Benefits and Risks of Weight-Loss Treatment for Older, Obese Women

Background: A key issue in the treatment of obesity in older adults is whether the health benefits of weight loss outweigh the potential risks with respect to musculoskeletal injury. Objective: To compare change in weight, improvements in metabolic risk factors, and reported musculoskeletal adverse events in middle-aged (50-59 years) and older (65-74 years), obese women. Materials and methods: Participants completed an initial 6-month lifestyle intervention for weight loss, comprised of weekly group sessions, followed by 12 months of extended care with biweekly contacts. Weight and fasting blood samples were assessed at baseline, month 6, and month 18; data regarding adverse events were collected throughout the duration of the study. Results: Both middle-aged (n = 162) and older (n = 56) women achieved significant weight reductions from baseline to month 6 (10.1 +/- 0.68 kg and 9.3 +/- 0.76 kg, respectively) and maintained a large proportion of their losses at month 18 (7.6 +/- 0.87 kg and 7.6 +/- 1.3 kg, respectively); there were no significant differences between the two groups with respect to weight change. Older women further experienced significant reductions in systolic blood pressure, HbA(1c), and C-reactive protein from baseline to month 6 and maintained these improvements at month 18. Despite potential safety concerns, we found that older women were no more likely to experience musculoskeletal adverse events during the intervention as compared with their middle-aged counterparts. Conclusion: These results suggest that older, obese women can experience significant health benefits from lifestyle treatment for obesity, including weight loss and improvements in disease risk factors. Further investigation of the impact of weight loss on additional health-related parameters and risks (eg, body composition, muscular strength, physical functioning, and injuries) in older adults is needed.National Heart, Lung and Blood Institute R18HL73326University of FloridaDivision of Statistics and Scientific Computatio

Improving Colorectal Cancer Screening Decision Making Processes

Introduction: Although shared decision making is recommended for cancer screening, it is not routinely completed in practice because of time constraints. We evaluated a process for improving decision making about colorectal cancer (CRC) screening using mailed decision aids (DA) with follow-up telephone support in primary care practices. Methods: We identified patients aged 50-75 who were not up to date with CRC screening in three primary care practices. DA were distributed via mail with telephone follow-up to eligible patients, and charts were reviewed six months later for CRC screening completion. Results: Among 1,064 eligible patients who received the mailed DA, 513 (48.2%) were reached by phone. During the six months after the intervention, 148/1064 (13.9%) patients were screened for CRC (4.8% underwent FIT, 9.1% underwent colonoscopy). Younger patients (aged 50-54) had higher rates of any screening (32.4%) compared with all other age groups (range 12.8%-19.6%), p=0.026, while Medicaid patients had the lowest rates of screening (4.0%), and insured patients had the highest rates (45.3%), p=0.003. Overall, 113/513 (22.0%) who were reached by phone went on to complete screening within 6 months, compared with 35/551 (6.4%) of patients who were not reached by phone (p Conclusion: A standard process for identifying patients unscreened for CRC and DA distribution via mail with telephone decision support modestly increased CRC screening and is consistent with the goal of providing preference-sensitive care and informed decision making. Improving care processes to include decision support outside of office visits is possible in primary care practices

Assessment of Brain Age in Posttraumatic Stress Disorder: Findings from the ENIGMA PTSD and Brain Age Working Groups

Background Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan

The North American tree-ring fire-scar network

Fire regimes in North American forests are diverse and modern fire records are often too short to capture important patterns, trends, feedbacks, and drivers of variability. Tree-ring fire scars provide valuable perspectives on fire regimes, including centuries-long records of fire year, season, frequency, severity, and size. Here, we introduce the newly compiled North American tree-ring fire-scar network (NAFSN), which contains 2562 sites, >37,000 fire-scarred trees, and covers large parts of North America. We investigate the NAFSN in terms of geography, sample depth, vegetation, topography, climate, and human land use. Fire scars are found in most ecoregions, from boreal forests in northern Alaska and Canada to subtropical forests in southern Florida and Mexico. The network includes 91 tree species, but is dominated by gymnosperms in the genus Pinus. Fire scars are found from sea level to >4000-m elevation and across a range of topographic settings that vary by ecoregion. Multiple regions are densely sampled (e.g., >1000 fire-scarred trees), enabling new spatial analyses such as reconstructions of area burned. To demonstrate the potential of the network, we compared the climate space of the NAFSN to those of modern fires and forests; the NAFSN spans a climate space largely representative of the forested areas in North America, with notable gaps in warmer tropical climates. Modern fires are burning in similar climate spaces as historical fires, but disproportionately in warmer regions compared to the historical record, possibly related to under-sampling of warm subtropical forests or supporting observations of changing fire regimes. The historical influence of Indigenous and non-Indigenous human land use on fire regimes varies in space and time. A 20th century fire deficit associated with human activities is evident in many regions, yet fire regimes characterized by frequent surface fires are still active in some areas (e.g., Mexico and the southeastern United States). These analyses provide a foundation and framework for future studies using the hundreds of thousands of annually- to sub-annually-resolved tree-ring records of fire spanning centuries, which will further advance our understanding of the interactions among fire, climate, topography, vegetation, and humans across North America

A Comparison of Methods to Harmonize Cortical Thickness Measurements Across Scanners and Sites

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LME INT), (2) LME that models both site-specific random intercepts and age-related random slopes (LME INT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ 2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ 2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder:Results from the ENIGMA-PGC PTSD Consortium

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1,300 PTSD cases and >2,000 trauma-exposed controls (age 6.2-85.2 years) by the ENIGMA-PGC PTSD working group. Cortical regions in the network were rank-ordered by effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2 to 148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared to the mean SC of 5,000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD controls, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The structural covariance networks that are perturbed in PTSD comport with converging evidence from resting state functional connectivity networks and networks impacted by inflammatory processes, and stress hormones in PTSD

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Post-Operative Functional Outcomes in Early Age Onset Rectal Cancer

Background: Impairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (&lt;50 years) is rising, there is little data on functional outcomes in this group. Methods: The REACCT international collaborative database was reviewed and data on eligible patients analysed. Inclusion criteria comprised patients with a histologically confirmed rectal cancer, &lt;50 years of age at time of diagnosis and with documented follow-up including functional outcomes. Results: A total of 1428 (n=1428) patients met the eligibility criteria and were included in the final analysis. Metastatic disease was present at diagnosis in 13%. Of these, 40% received neoadjuvant therapy and 50% adjuvant chemotherapy. The incidence of post-operative major morbidity was 10%. A defunctioning stoma was placed for 621 patients (43%); 534 of these proceeded to elective restoration of bowel continuity. The median follow-up time was 42 months. Of this cohort, a total of 415 (29%) reported persistent impairment of functional outcomes, the most frequent of which was bowel dysfunction (16%), followed by bladder dysfunction (7%), sexual dysfunction (4.5%) and infertility (1%). Conclusion: A substantial proportion of patients with early-onset rectal cancer who undergo surgery report persistent impairment of functional status. Patients should be involved in the discussion regarding their treatment options and potential impact on quality of life. Functional outcomes should be routinely recorded as part of follow up alongside oncological parameters