NSAID prescribing and adverse outcomes in common infections: a population-based cohort study.

OBJECTIVES: Infections in primary care are often treated with non-steroidal anti-inflammatory drugs (NSAIDs). This study evaluates whether NSAID prescribing is associated with adverse outcomes for respiratory (RTIs) or urinary track (UTI) infections. OBJECTIVES: To determine whether there is an association between NSAID prescribing and the rate of adverse outcomes for infections for individual consulting in primary care. DESIGN: Cohort study of electronic health records. SETTING: 87 general practices in the UK Clinical Practice Research Datalink GOLD. PARTICIPANTS: 142 925 patients consulting with RTI or UTI. PRIMARY AND SECONDARY OUTCOME MEASURES: Repeat consultations, hospitalisation or death within 30 days of the initial consultation for RTI or UTI. Poisson models estimated the associations between NSAID exposure and outcome. Rate ratios were adjusted for gender, age, ethnicity, deprivation, antibiotic use, seasonal influenza vaccination status, comorbidities and general practice. Since prescribing variations by practice are not explained by case mix-hence, less impacted by confounding by indication-both individual-level and practice-level analyses are included. RESULTS: There was an increase in hospital admission/death for acute NSAID prescriptions (RR 2.73, 95% CI 2.10 to 3.56) and repeated NSAID prescriptions (6.47, 4.46-9.39) in RTI patients, and for acute NSAID prescriptions for UTI (RR 3.03; 1.92 to 4.76). Practice-level analysis, controlling for practice population characteristics, found that for each percentage point increase in NSAID prescription, the percentages of hospital admission/death within 30 days increased by 0.32 percentage points (95% CI 0.16 to 0.47). CONCLUSIONS: In this non-randomised study, prescription of NSAIDs at consultations for RTI or UTIs in primary care is infrequent but may be associated with increased risk of hospital admission. This supports other observational and limited trial data that NSAID prescribing might be associated with worse outcomes following acute infection and should be prescribed with caution.

Derivation and validation of a novel functional FFRCT score incorporating the burden of coronary stenosis severity and flow impairment to predict clinical events.

BACKGROUND: A score combining the burden of stenosis severity on coronary computed tomography angiography (CCTA) and flow impairment by fractional flow reserve derived from computed tomography (FFRCT) may be a better predictor of clinical events than either parameter alone. METHODS: The Functional FFRCT Score (FFS) combines CCTA and FFRCT parameters in an allocated point-based system. The feasibility of the FFS was assessed in cohort of 72 stable chest pain patients with matched CCTA and FFRCT datasets. Validation was performed using 2 cohorts: (a) 4468 patients from the ADVANCE Registry to define its association with revascularization and major adverse cardiovascular events (MACE); (b) 212 patients from the FORECAST trial to determine predictors of MACE. RESULTS: The median calculation time for the FFS was 10 (interquartile range 6-17) seconds, with strong intra-operator and inter-operator agreement (Cohen's Kappa 0.89 (±0.37, p â€‹< â€‹0.001) and 0.83 (±0.04, p â€‹< â€‹0.001, respectively). The FFS correlated strongly with both the CT-SYNTAX and the Functional CT-SYNTAX scores (rS â€‹= â€‹0.808 for both, p â€‹< â€‹0.001). In the ADVANCE cohort the FFS had good discriminatory abilities for revascularization with an area under the curve of 0.82, 95 â€‹% confidence interval (CI) 0.81-0.84, p â€‹< â€‹0.001. Patients in the highest FFS tertile had significantly higher rates of revascularization (61 â€‹% vs 5 â€‹%, p â€‹< â€‹0.001) and MACE (1.9 â€‹% vs 0.5 â€‹%, p â€‹= â€‹0.001) compared with the lowest FFS tertile. In the FORECAST cohort the FFS was an independent predictor of MACE at 9-month follow-up (hazard ratio 1.04, 95 â€‹% CI 1.01-1.08, p â€‹< â€‹0.01). CONCLUSION: The FFS is a quick-to-calculate and reproducible score, associated with revascularization and MACE in two distinct populations of stable symptomatic patients.

Utilising Pancreatic Exocrine Insufficiency in the Detection of Resectable Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed late, leading to a high mortality rate. Early detection facilitates better treatment options. The aim of this UK-based case-control study was to determine whether two validated tests for pancreatic exocrine insufficiency (PEI), namely, the 13C-mixed triglyceride breath test (13C-MTGBT) and a faecal elastase (FE-1) test, can discriminate between patients with resectable PDAC versus healthy volunteers (HVs) along with a comparison group with chronic pancreatitis (CP). Discrimination between disease states and HVs was tested with receiver operator characteristic (ROC) curves. In total, 59 participants (23 PDAC (16 men), 24 HVs (13 men) and 12 CP (10 men)) were recruited, with a similar age in each population, and a combined median (IQR) age of 66 (57-71). The areas under the ROC curve for discriminating between PDAC and HVs were 0.83 (95% CI: 0.70-0.96) for the 13C-MTGBT, and 0.85 (95% CI: 0.75-0.95) for the FE-1 test. These were similar to CP vs. HV. In conclusion, PEI occurs in resectable PDAC to a similar extent as in CP; further large-scale, prospective studies using these tests in the primary care setting on high-risk groups are warranted.

Elevated Glycated Haemoglobin (HbA1c) Is Associated with an Increased Risk of Pancreatic Ductal Adenocarcinoma: A UK Biobank Cohort Study.

BACKGROUND: The role of dysglycaemia as a risk marker for Pancreatic Ductal Adenocarcinoma (PDAC) is uncertain. We investigated the relationship between glycated haemoglobin (HbA1c) and incident PDAC using a retrospective cohort study within the UK Biobank. METHODS: A study involving 499,804 participants from the UK Biobank study was undertaken. Participants were stratified by diabetes mellitus (DM) status, and then by HbA1c values < 42 mmol/mol, 42-47 mmol/mol, or ≥48 mmol/mol. Cox proportional hazard models were used to describe the association between HbA1c category (with time-varying interactions) and incident PDAC. RESULTS: PDAC occurred in 1157 participants during 11.6 (10.9-12.3) years follow up [(median (interquartile range)]. In subjects without known DM at baseline, 12 months after recruitment, the adjusted hazard ratios (aHR, 95% CI) for incident PDAC for HbA1c 42-47 mmol/mol compared to HbA1c < 42 mmol/mol (reference group) was 2.10 (1.31-3.37, p = 0.002); and was 8.55 (4.58-15.99, p < 0.001) for HbA1c ≥ 48 mmol/mol. The association between baseline HbA1c and incident PDAC attenuated with increasing duration of time of follow-up to PDAC diagnosis. CONCLUSIONS: Dysglycaemia detected by elevated HbA1c is associated with an increased risk of PDAC. The strength of the association between elevated HbA1c and incident PDAC is inversely proportional to the time from detecting dysglycaemia but remains significant for at least 60 months following HbA1c testing.

A multicentre randomised controlled trial of a guided self-help cognitive behavioural therapy to MANage the impact of hot flushes and night sweats in patients with prostate CANcer undergoing androgen deprivation therapy (MANCAN2).

BACKGROUND: Androgen deprivation therapy (ADT) is prescribed to almost half of all men diagnosed with prostate cancer. Although ADT is effective treatment, with virtually all men with advanced disease showing initial clinical response, it is associated with troublesome side effects including hot flushes and night sweats (HFNS). HFNS can be both frequent and severe and can have a significant impact on quality of life (QoL). They can occasionally be so debilitating that patients stop ADT altogether, despite the increased risk of disease relapse or death. Previous research has found that guided self-help cognitive behavioural therapy (CBT) can be effective in reducing HFNS due to ADT when delivered by a clinical psychologist. MANCAN2 aims test whether we can train the existing NHS Prostate Cancer Nurse Specialist (CNS) team to deliver guided self-help CBT and whether it is effective in reducing the impact of HFNS in men undergoing ADT. METHODS: MANCAN2 is a phase III multicentre randomised controlled trial and process evaluation. Between 144 and 196 men with prostate cancer who are currently receiving ADT and are experiencing problematic HFNS will be individually randomised in a 1:1 ratio in groups of 6-8 participants to either treatment as usual (TAU) or participation in the guided self-help CBT intervention plus TAU. A process evaluation using the normalisation process theory (NPT) framework will be conducted, to understand the CNS team's experiences of delivering the intervention and to establish the key influencers to its implementation as a routine practice service. Fidelity of implementation of the intervention will be conducted by expert assessment. The cost-effectiveness of the intervention and participant adherence to the trial intervention will also be assessed. DISCUSSION: MANCAN2 will advance the program of work already conducted in development of management strategies for HFNS. This research will determine whether the severity of ADT-induced HFNS in men with prostate cancer can be reduced by a guided self-help CBT intervention, delivered by the existing NHS prostate cancer CNS team, within a multicentre study. The emphasis on this existing team, if successful, should facilitate translation through to implementation in routine practice. TRIAL REGISTRATION: ISRCTN reference 58720120 . Registered 13 December 2022.

Differential Efficacy From the Addition of Bortezomib to R-CHOP in Diffuse Large B-Cell Lymphoma According to the Molecular Subgroup in the REMoDL-B Study With a 5-Year Follow-Up.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The REMoDL-B phase III adaptive trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), stratified by molecular subtype. Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS). Retrospective analysis using a gene expression-based classifier identified a molecular high-grade (MHG) group with worse outcomes. We present an updated analysis for patients successfully classified by the gene expression profile (GEP). Eligible patients were age older than 18 years with untreated DLBCL, fit enough for full-dose chemotherapy, and with adequate biopsies for GEP. Of 1,077 patients registered, 801 were identified with Activated B-Cell (ABC), Germinal Center B-cell, or MHG lymphoma. At a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS or OS (5-year PFS hazard ratio [HR], 0.81; P = .085; OS HR, 0.86; P = .32). However, improved PFS and OS were seen in ABC lymphomas after RB-CHOP: 5-year OS 67% with R-CHOP versus 80% with RB-CHOP (HR, 0.58; 95% CI, 0.35 to 0.95; P = .032). Five-year PFS was higher in MHG lymphomas: 29% versus 55% (HR, 0.46; 95% CI, 0.26 to 0.84). Patients with ABC and MHG DLBCL may benefit from the addition of bortezomib to R-CHOP in initial therapy.

Randomized comparison of chest pain evaluation with FFRCT or standard care: Factors determining US costs.

BACKGROUND: FFRCT assesses the functional significance of lesions seen on CTCA, and may be a more efficient approach to chest pain evaluation. The FORECAST randomized trial found no significant difference in costs within the UK National Health Service, but implications for US costs are unknown. The purpose of this study was to compare costs in the FORECAST trial based on US healthcare cost weights, and to evaluate factors affecting costs. METHODS: Patients with stable chest pain were randomized either to the experimental strategy (CTCA with selective FFRCT), or to standard clinical pathways. Pre-randomization, the treating clinician declared the planned initial test. The primary outcome was nine-month cardiovascular care costs. RESULTS: Planned initial tests were CTCA in 912 patients (65%), stress testing in 393 (28%), and invasive angiography in 94 (7%). Mean US costs did not differ overall between the experimental strategy and standard care (cost difference +7% (+$324), CI -12% to +26%, p â€‹= â€‹0.49). Costs were 4% lower with the experimental strategy in the planned invasive angiography stratum (p for interaction â€‹= â€‹0.66). Baseline factors independently associated with costs were older age (+43%), male sex (+55%), diabetes (+37%), hypertension (+61%), hyperlipidemia (+94%), prior angina (+24%), and planned invasive angiography (+160%). Post-randomization cost drivers were coronary revascularization (+348%), invasive angiography (267%), and number of tests (+35%). CONCLUSIONS: Initial evaluation of chest pain using CTCA with FFRCT had similar US costs as standard care pathways. Costs were increased by baseline coronary risk factors and planned invasive angiography, and post-randomization invasive procedures and the number of tests. Registration at ClinicalTrials.gov (NCT03187639).

Planning a digital intervention for adolescents with asthma (BREATHE4T): A theory-, evidence- and Person-Based Approach to identify key behavioural issues.

OBJECTIVES: To describe a transparent approach to planning a digital intervention for adolescents to self-manage their asthma using breathing retraining (BRT), based on an existing, effective adult intervention (BREATHE). METHODS: A theory-, evidence-, and Person-Based Approach was used to maximise the effectiveness and persuasiveness of the intervention. A scoping review and semistructured interviews with target intervention users (N = 18, adolescents aged 12-17 years with asthma and parents) were carried out to explore user perspectives, barriers, and facilitators towards the intended behaviours and potential intervention features. The combined evidence was used alongside and to inform theory-based activities and enabled iterative planning of the intervention. RESULTS: The scoping review identified themes relating to user-specific self-management issues, content, education, training needs, and features for a digital intervention. Interviews elicited potential barriers to intended behaviours such as the anticipated embarrassment of using BRT and concerns around remaining calm. Facilitators included BRT delivered by adolescents who share experiences of asthma and information for performing exercises discreetly. Relevant theoretical frameworks ensured that appropriate psychological constructs were targeted. A behavioural analysis identified six intervention functions and thirty behaviour change techniques. Logic modelling mapped the programme theory and mechanisms, which aims to improve adolescent asthma-related quality of life. CONCLUSIONS: This study gives a transparent insight into the approach followed to plan a self-guided BRT intervention for adolescents and has led to identification of key behavioural issues, enabling relevant intervention content to be chosen. Insight has been given into adolescent perceptions of BRT, which facilitated development of the prototype intervention.

Overall Survival Update for Patients with Metastatic Castration-resistant Prostate Cancer Treated with Capivasertib and Docetaxel in the Phase 2 ProCAID Clinical Trial.

The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47-1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36-0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63-3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor-targeted agents, which should be evaluated in prospective trials. PATIENT SUMMARY: The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.

DEPEND study protocol: early detection of patients with pancreatic cancer - a pilot study to evaluate the utility of faecal elastase-1 and 13C-mixed triglyceride breath test as screening tools in high-risk individuals.

INTRODUCTION: Pancreatic cancer (PC) is the fifth leading cause of cancer-related death in the UK. The incidence of PC is increasing, with little or no improvement in overall survival and the best chance for long-term survival in patients with PC relies on early detection and surgical resection. In this study, we propose the use of a diagnostic algorithm that combines tests of pancreatic exocrine function (faecal elastase-1 (FE-1) test and the 13C-mixed triglyceride (13C-MTG) breath test) to identify patients with PC that urgently needs imaging studies. METHODS AND ANALYSIS: This prospective pilot (proof of concept) study will be carried out on 25 patients with resectable PC, 10 patients with chronic pancreatitis and 25 healthy volunteers. This study will construct a predictive algorithm for PC, using two tests of pancreatic exocrine function, FE-1 test and the 13C-MTG breath test. Continuous flow isotope ratio mass spectrometry in the 13C-MTG breath test will be used to analyse enriched 13CO2 in exhaled breath samples. The additional predictive benefit of other potential biomarkers of PC will also be considered. Potential biomarkers of PC showing abilities to discriminate between patients with PC from healthy subjects or patients with chronic pancreatitis will be selected by metabolomic analysis. ETHICS AND DISSEMINATION: The study was approved by the North of Scotland Research and Ethics Committee on 1 October 2020 (reference: 20/NS/0105, favourable opinion granted). The results will be disseminated in presentations at academic national/international conferences and publication in peer-review journals.

Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial.

AIMS: Fractional flow reserve (FFRCT) using computed tomography coronary angiography (CTCA) determines both the presence of coronary artery disease and vessel-specific ischaemia. We tested whether an evaluation strategy based on FFRCT would improve economic and clinical outcomes compared with standard care. METHODS AND RESULTS: Overall, 1400 patients with stable chest pain in 11 centres were randomized to initial testing with CTCA with selective FFRCT (experimental group) or standard clinical care pathways (standard group). The primary endpoint was total cardiac costs at 9 months. Secondary endpoints were angina status, quality of life, major adverse cardiac and cerebrovascular events, and use of invasive coronary angiography. Randomized groups were similar at baseline. Most patients had an initial CTCA: 439 (63%) in the standard group vs. 674 (96%) in the experimental group, 254 of whom (38%) underwent FFRCT. Mean total cardiac costs were higher by £114 (+8%) in the experimental group, with a 95% confidence interval from -£112 (-8%) to +£337 (+23%), though the difference was not significant (P = 0.10). Major adverse cardiac and cerebrovascular events did not differ significantly (10.2% in the experimental group vs. 10.6% in the standard group) and angina and quality of life improved to a similar degree over follow-up in both randomized groups. Invasive angiography was reduced significantly in the experimental group (19% vs. 25%, P = 0.01). CONCLUSION: A strategy of CTCA with selective FFRCT in patients with stable angina did not differ significantly from standard clinical care pathways in cost or clinical outcomes, but did reduce the use of invasive coronary angiography.

Pelargonium sidoides root extract for the treatment of acute cough due to lower respiratory tract infection in adults: a feasibility double-blind, placebo-controlled randomised trial.

BACKGROUND: Pelargonium sidoides DC (Geraniaceae) root extract, EPs®7630 or "Kaloba®", is a widely used herbal remedy for respiratory infections, with some evidence of effectiveness for acute bronchitis. However, it is not yet widely recommended by medical professionals in the UK. There is a need to undertake appropriately designed randomised trials to test its use as an alternative to antibiotics. The aim was to assess the feasibility of conducting a double-blind randomised controlled trial of Pelargonium sidoides root extract for treatment of acute bronchitis in UK primary care, investigating intervention compliance, patient preference for dosage form and acceptability of patient diaries. STUDY DESIGN: Feasibility double-blind randomised placebo-controlled clinical trial. METHODS: We aimed to recruit 160 patients with cough (≤ 21 days) caused by acute bronchitis from UK general practices. Practices were cluster-randomised to liquid or tablet preparations and patients were individually randomised to Kaloba® or placebo. We followed participants up for 28 days through self-reported patient diaries with telephone support and reviewed medical records at one month. Outcomes included recruitment, withdrawal, safety, reconsultation and symptom diary completion rates. We also assessed treatment adherence, antibiotic prescribing and consumption, mean symptom severity (at days 2-4 after randomisation) and time to symptom resolution. We interviewed 29 patients and 11 health professionals to identify barriers and facilitators to running such a randomised trial. RESULTS: Of 543 patients screened, 261 were eligible, of whom 134 (51%) were recruited and 103 (77%) returned a completed diary. Overall, 41% (41/100) of patients took antibiotics (Kaloba® liquid group: 48% [15/31]; placebo liquid group: 23% [6/26]; Kaloba® tablet group: 48% [9/21]; placebo tablet group: 50% [11/22]). Most patients adhered to the study medication (median 19 out of 21 doses taken in week 1, IQR 18-21 - all arms combined). There were no serious adverse events relating to treatment. Most patients interviewed found study recruitment to be straightforward, but some found the diary too complex. CONCLUSIONS: It was feasible and acceptable to recruit patients from UK primary care to a double-blind placebo-controlled trial of herbal medicine (Kaloba®) for the treatment of acute bronchitis, with good retention and low data attrition. TRIAL REGISTRATION: HATRIC was registered on the ISRCTN registry ( ISRCTN17672884 ) on 16 August 2018, retrospectively registered. The record can be found at http://www.isrctn.com/ISRCTN17672884 .

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID).

PURPOSE: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. PATIENTS AND METHODS: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. RESULTS: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. CONCLUSION: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.

Change in modifiable maternal characteristics and behaviours between consecutive pregnancies and offspring adiposity: A systematic review.

Causal evidence links modifiable maternal exposures during the periconceptional period with offspring obesity. The interconception period may be an important time to intervene. We systematically identified studies examining change in modifiable maternal exposures between pregnancies and offspring adiposity. We searched for longitudinal studies published between 1990 and 2019, which included measurements taken on at least two occasions in the period from 1 year prior to the conception of the first birth to the time of the second birth, and which included a measure of adiposity in second, or higher order, siblings. Age, ethnicity and genetics were not considered modifiable; all other factors including length of the interpregnancy interval were. Eleven studies satisfied the inclusion criteria. Higher interpregnancy weight gain or loss, maternal smoking inception, mothers smoking in their first pregnancy and quitting, increasing the number of cigarettes smoked and longer interpregnancy intervals were positively associated with adiposity in second or higher order children. Vaginal birth after caesarean delivery was protective. Further research is needed to ascertain whether the risk of adiposity is fixed based on first pregnancy exposures or if interpregnancy change alters the risk for a subsequent child. This can inform the type and effectiveness of interventions for mothers prior to a subsequent pregnancy.

Predicting the risk of childhood overweight and obesity at 4-5 years using population-level pregnancy and early-life healthcare data.

BACKGROUND: Nearly a third of children in the UK are overweight, with the prevalence in the most deprived areas more than twice that in the least deprived. The aim was to develop a risk identification model for childhood overweight/obesity applied during pregnancy and early life using routinely collected population-level healthcare data. METHODS: A population-based anonymised linked cohort of maternal antenatal records (January 2003 to September 2013) and birth/early-life data for their children with linked body mass index (BMI) measurements at 4-5 years (n = 29,060 children) in Hampshire, UK was used. Childhood age- and sex-adjusted BMI at 4-5 years, measured between September 2007 and November 2018, using a clinical cut-off of ≥ 91st centile for overweight/obesity. Logistic regression models together with multivariable fractional polynomials were used to select model predictors and to identify transformations of continuous predictors that best predict the outcome. RESULTS: Fifteen percent of children had a BMI ≥ 91st centile. Models were developed in stages, incorporating data collected at first antenatal booking appointment, later pregnancy/birth, and early-life predictors (1 and 2 years). The area under the curve (AUC) was lowest (0.64) for the model only incorporating maternal predictors from early pregnancy and highest for the model incorporating all factors up to weight at 2 years for predicting outcome at 4-5 years (0.83). The models were well calibrated. The prediction models identify 21% (at booking) to 24% (at ~ 2 years) of children as being at high risk of overweight or obese by the age of 4-5 years (as defined by a ≥ 20% risk score). Early pregnancy predictors included maternal BMI, smoking status, maternal age, and ethnicity. Early-life predictors included birthweight, baby's sex, and weight at 1 or 2 years of age. CONCLUSIONS: Although predictive ability was lower for the early pregnancy models, maternal predictors remained consistent across the models; thus, high-risk groups could be identified at an early stage with more precise estimation as the child grows. A tool based on these models can be used to quantify clustering of risk for childhood obesity as early as the first trimester of pregnancy, and can strengthen the long-term preventive element of antenatal and early years care.

Are environmental area characteristics at birth associated with overweight and obesity in school-aged children? Findings from the SLOPE (Studying Lifecourse Obesity PrEdictors) population-based cohort in the south of England.

BACKGROUND: Geographical inequalities in overweight and obesity prevalence among children are well established in cross-sectional research. We aimed to examine how environmental area characteristics at birth are related to these outcomes in childhood. METHODS: Anonymised antenatal and birth data recorded by University Hospital Southampton linked to school-measured weight and height data for children within Southampton, UK, were utilised (14,084 children at ages 4-5 and 5637 at ages 10-11). Children's home address at birth was analysed at the Lower and Middle layer Super Output Area (LSOA/MSOA) levels (areas with average populations of 1500 and 7000, respectively). Area-level indices (walkability, relative density of unhealthy food outlets, spaces for social interaction), natural greenspace coverage, supermarket density and measures of air pollution (PM2.5, PM10 and NOx) were constructed using ArcGIS Network Analyst. Overweight/obesity was defined as a body mass index (BMI; kg/m2) greater than the 85th centile for sex and age. Population-average generalised estimating equations estimated the risk of being overweight/obese for children at both time points. Confounders included maternal BMI and smoking in early pregnancy, education, ethnicity and parity. We also examined associations for a subgroup of children who moved residence between birth and outcome measurement. RESULTS: There were mixed results between area characteristics at birth and overweight/obesity at later ages. MSOA relative density of unhealthy food outlets and PM10 were positively associated with overweight/obesity, but not among children who moved. LSOA greenspace coverage was negatively associated with the risk of being overweight/obese at ages 10-11 in all children (relative risk ratio 0.997, 95% confidence interval 0.995-0.999, p = 0.02) and among children who moved. CONCLUSIONS: Local access to natural greenspaces at the time of birth was inversely associated with becoming overweight or obese by age 10-11, regardless of migration. Increased access/protection of greenspace may have a role in the early prevention of childhood obesity.

Immune reconstitution in children following chemotherapy for acute leukemia.

Although survival rates for pediatric acute lymphoblastic leukemia are now excellent, this is at the expense of prolonged chemotherapy regimens. We report the long-term immune effects in children treated according to the UK Medical Research Council UKALL 2003 protocol. Peripheral blood lymphocyte subsets and immunoglobulin levels were studied in 116 participants, at six time points, during and for 18-month following treatment, with 30-39 patients analyzed at each time point. Total lymphocytes were reduced during maintenance chemotherapy and remained low 18 months following treatment completion. CD4 T cells remained significantly reduced 18 months after treatment, but CD8 cells and natural killer cells recovered to normal values. The fall in naïve B-cell numbers during maintenance was most marked, but numbers recovered rapidly after cessation of treatment. Memory B cells, particularly nonclass-switched memory B cells, remained below normal levels 18 months following treatment. All immunoglobulin subclasses were reduced during treatment compared to normal values, with IgM levels most affected. This study demonstrates that immune reconstitution differs between lymphocyte compartments. Although total B-cell numbers recover rapidly, disruption of memory/naïve balance persists and T-cell compartment persist at 18 months. This highlights the impact of modern chemotherapy regimens on immunity, and thus, infectious susceptibility and response to immunization.

Are socioeconomic inequalities in the incidence of small-for-gestational-age birth narrowing? Findings from a population-based cohort in the South of England.

OBJECTIVES: To investigate socioeconomic inequalities, using maternal educational attainment, maternal and partner employment status, and lone motherhood indicators, in the risk of small-for-gestational-age (SGA) births, their time trend, potential mediation by maternal smoking and body mass index, and effect modification by parity. DESIGN: Population-based birth cohort using routine antenatal healthcare data. SETTING: Babies born at University Hospital Southampton, UK, between 2004 and 2016. PARTICIPANTS: 65 909 singleton live births born to mothers aged ≥18 years between 24-week and 42-week gestation. MAIN OUTCOME MEASURES: SGA (birth weight <10th percentile for others born at the same number of completed weeks compared with 2013/2014 within England and Wales). RESULTS: Babies born to mothers educated up to secondary school level (adjusted OR (aOR) 1.32, 99% CI 1.19 to 1.47), who were unemployed (aOR 1.27, 99% CI 1.16 to 1.38) or with unemployed partners (aOR 1.27, 99% CI 1.13 to 1.43), were at greater risk of being SGA. There was no statistically significant change in the magnitude of this risk difference by these indicators over time between 2004 and 2016, as estimated by linear interactions with year of birth. Babies born to lone mothers were not at higher risk compared with partnered mothers after adjusting for maternal smoking (aOR 1.05, 99% CI 0.93 to 1.20). The inverse association between maternal educational attainment and SGA risk appeared greater in multiparous (aOR 1.40, 99% CI 1.10 to 1.77) compared with primiparous women (aOR 1.28, 99% CI 1.12 to 1.47), and the reverse was true for maternal and partner's unemployment where the association was stronger in primiparous women. CONCLUSIONS: Socioeconomic inequalities in SGA risk by educational attainment and employment status are not narrowing over time, with differences in association strength by parity. The greater SGA risk in lone mothers was potentially explained by maternal smoking. Preventive interventions should target socially disadvantaged women, including preconception and postpartum smoking cessation to reduce SGA risk.

Is maternal weight gain between pregnancies associated with risk of large-for-gestational age birth? Analysis of a UK population-based cohort.

OBJECTIVE: Maternal overweight and obesity during pregnancy increases the risk of large-for-gestational age (LGA) birth and childhood obesity. We aimed to investigate the association between maternal weight change between subsequent pregnancies and risk of having a LGA birth. DESIGN: Population-based cohort. SETTING: Routinely collected antenatal healthcare data between January 2003 and September 2017 at University Hospital Southampton, England. PARTICIPANTS: Health records of women with their first two consecutive singleton live-birth pregnancies were analysed (n=15 940). PRIMARY OUTCOME MEASURE: Risk of LGA, recurrent LGA and new LGA births in the second pregnancy. RESULTS: Of the 15 940 women, 16.0% lost and 47.7% gained weight (≥1 kg/m2) between pregnancies. A lower proportion of babies born to women who lost ≥1 kg/m2 (12.4%) and remained weight stable between -1 and 1 kg/m2 (11.9%) between pregnancies were LGA compared with 13.5% and 15.9% in women who gained 1-3 and ≥3 kg/m2, respectively. The highest proportion was in obese women who gained ≥3 kg/m2 (21.2%). Overweight women had a reduced risk of recurrent LGA in the second pregnancy if they lost ≥1 kg/m2 (adjusted relative risk (aRR) 0.69, 95% CI 0.48 to 0.97) whereas overweight women who gained ≥3 kg/m2 were at increased risk of new LGA after having a non-LGA birth in their first pregnancy (aRR 1.35, 95% CI 1.05 to 1.75). Normal-weight women who gained weight were also at increased risk of new LGA in the second pregnancy (aRR 1.26, 95% CI 1.06 to 1.50 with gain of 1-3 kg/m2 and aRR 1.34, 95% CI 1.09 to 1.65 with gain of ≥3 kg/m2). CONCLUSIONS: Losing weight after an LGA birth was associated with a reduced LGA risk in the next pregnancy in overweight women, while interpregnancy weight gain was associated with an increased new LGA risk. Preventing weight gain between pregnancies is an important measure to achieve better maternal and offspring outcomes.

Maternal and early-life area-level characteristics and childhood adiposity: A systematic review.

There is a cross-sectional evidence that physical and social environments are linked to childhood adiposity. Evidence is scarce for the role of preconception, pregnancy, and early-life area-level characteristics in shaping childhood adiposity. We aimed to systematically review evidence for associations between physical and social environmental conditions experienced in these periods and childhood adiposity. Published literature was identified from the CINAHL, Embase, MEDLINE, and PsycINFO databases. Longitudinal studies linking an area-level environmental exposure in the preconception, pregnancy, or early-life (less than 1 year) periods and a measure of adiposity between the ages of 2 and 12 years were examined. Eight studies in the United States, Denmark, South Korea, United Kingdom, and Canada satisfied the inclusion criteria. Storm-induced maternal stress, nitrogen oxides exposure, traffic noise, and proximity were associated with greater childhood adiposity. Frequent neighbourhood disturbances were associated with lower adiposity, while particulate matter exposure was associated with both higher and lower adiposity in childhood. Area-level characteristics may play a role in the ongoing obesity epidemic. There is a limited evidence of longitudinal associations between preconception, pregnancy, and early-life area-level characteristics with childhood adiposity. Numerous factors that appear important in cross-sectional research have yet to be assessed longitudinally, both individually and in combination.