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Objectives: Malnutrition, particularly protein insufficiency, is common in institutionalised older adults and increases morbidity, mortality, and costs. We aimed to determine whether 12 months supplementation using high-protein foods (milk, cheese, yoghurt) prevents malnutrition in older adults. Design: Cluster randomised control study. Setting: Sixty Australian aged care facilities. Participants: Older adults living in aged care homes (n=654, mean age 86.7±7.2 years, 72% females). Intervention: Facilities randomly allocated to a high-protein (n=30 intervention) or regular (n=30 controls) menu. Measurements: Nutritional status assessed using the Mini Nutrition Assessment (MNA) tool and fasting morning blood samples (n=302) assayed for haemoglobin (Hb) and albumin. Food intake was monitored 3-monthly using visual plate waste assessment. Measurements at baseline and month 12 were analysed using random effects model accounting for clustering (facility), repeated measure and confounders. Results: Addition of 11g of protein as 1.5 servings of high-protein foods daily preserved nutritional status that deteriorated in controls [MNA screen (−0.68, 95%CI: −1.03, −0.32, p<0.001) and total (−0.90, 95%CI: −1.45, −0.35, p=0.001) scores], resulting in group differences in MNA screen (0.62, 95%CI: 0.17, 1.06, p=0.007) and total (0.81, 95%CI: 0.11, 1.51, p=0.023) scores and group difference in Hb (3.60g/L, 95%CI: 0.18, 7.03, p=0.039), the net result of preservation with intervention (0.19g/L, 95%CI: −2.04, 2.42, p=0.896) and a decline in controls (−3.41g/L, 95%CI: −6.01, −0.82, p=0.010). No group differences were observed for serum albumin. Conclusion: Consumption of high-protein foods is a pragmatic approach to maintaining nutritional status in older adults in aged-care. [ABSTRACT FROM AUTHOR]

This study describes a protocol to assess a novel workflow called Epi-Genomic Newborn Screening (EpiGNs) on 100,000 infants from the state of Victoria, Australia. The workflow uses a first-tier screening approach called methylation-specific quantitative melt analysis (MS-QMA), followed by second and third tier testing including targeted methylation and copy number variation analyzes with droplet digital PCR, EpiTYPER system and low-coverage whole genome sequencing. EpiGNs utilizes only two 3.2 mm newborn blood spot punches to screen for genetic conditions, including fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, Dup15q syndrome and sex chromosome aneuploidies. The program aims to: identify clinically actionable methylation screening thresholds for the first-tier screen and estimate prevalence for the conditions screened.

Background: Mammogram risk scores based on texture and density defined by different brightness thresholds are associated with breast cancer risk differently and could reveal distinct information about breast cancer risk. We aimed to investigate causal relationships between these intercorrelated mammogram risk scores to determine their relevance to breast cancer aetiology., Methods: We used digitised mammograms for 371 monozygotic twin pairs, aged 40-70 years without a prior diagnosis of breast cancer at the time of mammography, from the Australian Mammographic Density Twins and Sisters Study. We generated normalised, age-adjusted, and standardised risk scores based on textures using the Cirrus algorithm and on three spatially independent dense areas defined by increasing brightness threshold: light areas, bright areas, and brightest areas. Causal inference was made using the Inference about Causation from Examination of FAmilial CONfounding (ICE FALCON) method., Results: The mammogram risk scores were correlated within twin pairs and with each other (r = 0.22-0.81; all P < 0.005). We estimated that 28-92% of the associations between the risk scores could be attributed to causal relationships between the scores, with the rest attributed to familial confounders shared by the scores. There was consistent evidence for positive causal effects: of Cirrus, light areas, and bright areas on the brightest areas (accounting for 34%, 55%, and 85% of the associations, respectively); and of light areas and bright areas on Cirrus (accounting for 37% and 28%, respectively)., Conclusions: In a mammogram, the lighter (less dense) areas have a causal effect on the brightest (highly dense) areas, including through a causal pathway via textural features. These causal relationships help us gain insight into the relative aetiological importance of different mammographic features in breast cancer. For example our findings are consistent with the brightest areas being more aetiologically important than lighter areas for screen-detected breast cancer; conversely, light areas being more aetiologically important for interval breast cancer. Additionally, specific textural features capture aetiologically independent breast cancer risk information from dense areas. These findings highlight the utility of ICE FALCON and family data in decomposing the associations between intercorrelated disease biomarkers into distinct biological pathways., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To assess the antifracture efficacy and safety of a nutritional intervention in institutionalised older adults replete in vitamin D but with mean intakes of 600 mg/day calcium and <1 g/kg body weight protein/day., Design: Two year cluster randomised controlled trial., Setting: 60 accredited residential aged care facilities in Australia housing predominantly ambulant residents., Participants: 7195 permanent residents (4920 (68%) female; mean age 86.0 (SD 8.2) years)., Intervention: Facilities were stratified by location and organisation, with 30 facilities randomised to provide residents with additional milk, yoghurt, and cheese that contained 562 (166) mg/day calcium and 12 (6) g/day protein achieving a total intake of 1142 (353) mg calcium/day and 69 (15) g/day protein (1.1 g/kg body weight). The 30 control facilities maintained their usual menus, with residents consuming 700 (247) mg/day calcium and 58 (14) g/day protein (0.9 g/kg body weight)., Main Outcome Measures: Group differences in incidence of fractures, falls, and all cause mortality., Results: Data from 27 intervention facilities and 29 control facilities were analysed. A total of 324 fractures (135 hip fractures), 4302 falls, and 1974 deaths were observed. The intervention was associated with risk reductions of 33% for all fractures (121 v 203; hazard ratio 0.67, 95% confidence interval 0.48 to 0.93; P=0.02), 46% for hip fractures (42 v 93; 0.54, 0.35 to 0.83; P=0.005), and 11% for falls (1879 v 2423; 0.89, 0.78 to 0.98; P=0.04). The risk reduction for hip fractures and falls achieved significance at five months (P=0.02) and three months (P=0.004), respectively. Mortality was unchanged (900 v 1074; hazard ratio 1.01, 0.43 to 3.08)., Conclusions: Improving calcium and protein intakes by using dairy foods is a readily accessible intervention that reduces the risk of falls and fractures commonly occurring in aged care residents., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12613000228785., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: funding support from the organisations listed above; SI has received lecture fees from Abbott; TVN has received research support and lecture fees from Amgen, MSD, and Novartis; ES has received research support from Amgen and MSD and lecture fees from Amgen, Eli Lilly, and Allergan; ES is a scientific consultant for StraxCorp and shareholder; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥ 200 CGG repeats, and a decrease in FMR1 mRNA and its protein. However, incomplete silencing from FM alleles has been associated with more severe autism features in FXS males. This study compared scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-C FX ) in 62 males affected with FXS (3 to 32 years) stratified based on presence or absence of mosaicism and/or FMR1 mRNA silencing. Associations between ABC-C FX subscales and FMR1 mRNA levels, assessed using real-time PCR relative standard curve method, were also examined. The FXS group mosaic for premutation (PM: 55-199 CGGs) and FM alleles had lower irritability (p = 0.014) and inappropriate speech (p < 0.001) scores compared to males with only FM alleles and complete loss of FMR1 mRNA. The PM/FM mosaic group also showed lower inappropriate speech scores compared to the incomplete silencing (p = 0.002) group. Increased FMR1 mRNA levels were associated with greater irritability (p < 0.001), and lower health-related quality of life scores (p = 0.004), but only in the incomplete silencing FM-only group. The findings suggest that stratification based on CGG sizing and FMR1 mRNA levels may be warranted in future research and clinical trials utilising ABC-C FX subscales as outcome measures.

Advancing age is accompanied by a reduction in bone formation and remodeling imbalance, which produces microstructural deterioration. This may be partly caused by a diversion of mesenchymal cells towards adipocytes rather than osteoblast lineage cells. We hypothesized that microstructural deterioration would be associated with an increased marrow adiposity, and each of these traits would be independently associated with nonvertebral fractures and improve discrimination of women with fractures from controls over that achieved by femoral neck (FN) areal bone mineral density (aBMD) alone. The marrow adiposity and bone microstructure were quantified from HR-pQCT images of the distal tibia and distal radius in 77 women aged 40 to 70 years with a recent nonvertebral fracture and 226 controls in Melbourne, Australia. Marrow fat measurement from HR-pQCT images was validated using direct histologic measurement as the gold standard, at the distal radius of 15 sheep, with an agreement (R 2 = 0.86, p < 0.0001). Each SD higher distal tibia marrow adiposity was associated with 0.33 SD higher cortical porosity, and 0.60 SD fewer, 0.24 SD thinner, and 0.72 SD more-separated trabeculae (all p < 0.05). Adjusted for age and FN aBMD, odds ratios (ORs) (95% CI) for fracture per SD higher marrow adiposity and cortical porosity were OR, 3.39 (95% CI, 2.14 to 5.38) and OR, 1.79 (95% CI, 1.14 to 2.80), respectively. Discrimination of women with fracture from controls improved when cortical porosity was added to FN aBMD and age (area under the receiver-operating characteristic curve [AUC] 0.778 versus 0.751, p = 0.006) or marrow adiposity was added to FN aBMD and age (AUC 0.825 versus 0.751, p = 0.002). The model including FN aBMD, age, cortical porosity, trabecular thickness, and marrow adiposity had an AUC = 0.888. Results were similar for the distal radius. Whether marrow adiposity and cortical porosity indices improve the identification of women at risk for fractures requires validation in prospective studies. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

CVD is common in older adults. Consumption of 'meat' (beef, pork, lamb, game, poultry, seafood, eggs) and dairy foods (milk, cheese, yoghurt) is encouraged in older adults as these foods provide protein and nutrients such as essential fatty acids, Ca, Fe, Zn and vitamins A, D and B 12 required for healthy ageing. However, these foods also contain saturated fats considered detrimental to cardiovascular health. To determine the effect of their consumption on CVD risk we assessed associations between fat intake from 'meat' and dairy foods and serum cholesterol levels in 226 aged-care residents (mean age 85·5 years, 70 % female). Dietary intake was determined over 2 d using visual estimation of plate waste. Fat content of foods was determined using nutrition analysis software (Xyris, Australia). Fasting serum total cholesterol (TC), LDL-cholesterol and HDL-cholesterol were measured, and the TC:HDL-cholesterol ratio calculated. Associations were determined using random-effect models adjusted for CVD risk factors using STATA/IC 13.0. Total fat and saturated fat from 'meat' and dairy foods were associated with higher serum HDL-cholesterol levels, and dairy fat intake and number of servings were associated with a lower TC:HDL-cholesterol ratio. Every 10 g higher intake of fat and saturated fat from dairy products, and each additional serving was associated with a -0·375 (95 % CI -0·574, -0·175; P = 0·0002), a -0·525 (95 % CI -0·834, -0·213; P = 0·001) and a -0·245 (95 % CI -0·458, -0·033; P = 0·024) lower TC:HDL-cholesterol ratio, respectively. Provision of dairy foods and 'meat' in recommended amounts to institutionalised older adults potentially improves intakes of key nutrients with limited detriment to cardiovascular health.

Background: Several studies have reported DNA methylation in blood to be associated with body mass index (BMI), but few have investigated causal aspects of the association. We used a twin family design to assess this association at two life points and applied a novel analytical approach to appraise the evidence for causality., Methods: The methylation profile of DNA from peripheral blood was measured for 479 Australian women from 130 twin families. Linear regression was used to estimate the associations of DNA methylation at ~410,000 cytosine-guanine dinucleotides (CpGs), and of the average DNA methylation at ~20,000 genes, with current BMI, BMI at age 18-21 years, and the change between the two (BMI change). A novel regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess causation., Results: At a 5% false discovery rate, nine, six and 12 CpGs at 24 loci were associated with current BMI, BMI at age 18-21 years and BMI change, respectively. The average DNA methylation of the BHLHE40 and SOCS3 loci was associated with current BMI, and of the PHGDH locus with BMI change. From the ICE FALCON analyses with BMI as the predictor and DNA methylation as the outcome, a woman's DNA methylation level was associated with her co-twin's BMI, and the association disappeared after conditioning on her own BMI, consistent with BMI causing DNA methylation. To the contrary, using DNA methylation as the predictor and BMI as the outcome, a woman's BMI was not associated with her co-twin's DNA methylation level, consistent with DNA methylation not causing BMI., Conclusion: For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with current BMI, BMI at age 18-21 years and BMI change. Our study suggests that BMI has a causal effect on peripheral blood DNA methylation.

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders that are caused by abnormal expression of imprinted genes in the 15q11-13 region. Dysregulation of genes located in this region has been proposed as a susceptibility factor for autism spectrum disorder (ASD) in both disorders., Methods: This study aimed to explore symptoms of ASD in 25 PWS and 19 AS individuals aged between 1 and 39 years via objective assessment. Participants completed the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) and a developmentally or age-appropriate intellectual functioning assessment. All participants had their genetic diagnosis confirmed using DNA methylation analysis and microarray testing of copy number changes within the 15q11-13 region., Results: Participants with PWS had significantly higher overall and social affect calibrated severity scores (CSS) on the ADOS-2 compared to AS participants (p = .0055 and .0015, respectively), but the two groups did not differ significantly on CSS for the repetitive and restricted behaviour domain., Conclusions: PWS cases presented with greater symptoms associated with ASD compared to individuals with AS. Mental health issues associated with PWS may contribute to elevated symptoms of ASD, particularly in adolescents and adults with PWS.

Recent findings suggest that children with Autism Spectrum Disorder (ASD) are larger in size for head circumference (HC), height, and weight compared to typically developing (TD) children; however, little is known about their rate of growth, especially in height and weight. The current study aimed to: (a) confirm and extend upon previous findings of early generalized overgrowth in ASD; and (b) determine if there were any differences in the rate of growth between infants and toddlers with ASD compared to their TD peers. Measurements of HC, height, and weight were available for 135 boys with ASD and 74 TD boys, from birth through 3 years of age. Size and growth rate in HC, height, and weight were analyzed using a linear mixed-effects model. Infants with ASD were significantly smaller in size at birth for HC, body length, and weight compared to TD infants (all P < 0.05); however, they grew at a significantly faster rate in HC and height in comparison to the TD children (P < 0.001); there was no significant difference between the groups in growth rate for weight (P > 0.05). The results confirmed that male infants and toddlers with ASD exhibit skeletal growth dysregulation early in life. Autism Res 2018, 11: 846-856. © 2018 International Society for Autism Research, Wiley Periodicals, Inc., Lay Summary: Recent findings suggest that infants with Autism Spectrum Disorder (ASD) are smaller in size at birth compared to typically developing infants but grow larger than their peers during the first year. Little is known about their rate of growth, especially for height and weight. Our findings confirmed that infants with ASD are smaller in size at birth for head circumference (HC), height, and weight, but grow at a faster rate in HC and height than their peers from birth to 3 years., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Objective: The question of how to best conceptualize health anxiety (HA) from a diagnostic and etiological perspective remains debated. The aim was to examine the relationship between HA and the symptoms of anxiety and obsessive-compulsive-related disorders in a normative twin population., Method: Four hundred and ninety-six monozygotic adult twin pairs from the Australian Twin Registry participated in the study (age, 34.4 ± 7.72 years; 59% females). Validated scales were used to assess each domain. We applied a twin regression methodology-ICE FALCON-to determine whether there was evidence consistent with 'causal' relationships between HA and other symptoms by fitting and comparing model estimates., Results: Estimates were consistent with higher levels of obsessing ('unwanted thoughts') (P = 0.008), social anxiety (P = 0.03), and body dysmorphic symptoms (P = 0.008) causing higher levels of HA symptoms, and with higher levels of HA symptoms causing higher levels of physical/somatic anxiety symptoms (P = 0.001)., Conclusion: Obsessional thoughts, body dysmorphic concerns, and social anxiety symptoms may have a causal influence on HA. To report physical/somatic anxiety appears to be a consequence of the underlying presence of HA-related fears. Should our results be confirmed by longitudinal studies, the evaluation and treatment of HA may benefit from the consideration of these identified risk factors., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation., Methods: The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin pairs, and 215 sisters of twins from 130 twin families using the Infinium HumanMethylation450K BeadChip array. Linear regression was used to estimate associations between methylation at ~ 410,000 cytosine-guanine dinucleotides (CpGs) and smoking status. A regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess putative causation., Results: At a 5% false discovery rate, 39 CpGs located at 27 loci, including previously reported AHRR , F2RL3 , 2q37.1 and 6p21.33 , were found to be differentially methylated across never, former and current smokers. For all 39 CpG sites, current smokers had the lowest methylation level. Our study provides the first replication for two previously reported CpG sites, cg06226150 ( SLC2A4RG ) and cg21733098 ( 12q24.32 ). From the ICE FALCON analysis with smoking status as the predictor and methylation score as the outcome, a woman's methylation score was associated with her co-twin's smoking status, and the association attenuated towards the null conditioning on her own smoking status, consistent with smoking status causing changes in methylation. To the contrary, using methylation score as the predictor and smoking status as the outcome, a woman's smoking status was not associated with her co-twin's methylation score, consistent with changes in methylation not causing smoking status., Conclusions: For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with smoking. Our study suggests that smoking has a causal effect on peripheral blood DNA methylation, but not vice versa., Competing Interests: The study was approved by the Human Research Ethics Committee of the University of Melbourne. All participants provided written informed consent.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Common childhood pain conditions (nonmigraine headache, migraine, recurrent abdominal pain, growing pains, low back pain) and persistent pains are often associated with each other and have significant implications in later life. Emerging evidence suggests additional associations between these pain conditions and restless legs syndrome, iron deficiency, anxiety, and depression. The aim of this cross-sectional study in pediatric twin individuals and their siblings was to investigate these associations., Materials and Methods: Surveys were sent to Australian twin families via the Australian Twin Registry, yielding responses from 2530 pediatric individuals. The lifetime prevalence of the common pain disorders of childhood and of other persistent pains, restless legs syndrome and iron deficiency, and anxious/depressed score were determined by questionnaires. Random-effects logistic regression modeling was used to investigate univariate and multivariate associations between conditions., Results: Univariate associations were found between each of the pain conditions and persistent pain, and between the pain conditions with restless legs syndrome, iron deficiency, and anxious/depressed score. Derivative multivariate analyses retained statistically significant associations between each of the pain disorders included in the respective models (odds ratios [OR], 1.69-7.04) with the exception of growing pains with persistent pain. Of the nonpain conditions included in the multivariate analyses, restless legs syndrome remained associated with growing pains (OR, 8.50) and persistent pain (OR, 2.01). Iron deficiency remained significantly associated with migraine (OR, 2.38), persistent pain (OR, 3.70), and restless legs syndrome (OR, 5.10)., Conclusions: In light of their extensive associations, the common pain conditions, persistent pain, restless legs syndrome, iron deficiency, anxiety and depression, are likely to involve common etiological mechanisms that warrant further investigation.