The overlap between randomised evaluations of recruitment and retention interventions: An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature.

BACKGROUND: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. METHODS: Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. RESULTS: In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as 'randomised evaluation', of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. CONCLUSION: Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.

Novel approaches for leadless pacemaker implantation in the extra-cardiac Fontan cohort: Options to avoid leaded systems or epicardial pacing.

BACKGROUND: Fontan surgery, a palliative procedure for single ventricle patients, often leads to the need for permanent pacing. Epicardial pacing has limitations, while transvenous pacing carries risks in the Fontan circulation. This case series introduces a novel approach of leadless pacemaker implantation in the extra-cardiac Fontan (ECF) cohort to overcome these limitations. METHODS: The study includes four cases of leadless pacemaker (Micra™) implantation in patients with ECF. Procedures were performed under general anesthesia with guidance from trans-esophageal echocardiography. Various access routes were used, including trans-carotid and trans-fenestration approaches. Procedural details, parameters, and follow-up data were collected. RESULTS: All leadless pacemaker implantations were successful, with satisfactory electrical parameters and stable pacing postprocedural outcomes during short-term follow-up. One patient required closure of their fenestration for symptomatic desaturation post procedurally. CONCLUSIONS: Leadless pacemaker implantation via trans-carotid and trans-fenestration approaches appears to be a feasible back up option for pacing in Fontan patients where other options have been exhausted or there is a patient choice to avoid surgery. These techniques provide an option to avoid leaded systems or epicardial pacing, reducing the need for multiple thoracotomies and addressing challenges associated with surgical pacing leads. Further studies are needed to evaluate long-term outcomes and assess the broader application of leadless pacemakers in the Fontan population.

Delayed pregnancy detection and return to fertility with extended levonorgestrel-containing oral contraceptives: A real world setting cohort study.

PURPOSE: As part of the European risk management plan of a 91-day extended levonorgestrel-containing combined oral contraceptive (COCLNG ), a study was performed to assess its safety. This analysis was conducted to examine delayed pregnancy detection and return to fertility with extended combined oral contraceptives (COC). METHODS: We conducted a retrospective cohort study in new users of 91-day COCLNG or 28-day COCLNG within a US-based healthcare claims database from 2006 to 2017. Delayed pregnancy detection during current COCLNG exposure was defined as the time between estimated pregnancy start and first prenatal care encounter. Additionally, the time between estimated pregnancy start and COCLNG discontinuation was measured. To measure return to fertility, pregnancy rates were estimated among females who discontinued treatment. 91-day COCLNG users were propensity score-matched to 28-day COCLNG users. Hazard ratio for pregnancy was calculated using Cox proportional hazards models. RESULTS: The 91-day and 28-day COCLNG users had 25 593 and 76 586 treatment episodes, respectively. The median time to pregnancy detection was 64.5 and 61.0 days (p = 0.24) in users of 91-day COCLNG and 28-day COCLNG . The median exposure time to treatment after estimated pregnancy start was 54.0 and 38.0 days (p < 0.01). In the fertility analysis, pregnancy rates were 54.82 (95% CI, 50.05-59.93) and 69.30 (95% CI, 64.98-73.82) per 1000 person-years in extended COCLNG discontinuers and 28-day COCLNG discontinuers. The adjusted hazard ratio of pregnancy was 0.77 (95% CI, 0.69-0.85). CONCLUSIONS: Small differences were observed for pregnancy rates and delayed pregnancy detection between 91-day extended COCLNG and 28-day COCLNG , which may be related to the longer days' supply of extended COCLNG . Differences in the fertility analysis may be related to unmeasured residual confounding.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.

Predictors of health-related quality of life among military HIV-infected individuals.

OBJECTIVES: To determine long-term predictors of health-related quality of life (HRQOL) and evaluate the treatment effect of highly active antiretroviral therapy (HAART) on HRQOL in the US Military HIV Natural History Study (NHS) cohort. METHODS: Participants were a nested cohort of the NHS who responded to the Rand Short Form 36 questionnaire administered from 2006 to 2010. Physical component summary scores (PCS) and mental component summary scores (MCS) were computed using standard algorithms. HAART-status was categorized as non-protease inhibitor-based (NPI-HAART), protease inhibitor-based (PI-HAART), HAART-naïve, or off-HAART. Mixed linear random effects models were used to estimate changes in PCS and MCS over time for treatment and covariates (including CD4 count, HIV viral load, medical and mental comorbidities). RESULTS: Eight hundred and twelve participants met the inclusion criteria. There was no difference in PCS or MCS between those on PI-HAART compared to NPI-HAART. Significant predictors of PCS were CD4 count < 200 cells/mm3 (ß = - 2.90), CD4 count 200-499 cells/mm3 (ß = - 0.80), and mental comorbidity (ß = - 3.23). Others were medical comorbidity, AIDS-defining illness, being on NPI-HAART, HAART-naïve, age, and rank. Those with medical comorbidities experienced yearly improvement in PCS. Predictors of MCS were CD4 count < 200 cells/mm3 (ß = - 2.53), mental comorbidity (ß = - 4.58), and being African American (ß = 2.59). CONCLUSION: HRQOL was significantly affected by low CD4 count, medical and mental comorbidities. Addressing these modifiable factors would be expected to improve the physical and mental HRQOL of the cohort. Our study did not find any treatment benefit of NPI-HAART over PI-HAART on HRQOL in the long term.

What matters to people with memory problems, healthy volunteers and health and social care professionals in the context of developing treatment to prevent Alzheimer's dementia? A qualitative study.

BACKGROUND: Alzheimer's disease (AD) is recognized as one of the greatest global public health challenges. There is increasing consensus that optimal disease modification using pharmaceuticals may best be achieved earlier in the disease continuum before symptoms occur. However, more needs to be understood about what outcomes are meaningful to potential participants in clinical trials within this preventative paradigm and how people make trade-offs between risks and benefits. The Electronic Person-Specific Outcome Measure (ePSOM) programme is developing an app to capture person-specific outcomes and preferences in clinical trials. OBJECTIVE: As one phase in the ePSOM programme, this study explored what matters when developing new treatments to prevent AD and how trade-offs are made between risks and benefits, from three perspectives. DESIGN: Focus groups were conducted with people living with memory problems (n = 21) and healthy volunteers (n = 10), and telephone interviews with health and social care professionals (n = 10). Differences and overlap between the three groups were explored. RESULTS: Outcomes that matter lie in five key domains in relation to what matters in everyday life: Everyday Functioning; Relationships and Social Connections; Enjoying Life; Sense of Identity; and Alleviating  Symptoms. Insights were gained into the significance of reducing the risk of developing dementia with drugs and the processes of weighing up risks versus benefits. DISCUSSION AND CONCLUSIONS: The key domains identified are being used to inform the next stage of the ePSOM programme which is to develop a survey to be distributed nationally in the UK to explore these issues further.

Lower health-related quality of life predicts all-cause hospitalization among HIV-infected individuals.

BACKGROUND: Health-related quality of life (HRQOL) is a patient-centered outcome measure used in assessing the individual's overall functional health status but studies looking at HRQOL as a predictive tool are few. This work examines whether summary scores of HRQOL are predictive of all-cause hospitalization in the US Military HIV Natural History Study (NHS) cohort. METHODS: The Short Form 36 (SF-36) was administered between 2006 and 2010 to 1711 NHS cohort members whose hospitalization records we had also obtained. Physical component summary scores (PCSS) and mental component summary scores (MCSS) were computed based on standard algorithms. Terciles of PCSS and MCSS were generated with the upper terciles (higher HRQOL) as referent groups. Proportional hazards multivariate regression models were used to estimate the hazard of hospitalization for PCSS and MCSS separately (models 1 and 2, respectively) and combined (model 3). RESULTS: The hazard ratios (HR) of hospitalization were respectively 2.12 times (95% CI: 1.59-2.84) and 1.59 times (95% CI: 1.19-2.14) higher for the lower and middle terciles compared to the upper PCSS tercile. The HR of hospitalization was 1.33 times (95% CI: 1.02-1.73) higher for the lower compared to the upper MCSS tercile. Other predictors of hospitalization were CD4 count < 200 cells/mm3 (HR = 2.84, 95% CI: 1.96, 4.12), CD4 count 200-349 cells/mm3 (HR = 1.67, 95% CI: 1.24, 2.26), CD4 count 350-499 cells/mm3 (HR = 1.41, 95% CI: 1.09, 1.83), plasma viral load > 50 copies/mL (HR = 1.82, 95% CI: 1.46, 2.26), and yearly increment in duration of HIV infection (HR = 0.94, 95% CI: 0.93, 0.96) (model 3). CONCLUSION: After controlling for factors associated with hospitalization among those with HIV, both PCSS and MCSS were predictive of all-cause hospitalization in the NHS cohort. HRQOL assessment using the SF-36 may be useful in stratifying hospitalization risk among HIV-infected populations.

Real-time ultrasound-guided pigtail catheter chest drain for complicated parapneumonic effusion and empyema in children - 16-year, single-centre experience of radiologically placed drains.

BACKGROUND: Chest tube drainage with fibrinolytics is a cost-effective treatment option for parapneumonic effusion and empyema in children. Although the additional use of ultrasound (US) guidance is recommended, this is rarely performed in real time to direct drain insertion. OBJECTIVE: To evaluate the effectiveness and safety of real-time US-guided, radiologically placed chest drains at a tertiary university hospital. MATERIALS AND METHODS: This was a retrospective review over a 16-year period of all children with parapneumonic effusion or empyema undergoing percutaneous US-guided drainage at our centre. RESULTS: Three hundred and three drains were placed in 285 patients. Treatment was successful in 93% of patients after a single drain (98.2% success with 2 or 3 drains). Five children had peri-insertion complications, but none was significant. The success rate improved with experience. Although five patients required surgical intervention, all children treated since 2012 were successfully treated with single-tube drainage only and none has required surgery. CONCLUSION: Our technique for inserting small-bore (≤8.5 F) catheter drains under US guidance is effective and appears to be a safe procedure for first-line management of complicated parapneumonic effusion and empyema.

Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial.

BACKGROUND: Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence. Maintenance antidepressants for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to medication. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce risk of relapse or recurrence compared with usual care, but has not yet been compared with maintenance antidepressant treatment in a definitive trial. We aimed to see whether MBCT with support to taper or discontinue antidepressant treatment (MBCT-TS) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months. METHODS: In this single-blind, parallel, group randomised controlled trial (PREVENT), we recruited adult patients with three or more previous major depressive episodes and on a therapeutic dose of maintenance antidepressants, from primary care general practices in urban and rural settings in the UK. Participants were randomly assigned to either MBCT-TS or maintenance antidepressants (in a 1:1 ratio) with a computer-generated random number sequence with stratification by centre and symptomatic status. Participants were aware of treatment allocation and research assessors were masked to treatment allocation. The primary outcome was time to relapse or recurrence of depression, with patients followed up at five separate intervals during the 24-month study period. The primary analysis was based on the principle of intention to treat. The trial is registered with Current Controlled Trials, ISRCTN26666654. FINDINGS: Between March 23, 2010, and Oct 21, 2011, we assessed 2188 participants for eligibility and recruited 424 patients from 95 general practices. 212 patients were randomly assigned to MBCT-TS and 212 to maintenance antidepressants. The time to relapse or recurrence of depression did not differ between MBCT-TS and maintenance antidepressants over 24 months (hazard ratio 0·89, 95% CI 0·67-1·18; p=0·43), nor did the number of serious adverse events. Five adverse events were reported, including two deaths, in each of the MBCT-TS and maintenance antidepressants groups. No adverse events were attributable to the interventions or the trial. INTERPRETATION: We found no evidence that MBCT-TS is superior to maintenance antidepressant treatment for the prevention of depressive relapse in individuals at risk for depressive relapse or recurrence. Both treatments were associated with enduring positive outcomes in terms of relapse or recurrence, residual depressive symptoms, and quality of life. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula.

Breast Rash After Breast Reduction: A Case Study.

Breast reduction surgery is one of the most common procedures done by plastic surgeons. Although not detrimental to the final outcome, allergic reaction can negatively impact the postoperative course. This case presentation paints the classic picture of allergic reaction after breast surgery, likely due to skin glue. The typical signs of intense pruritus and erythematous rash surrounding incisions bilaterally are present. The patient was treated with our institutional protocol with good results. Our protocol is presented and further questions posed.

Nasendoscopic evaluation of stress velopharyngeal insufficiency in wind musicians: a pilot study.

OBJECTIVE: To investigate the anatomy and function of the velopharyngeal mechanism in musicians who experience symptoms of stress velopharyngeal insufficiency (VPI) compared to musicians who do not. METHODS: The velopharyngeal mechanism of 13 musicians, 8 with reported symptoms of stress VPI and 5 without, were evaluated using video nasendoscopy before and after 30 minutes of playing. All nasendoscopic recordings were rated by an external speech-language pathologist and ear, nose and throat surgeon for maintenance of velopharyngeal closure, type of velopharyngeal closure pattern, and velopharyngeal gap. RESULTS: Six out of 8 cases with stress VPI had nasal air leak during the assessment, 2 of whom had fatigue-related increased symptoms. Three controls had mild nasal air leak without affecting the consistency of soft palate seal nor quality of playing, suggesting that evidence of nasal air leak is not always symptomatic of stress VPI. All cases had unusual anatomical characteristics, such as the soft palate closing against an irregular surface on the posterior nasopharyngeal wall, which may cause insufficient velopharyngeal closure. Typically the soft palate contacted the nasopharyngeal wall higher when playing a wind instrument compared to during speech. CONCLUSION: Specific anatomical features and factors such as fatigue and stress may affect maintenance of velopharyngeal closure in persons with stress VPI. It is important that musicians with stress VPI are evaluated while playing their instrument. Future studies into stress VPI would benefit by including objective assessment components and some degree of quantifiable measurements.

Gateway to Care campaign: a public health initiative to reduce the burden of hepatitis B in Haimen City, China.

BACKGROUND: An estimated one million people worldwide die each year from complications of chronic hepatitis B infection (CHB), including liver cancer. A disproportionate number of infections and deaths occur in China. The incidence and mortality of liver cancer in Haimen City is among the highest in China, and in the world. A multi-year citywide campaign was aimed at eliminating hepatitis B virus (HBV) infection and significantly reducing the number of liver cancer deaths due to CHB in Haimen City, China. METHODS: Strategies included a public health information campaign targeting the 1.03 million city residents; specialized health education for leaders and providers to increase adoption of evidence-based HBV management protocols; establishment of health care infrastructure and management systems; and increased prevention and care delivery to key subpopulations (especially pregnant women). RESULTS: The project developed and deployed broad-reaching public awareness and health education tools and modules to 280,000 households and at community-based events. More than 90% of targeted healthcare providers and 80% of the community leaders/government officials attended educational seminars during the project period (1,441 health care providers; 1,883 local government officials). A centralized registration and management system for pregnant women was developed and instituted, 100% of pregnant women were enrolled (5,407 women over one year), and all infants born to HBV-infected mothers received one dose of HBIG and the first dose of HBV vaccine by 24 hours of birth. CONCLUSIONS: Lessons from the implementation phase of the project include the importance of: gaining early and ongoing support from the local government and health bureau for success in reaching the targeted populations; and having project management by a local, experienced, and trusted health expert to navigate implementation and relationships, and help develop culturally and linguistically appropriate materials.

Anti-TNF (adalimumab) injection for the treatment of pain-predominant early-stage frozen shoulder: the Anti-Freaze-Feasibility randomised controlled trial.

OBJECTIVE: The Anti-Freaze-F (AFF) trial assessed the feasibility of conducting a definitive trial to determine whether intra-articular injection of adalimumab can reduce pain and improve function in people with pain-predominant early-stage frozen shoulder. DESIGN: Multicentre, randomised feasibility trial, with embedded qualitative study. SETTING: Four UK National Health Service (NHS) musculoskeletal and related physiotherapy services. PARTICIPANTS: Adults ≥18 years with new episode of shoulder pain attributable to early-stage frozen shoulder. INTERVENTIONS: Participants were randomised (centralised computer generated 1:1 allocation) to either ultrasound-guided intra-articular injection of: (1) adalimumab (160 mg) or (2) placebo (saline (0.9% sodium chloride)). Participants and outcome assessors were blinded to treatment allocation. Second injection of allocated treatment (adalimumab 80 mg) or equivalent placebo was administered 2-3 weeks later. PRIMARY FEASIBILITY OBJECTIVES: (1) Ability to screen and identify participants; (2) willingness of eligible participants to consent and be randomised; (3) practicalities of delivering the intervention; (4) SD of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months. RESULTS: Between 31 May 2022 and 7 February 2023, 156 patients were screened of whom 39 (25%) were eligible. The main reasons for ineligibility were other shoulder disorder (38.5%; n=45/117) or no longer in pain-predominant frozen shoulder (33.3%; n=39/117). Of the 39 eligible patients, nine (23.1%) consented to be randomised (adalimumab n=4; placebo n=5). The main reason patients declined was because they preferred receiving steroid injection (n=13). All participants received treatment as allocated. The mean time from randomisation to first injection was 12.3 (adalimumab) and 7.2 days (placebo). Completion rates for patient-reported and clinician-assessed outcomes were 100%. CONCLUSION: This study demonstrated that current NHS musculoskeletal physiotherapy settings yielded only small numbers of participants, too few to make a trial viable. This was because many patients had passed the early stage of frozen shoulder or had already formulated a preference for treatment. TRIAL REGISTRATION NUMBER: ISRCTN 27075727, EudraCT 2021-03509-23, ClinicalTrials.gov NCT05299242 (REC 21/NE/0214).

A systematic review of flurbiprofen 8.75 mg dose and risk of adverse events (excluding haemorrhagic) resulting from drug-drug interactions.

Background: Flurbiprofen 8.75 mg lozenges and oromucosal sprays are used for symptomatic relief of sore throat in patients aged 12 years and over. The documented adverse events of flurbiprofen use include those related to its pharmacological actions, namely, increased risk of haemorrhagic events, however other adverse events (such as nephrotoxicity and cardiac failure) have been known to occur. The likelihood of occurrence of adverse events increases when flurbiprofen is used concomitantly with some other medications. Therefore, the objective of this systematic review was to collate the current evidence on adverse events which occur with flurbiprofen 8.75 mg dose (any formulation), in particular as a result of interaction with other medicinal products, with a focus on non-haemorrhagic events. Methods: Systematic searches of the literature were conducted to identify literature on any formulation of flurbiprofen 8.75 mg up to the date of the electronic database search (data lock: 28 April 2020). Publications were screened to identify studies reporting non-haemorrhagic adverse events with flurbiprofen 8.75 mg and/or non-haemorrhagic adverse events in the comparator arm. Data extraction was performed for eligible studies according to pre-defined criteria and summarised in narratives, tables and figures. Risk of bias and certainty of evidence assessments were planned for each included study where results relating to the primary objective of the systematic review were available. Results: Of 1,528 publications identified by systematic literature searches, 26 met the inclusion criteria and were included in this review. None of these 26 studies contained information on non-haemorrhagic adverse events occurring as a result of a drug-drug interaction (interaction with concomitant medication used with flurbiprofen 8.75 mg), as per the primary objective and secondary objectives of the systematic review. Conclusion: Results from this systematic review on the risk of non-haemorrhagic events did not provide evidence for these events occurring as a result of interaction with other medicinal products. Additional appropriately designed studies would be required to confirm whether these findings suggest a true absence of risk or limitations in reporting.

Reducing pressure damage: care bundles and collaborative learning.

Reduction of hospital-acquired pressure ulcers is a patient and nursing priority. Although evidence-based interventions to prevent such ulcers are well known, reducing this healthcare burden has proven consistently difficult. Via case studies, this article describes how a bundle approach to pressure ulcer prevention may be adapted for use within different clinical areas. It illustrates how collaborative learning may facilitate the spread of improvement work across a health board and build improvement skills within nursing.

NIMBUS study protocol: a single-centre feasibility study of non-invasive monitoring with bowel ultrasound in paediatric inflammatory bowel disease.

INTRODUCTION: Incidence of inflammatory bowel disease (IBD) is increasing in childhood and treatment increasingly targets mucosal healing. Monitoring bowel inflammation requires endoscopy or MRI enterography which are invasive, expensive and have long waiting lists.We aim to examine the feasibility of a non-invasive monitoring tool-bowel ultrasound (BUS)-in children with IBD and explore correlations with inflammatory markers and disease activity measures. Some BUS criteria have been found to correlate with these markers; however, this has not been validated in children.We aim to examine the feasibility of BUS for monitoring inflammation in this population; highlighting useful parameters for this purpose. We aim to inform a larger scale randomised controlled trial using BUS. METHODS AND ANALYSIS: This prospective observational feasibility study will be carried out over 24 months at the Noah's Ark Children's Hospital for Wales, Cardiff; with the endpoint recruitment of 50 participants. Children aged 2-18 years with a modified Porto criteria diagnosis of IBD will be included.Patients without IBD or who have previously undergone IBD-related surgery will be excluded; as will families unable to give informed consent.Ultrasound scan images and reports will be collected, as well as laboratory results and clinical outcomes.The primary aim will assess the feasibility of targeted BUS for disease monitoring; including recruitment statistics. The secondary aims will involve data collection and correlation analysis for targeted ultrasound parameters, biomarkers, disease activity scores and prediction of changes in treatment. The statistical methods will include: feasibility metrics, descriptive statistics, cross-tabulation and χ2 analysis, correlation analysis, regression analysis. ETHICS AND DISSEMINATION: Ethical approval is granted by NHS Research Ethics Committee. The sponsor is Cardiff and Vale University Health Board. We will publish the results in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER: NCT05673278.

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Dichlorodiphenyltrichloroethane and risk of hepatocellular carcinoma.

Dichlorodiphenyltrichloroethane (p,p'-DDT), an organochlorine pesticide known to have deleterious health effects in humans, has been linked to hepatocellular carcinoma (HCC) in rodents. A recent study has reported that p,p'-DDT and its most persistent metabolite, dichlorodiphenyldichloroethylene (p,p'-DDE), may also be associated with HCC in humans. To examine whether there is an association between p,p'-DDT and/or p,p'-DDE in a population at high-risk of developing HCC, a nested case-control study was conducted within the 83,794 person Haimen City Cohort in China. Sera and questionnaire data were collected from all participants between 1992 and 1993. This study included 473 persons who developed HCC and 492 who did not, frequency matched on sex, age and area of residence. p,p'-DDT and p,p'-DDE levels were determined by mass spectrometry. Hepatitis B viral infection status (based on hepatitis B virus surface antigen; HBsAg) was also determined. p,p'-DDT and/or p,p'-DDE serum levels were significantly associated with sex, area of residence, occupation, alcohol consumption and cigarette smoking. Adjusting for age, sex, area of residence, HBsAg, family history of HCC, history of acute hepatitis, smoking, alcohol, occupation (farmer vs. other) and levels of p,p'-DDT or p,p'-DDE, odds ratios (OR) and 95% confidence intervals (CI) were calculated via unconditional logistic regression. Overall, the highest quintile of p,p'-DDT was associated with an increased risk of HCC, OR = 2.96 95% CI; 1.19-7.40. There were no statistically significant associations with p,p'-DDE. Overall, these results suggest that recent exposure to p,p'-DDT may increase risk of HCC.

Quantitative dynamics of hepatitis B basal core promoter and precore mutants before and after HBeAg seroconversion.

BACKGROUND & AIMS: Hepatitis B e antigen (HBeAg) seroconversion is an important clinical and virological "landmark" during chronic hepatitis B virus (HBV) infection. Mutant viruses carrying the precore G1896A and/or the basal core promoter (BCP) A1762T/G1764A mutations are associated with HBeAg seroconversion. However, the exact role of these mutants in HBeAg seroconversion remains unclear, partly because the evolution of these mutant viruses before and after seroconversion has not been well studied. METHODS: Using our novel mutant quantification methods, the percentage of the mutant viruses was analyzed both cross-sectionally and longitudinally, before and after seroconversion. RESULTS: Cross-sectional analysis showed that the percentage of both precore and BCP mutants gradually increased with age in the HBeAg-positive population. Follow-up of 18 HBeAg-positive patients revealed that the mutant percentage may stay low and stable for many years, followed by a steady increase in the percentage of G1896A and/or A1762T/G1764A mutants, from <10% to 50-100%, within about 3 years prior to seroconversion. In all cases, increase of mutant percentage was preceded or accompanied by elevated serum alanine aminotransferase. After the seroconversion, the mutant percentage could remain high or decrease significantly, sometimes to below 20%. CONCLUSIONS: Levels of G1896A and A1762T/G1764A mutants (of genotypes B and C) in the HBeAg-positive patients may predict the time of HBeAg seroconversion. The dominance of these mutants in the HBeAg-positive phase is more likely the result of immune selection rather than the enhanced replication capability of the mutants. However, anti-HBe antibody may not be a major selection force for these mutants.