A hyper-quiescent chromatin state formed during aging is reversed by regeneration.

Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach and the first direct visualization of aged chromatin, we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcriptional suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver.

Nintedanib in children and adolescents with fibrosing interstitial lung diseases.

BACKGROUND: Childhood interstitial lung disease (ILD) comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. METHODS: Patients aged 6-17 years with fibrosing ILD on high-resolution computed tomography and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks and then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary end-points were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. RESULTS: 26 patients received nintedanib and 13 patients received placebo. The geometric mean (geometric coefficient of variation) AUCτ,ss for nintedanib was 175 µg·h·L-1 (85.1%) in patients aged 6-11 years and 160 µg·h·L-1 (82.7%) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean±se changes in percentage predicted forced vital capacity at week 24 were 0.3±1.3% in the nintedanib group and -0.9±1.8% in the placebo group. CONCLUSIONS: In children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

Seasonality in General Surgery Hospitalizations and Procedures in the US: Workflow Implications.

INTRODUCTION: Seasonality has been studied in select conditions treated by surgeons and internists, but is not well understood regarding overall procedural volume in general surgery. Furthermore, much of the literature is limited due to lack of use of seasonal-trend-decomposition analyses. METHODS: All admissions with general surgery procedures were pooled from NIS 2002-2014, monthly hospitalization rates calculated, and seasonal-trend decomposition performed. RESULTS: Emergent admissions, accounting for 9% of the average annual incidence, had more prominent seasonality than elective admissions. Inpatient surgical-procedural volume remained relatively stable throughout the year and decreased only in the third quarter. Procedures for acute intra-abdominal conditions and traumas peaked in summer months, while endoscopies, tracheostomies and gastrostomies peaked in winter months. CONCLUSIONS: Many surgical pathologies and corresponding general-surgery procedures obey circannual patterns. Surgical workforce remains in high demand throughout the year except for fall and winter holidays. Understanding seasonal variation in such demand may be important for staffing and resource planning.

Trends and seasonality in hospitalizations for acute alcohol-related and biliary pancreatitis in the USA.

BACKGROUND: The incidence of acute pancreatitis (AP) is characterized by circannual and geographical variation. The aim of this study was to describe seasonal variation and trends in hospitalizations for AP in the USA with respect to AP etiology. METHODS: The Nationwide Inpatient Sample data (2000-2016) from the Healthcare Cost and Utilization Project were used. The study population included all primary hospitalizations for AP. Biliary AP (BAP) and alcohol-induced AP (AAP) were distinguished by diagnostic and procedural ICD codes. Seasonal trend decomposition was performed. RESULTS: There was a linear increase in annual incidence (per 100 000 population) of AAP in the USA (from 17.0 in 2000 to 22.9 in 2016), while incidence of BAP, equaled 19.9 in 2000, peaked at 22.1 in 2006 and decreased to 17.4 in 2016. AP incidence demonstrated 18% annual incidence amplitude with summer peak and winter trough, more prominent in AAP. In 2016, within AAP, the highest incidence (per 100 000 population) was noted among African-Americans (up to 50.4), followed by males aged 56-70 years (26.5) and Asians of low income (25.5); within BAP, above the average incidence was observed in Hispanic (up to 25.8) and Asian (up to 25.0) population. The most consistent and rapid increase in AP incidence was noted in males aged 56-70 years with an alcoholic etiology (average 6% annual incidence growth). CONCLUSIONS: The incidence and annual trends of AP vary significantly among demographic and socioeconomic groups and this knowledge may be useful for the planning of healthcare resources and identification of at-risk populations.

Predictors of same-admission cholecystectomy in mild, acute, biliary pancreatitis.

BACKGROUND: Failure to perform same-admission cholecystectomy (SA-CCY) for mild, acute, biliary pancreatitis (MABP) is a recognized risk factor for recurrence and readmission. However, rates of SA-CCY are low and factors associated with these low rates require elucidation. METHODS: Primary MAPB admissions were pooled from NIS 2000-2014 (weighted n = 578 258). Patients with chronic pancreatitis, pancreatic masses, alcohol-related disorders, hypertriglyceridemia, acute cholecystitis and AP-related organ dysfunction or complications were excluded. Annual rates of SA-CCY were calculated. Regression model for prediction of SA-CCY was built on 2010-2011 subset (weighted n = 74 169), yielding 96.3% of complete observations. RESULTS: Nationwide rate of SA-CCY in the U.S. was 40.8%. In multivariate analysis, SA-CCY was positively associated with BMI>30 (OR = 1.4, 95%CI 1.2-1.6), Asian ethnicity (vs. Black; OR = 1.2, 95%CI 1.0-1.5), private insurance (vs. Medicare; OR = 1.1, 95%CI 1.0-1.3), large (vs. small; OR = 1.3, 95%CI 1.2-1.4) urban hospitals (vs. rural; OR = 1.5 95%CI 1.3-1.7) of the South (vs. Northeast; OR = 1.5, 95%CI 1.3-1.7), as well as with chronic cholecystitis (OR = 17.0, 95%CI 15.4-18.7) and abdominal-wall hernias (OR = 5.2; 95%CI 3.0-8.9); the latter two predictors were not included in the final model. SA-CCY was negatively associated with age >40 (OR = 0.72; 95%CI 0.66-0.79), male gender (OR = 0.86, 95%CI 0.80-0.93), dementia (OR = 0.88, 95%CI 0.72-1.1), chronic comorbidities (OR = 0.64; 95%CI 0.54-0.77) and ostomies (OR = 0.51; 95%CI 0.31-0.86). CONCLUSION: Adherence to SA-CCY guidelines for MABP remains inadequate. Independent geographic variation in SA-CCY rates may be related to reimbursement differences, ownership of AP patients, accessibility to surgical care, or cultural characteristics of the patient population.

How much pain relief do patients expect after cholecystectomy?

BACKGROUND: Cholecystectomy is a common operation, increasingly performed, in the USA, for "functional gall bladder disorder" (FGBD). Outcomes of these surgeries are uncertain. In planning a study of FGBD, we needed to define the best outcome measures. METHODS: We sought the opinions of patients (52 with FGBD and 100 with stones for comparison) coming to cholecystectomy. They were asked to respond in four ways about the minimum benefit they would count as "success." RESULTS: We found that most patients do not expect cholecystectomy to relieve their pain-related disability completely, regardless of the presence or absence of stones. CONCLUSIONS: Future studies of the success of surgery should use patient-centered outcome assessments, such as PGIC (patient's global impression of change), in addition to objective measures of the impact of treatment on key symptoms, such as pain.

Detecting accidental punctures and lacerations during cholecystectomy in large datasets: Two methods of analysis.

BACKGROUND: After the Institute of Medicine (IOM) report To Err Is Human highlighted the impact of medical errors, the Agency for Healthcare Research and Quality (AHRQ) developed Patient-Safety Indicators (PSI) to improve quality by identifying potential inpatient safety problems. PSI-15 was created to study accidental punctures and lacerations (APL), but PSI-15 may underestimate APLs in populations of patients. This study compares PSI-15 with a more inclusive approach using a novel composite of secondary diagnostic and procedural codes. METHODS: We used Nationwide Inpatient Sample (NIS) data (2000-2012) from AHRQ's Healthcare Cost and Utilization Project (H-CUP). We analyzed PSI-15-positive and -negative cholecystectomies. Cross tabulations identified codes that were significantly more frequent among PSI-15-positive cases; these secondary diagnostic and procedural codes were selected as candidate members of a composite marker (CM) of APL. We chose cholecystectomy patients for study because this is one of the most common general operations, and the large size of NIS allows for meaningful analysis of infrequent occurrences such as APL rates. RESULTS: CM identified 1.13 times more APLs than did PSI-15. Patients with CM-detected APLs were significantly older and had worse mortality, comorbidities, lengths of stay, and charges than those detected with PSI-15. Further comparison of these two approaches revealed that time-series analysis for both APL markers revealed parallel trends, with inflections in 2007, and lowest APL rates in July. CONCLUSIONS: Although CM may yield more false positives, it appears more inclusive, identifying more clinically significant APLs, than PSI-15. Both measures presented similar trends over time, arguing against inflation in PSI-15 reporting. While arguably less specific, CM may increase sensitivity for detecting APL events during cholecystectomies. These results may inform the interpretation of other large population studies of APLs following abdominal operations.

Clues to predict incidental gallbladder cancer.

BACKGROUND: Consequences of incidental gallbladder cancer (iGBC) following cholecystectomy may include repeat operation (depending on T stage) and worse survival (if bile spillage occurred), both avoidable if iGBC were suspected preoperatively. METHODS: A retrospective single-institution review was done. Ultrasound images for cases and controls were blindly reviewed by a radiologist. Chi-square and Student's t tests, as well as logistic regression and Kaplan-Meier analyses were used. A P ≤ 0.01 was considered significant. RESULTS: Among 5796 cholecystectomies performed 2000-2013, 26 (0.45%) were iGBC cases. These patients were older (75.61 versus 52.27 years), had more laparoscopic-to-open conversions (23.1% versus 3.9%), underwent more imaging tests, had larger common bile duct diameter (7.13 versus 5.04 mm) and higher alkaline phosphatase. Ultrasound imaging showed that gallbladder wall thickening (GBWT) without pericholecystic fluid (PCCF), but not focal-versus-diffuse GBWT, was associated significantly with iGBC (73.9% versus 47.4%). On multivariable logistic regression analysis, GBWT without PCCF, and age were the strongest predictors of iGBC. The consequences iGBC depended significantly on intraoperative bile spillage, with nearly all such patients developing carcinomatosis and significantly worse survival. CONCLUSIONS: Besides age, GBWT, dilated common bile duct, and elevated alkaline phosphatase, number of preoperative imaging modalities and the presence of GBWT without PCCF are useful predictors of iGBC. Bile spillage causes poor survival in patients with iGBC.

Minimally invasive and open gallbladder cancer resections: 30- vs 90-day mortality.

BACKGROUND: Minimally invasive surgery is increasingly used for gallbladder cancer resection. Postoperative mortality at 30 days is low, but 90-day mortality is underreported. METHODS: Using National Cancer Database (1998-2012), all resection patients were included. Thirty- and 90-day mortality rates were compared. RESULTS: A total of 36 067 patients were identified, 19 139 (53%) of whom underwent resection. Median age was 71 years and 70.7% were female. Ninety-day mortality following surgical resection was 2.3-fold higher than 30-mortality (17.1% vs 7.4%). There was a statistically significant increase in 30- and 90-day mortality with poorly differentiated tumors, presence of lymphovascular invasion, tumor stage, incomplete surgical resection and low-volume centers (P<0.001 for all). Even for the 1885 patients who underwent minimally invasive resection between 2010 and 2012, the 90-day mortality was 2.8-fold higher than the 30-day mortality (12.0% vs 4.3%). CONCLUSIONS: Ninety-day mortality following gallbladder cancer resection is significantly higher than 30-day mortality. Postoperative mortality is associated with tumor grade, lymphovascular invasion, tumor stage, type and completeness of surgical resection as well as type and volume of facility.

The "Colonial Wig" pancreaticojejunostomy: zero leaks with a novel technique for reconstruction after pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains common and morbid after pancreaticoduodenectomy (PD). A major advance in the study of POPF is the fistula risk score (FRS). METHODS: We analyzed 48 consecutive patients undergoing PD. The "Colonial Wig" pancreaticojejunostomy (CWPJ) technique was used in the last 22 PDs, we compared 22 CWPJ to 26 conventional PDs. RESULTS: Postoperative morbidity was 49% (27% Clavien grade >2). The median length of hospital stay was 11 days. In the first 26 PDs, the PJ was performed according to standard techniques and the clinically relevant POPF (CR-POPF) rate was 15%, similar to the FRS-predicted rate (14%). In the next 22 PJs, the CWPJ was employed. Although the FRS-predicted rates were similar in these two groups (14% vs 13%), the CR-POPF rate in the CWPJ group was 0 (P=0.052). CONCLUSION: Early experience with the CWPJ is encouraging, and this anastomosis may be a safe and effective way to lower POPF rates.

HIDA scan for functional gallbladder disorder: ensure that you know how the scan was done.

BACKGROUND: Despite the increasing use of fatty meal (FM) as a substitute for cholecystokinin (CCK) in pain reproduction during hepato-imino-diacetic acid (HIDA) scan in functional gallbladder disorder, there are no studies comparing the differences between CCK and FM. The present study was to compare the efficacy of FM in comparison of CCK in FGBD application. METHODS: Patients undergoing HIDA scans from August 2013 to May 2014 were divided into two groups: those undergoing CCK-stimulated HIDA scan versus FM-stimulated HIDA scan. These groups were compared according to demographics and HIDA results. RESULTS: Of 153 patients, 70 received CCK and 83 FM. There was no difference regarding age, gender, gallstones, gallbladder ejection fraction and time to visualization. However, significantly more of the patients receiving CCK than FM experienced pain reproduction (61% vs 30%, P<0.01). CONCLUSIONS: Stimulation of gallbladder contractility with a FM during HIDA is less than half as likely to reproduce biliary symptoms compared to CCK, despite similar ejection fractions and other parameters. It is essential that providers account for this difference when counseling patients regarding cholecystectomy for functional gallbladder disorder.

Implications of gallbladder cholesterolosis and cholesterol polyps?

BACKGROUND: The clinical significance of cholesterolosis has not been well established but there are some provocative, if not robust, studies of the role it may play in the pathophysiology of pancreatitis and biliary dyskinesia, as well as hypercholesterolemia. Our aim was to take advantage of a very large cholecystectomy (CCY) database to support or refute these potentially important reported associations. MATERIALS AND METHODS: A retrospective review of 6868 patients who underwent CCY from 2001-2013 was performed. Comparisons were made using the student t-test for continuous and chi-square analysis for categorical, variables. RESULTS: Among patients for whom the CCY was the primary operation, 1053 (18%) had cholesterolosis and 4596 did not. Compared to those without cholesterolosis, those with cholesterolosis were no more likely to have elevated cholesterol levels (P = 0.64) nor low gallbladder ejection fraction (P = 0.2). To evaluate cholesterolosis as a cause of pancreatitis, all patients with gallstones were eliminated, leaving 639 patients. Among these, not only was cholesterolosis not associated with more pancreatitis, but rather there was not a single patient with or without cholesterolosis who had pancreatitis. CONCLUSIONS: Despite prior reports of associations between cholesterolosis and elevated serum cholesterol, depressed ejection fraction, and increased risk of pancreatitis, careful analysis of this current, larger data set does not support these associations. Any patient with stones or sludge, or with biliary dyskinesia, and appropriate symptoms, should be considered for CCY, with or without suspected cholesterolosis.

Necrotizing pancreatitis: a review of multidisciplinary management.

The objective of this review is to summarize the current state of the art of the management of necrotizing pancreatitis, and to clarify some confusing points regarding the terminology and diagnosis of necrotizing pancreatitis, as these points are essential for management decisions and communication between providers and within the literature. Acute pancreatitis varies widely in its clinical presentation. Despite the publication of the Atlanta guidelines, misuse of pancreatitis terminology continues in the literature and in clinical practice, especially regarding the local complications associated with severe acute pancreatitis. Necrotizing pancreatitis is a manifestation of severe acute pancreatitis associated with significant morbidity and mortality. Diagnosis is aided by pancreas-protocol computed tomography or magnetic resonance imaging, ideally 72 h after onset of symptoms to achieve the most accurate characterization of pancreatic necrosis. The extent of necrosis correlates well with the incidence of infected necrosis, organ failure, need for debridement, and morbidity and mortality. Having established the diagnosis of pancreatic necrosis, goals of appropriately aggressive resuscitation should be established and adhered to in a multidisciplinary approach, ideally at a high-volume pancreatic center. The role of antibiotics is determined by the presence of infected necrosis. Early enteral feeds improve outcomes compared with parenteral nutrition. Pancreatic necrosis is associated with a multitude of complications which can lead to long-term morbidity or mortality. Interventional therapy should be guided by available resources and the principle of a minimally invasive approach. When open debridement is necessary, it should be delayed at least 3-6 weeks to allow demarcation of necrotic from viable tissue.

A breath of fresh air: a quality-improvement study comparing an air-circulating technique versus conventional technique to prevent nasogastric tube dysfunction.

BACKGROUND: Nasogastric tubes are an important component of care in patients with gastrointestinal obstructions. However, they are prone to malfunction despite conventional flushing techniques, with potentially severe consequences. There is no widely accepted, gold-standard way to ensure that a nasogastric tube succeeds in maintaining an empty stomach following flushing. METHODS: We have developed a flushing technique to better ensure successful tube function. We compared this technique to conventional flushing both in vitro (using a plastic stomach model) and in vivo (in a pig model), and we provide a didactic video. RESULTS: The mean gastric residual volume following our novel flushing technique is nearly 25-fold lower than following conventional flushing (13 mL vs. 330 mL). CONCLUSIONS: Our simple technique is more effective than conventional techniques in maintaining nasogastric tube function and therefore should prevent dangerous vomiting and aspiration pneumonia better than conventional techniques.

Gallbladder dysfunction: how much longer will it be controversial?

BACKGROUND: Motility disorders of the biliary tree [biliary dyskinesia, including both gallbladder dysfunction (GBD), and sphincter of Oddi dysfunction] are difficult to diagnose and to treat. SUMMARY: There is controversy in the literature in particular regarding the criteria that should be used to select patients for cholecystectomy (CCY) in cases of suspected GBD. The current review covers the history, diagnosis, and treatment of GBD. Key Messages: Only >85% of patients with suspected GBD have relief following CCY, a much lower rate than the nearly 100% success rate following CCY for gallstone disease. Unfortunately, the literature is lacking, and there are no universally agreed-upon criteria for selecting which patients to refer for operation, although cholecystokinin (CCK)-enhanced hepatobiliary iminodiacetic acid scan is often used, with emphasis on an abnormally low gallbladder ejection fraction or pain reproduction at CCK administration. There is a clear need for large, well-designed, more definitive, prospective studies to better identify the indications for and efficacy of CCY in cases of GBD.

Hemosuccus pancreaticus due to a noninflammatory pancreatic pseudotumor.

CONTEXT: Hemosuccus pancreaticus is a rare source of gastrointestinal bleeding, the most frequent cause of which is pancreatitis, followed by tumors, but nearly all these tumors are true neoplasms, and not pseudotumors. Furthermore, nearly all pseudotumors of the pancreas and retroperitoneum are inflammatory. CASE REPORT: We present a case of hemosuccus pancreaticus associated with a nonneoplastic noninflammatory pseudotumor of the pancreas. CONCLUSIONS: Pancreatic pseudotumors are not always inflammatory and should be considered in the differential diagnosis of gastrointestinal bleeding associated with hemosuccus pancreaticus.

Predicting gangrenous cholecystitis.

BACKGROUND: Gangrenous cholecystitis (GC) is often challenging to treat. The objectives of this study were to determine the accuracy of pre-operative diagnosis, to assess the rate of post-cholecystectomy complications and to assess models to predict GC. METHODS: A retrospective single-institution review identified patients undergoing a cholecystectomy. Logistic regression models were used to examine the association of variables with GC and to build risk-assessment models. RESULTS: Of 5812 patients undergoing a cholecystectomy, 2219 had acute, 4837 chronic and 351 GC. Surgeons diagnosed GC pre-operatively in only 9% of cases. Patients with GC had more complications, including bile-duct injury, increased estimated blood loss (EBL) and more frequent open cholecystectomies. In unadjusted analyses, variables significantly associated with GC included: age >45 years, male gender, heart rate (HR) >90, white blood cell count (WBC) >13,000/mm(3), gallbladder wall thickening (GBWT) ≥ 4 mm, pericholecystic fluid (PCCF) and American Society of Anesthesiology (ASA) >2. In adjusted analyses, age, WBC, GBWT and HR, but not gender, PCCF or ASA remained statistically significant. A 5-point scoring system was created: 0 points gave a 2% probability of GC and 5 points a 63% probability. CONCLUSION: Using models can improve a diagnosis of GC pre-operatively. A prediction of GC pre-operatively may allow surgeons to be better prepared for a difficult operation.

Functional gallbladder disorder: Interim analysis of a prospective cohort study.

BACKGROUND: Functional gallbladder disorder (FGBD) remains a controversial indication for cholecystectomy. METHODS: A prospective cohort study enrolled patients strictly meeting Rome criteria for FGBD, and cholecystectomy was performed. They were assessed pre- and 3 and 6 months postoperatively with surveys of abdominal pain and quality of life (RAPID and SF-12 surveys, respectively). Interim analysis was performed. RESULTS: Although neither ejection fraction nor pain reproduction predicted success after cholecystectomy, the vast majority of enrolled patients had a successful outcome after undergoing cholecystectomy for FGBD: of a planned 100 patients, 46 were enrolled. Of 31 evaluable patients, 26 (83.9 â€‹%) reported RAPID improvement and 28 (93.3 â€‹%) SF12 improvement at 3- or 6-month follow-up. CONCLUSION: FGBD, strictly diagnosed, should perhaps no longer be a controversial indication for cholecystectomy, since its success rate for biliary pain in this study was similar to that for symptomatic cholelithiasis. Larger-scale studies or randomized trials may confirm these findings.

Treating severe paediatric asthma with mepolizumab or omalizumab: a protocol for the TREAT randomised non-inferiority trial.

INTRODUCTION: A minority of school-aged children with asthma have persistent poor control and experience frequent asthma attacks despite maximal prescribed maintenance therapy. These children have higher morbidity and risk of death. The first add-on biologic therapy, omalizumab, a monoclonal antibody that blocks immunoglobulin (Ig)E, was licensed for children with severe asthma in 2005. While omalizumab is an effective treatment, non-response is common. A second biologic, mepolizumab which blocks interleukin 5 and targets eosinophilic inflammation, was licensed in 2018, but the licence was granted by extrapolation of adult clinical trial data to children. This non-inferiority (NI) trial will determine whether mepolizumab is as efficacious as omalizumab in reducing asthma attacks in children with severe therapy resistant asthma (STRA) and refractory difficult asthma (DA). METHODS AND ANALYSIS: This is an ongoing multicentre 1:1 randomised NI open-label trial of mepolizumab and omalizumab. Up to 150 children and young people (CYP) aged 6-17 years with severe asthma will be recruited from specialist paediatric severe asthma centres in the UK. Prior to randomisation, children will be monitored for medication adherence for up to 16 weeks to determine STRA and refractory DA diagnoses. Current prescribing recommendations of serum IgE and blood eosinophils will not influence eligibility or enrolment. The primary outcome is the 52-week asthma attack rate. Bayesian analysis using clinician-elicited prior distributions will be used to calculate the posterior probability that mepolizumab is not inferior to omalizumab. Secondary outcomes include Composite Asthma Severity Index, Paediatric Asthma Quality of Life Questionnaire, lung function measures (forced expiratory volume in one second (FEV1), bronchodilator reversibility), fractional exhaled nitric oxide, Asthma Control Test (ACT), health outcomes EuroQol 5 Dimension (EQ-5D) and optimal serum IgE and blood eosinophil levels that may predict a response to therapy. These outcomes will be analysed in a frequentist framework using longitudinal models. ETHICS AND DISSEMINATION: The study has been approved by the South Central-Berkshire Research Ethics Committee REC Number 19/SC/0634 and had Clinical Trials Authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT 2019-004085-17). All parents/legal guardians will give informed consent for their child to participate in the trial, and CYP will give assent to participate. The results will be published in peer-reviewed journals, presented at international conferences and disseminated via our patient and public involvement partners. TRIAL REGISTRATION NUMBER: ISRCTN12109108; EudraCT Number: 2019-004085-17.