ABSTRACT
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.
Subject(s)
Prostatectomy , Prostatic Neoplasms , Salvage Therapy , Humans , Male , Prostatectomy/methods , Prostatic Neoplasms/radiotherapy , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Aged , Salvage Therapy/methods , Middle Aged , Radiotherapy, Adjuvant/adverse effects , Radiotherapy, Adjuvant/methods , Prostate-Specific Antigen/blood , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/prevention & control , Neoplasm Grading , Time FactorsABSTRACT
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.
ABSTRACT
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.
Subject(s)
Muscular Dystrophy, Duchenne , Osteoporotic Fractures , Spinal Fractures , Male , Humans , Child , Spinal Fractures/diagnostic imaging , Spinal Fractures/therapy , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/diagnostic imaging , Muscular Dystrophy, Duchenne/drug therapy , Spine , Osteoporotic Fractures/diagnostic imaging , Osteoporotic Fractures/therapy , DiphosphonatesSubject(s)
Muscular Dystrophy, Duchenne , Male , Humans , Muscular Dystrophy, Duchenne/therapy , Standard of Care , Men , Bone and Bones , Reference StandardsABSTRACT
INTRODUCTION: Mechanisms underlying lung dysfunction after preterm birth are poorly understood. Studying phenotypes of prematurity-associated lung disease may aid understanding of underlying mechanisms. Preterm-born children with and without lung dysfunction and term controls were assessed using oscillometry before and after exercise, and after postexercise bronchodilation. METHODS: Preterm-born children, born at gestation of 34 weeks or less, were classified into those with prematurity-associated obstructive lung disease (POLD; FEV1 < LLN, FEV1 /FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (pPRISm; FEV1 < LLN, FEV1 /FVC ≥ LLN) and compared to preterm (FEV1 ≥ LLN) and term controls (%predicted FEV1 > 90%). All children underwent cardiopulmonary exercise, and oscillometry assessment at baseline, postexercise, and after postexercise bronchodilator administration. RESULTS: From 241 participants aged 7-12 years, complete data were available from 179: 15 children with POLD and 11 with pPRISm were compared with 93 preterm and 60 term controls. POLD group, when compared to both control groups, had impaired impedance, greater resistance, more negative (greater magnitude) reactance at low frequencies, and also had decreased compliance. pPRISm group demonstrated impaired reactance and compliance compared to term controls. No differences were noted between the preterm and term controls. Exercise had little impact on oscillometry values, but children with POLD had greatest improvements after postexercise bronchodilator administration, with decreased resistance and decreased magnitude of reactance, particularly at low frequencies. CONCLUSION: Preterm-born children with obstructive airway disease had the greatest oscillometry impairments and the largest improvements after postexercise bronchodilator compared to control groups. Oscillometry can potentially be used to identify preterm-born children with lung disease to institute treatment.
Subject(s)
Infant, Newborn, Diseases , Lung Diseases, Obstructive , Lung Diseases , Premature Birth , Child , Female , Humans , Infant, Newborn , Bronchodilator Agents/therapeutic use , Bronchodilator Agents/pharmacology , Oscillometry , Forced Expiratory Volume , Lung , SpirometryABSTRACT
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)Subject(s)
Bronchopulmonary Dysplasia
, Lung Diseases, Obstructive
, Pulmonary Disease, Chronic Obstructive
, Humans
, Infant, Newborn
, Bronchodilator Agents/therapeutic use
, Bronchopulmonary Dysplasia/complications
, Forced Expiratory Volume/physiology
, Lung
, Spirometry
, Vital Capacity/physiology
, Premature Birth
, Infant, Premature
ABSTRACT
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.
Subject(s)
Anti-Infective Agents , Nocardia Infections , Nocardia , Adult , Humans , Male , Female , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Retrospective Studies , Queensland/epidemiology , Nocardia Infections/drug therapy , Nocardia Infections/epidemiology , Nocardia Infections/microbiology , Australia/epidemiology , Anti-Infective Agents/therapeutic use , Microbial Sensitivity TestsABSTRACT
BACKGROUND: Breast cancer has a significant heritable basis, of which â¼60% 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.
Subject(s)
Breast Neoplasms , Ovarian Neoplasms , Triple Negative Breast Neoplasms , Female , Humans , Adult , Germ-Line Mutation , Breast Neoplasms/genetics , Breast Neoplasms/diagnosis , Retrospective Studies , Genetic Predisposition to Disease , Ovarian Neoplasms/geneticsABSTRACT
This study investigates how culture and priming 3- to 7-year-old children (N = 186) with third-party social exclusion affects their subsequent inclusion of out-group members. Children in societies that tend to value social independence (Germany, New Zealand) and interdependence (Northern Cyprus) were randomly assigned to minimal groups. Next, they watched video stimuli depicting third-party social exclusion (exclusion condition) or neutral content (control condition). We assessed children's recognition of the social exclusion expressed in the priming videos and their understanding of the emotional consequences thereof. We furthermore assessed children's inclusion behaviour in a ball-tossing game in which participants could include an out-group agent into an in-group interplay. Children across societies detected third-party social exclusion and ascribed lower mood to excluded than non-excluded protagonists. Children from Germany and New Zealand were more likely to include the out-group agent into the in-group interaction than children from Northern Cyprus. Children's social inclusion remained unaffected by their exposure to third-party social exclusion primes. These results suggest that children from diverse societies recognize social exclusion and correctly forecast its negative emotional consequences, but raise doubt on the notion that social exclusion exposure affects subsequent social inclusion.
ABSTRACT
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.
Subject(s)
Bacteremia , Cefazolin , Staphylococcal Infections , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Australia , Bacteremia/drug therapy , Bacteremia/microbiology , Cefazolin/pharmacology , Coagulase , Humans , Infant, Newborn , Microbial Sensitivity Tests , Oxacillin/pharmacology , Staphylococcal Infections/drug therapyABSTRACT
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 33-34â 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 7-12â 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 ≤34â 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=â-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.
Subject(s)
Bronchopulmonary Dysplasia , Premature Birth , Bronchopulmonary Dysplasia/complications , Child , Female , Humans , Infant, Newborn , Lung , Pregnancy , Prospective Studies , SpirometryABSTRACT
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.
ABSTRACT
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.
Subject(s)
Cholinergic Antagonists , Intellectual Disability , Adolescent , Adult , Aged , Aged, 80 and over , Cholinergic Antagonists/adverse effects , Cross-Sectional Studies , Female , Humans , Intellectual Disability/epidemiology , Male , Medication Review , Middle Aged , Retrospective Studies , Scotland/epidemiology , Young AdultABSTRACT
Direct evidence of ancient human occupation is typically established through archaeological excavation. Excavations are costly and destructive, and practically impossible in some lake and wetland environments. We present here an alternative approach, providing direct evidence from lake sediments using DNA metabarcoding, steroid lipid biomarkers (bile acids) and from traditional environmental analyses. Applied to an early Medieval Celtic settlement in Ireland (a crannog) this approach provides a site chronology and direct evidence of human occupation, crops, animal farming and on-site slaughtering. This is the first independently-dated, continuous molecular archive of human activity from an archeological site, demonstrating a link between animal husbandry, food resources, island use. These sites are under threat but are impossible to preserve in-situ so this approach can be used, with or without excavation, to produce a robust and full site chronology and provide direct evidence of occupation, the use of plants and animals, and activities such as butchery.
Subject(s)
Archaeology , Biomarkers , DNA, Ancient , Lakes , Lipids , Animals , Archaeology/methods , History, Medieval , Humans , Ireland , Minerals/analysis , Radiometric Dating , United KingdomABSTRACT
BACKGROUND: The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood. METHODS: DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex. RESULTS: High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases. CONCLUSION: The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.
Subject(s)
DNA Methylation/drug effects , DNA Methylation/genetics , Environmental Exposure/adverse effects , Environmental Pollutants/adverse effects , Lung Diseases/chemically induced , Lung Diseases/physiopathology , Adolescent , Adult , Age Factors , Child , Child, Preschool , Female , Genome-Wide Association Study , Humans , Infant , Infant, Newborn , Longitudinal Studies , Male , Sex Factors , United KingdomABSTRACT
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.
Subject(s)
Air Pollutants/adverse effects , Birth Weight/drug effects , Maternal Exposure/adverse effects , Particulate Matter/adverse effects , Adult , Female , Humans , Infant, Newborn , Longitudinal Studies , Male , Pregnancy , Pregnancy Outcome , Pregnancy Trimesters , Vehicle Emissions , Young AdultABSTRACT
Members of sexual minority groups confront a dearth of fictional characters in k-12 curricula with whom they can feel any affinity, particularly in regard to sexual orientation. This is especially problematic for readers who are at odds with themselves and/or society over cultural constructions of normalcy. Queer theory can address this issue by encouraging readers to contest the putative heteronormativity in works of literature. The perennially popular novel Johnny Tremain provides such an opportunity. Though the author, Esther Forbes, depicts the main protagonist as heterosexual, a queer analysis of the novel and comparison to the subsequent film version by Walt Disney suggest that other interpretations are possible. This is significant because healthy identity formation can be fostered by encountering positive portrayals of fictional individuals like oneself. Moreover, promoting self-esteem is consistent with the praxis - the "activist agenda" - that has become an important element of queer criticism.
Subject(s)
Literature, Modern , Sexual and Gender Minorities/psychology , Female , Heterosexuality , History, 20th Century , Humans , Literature, Modern/history , Male , Psychological Theory , Sexual and Gender Minorities/historyABSTRACT
OBJECTIVES: We examined whether provision of contraception at discharge following delivery was associated with lower rates of postpartum visit (PPV) attendance. METHODS: We conducted a retrospective cohort study of women who received pregnancy care at a Midwestern medical center in 2013. Attendance at the postpartum visit was compared for women with sterilization, contraception initiated prior to discharge (depot medroxyprogesterone acetate or etonogestrel implant), hormonal contraception prescription, or no contraception provided at postpartum discharge. Poisson regression models with robust standard errors were used to estimate the relative risk of postpartum visit attendance controlling for age, race, and parity, insurance status, and histories of both depression and drug abuse. RESULTS: Of the 1015 women who met inclusion criteria, 55% had been prescribed contraception, had initiated contraception prior to discharge, or were sterilized at the time of discharge following delivery. After adjustment for confounders, there was no association between receiving contraception and PPV attendance (relative risk for prescribed contraceptionâ¯=â¯1.09 [95% CI 0.85, 1.39], for contraception initiated prior to dischargeâ¯=â¯0.83 [95% CI 0.67, 1.03], for sterilizationâ¯=â¯0.86 [95% CI 0.63, 1.17] compared to no contraception). CONCLUSIONS: We found no evidence that prescribing or administering contraception post-delivery was associated with lower rates of return for postpartum follow up. IMPLICATIONS: This single site study suggests that providing effective contraception at discharge following delivery does not appear to impact PPV attendance.
Subject(s)
Contraception , Patient Discharge , Female , Humans , Postpartum Period , Pregnancy , Retrospective Studies , Sterilization, ReproductiveABSTRACT
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 26â 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 24â 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 18â 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.