START-online: acceptability and feasibility of an online intervention for carers of people living with dementia

BACKGROUND: With increasing numbers of people living with dementia relying on family to care for them at home, there is an urgent need for practical and evidence-based programs to support carers in maintaining their mental health and well-being. The objective of this study was to evaluate the acceptability and feasibility of a modified STrAtegies for RelaTives (START) program delivered online (START-online). METHOD: A mixed-methods non-blinded evaluation of START-online (using Zoom as videoconferencing platform) for acceptability and feasibility (completion rates and qualitative feedback through surveys and focus groups) and quantitative evaluation. This occurred at the National Ageing Research Institute, in metropolitan Victoria, Australia. RESULTS: Twenty-nine eligible carers were referred, 20 (70%) consented to the study. Of these, 16 (80%) completed all 8 sessions, 2 completed only 3 sessions, and 2 withdrew. Carers' qualitative feedback indicated that the therapist interaction was valued, content and online delivery of the program was acceptable. Feedback was mixed on the appropriate stage of caring. CONCLUSION: START-online was feasible and acceptable for carers, including those living outside of metropolitan areas who might otherwise be unable to access face-to-face programs. With the recent COVID-19 pandemic necessitating social distancing to avoid infection, interventions such as this one have increasing relevance in the provision of flexible services

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Urinary phthalate metabolite concentrations and serum hormone levels in pre- and perimenopausal women from the Midlife Women’s Health Study

Background: Phthalate exposure is associated with altered reproductive function, but little is known about associations between phthalate and hormone levels in midlife women. Methods: This cross-sectional analysis includes 45–54-year-old pre- and perimenopausal women from Baltimore, MD and its surrounding counties enrolled in the Midlife Women’s Health Study (n = 718). Serum and urine samples were collected from participants once a week for four consecutive weeks to span the menstrual cycle. Serum samples were assayed for estradiol, testosterone, progesterone, sex hormone binding globulin (SHBG), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH), and geometric means were calculated for each hormone across all four weeks. Urine samples were analyzed for nine phthalate metabolites from pools of one-to-four urine samples. Phthalate metabolite concentrations were specific gravity-adjusted and assessed as individual metabolites or as molar sums of metabolites from common parents (di(2-ethylhexyl) phthalate metabolites, ∑DEHP), exposure sources (plastic, ∑Plastics; personal care products, ∑PCP), biological activity (anti-androgenic, ∑AA), and sum of all metabolites (∑Phthalates). We used linear regression models to assess overall associations of phthalate metabolites with hormones, controlling for important demographic, lifestyle, and health factors. We also explored whether associations differed by menopause status, body mass index (BMI), and race/ethnicity. Results: Most participants were non-Hispanic white (67%) or black (29%), college-educated (65%), employed (80%), and had somewhat higher mean urinary phthalate metabolite concentrations than other U.S. women. Overall, the following positive associations were observed between phthalate metabolites and hormones: ∑DEHP (%Δ: 4.9; 95%CI: 0.5, 9.6), ∑Plastics (%Δ: 5.1; 95%CI: 0.3, 10.0), and ∑AA (%Δ: 7.8; 95%CI: 2.3, 13.6) with estradiol; MiBP (%Δ: 6.6; 95%CI: 1.5, 12.1) with testosterone; ∑DEHP (%Δ: 8.3; 95%CI: 1.5, 15.6), ∑Plastics (%Δ: 9.8; 95%CI: 2.4, 17.7), MEP (%Δ: 4.6; 95%CI: 0.1, 9.2), ∑PCP (%Δ: 6.0; 95%CI: 0.2, 12.2), ∑Phthalates (%Δ: 9.0; 95%CI: 2.1, 16.5), and ∑AA (%Δ: 12.9; 95%CI: 4.4, 22.1) with progesterone; and MBP (%Δ: 8.5; 95%CI: 1.2, 16.3) and ∑AA (%Δ: 9.0; 95%CI: 1.3, 17.4) with AMH. Associations of phthalate metabolites with hormones differed by menopause status (strongest in premenopausal women for estradiol, progesterone, and FSH), BMI (strongest in obese women for progesterone), and race/ethnicity (strongest in non-Hispanic white women for estradiol and AMH). Conclusions: We found that phthalate metabolites were positively associated with several hormones in midlife women, and that some demographic and lifestyle characteristics modified these associations. Future longitudinal studies are needed to corroborate these findings in more diverse midlife populations

Patterns and severity of vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia.

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine‐induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1–18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score‐Pediatric Vincristine (TNS©‐PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©–Five (PNPS©‐5). Of children who provided a full TNS©‐PV score, 85/109 (78%) developed VIPN (TNS©‐PV ≥4). Mean TNS©‐PV, grading scale, and pain scores were low. CTCAE©‐derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8–12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2–3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111980/1/jns12114.pd

AN OPTIMIZATION PROBLEM FOR A PRODUCTION SYSTEM WITH REAL OPTION APPROACH (Nonlinear Analysis and Convex Analysis)

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes

Impact of the HIV Tat C30C31S dicysteine substitution on neuropsychological function in patients with clade C disease

Previous animal studies have identified a C31S residue substitution in the C30C31 dicysteine motif of the Tat protein that is associated with reduced neurovirulence in clade C HIV. However, clinical studies of patients infected with clade C HIV have reported significant levels of cognitive impairment. To date no study has specifically examined cognitive function in clade C-infected patients as a function of the presence or absence of the Tat C31 substitution. The present study investigated the impact of the Tat C30C31S genetic substitution among individuals residing in South Africa infected with clade C HIV that either exhibited the C30C31 motif (n = 128) or the C31S motif (n = 46). A control group of seronegative individuals were included to examine the overall impact of HIV on cognitive performance. All individuals completed a comprehensive neuropsychological battery consisting of tests sensitive to HIV. Results revealed that clade C-infected individuals performed significantly worse across cognitive tests compared to seronegative controls. However, there were no significant differences in cognitive performances between individuals with the C31S motif versus those without the C31S substitution. Proximal CD4 cell count and plasma viral load were unrelated to cognitive performances for either group. Results confirm that the C31S dicysteine motif substitution of the Tat protein does not appreciably moderate neuropsychological outcomes in clade C. Further, these findings highlight the importance of clinical management of cognitive symptoms among individuals infected with this viral clade worldwide