidence for modest weight loss with a BMI <35 kg/m2 (grade B). Longer-term outcomes for weight management interventions in people with IIH are required to determine whether there is a superior weight loss intervention for IIH.

B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection.

INTRODUCTION: Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection. METHODS: B-Clear is a phase 2b, multicenter, randomized, partial-blind (sponsor/participant-blinded, investigator-unblinded) study in participants with chronic HBV infection receiving stable nucleos(t)ide analogue (On-NA) or not currently receiving NA therapy (Not-on-NA). Eligibility criteria included HBsAg > 100 IU/mL, HBV DNA < 90 IU/mL (On-NA) or > 2000 IU/mL (Not-on-NA), and alanine aminotransferase ≤ 2 × upper limit of normal (ULN; On-NA) or < 3 × ULN (Not-on-NA). Participants were randomized 3:3:3:1 to one of four treatment arms, with treatment administered weekly as subcutaneous injections with or without loading doses (LD) on days 4 and 11: bepirovirsen 300 mg (with 300 mg LD) for 24 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then bepirovirsen 150 mg for 12 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then placebo for 12 weeks; placebo for 12 weeks (with placebo LD) then bepirovirsen 300 mg without LD for 12 weeks. PLANNED OUTCOMES: The primary endpoint of the study was HBsAg < lower limit of detection and HBV DNA < lower limit of quantification for 24 weeks after the end of bepirovirsen treatment in the absence of rescue medication. The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022. The novel design of the B-Clear study will allow assessment of HBsAg and HBV DNA seroclearance post bepirovirsen treatment discontinuation in the presence and absence of background NA therapy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT04449029; GSK study 209668).

Pain, mental health and healthcare utilization: Impact of the COVID-19 pandemic on youth with chronic pain, parents and siblings.

BACKGROUND: Paediatric chronic pain was a public health emergency before the novel coronavirus (COVID-19) pandemic, and this problem is predicted to escalate. Pain tends to occur intergenerationally in families, and youth with chronic pain and their parents have high rates of mental health issues, which can further exacerbate pain. Siblings of youth with chronic pain have been largely overlooked in research, as well as the impact of the pandemic on posttraumatic stress disorder (PTSD) symptoms and healthcare utilization. METHODS: This cross-sectional study examined pain, mental health and healthcare utilization in three groups: youth with chronic pain (n = 357), parents of youth with chronic pain (n = 233) and siblings of youth with chronic pain (n = 156) during the COVID-19 pandemic in Canada. RESULTS: More so than with pain symptoms, the results revealed high levels of mental health symptoms (i.e. anxiety, depressive, and PTSD), particularly in individuals more personally impacted by the pandemic. The largest effect was seen on PTSD symptoms for all groups. For parents with chronic pain, greater personal COVID-19 impact was related to worse pain interference. Reported rates of healthcare utilization were strikingly high, with youth with chronic pain, parents (reporting on behalf of their children with chronic pain), and siblings of youth with chronic pain reporting that most consultations were due to pain. CONCLUSIONS: Longitudinal research assessing these outcomes across continued waves of the pandemic is needed to ensure timely, tailored and equitable access to pain and mental health assessment and treatment. SIGNIFICANCE: This study examined pain, mental health, substance use and healthcare utilization in youth with chronic pain, siblings and parents during the COVID-19 pandemic. Greater personal impact of the pandemic was not largely associated with poorer pain outcomes; however, it was associated with mental health, with the largest effect on PTSD symptoms. The high rates and significant association of COVID-19 impact with PTSD symptoms underscore the importance of including PTSD assessment as part of routine screening practices in pain clinics.

PROTOCOL: What is the effect of intergenerational activities on the wellbeing and mental health of children and young people?

This is the protocol for a Campbell systematic review. The objectives are as follows: this systematic review will examine the impact of intergenerational interventions on the wellbeing and mental health in children and young people and will identify areas for future research as well as key messages for service commissioners.