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AbstractBackgroundADS‐5102 (amantadine) extended release capsules (GOCOVRI™) are a treatment for dyskinesia in patients with Parkinson's disease (PD). ADS‐5102 reduced dyskinesia and OFF time in phase 3 controlled trials of up to six months. Amantadine immediate release (IR) is used for dyskinesia, but suboptimal durability and tolerability limit its clinical utility.MethodsIn an ongoing, open‐label, phase 3 study in the US and Western Europe (NCT02202551), patients with PD received 274 mg of ADS‐5102 (equivalent to 340 mg amantadine HCl) once daily at bedtime for up to two years. Study outcomes included safety and assessment of motor complications, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part IV. This manuscript focuses on those patients switched to ADS‐5102 from amantadine IR. Results in two groups of patients who previously completed a randomized controlled trial (EASE LID or EASE LID 3) are also presented according to use of ADS‐5102 or placebo in that study before enrollment in the open‐label study.ResultsChange in MDS‐UPDRS Part IV at week 8 was –0.3 in the previous ADS‐5102 subgroup (n = 61), –3.4 in the previous placebo subgroup (n = 79), and –3.4 in the previous amantadine IR subgroup (n = 32). Effects were maintained to week 64. In the previous amantadine IR subgroup (mean treatment duration, 2.5 years), mean amantadine IR dose was 221 mg. Safety data were consistent with previous randomized controlled trials of ADS‐5102.ConclusionThese open‐label data suggest ADS‐5102 provides incremental reduction from baseline in MDS‐UDPRS Part IV score in patients switched directly from amantadine IR, without exacerbating adverse events.

Giving support may be a stressful or rewarding experience, and little is known about how family members perceive giving support amid problems or crises. Using a sample of 226 mother–child dyads (mother mean age = 75.04 years; child mean age = 49.57 years), we examine how mothers and their middle-aged children perceive giving support in the context of life problems. Actor–partner interdependence models tested whether associations between problems and perceptions of support are moderated by frequency of support given and if associations were stronger for daughters or sons. Children perceived giving support to their mother as more stressful when they had more of their own problems and gave high levels of support. Daughters, but not sons, considered helping their mother more stressful when their mother had more problems and they gave high levels of support. Distinctions between mother–son and mother–daughter dyads demonstrate the merit of a dyadic approach to understanding mother–child relationships.

ABSTRACTU.S. guidelines recommend BRCA1/2 mutation testing for women diagnosed with high‐grade ovarian cancer (HGOC) to increase recognition of carriers, but most remain unidentified and at risk. Accordingly, an approach termed “Traceback” has been proposed in which probands are retrospectively identified by testing archived pathology specimens, and family members are traced to provide genetic counseling and testing. We used population‐based data to estimate the number of family members who might be contacted through such a program. We used incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the number of women diagnosed with HGOC from 2005 to 2016, and census data to estimate the number of spouses, offspring, and siblings (both sexes). Using overall survival for HGOC from SEER and all‐cause mortality rates from the Centers for Diseases Control and Prevention, we estimated the number of patients, spouses, offspring, and siblings of HGOC cases living in 2017. Due to the high mortality rate of HGOC, consent from living probands may be possible in only 42% of the cases; consent to test pathology specimens would need to be sought from next of kin for the remainder. In 2017, an estimated 406,919 living next of kin (spouses, siblings, offspring) would be available for potential consent. Testing archived ovarian cancer pathology specimens may enable the identification of BRCA1/2 mutation carriers, but consent from next of kin would be required in in 58% of cases. Although Traceback offers the possibility of identifying unaffected BRCA1/2 mutation carriers, pilot feasibility studies that include assessment of methods to secure consent are needed.

Purpose: To evaluate a healthy eating and physical activity intervention for immigrant families, derived through community-based participatory research. Design: The Healthy Immigrant Families study was a randomized controlled trial with delayed intervention control group, with families as the randomization unit. Setting: US Midwest city. Participants: Participants were recruited by community partners from Hispanic, Somali, and Sudanese immigrant communities. Intervention: Family health promoters from participating communities delivered 6 healthy eating modules, 4 physical activity modules, and 2 modules synthesizing information in 12 home visits (60-90 minutes) within the first 6 months. Up to 12 follow-up phone calls to each participant occurred within the second 6 months. Measures: Primary measures were dietary quality measured with weekday 24-hour recall and reported as Healthy Eating Index score (0-100) and physical activity measured with accelerometers (14 wear days) at baseline, 6, 12, and 24 months. Results: In total, 151 persons (81 adolescents and 70 adults; 44 families) were randomly assigned. At 12 months, significant improvement occurred in Healthy Eating Index scores for adults in the intervention group compared with controls (change, +8.6 vs −4.4; P < .01) and persisted at 24 months (+7.4 from baseline; P < .01). No differences were observed for adolescents and no significant differences occurred between groups for physical activity. Conclusion: This intervention produced sustained dietary quality improvement among adults but not among adolescents. Program outcomes are relevant to communities working to decrease cardiovascular risk among immigrant populations.

The testis‐specific Y‐encoded‐like protein (TSPYL) gene family includes TSPYL1 to TSPYL6. We previously reported that TSPYL5 regulates cytochrome P450 (CYP) 19A1 expression. Here we show that TSPYLs, especially TSPYL 1, 2, and 4, can regulate the expression of many CYP genes, including CYP17A1, a key enzyme in androgen biosynthesis, and CYP3A4, an enzyme that catalyzes the metabolism of abiraterone, a CYP17 inhibitor. Furthermore, a common TSPYL1 single nucleotide polymorphism (SNP), rs3828743 (G/A) (Pro62Ser), abolishes TSPYL1's ability to suppress CYP3A4 expression, resulting in reduced abiraterone concentrations and increased cell proliferation. Data from a prospective clinical trial of 87 metastatic castration‐resistant prostate cancer patients treated with abiraterone acetate/prednisone showed that the variant SNP genotype (A) was significantly associated with worse response and progression‐free survival. In summary, TSPYL genes are novel CYP gene transcription regulators, and genetic alteration within these genes significantly influences response to drug therapy through transcriptional regulation of CYP450 genes.

Abstract Aims Patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction demonstrate an increased ventilatory equivalent for carbon dioxide (V̇E/V̇CO2) slope. The physiological correlates of the V̇E/V̇CO2 slope remain unclear in the two HF phenotypes. We hypothesized that changes in the physiological dead space to tidal volume ratio (VD/VT) and arterial CO2 tension (PaCO2) differentially contribute to the V̇E/V̇CO2 slope in HFrEF vs. HFpEF. Methods and results Adults with HFrEF (n = 32) and HFpEF (n = 27) [mean ± standard deviation (SD) left ventricular ejection fraction: 22 ± 7% and 61 ± 9%, respectively; mean ± SD body mass index: 28 ± 4 kg/m2 and 33 ± 6 kg/m2, respectively; P &lt; 0.01] performed cardiopulmonary exercise testing with breath-by-breath ventilation and gas exchange measurements. PaCO2 was measured via radial arterial catheterization. We calculated the V̇E/V̇CO2 slope via linear regression, and VD/VT = 1 − [(863 × V̇CO2)/(V̇E × PaCO2)]. Resting VD/VT (0.48 ± 0.08 vs. 0.41 ± 0.11; P = 0.04), but not PaCO2 (38 ± 5 mmHg vs. 40 ± 3 mmHg; P = 0.21) differed between HFrEF and HFpEF. Peak exercise VD/VT (0.39 ± 0.08 vs. 0.32 ± 0.12; P = 0.02) and PaCO2 (33 ± 6 mmHg vs. 38 ± 4 mmHg; P &lt; 0.01) differed between HFrEF and HFpEF. The V̇E/V̇CO2 slope was higher in HFrEF compared with HFpEF (44 ± 11 vs. 35 ± 8; P &lt; 0.01). Variance associated with the V̇E/V̇CO2 slope in HFrEF and HFpEF was explained by peak exercise VD/VT (R2 = 0.30 and R2 = 0.50, respectively) and PaCO2 (R2 = 0.64 and R2 = 0.28, respectively), but the relative contributions of each differed (all P &lt; 0.01). Conclusions Relationships between the V̇E/V̇CO2 slope and both VD/VT and PaCO2 are robust, but differ between HFpEF and HFrEF. Increasing V̇E/V̇CO2 slope appears to be strongly explained by mechanisms influential in regulating PaCO2 in HFrEF, which contrasts with the strong role of increased VD/VT in HFpEF.