Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Reporting of paediatric osteoporotic vertebral fractures in Duchenne muscular dystrophy and potential impact on clinical management: the need for standardised and structured reporting.

BACKGROUND: In boys with Duchenne muscular dystrophy (DMD), initiation of bisphosphonate is recommended upon identification of moderate or severe vertebral fractures, even if asymptomatic. Clear radiological reporting is important for consistency of clinical interpretation and management. OBJECTIVES: To audit radiology reports of spine imaging for vertebral fracture assessment in DMD, and assess potential impact on diagnosis and management. MATERIALS AND METHODS: Lateral thoracolumbar spine imaging (71 lateral spine radiographs and 13 lateral dual energy absorptiometry spine image) in 84 boys with DMD performed across two centres. Anonymised radiology reports by paediatric radiologists were circulated to two neuromuscular clinicians and two endocrinologists. Clinicians determined if there was vertebral fracture, no vertebral fracture, or unclear interpretation. Endocrinologists also determined if bisphosphonate was indicated. A single observer (a clinician with expertise in vertebral fracture assessment) performed vertebral fracture assessment in 37 images and re-reported using a structured format. Structured reports were re-circulated to the four clinicians to re-evaluate the degree of concordance in clinical diagnosis of vertebral fracture and treatment decisions with bisphosphonate. RESULTS: The term "fracture" was used in 25/84 (30%) radiology reports and only in 8/43 (19%) with description of vertebral body abnormalities. Fracture grading was included in 7/43 (16%) radiology reports. Diagnostic concordance by the clinicians was noted in 36/84 (43%). Unclear interpretation was noted in 22% to 51% based on radiology reports. No unclear interpretation was noted with structured reports. Complete diagnostic (37/37, 100%) and treatment (37/37, 100%) concordance was noted with the structured reports, whereas complete diagnostic and treatment concordance was noted in only 16/37 (43%) and 17/37 (46%) of the radiology reports, respectively. CONCLUSION: Only a third of radiology reports of spine imaging in DMD explicitly used the terminology "fracture". Grading was only noted in a small percentage. Variability in diagnostic interpretation by clinicians may lead to differing management plans. As identification of vertebral fracture is a trigger for treatment, developing reporting guidelines for paediatric vertebral fracture assessment will improve care. A structured template should be introduced for radiological reporting of paediatric vertebral fracture assessment.

Why don't women engage in muscle strength exercise? An integrative review.

ISSUE ADDRESSED: Women are 'at-risk' population for failing to meet muscle strengthening guidelines. Health benefits specific to this exercise mode include maintenance of muscle mass, which is associated with reduced risk of chronic disease and falls. Of significance is the progressive decline in muscle strength exercise participation in women aged 35-54 in Australia. This period is critical for maintaining muscle strength as it establishes foundations for older women's engagement. This integrative review examined available evidence regarding factors influencing muscle strength exercise participation, specifically in women aged 35-54. METHODS: Seven databases were searched. Study inclusion criteria were: (1) peer reviewed, (2) English language, (3) sample populations of healthy female adults or general adult sample population differentiating females from males, (4) mean age between 35 and 54 years, (5) focused on muscle strength exercise and measured as the primary outcome factors of participation in muscle strength exercise. FINDINGS: Five of 1895 studies met inclusion criteria. Five key factors were associated with participation in muscle strength exercise of women aged 35-54 years: perceived time constraints; knowledge and education; modality and intensity; social support and behavioural strategies. CONCLUSIONS: Focused education on strength exercise and guidelines, plus initiatives and strategies that suit the needs of this cohort, are necessary to achieve health and wellbeing benefits. Responsive approaches by health professionals to these women's circumstances can potentially address current low participation levels. SO WHAT?: Creating conditions where health professionals respect a woman's exercise preferences can positively impact these women's musculoskeletal health into older age.

Characterising airway obstructive, dysanaptic and PRISm phenotypes of prematurity-associated lung disease.

INTRODUCTION: Although obstructive airway disease has been shown to be associated with prematurity, other spirometry phenotypes are less well described. OBJECTIVES: We characterised abnormal spirometry phenotypes in preterm-born children, including prematurity-associated obstructive lung disease (POLD, forced expiratory volume in 1 s (FEV1)

A multi-centre retrospective study of Nocardia speciation and antimicrobial susceptibility in Queensland, Australia.

The study aims to characterise the species identification and antimicrobial susceptibility testing (AST) results of Nocardial isolates from adult patients across major public hospitals in Queensland, Australia, over a 15-year period. A multi-centre retrospective observational study of Nocardia sp. isolates was conducted from 7 major public hospitals in Queensland, Australia, over a 15-year period. Clinical samples from patients aged ≥ 18 years that isolated Nocardia sp. were included. Demographic and clinical data were collected, along with species identification and AST results. Overall, 484 Nocardia sp. were isolated. Most patients were male (297, 61%) with a mean (IQR) age of 60 (51-75) and a median (IQR) Charlson Comorbidity Index of 4 (2-6). Of these, 239 (49%) patients were immunosuppressed. Organisms were most frequently isolated from sputum (174, 36%), and superficial swabs (102, 21%). Patients presented with pulmonary infections (165, 35%) and superficial skin and soft tissue infections (87, 18%) most commonly. One hundred (21%) isolates were deemed pulmonary colonisation and were not treated. Of the speciated organisms, N. nova complex was the most common (93, 19%), followed by N. farcinica complex (79, 16%). Organisms were reliably susceptible to linezolid (240/245, 98%), amikacin (455/470, 97%), and trimethoprim/sulfamethoxazole (459/476, 96%), but less so to imipenem (243/472, 51%) and ceftriaxone (261/448, 58%). This is the largest Australian description of Nocardia sp. to date. Given antimicrobials are often commenced prior to AST results and sometimes even speciation, characterisation of local species and antibiogram data is important to guide empiric choices and local guidelines.

Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Association of early-life factors with prematurity-associated lung disease: prospective cohort study.

BACKGROUND: Although bronchopulmonary dysplasia (BPD) is associated with lung function deficits in childhood, many who develop BPD have normal lung function in childhood and many without BPD, including those born at 33-34 weeks of gestation, have lung dysfunction in childhood. Since the predictability of BPD for future lung deficits is increasingly doubted, we prospectively recruited preterm-born children to identify early-life factors associated with lung function deficits after preterm birth. METHODS: From 767 children aged 7-12 years who had their respiratory symptoms assessed, and had spirometry before and after a bronchodilator in our Respiratory Health Outcomes in Neonates (RHiNO) study, 739 (544 preterm-born at ≤34 weeks of gestation and 195 term-born) had satisfactory lung function. Data were analysed using multivariable logistic regression and mediation. RESULTS: When preterm-born children were classified according to their lung function, low lung function (prematurity-associated lung disease (PLD)) was associated with BPD, gestation and intra-uterine growth restriction (IUGR) on univariable logistic regression analyses. However, on multivariable logistic regression analyses, gestation (ß= -0.153, se 0.051; p=0.003) and IUGR (OR 1.783, 95% CI 1.06-3.00; p=0.029) remained significantly associated with later deficits of lung function, but BPD (OR 0.99, 95% CI 0.52-1.89; p=0.974) did not. Mediation analyses confirmed these results. CONCLUSIONS: Although traditionally BPD has been associated with low lung function in later life, the data show that gestation and IUGR are significantly associated with PLD in childhood, but BPD is not. By identifying children with PLD, we can better understand the underlying mechanisms and develop optimal therapies.

Cefazolin susceptibility of coagulase-negative staphylococci (CoNS) causing late-onset neonatal bacteraemia.

BACKGROUND: CoNS bacteraemia causes significant neonatal morbidity. Previous work has suggested that ß-lactam antibiotics vary in their binding affinity to PBP2a (produced by the mecA gene) present in most CoNS. OBJECTIVES: We evaluated cefazolin MICs for CoNS isolated in an Australian neonatal ICU (NICU) and correlated them with isolate genotype and phenotype. METHODS: Significant blood isolates from 2009 to 2017 were speciated and underwent broth microdilution testing for cefazolin, cefoxitin, oxacillin and flucloxacillin. Correlation with mecA presence and PBP2a expression was evaluated. A selection of Staphylococcus capitis isolates underwent WGS. RESULTS: The CoNS (n = 99) isolates were confirmed as S. capitis (n = 57), Staphylococcus epidermidis (n = 32), Staphylococcus haemolyticus (n = 2) and Staphylococcus warneri (n = 8). The MIC of cefazolin was ≤2 mg/L for 30% of isolates and 75% had an MIC of ≤8 mg/L (MIC90 = 16 mg/L). This contrasted with MIC90s of cefoxitin, oxacillin and flucloxacillin, which were all ≥32 mg/L. WGS found a number of S. capitis isolates closely related to the globally established NRCS-A clone. CONCLUSIONS: CoNS displayed distinctly lower MIC values of cefazolin than of other agents tested. MIC variation may be related to binding affinity of PBP2a or regulation of expression of mecA by mecR1-mecI functional genes. Further, NRCS-A S. capitis strains were present in this Australian NICU before and after the unit underwent physical relocation, which raised questions about a common environmental source. It is considered justified to conduct a randomized clinical trial that assesses cefazolin versus vancomycin for management of late-onset neonatal sepsis.

Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

DNA methylation at birth is associated with lung function development until age 26†years.

Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (forced expiratory volume in 1 s, forced vital capacity, their ratio, and forced expiratory flow at 25-75% of forced vital capacity) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys and 390 girls of IOWBC-F1. Replication in ALSPAC focussed on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of eight CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, aged 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBC-F2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

Phase Diagram for Light-Induced Superconductivity in κ-(ET)_{2}-X.

Resonant optical excitation of certain molecular vibrations in κ-(BEDT-TTF)_{2}Cu[N(CN)_{2}]Br has been shown to induce transient superconductinglike optical properties at temperatures far above equilibrium T_{c}. Here, we report experiments across the bandwidth-tuned phase diagram of this class of materials, and study the Mott insulator κ-(BEDT-TTF)_{2}Cu[N(CN)_{2}]Cl and the metallic compound κ-(BEDT-TTF)_{2}Cu(NCS)_{2}. We find nonequilibrium photoinduced superconductivity only in κ-(BEDT-TTF)_{2}Cu[N(CN)_{2}]Br, indicating that the proximity to the Mott insulating phase and possibly the presence of preexisting superconducting fluctuations are prerequisites for this effect.

Trimester effects of source-specific PM10 on birth weight outcomes in the Avon Longitudinal Study of Parents and Children (ALSPAC).

BACKGROUND: Evidence suggests that exposure to particulate matter with aerodynamic diameter less than 10 µm (PM10) is associated with reduced birth weight, but information is limited on the sources of PM10 and exposure misclassification from assigning exposures to place of residence at birth. METHODS: Trimester and source-specific PM10 exposures (PM10 from road source, local non-road source, and total source) in pregnancy were estimated using dispersion models and a full maternal residential history for 12,020 births from the Avon longitudinal study of parents and children (ALSPAC) cohort in 1990-1992 in the Bristol area. Information on birth outcomes were obtained from birth records. Maternal sociodemographic and lifestyle factors were obtained from questionnaires. We used linear regression models for continuous outcomes (birth weight, head circumference (HC), and birth length (BL) and logistic regression models for binary outcomes (preterm birth (PTB), term low birth weight (TLBW) and small for gestational age (SGA)). Sensitivity analysis was performed using multiple imputation for missing covariate data. RESULTS: After adjustment, interquartile range increases in source specific PM10 from traffic were associated with 17 to 18% increased odds of TLBW in all pregnancy periods. We also found odds of TLBW increased by 40% (OR: 1.40, 95%CI: 1.12, 1.75) and odds of SGA increased by 18% (OR: 1.18, 95%CI: 1.05, 1.32) per IQR (6.54 µg/m3) increase of total PM10 exposure in the third trimester. CONCLUSION: This study adds to evidence that maternal PM10 exposures affect birth weight, with particular concern in relation to exposures to PM10 from road transport sources; results for total PM10 suggest greatest effect in the third trimester. Effect size estimates relate to exposures in the 1990s and are higher than those for recent studies - this may relate to reduced exposure misclassification through use of full residential history information, changes in air pollution toxicity over time and/or residual confounding.

Prenatal, Early-Life, and Childhood Exposure to Air Pollution and Lung Function: The ALSPAC Cohort.

Rationale: Exposure to air pollution during intrauterine development and through childhood may have lasting effects on respiratory health.Objectives: To investigate lung function at ages 8 and 15 years in relation to air pollution exposures during pregnancy, infancy, and childhood in a UK population-based birth cohort.Methods: Individual exposures to source-specific particulate matter ≤10 µm in aerodynamic diameter (PM10) during each trimester, 0-6 months, 7-12 months (1990-1993), and up to age 15 years (1991-2008) were examined in relation to FEV1% predicted and FVC% predicted at ages 8 (n = 5,276) and 15 (n = 3,446) years using linear regression models adjusted for potential confounders. A profile regression model was used to identify sensitive time periods.Measurements and Main Results: We did not find clear evidence of a sensitive exposure period for PM10 from road traffic. At age 8 years, 1 µg/m3 higher exposure during the first trimester was associated with lower FEV1% predicted (-0.826; 95% confidence interval [CI], -1.357 to -0.296) and FVC% predicted (-0.817; 95% CI, -1.357 to -0.276), but similar associations were seen for exposures for other trimesters, 0-6 months, 7-12 months, and 0-7 years. Associations were stronger among boys, as well as children whose mother had a lower education level or smoked during pregnancy. For PM10 from all sources, the third trimester was associated with lower FVC% predicted (-1.312; 95% CI, -2.100 to -0.525). At age 15 years, no adverse associations with lung function were seen.Conclusions: Exposure to road-traffic PM10 during pregnancy may result in small but significant reductions in lung function at age 8 years.

Risk of anticholinergic burden in adults with intellectual disabilities: a Scottish retrospective cohort study of n = 17 220.

BACKGROUND: Several drugs have anticholinergic side effects that are associated with adverse health outcomes. Anticholinergic burden studies in adults with intellectual disabilities (ID) have focused exclusively on older adults. This study investigates anticholinergic burden and its associations in adults with ID of all ages (17-94 years). METHODS: Adults with ID (n = 4 305), each with three general population age-sex-neighbourhood-matched controls (n = 12 915), were linked to their prescribed medications with anticholinergic effects between 2009 and 2017. Analyses were undertaken using logistic regression models. RESULTS: Adults with ID were more likely to be prescribed any anticholinergic medicines, odds ratio (OR) = 1.49 (1.38-1.59), especially 'very strong' risk medicines, OR = 2.59 (2.39-2.81); 48.5% had very high total anticholinergic burden (3+) compared with 35.4% of the general population, OR = 1.77 (1.64-1.90). This group difference was greater for males, OR = 2.02 (1.84-2.22), than females, OR = 1.48 (1.33-1.65). Adults with ID had significantly higher odds of having very high total anticholinergic burden up to 75 years old, with the greatest group effect occurring in younger ages, 17-24-year-olds, OR = 3.05 (2.39-3.89), and the extent of the difference decreased as age increased. The main effect of neighbourhood deprivation showed greater group differences with increasing affluence of neighbourhood. Results examining only the ID group showed that very high total anticholinergic burden was greatest for females, OR = 1.21 (1.07-1.37), and those over age 55, and extent of neighbourhood deprivation was not significant. CONCLUSIONS: Adults with ID are at higher risk of anticholinergic burden than the general population, especially young adults. Overall anticholinergic burden increased with age, but burden was high across all ages in the ID group. Very high total anticholinergic burden is prevalent across all types of neighbourhoods for the adults with ID, in contrast to the steeper gradient seen in the general population. Adults with ID have increased likelihood of unintended adverse effects, regardless of potential confounds, so clinicians undertaking medication reviews need to consider anticholinergic side effects and cumulative burden across concomitant medications, including in young adults with ID, not just older adults, and particularly women.

Mediterranean diet during pregnancy and childhood respiratory and atopic outcomes: birth cohort study.

Evidence for associations between Mediterranean diet during pregnancy and childhood asthma, allergy and related outcomes is conflicting. Few cohorts have followed children to school age, and none have considered lung function.In the Avon Longitudinal Study of Parents and Children, we analysed associations between maternal Mediterranean diet score during pregnancy (estimated by a food frequency questionnaire, using an a priori defined score adapted to pregnant women; score ranging from 0 (low adherence) to 7 (high adherence)) and current doctor-diagnosed asthma, wheeze, eczema, hay fever, atopy and lung function in 8907 children at 7-9 years. Interaction between maternal Mediterranean diet and maternal smoking in pregnancy was investigated.The maternal Mediterranean diet score was not associated with asthma or other allergic outcomes. Weak positive associations were found between maternal Mediterranean diet score and childhood maximal mid-expiratory flow (forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%)) after controlling for confounders. Higher Mediterranean diet scores were associated with increased FEF25-75% z-scores adjusted for age, height and sex (ß 0.06, 95% CI 0.01-0.12; p=0.03, comparing a score of 4-7 versus a score of 0-3). Stratifying associations by maternal smoking during pregnancy showed that associations with FEF25-75% were only seen in children of never-/passive-smoking mothers, but no evidence for a statistically significant interaction was found.Results suggest adherence to a Mediterranean diet during pregnancy may be associated with increased small airway function in childhood, but we found no evidence for a reduced risk of asthma or other allergic outcomes.

Changes of DNA methylation are associated with changes in lung function during adolescence.

BACKGROUND: Adolescence is a significant period for the gender-dependent development of lung function. Prior studies have shown that DNA methylation (DNA-M) is associated with lung function and DNA-M at some cytosine-phosphate-guanine dinucleotide sites (CpGs) changes over time. This study examined whether changes of DNA-M at lung-function-related CpGs are associated with changes in lung function during adolescence for each gender, and if so, the biological significance of the detected CpGs. METHODS: Genome-scale DNA-M was measured in peripheral blood samples at ages 10 (n = 330) and 18 years (n = 476) from the Isle of Wight (IOW) birth cohort in United Kingdom, using Illumina Infinium arrays (450 K and EPIC). Spirometry was conducted at both ages. A training and testing method was used to screen 402,714 CpGs for their potential associations with lung function. Linear regressions were applied to assess the association of changes in lung function with changes of DNA-M at those CpGs potentially related to lung function. Adolescence-related and personal and family-related confounders were included in the model. The analyses were stratified by gender. Multiple testing was adjusted by controlling false discovery rate of 0.05. Findings were further examined in two independent birth cohorts, the Avon Longitudinal Study of Children and Parents (ALSPAC) and the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort. Pathway analyses were performed on genes to which the identified CpGs were mapped. RESULTS: For females, 42 CpGs showed statistically significant associations with change in FEV1/FVC, but none for change in FEV1 or FVC. No CpGs were identified for males. In replication analyses, 16 and 21 of the 42 CpGs showed the same direction of associations among the females in the ALSPAC and BAMSE cohorts, respectively, with 11 CpGs overlapping across all the three cohorts. Through pathway analyses, significant biological processes were identified that have previously been related to lung function development. CONCLUSIONS: The detected 11 CpGs in all three cohorts have the potential to serve as the candidate epigenetic markers for changes in lung function during adolescence in females.

Dental attendance, restoration and extractions in adults with intellectual disabilities compared with the general population: a record linkage study.

BACKGROUND: Oral health may be poorer in adults with intellectual disabilities (IDs) who rely on carer support and medications with increased dental risks. METHODS: Record linkage study of dental outcomes, and associations with anticholinergic (e.g. antipsychotics) and sugar-containing liquid medication, in adults with IDs compared with age-sex-neighbourhood deprivation-matched general population controls. RESULTS: A total of 2933/4305 (68.1%) with IDs and 7761/12 915 (60.1%) without IDs attended dental care: odds ratio (OR) = 1.42 [1.32, 1.53]; 1359 (31.6%) with IDs versus 5233 (40.5%) without IDs had restorations: OR = 0.68 [0.63, 0.73]; and 567 (13.2%) with IDs versus 2048 (15.9%) without IDs had dental extractions: OR = 0.80 [0.73, 0.89]. Group differences for attendance were greatest in younger ages, and restoration/extractions differences were greatest in older ages. Adults with IDs were more likely prescribed with anticholinergics (2493 (57.9%) vs. 6235 (48.3%): OR = 1.49 [1.39, 1.59]) and sugar-containing liquids (1641 (38.1%) vs. 2315 (17.9%): OR = 2.89 [2.67, 3.12]). CONCLUSION: Carers support dental appointments, but dentists may be less likely to restore teeth, possibly extracting multiple teeth at individual appointments instead.

Causes of variability in latent phenotypes of childhood wheeze.

BACKGROUND: Latent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies. OBJECTIVE: We sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood. METHODS: We used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years. RESULTS: A relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers. CONCLUSIONS: Sample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.

Comparison of the Associations of Early-Life Factors on Wheezing Phenotypes in Preterm-Born Children and Term-Born Children.

Although respiratory symptoms, including wheezing, are common in preterm-born subjects, the natural history of the wheezing phenotypes and the influence of early-life factors and characteristics on phenotypes are unclear. Participants from the Millennium Cohort Study who were born between 2000 and 2002 were studied at 9 months and at 3, 5, 7, and 11 years. We used data-driven methods to define wheezing phenotypes in preterm-born children and investigated whether the association of early-life factors and characteristics with wheezing phenotypes was similar between preterm- and term-born children. A total of 1,049/1,502 (70%) preterm-born children and 12,307/17,063 (72%) term-born children had recent wheeze data for 3 or 4 time points. Recent wheeze was more common at all time points in the preterm-born group than in term-born group. Four wheezing phenotypes were defined for both groups: no/infrequent, early, persistent, and late. Early-life factors and characteristics, especially antenatal maternal smoking, atopy, and male sex, were associated with increased rates for all phenotypes in both groups, and breastfeeding was protective in both groups, except late wheeze in the preterm group. Preterm-born children had similar phenotypes to term-born children. Although early-life factors and characteristics were similarly associated with the wheezing phenotypes in both groups, the preterm-born group had higher rates of early and persistent wheeze. However, a large proportion of preterm-born children had early wheeze that resolved with time.

Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course.

RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.