ORE THAN 2.4 MILLION breast cancer survivors live in the United States. 1 Lymphedema ranks high among their concerns because it causes swelling and discomfort, impairing arm function and quality of life 2,3 and increasing health care costs. 4 Lymphedema remains a frequent complication among survivors, despite lymphatic-sparing procedures such as sentinel lymph node biopsy. Of the 61% of patients who undergo sentinel lymph node biopsy, 5% to 7% develop breast cancer-related lymphedema. 5,6 However, one-third of patients with breast cancer require complete axillary dissection, 5 which is associated with 13% to 47% incident lymphedema. 7,8 Breast cancer survivors at risk for lymphedema alter activity, limit activity, or both from fear and uncertainty about their personal risk level, and upon guidance advising them to avoid lift-Context Clinical guidelines for breast cancer survivors without lymphedema advise against upper body exercise, preventing them from obtaining established health benefits of weight lifting. Objective To evaluate lymphedema onset after a 1-year weight lifting intervention vs no exercise (control) among survivors at risk for breast cancer-related lymphedema (BCRL). Design, Setting, and Participants A randomized controlled equivalence trial (Physical Activity and Lymphedema trial) in the Philadelphia metropolitan area of 154 breast cancer survivors 1 to 5 years postunilateral breast cancer, with at least 2 lymph nodes removed and without clinical signs of BCRL at study entry. Participants were recruited between Oc

We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.

ABSTRACT. Background. Currently, many states are upgrading their child restraint laws to include provisions for the use of age-appropriate restraints through 6 to 8 years of age, with some also requiring rear seating for children, enabling the laws to be in closer alignment with best-practice recommendations.Objective. To evaluate the relationships of seating position and restraint status to the risk of injury among children in passenger vehicle crashes.Methods. This was a cross-sectional study of children <16 years of age who were involved in crashes of insured vehicles in 15 states, with data collected via insurance claims records and a telephone survey. A probability sample of 17 980 children in 11 506 crashes, representing 229 106 children in 146 613 crashes, was collected between December 1, 1998, and November 30, 2002. Parent reports were used to define restraint status, seating position, and occurrence of clinically significant injuries, with the use of a previously validated instrument.Results. Approximately 62% of the children used seat belts, 35% used child restraints, and 3% used no restraint. Nearly 4 of 5 children sat in the rear seat, with one half of all children being restrained appropriately for their age in the rear, although this varied according to the age of the child. Overall, 1.6% of children suffered serious injuries, 13.5% had minor injuries, and 84.9% did not have any injury. Unrestrained children in the front were at the highest risk of injury and appropriately restrained children in the rear were at the lowest risk, for all age groups. Inappropriately restrained children were at nearly twice the risk of injury, compared with appropriately restrained children (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.4 -2.3), whereas unrestrained children were at >3 times the risk (OR: 3.2; 95% CI: 2.5-4.1). The effect of seating row was smaller than the effect of restraint status; children in the front seat were at 40% greater risk of injury, compared with children in the rear seat (OR: 1.4; 95% CI: 1.2-1.7). Had all children in the study population been appropriately restrained in the rear seat, 1014 serious injuries (95% CI: 675-1353 injuries) would have been prevented (with the assumption that restraint effectiveness does not depend on a variety of other driver-related, child-related, crash-related, vehiclerelated, and environmental factors).Conclusions. Age-appropriate restraint confers relatively more safety benefit than rear seating, but the 2 work synergistically to provide the best protection for children in crashes. These results support the current focus on age-appropriate restraint in recently upgraded state child restraint laws. However, it is important to note that considerable added benefit would be realized with additional requirements for rear seating. E xisting guidelines for the optimal protection of children in automobiles recommend rear seating for all children Ͻ13 years of age and the use of age-appropriate restraints, including child safety seats and belt-positioning...

Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

BackgroundLate-onset Alzheimer’s disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD.ResultsWe identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (− 3.76% 5mC, pŠidák = 1.07E−06), CHRNB1 (+ 1.46% 5hmC, pŠidák = 4.01E−04), RHBDF2 (− 3.45% UC, pŠidák = 4.85E−06), and C3 (− 1.20% UC, pŠidák = 1.57E−03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, pŠidák = 7.14E−04).ConclusionsThe implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

BackgroundAlzheimer’s disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. Previous studies of DNA modifications in Alzheimer’s disease have been unable to distinguish between DNA methylation and DNA hydroxymethylation. DNA hydroxymethylation has been shown to be enriched in the human brain, although its role in Alzheimer’s disease has not yet been fully explored. Here, we utilize oxidative bisulfite conversion, in conjunction with the Illumina Infinium Human Methylation 450K microarray, to identify neuropathology-associated differential DNA methylation and DNA hydroxymethylation in the entorhinal cortex.ResultsWe identified one experiment-wide significant differentially methylated position residing in the WNT5B gene. Next, we investigated pathology-associated regions consisting of multiple adjacent loci. We identified one significant differentially hydroxymethylated region consisting of four probes spanning 104 bases in the FBXL16 gene. We also identified two significant differentially methylated regions: one consisting of two probes in a 93 base-pair region in the ANK1 gene and the other consisting of six probes in a 99-base pair region in the ARID5B gene. We also highlighted three regions that show alterations in unmodified cytosine: two probes in a 39-base pair region of ALLC, two probes in a 69-base pair region in JAG2, and the same six probes in ARID5B that were differentially methylated. Finally, we replicated significant ANK1 disease-associated hypermethylation and hypohydroxymethylation patterns across eight CpG sites in an extended 118-base pair region in an independent cohort using oxidative-bisulfite pyrosequencing.ConclusionsOur study represents the first epigenome-wide association study of both DNA methylation and hydroxymethylation in Alzheimer’s disease entorhinal cortex. We demonstrate that previous estimates of DNA hypermethylation in ANK1 in Alzheimer’s disease were underestimates as it is confounded by hypohydroxymethylation.Electronic supplementary materialThe online version of this article (10.1186/s13148-019-0636-y) contains supplementary material, which is available to authorized users.

Objective: To evaluate the incidence of hypermobility in young female netball players and to determine the relation between hypermobility, previous injuries sustained in netball or other sports, and the use of protective equipment. Methods: Under 16 year old female netball players from a local suburban netball association were assessed for joint hypermobility using the validated Beighton score (0-9, with higher scores indicating increasing hypermobility). Player profiles and details of sporting injuries, both netball and non-netball, and the use of protective equipment were gathered by means of a self completed questionnaire. Parental and child consent was obtained. Results: Two hundred netball players were recruited for the study. Twenty one percent of the subjects with a Beighton hypermobility score of 0-2 had sustained previous netball injuries compared with 37% with Beighton scores of 3-4, and 43% with scores of 5-9. These differences were significant (p,0.025). Injuries were most common in the ankle (42%), knee (27%), and fingers (15%). Thirty nine players (19%) wore protective equipment, and within this group 30 (77%) had sustained previous injuries. No association was detected between hypermobile joints and non-netball sporting injuries. Conclusions: In this study hypermobility was significantly associated with an increased prevalence of injuries in junior netball players. A targeted interventional approach may help to reduce injuries in this susceptible group.

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.