Treatment Group Assignment Research Articles

Abstract P080: Health-related Quality Of Life Predictors Of Exercise Intervention Dropout

Introduction: Though many individuals know the health benefits of participating in exercise, few report sufficient activity to meet the US 2018 Physical Activity Guidelines. Current research assessing predictors of exercise adherence and dropout has primarily focused on cognitive factors, physiological factors, and demographic characteristics. The purpose of this analysis was to determine if baseline self-rated HrQoL measures are predictive of dropout from an exercise intervention across two STRRIDE trials. Methods: A total of 444 adults with dyslipidemia (STRRIDE AT/RT) or prediabetes (STRRIDE-PD) were randomized to one of seven exercise interventions, ranging from doses of 10-16 kcal/kg/week (KKW); intensities of 50-75% V̇O 2peak ; and durations of 6-9 months. Six groups included aerobic exercise, two groups included resistance training, and one group included dietary intervention (weight loss goal of 7%). Dropout was defined as a participant who did not complete the exercise intervention due to one or more of several reported reasons (e.g., time, motivation, re-occurring injury). Backwards stepwise logistic regression determined significant baseline HrQoL predictors of exercise intervention dropout, while controlling for age, sex, race, and intervention group assignment. Results: A total of 117 individuals were classified as being exercise intervention dropouts (STRRIDE AT/RT: n=55; STRRIDE-PD: n=62). In STRRIDE AT/RT, the logistic regression identified baseline sleep quality, sleep latency, sleep efficiency, sleep disturbance, bodily pain, and social functioning scores as predictors of dropout (R 2 =0.39). In STRRIDE-PD, the logistic regression identified baseline role-emotional, satisfaction with appearance, and physical component scores as predictors of dropout (R 2 =0.08). Conclusion: Among individuals with dyslipidemia, baseline HrQoL measures were able to explain about 39% of the variance in dropout from an exercise intervention, with primarily sleep measures, bodily pain, and social functioning being identified as important predictors of dropout. In contrast, among individuals farther along the disease spectrum, with prediabetes, baseline HrQoL measures only explained about 8% of the variance in dropout, with emotional well-being, perceived appearance, and physical function being important predictors of dropout. Future research should investigate molecular and biological predictors of dropout in combination with HrQoL, physiological, cognitive, and demographic factors to improve predictive power.

Associations between weight loss history and factors related to type 2 diabetes risk in the Stop Diabetes study

BackgroundFrequent weight loss attempts are related to maladaptive eating behaviours and higher body mass index (BMI). We studied associations of several type 2 diabetes (T2D) risk factors with weight loss history, defined as the frequency of prior weight loss attempts, among Finnish adults at increased risk for T2D.MethodsThis study (n = 2684, 80% women) is a secondary analysis of the 1-year StopDia lifestyle intervention with digital intervention group, digital intervention + face-to-face counselling group, or control group. The frequency of prior weight loss attempts was categorized into five groups: no attempts/no attempts to lose weight, but trying to keep weight stable/1–2 attempts/3 or more attempts/ continuous attempts. Data on emotional eating and social/emotional nutrition self-efficacy were collected with a digital questionnaire. We assessed baseline differences between categories of weight loss history as well as the intervention effects.ResultsAltogether 84% of participants had attempted weight loss. Those with one or more weight loss attempts had higher BMI, larger waist circumference, and more emotional eating compared to ‘no attempts’ and ‘no attempts to lose weight, but trying to keep weight stable’ categories. The ‘no attempts’ category had the highest baseline fasting insulin, whereas it showed the largest decrease in this measure with the intervention. This change in fasting insulin in the ‘no attempts’ category was significantly different from all the other categories. Emotional nutrition self-efficacy slightly improved in the ‘no attempts’ category, which was significantly different from its concomitant decrease in the categories ‘1-2 attempts’ and ‘3 or more attempts’. The intervention group assignment did not affect the results.ConclusionsMultiple attempts to lose weight may unfavourably affect T2D risk factors as well as lifestyle intervention outcomes. More research is needed on how weight loss frequency could affect T2D risk factors and how to design lifestyle interventions for individuals with frequent previous weight loss attempts.

Treatment for Chronic Sciatica: Do We Have New Evidence Showing That Discectomy Has Any Long-Term Benefits Over Conservative Care?

Treatment for Chronic Sciatica: Do We Have New Evidence Showing That Discectomy Has Any Long-Term Benefits Over Conservative Care?

Soluble Fluoride in Na2FPO3/CaCO3-Based Toothpaste as an Indicator of Systemically Bioavailable Fluoride

Fluoride chemically soluble in toothpaste is an indicator of fluoride bioavailability when the teeth are brushed, and the same should be expected systemically when toothpaste is ingested. A 4-phases study was conducted, in which 8 participants were subjected in each phase to one of the assigned treatment groups: group I: fresh sample of a Na₂FPO₃/CaCO₃ toothpaste with 1,334 μg F/g of total soluble fluoride (TSF) and groups II–IV: aged samples of toothpaste presenting TSF concentrations of 1,128, 808, and 687 μg F/g, respectively. In all phases, the participants ingested an amount of toothpaste equivalent to 70.0 μg F/kg body weight, as total fluoride (TF). Blood was collected before (baseline) and up to 180 min after toothpaste ingestion as indicator of fluoride bioavailability. Total urine (24 h before and 24 h after ingestion) was collected as indicator of absorbed fluoride that was excreted. F concentration in blood plasma and urine was determined with a fluoride ion-specific electrode. The areas under the curve (AUC) of F concentration versus time (AUC = ng F/mL × min) and the peaks of fluoride concentration in blood plasma (C_max) were calculated. The net amount of fluoride excreted (mg/day) was calculated by subtraction. A significant correlation of the amount (mg) of TSF ingested was found between the AUC (r = 0.76; p < 0.01) and C_max (r = 0.86; p < 0.01) in plasma, and the fluoride excreted (r = 0.65; p < 0.01). For TF, no statistical correlations were found (p > 0.05). Data suggest that the concentration of TSF found in Na₂FPO₃/CaCO₃-based toothpastes is a useful predictor of how much fluoride will be systemically bioavailable when this type of formulation is ingested.

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial

Impact of APOE Genotype on Neurocognitive Outcomes in Hippocampal Avoidance Whole Brain Radiotherapy for Brain Metastases: A Secondary Analysis of Phase II Blinded Randomized Trial

Apolipoprotein E (APOE) polymorphism is a well-known risk associated with Alzheimer's disease. Its role in neurocognition decline after whole brain radiotherapy (WBRT) for brain metastases is not well-investigated. The present secondary analysis of a prospective blinded randomized controlled phase II trial aimed to evaluate the impact of APOE genotypes upon neurocognitive outcomes after WBRT with or without hippocampal avoidance.Adult patients with brain metastases were stratified by prior radiosurgery and randomized to hippocampal avoidant conformal WBRT versus conformal WBRT without hippocampal avoidance to 30 Gy in 10 fractions from March 2015 to November 2018. Memantine was not used during or after WBRT. Standardized neurocognitive test battery (Hopkins Verbal Learning Test-Revised [HVLT-R], Trail Making Test), was performed at baseline, 1, 2, 4, 6, and every 3 months up to two years by trained independent health professionals. Both clinical trial participants and examiners were blinded to the treatment group assignment. APOE alleles were determined by the genome-wide genotyping. The association between APOE genotypes and neurocognitive outcomes was analyzed by general linear model. The role of APOE genotypes on the effect of hippocampal avoidance during WBRT was also evaluated. Factorial ANOVA was used to assess the independent factors associated with neurocognitive outcomes.Among 65 analyzable patients, APOE genotyping was available for 64.6% (n = 42) of patients. The most frequent APOE allele was ε3 homozygote (ε3/ε3, n = 24), followed by ε2 carrier (ε2/ε3, n = 11) and ε4 carrier (ε4/ε3, n = 7). No differences in baseline characteristics and cognitions between patients of different APOE genotypes. At 6-month, patients carrying APOE ε2 and ε4 allele had the best and worst preservation in HVLT-R total recall (mean difference, ε2: +3.18 versus ε4: -3.20, P = 0.008), and delayed recall (mean difference, ε2 carrier: +0.46 versus ε4 carrier: -2.40, P = 0.03), respectively. The effect of preservation in 6-month memory score is the strongest in the APOE ε2 carriers followed by the APOE ε3 homozygotes, and the least in the APEO ε4 carriers in order (P = 0.028). Only patients of APOE ε3 homozygotes showed improved preservation in late memory score by hippocampal avoidant WBRT at 6-month (mean difference, hippocampal avoidant: +3.67 versus conformal: -3.18, P = 0.037) and beyond. APOE genotyping was independent of age and hippocampal avoidance to be associated with the preservation of 6-month HVLT-R total recall (P = 0.042), and HVLT-R delayed recall (P = 0.032).The APOE genotype is associated with the risk of memory decline after WBRT. Specifically, APOE ε2 carriers exhibited better while ε4 carriers showed worse perpetuation in verbal memory function after WBRT. APOE ε3 homozygotes but not APOE ε2 or ε4 carriers benefit late memory preservation by hippocampal avoidant WBRT for brain metastases.

Association Between Baseline Diastolic Blood Pressure and the Efficacy of Intensive vs Standard Blood Pressure–Lowering Therapy

Low diastolic blood pressure (DBP) has been found to be associated with increased adverse cardiovascular events; however, it is unknown whether intensifying blood pressure therapy in patients with an already low DBP to achieve a lower systolic blood pressure (SBP) target is safe or effective. To evaluate whether there is an association of baseline DBP and intensification of blood pressure-lowering therapy with the outcomes of all-cause death and cardiovascular events. This cohort study analyzed patients who were randomized to intensive or standard BP control in the Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD-BP) trial and Systolic Blood Pressure Intervention Trial (SPRINT). Data were collected from September 1999 to June 2009 (ACCORD-BP) and from October 2010 to August 2015 (SPRINT). Data were analyzed from December 2020 to June 2021. Baseline DBP as a continuous variable. All-cause death and a composite cardiovascular end point (CVE) that included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. A total of 14 094 patients (mean [SD] age, 66.2 [8.9] years; 8504 [60.4%] men) were included in this analysis. There were significant nonlinear associations between baseline DBP and all-cause death (eg, baseline DBP 50 vs 80 mm Hg: hazard ratio [HR], 1.48; 95% CI, 1.06-2.08; P = .02) and the composite CVE (eg, baseline DBP 50 vs 80 mm Hg: HR, 1.45; 95% CI, 1.27-3.04; P = .003) observed among all participants. Findings for the interaction between baseline DBP and treatment group assignment for all cause death did not reach statistical significance. For intensive vs standard therapy, the HR of death for a baseline DBP of 50 mm Hg was 1.80 (95% CI, 0.95-3.39; P = .07) and that for a baseline DBP of 80 mm Hg was 0.77 (95% CI, 0.59-1.01; P = .05). Overall, there was no interaction found between baseline DBP and treatment group assignment for the composite CVE. Over the range of baseline DBP values, significant reductions in the composite CVE for patients assigned to intensive vs standard therapy were found for baseline DBP values of 80 mm Hg (HR, 0.78; 95% CI, 0.62-0.98; P = .03) and 90 mm Hg (HR, 0.74; 95% CI, 0.55-0.98; P = .04). This pooled cohort study found no evidence of a significant interaction between baseline DBP and treatment intensity for all-cause death or for a composite CVE. These results are hypothesis generating and merit further study.

O-187 Smartphone application improves fertility treatment-related literacy: A large-scale surveillance and randomized controlled trial in Japan

Abstract Study question Can providing quality-assured fertility-related information via a smartphone application improve fertility- and treatment-related literacy among smartphone application users? Summary answer Provision of quality-assured fertility-related information via a smartphone application contributed to enhancing fertility- and treatment-related literacy among the smartphone application users. What is known already For infertility patients, the interpretation of examination results may be overly complicated and complex, and patients may have difficulty in making sense of their own fertility problems. Accessing and learning about fertility-related information using the Internet via smartphone is reasonable; however, the information does not always reflect evidence-based recommendations and low-quality information may lead to adverse effects on users; thus, innovative methods to provide both accessible and high-quality information are desired. Study design, size, duration We performed a randomized control-group pretest posttest study and 4,137 smartphone application users were invited to participate between June 18 and 25, 2020. Participants’ fertility treatment-related literacy were assessed with a pretest that comprised of 28 questions and participants were allocated with stratified randomization to either intervention or control group. The intervention comprised a one-week smartphone application-based provision of information on fertility- and treatment-related information and the control group received general information about women’s healthcare. Participants/materials, setting, methods The 3,765 participants (91.0 %) who responded were randomly allocated into either the intervention group (N = 1883) or the control group (N = 1882). Characteristics of participants appeared similar between the groups reflecting that the randomization was successful in producing a balance in baseline characteristics. Effectiveness of intervention was assessed using pretest-posttest analysis. Ethical approval was obtained from the Institutional Review Board of the National Center for Child Health and Development of Japan (approval number: 2019-184). Main results and the role of chance The posttest was completed by 659 participants (17.5%), and finally 207 participants in the intervention group and 222 participants in the control group were available for pretest-posttest analysis. Demographic characteristics of these participants appeared similar between the groups. In comparing the demographic characteristics of participants who did and did not complete the posttest, there were significant differences between the two groups in age, overall test score, proportion living with a partner, and action for pregnancy. For the posttest, the overall mean test scores were significantly higher in the intervention group compared to the control group (P = 0.0082). Interestingly, we also observed that posttest scores were significantly improved compared to pretest scores in both the intervention group and control group (P &amp;lt; 0.001). When examining by specific test question, the proportion answering correctly appeared to generally increase at posttest compared to pretest for intervention (P &amp;lt; 0.001) and control (P &amp;lt; 0.001) groups. There was over 10% improvement in 7 questions, and particularly, over 20% improvement for a question about clinical significance of anti-Müllerian hormone. Furthermore, directly comparing the difference in posttest versus pretest scores between the two groups showed, on average, greater improvements in the intervention group than the control group (P &amp;lt; 0.001). Limitations, reasons for caution As the intervention was educational material, it was not possible to blind participants to intervention group assignment. We were not able to monitor the participants when completing the tests; thus, whether they accessed other resources could not be addressed. Wider implications of the findings Providing information through a smartphone application can be considered acceptable since retrieving information through a smartphone application is in line with the current modern day lifestyle. A smartphone application may offer alternatives such as chatbots and movie-based learning, and they have the potential to increase the effectiveness. Trial registration number UMIN Clinical Trials Registry number UMIN000040721.

Causal AI with Real World Data: Do Statins Protect from Alzheimer's Disease Onset?

Causal artificial intelligence aims at developing bias-robust models that can be used to intervene on, rather than just be predictive, of risks or outcomes. However, learning interventional models from observational data, including electronic health records (EHR), is challenging due to inherent bias, e.g., protopathic, confounding, collider. When estimating the effects of treatment interventions, classical approaches like propensity score matching are often used, but they pose limitations with large feature sets, nonlinear/nonparallel treatment group assignments, and collider bias. In this work, we used data from a large EHR consortium -OneFlorida- and evaluated causal statistical/machine learning methods for determining the effect of statin treatment on the risk of Alzheimer's disease, a debated clinical research question. We introduced a combination of directed acyclic graph (DAG) learning and comparison with expert's design, with calculation of the generalized adjustment criterion (GAC), to find an optimal set of covariates for estimation of treatment effects -ameliorating collider bias. The DAG/CAC approach was assessed together with traditional propensity score matching, inverse probability weighting, virtual-twin/counterfactual random forests, and deep counterfactual networks. We showed large heterogeneity in effect estimates upon different model configurations. Our results did not exclude a protective effect of statins, where the DAG/GAC point estimate aligned with the maximum credibility estimate, although the 95% credibility interval included a null effect, warranting further studies and replication.

Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial

In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial. This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133. Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events. The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR. Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health.

On Clinical Trials.

On Clinical Trials.

Change Mechanisms in Brief Interpersonal Psychotherapy for Women With Perinatal Depression: Qualitative Study.

Brief interpersonal psychotherapy (IPT-B) has been shown to be effective in treating perinatal depression and in preventing depressive relapse among socioeconomically disadvantaged women. Yet, it is unclear how IPT-B alleviates depression. Previous research has suggested four possible change mechanisms derived from IPT's interpersonal model: decreasing interpersonal stress, facilitating emotional processing, improving interpersonal skills, and enhancing social support. This study explored how women who received IPT-B or enhanced maternity support services (MSS-Plus) evaluated their respective experiences. A qualitative study was conducted with 16 women who had been recruited from public health clinics to participate in a larger, randomized controlled trial of women with major depression or dysthymia and who had been assigned to receive IPT-B or MSS-Plus. The sample was 63% non-Hispanic White, had an average age of 31.6 years, and was balanced in intervention group assignment, posttraumatic stress disorder status, and depression improvement. Telephone interviews included semistructured, open-ended questions eliciting participants' experiences with depression treatment. Predetermined, conceptually derived codes were based on the four postulated IPT change mechanisms. Thematic coded excerpts were collected and discussed. Excerpts lent support to the role of IPT-B in helping women decrease their interpersonal stress; identify, reflect on, and regulate their emotions; and improve their social skills. Evidence for increasing social support was mixed but highlighted the importance of the therapeutic relationship. Including qualitative findings into training in public health and other clinical settings will help illuminate the role of the provider in facilitating the change mechanisms that may lead to improved mental health among clients.

Investigating the effects of the Moms’ Empowerment Program on 8-year traumatic stress symptom trajectories in women with histories of IPV.

Intimate partner violence (IPV) is a pressing issue, affecting nearly one-third of women in the U.S. over their lifetimes, and has been linked with a number of deleterious outcomes, including the development of posttraumatic stress disorder (PTSD). Although IPV is often chronic, few studies have prospectively examined trajectories of PTSD symptoms (PTSS) in this population. The goal of the present study was to assess the effects of the Moms' Empowerment Program-an IPV-specific intervention; as well as trauma exposure, domestic violence (DV) shelter use, and depression symptoms on PTSS trajectories in women with histories of IPV. Data were drawn from a sample of 118 women who participated in a randomized controlled trial (RCT) of an intervention specifically designed for women and children experiencing IPV. Sixty-seven women from the original sample completed an assessment 8 years following the conclusion of the intervention. On average, women's PTSS decreased over time. Intervention group assignment did not affect these trajectories; however, women who attended more sessions had significantly fewer PTSS at the 8-year follow-up. Greater IPV exposure, higher depression symptoms, and shelter use were all associated with higher PTSS over time, with some variation across PTSS subdomains. These results provide preliminary evidence that brief intervention may have long-term effects. They also demonstrate how addressing ongoing IPV and concurrent symptoms of depression is likely an essential component of treating PTSS in this population. Finally, these results underscore the need for more research on relations between formal DV services and mental health. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Day-of-Surgery Video Calls and Phone Calls Increase Patient Satisfaction with Outpatient Surgery Experience: A Randomized Controlled Trial of Postoperative Communication Modalities.

With the increasing utilization of patient satisfaction as a metric for clinical care, there is growing interest in techniques that can be used to improve satisfaction in patients undergoing surgery. The purpose of this trial was to assess the impact of day-of-surgery video and phone calls on patient satisfaction. We enrolled 251 patients undergoing outpatient orthopaedic surgery with 3 participating surgeons. Surgeons were randomized to 1 of 3 patient communication modalities: no contact (standard of care), phone call, or video call. Several hours following discharge on the day of surgery, the surgeons contacted patients according to their assigned treatment group. At the initial postoperative office visit, satisfaction outcomes were assessed using the Consumer Assessment of Healthcare Providers and Systems Surgical Care (S-CAHPS) survey and an additional satisfaction questionnaire. Fifty-nine (97%) of 61 patients in the no-contact group, 118 (99%) of 119 patients in the phone group, and 71 (100%) of 71 patients in the video group completed follow-up assessment. The S-CAHPS top-box response rate in both the video group (0.86 ± 0.14, p < 0.001) and the phone group (0.84 ± 0.17, p < 0.001) was greater than in the no-contact group (0.68 ± 0.26). When asked to rate satisfaction with overall care, a greater proportion of patients in the video group (85.9%) gave the top-box response compared with both the phone group (71.8%, p = 0.040) and the no-contact group (60.7%, p = 0.002). Among the patients in the video group, 62.0% indicated that they would prefer a video call in future encounters with their surgeon compared with 1.8% of patients in the no-contact group (p < 0.001) and 1.7% of patients in the phone group (p < 0.001). Phone and video calls following discharge are an effective way of enhancing patient satisfaction with the clinical care experience as measured by the S-CAHPS survey. In terms of satisfaction with overall care, video calls may be superior to phone calls. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Reported chronic high glycemic diet intake predicts amyloid deposition in the precuneus of cognitively normal older adults over one year

AbstractBackgroundWe previously reported that high glycemic diet (HGD) was related to cerebral amyloid deposits, a pathologic hallmark of Alzheimer’s disease (AD), in multiple highly metabolic regions of interest (ROI). The purpose of this study was to test high glycemic diet’s relationship with longitudinal change in cerebral amyloid deposition in older adults.MethodsThis longitudinal study included 106 cognitively normal older adults with elevated (n=72) and non‐elevated (n=34) amyloid participating in a one‐year exercise intervention trial. Habitual dietary intake was collected at baseline using the National Cancer Institute’s Diet History Questionnaire (DHQ II) and intake was quantified using Diet*Calc software. We derived a HGD pattern using principal covariates regression (PCovR). Amyloid PET (Florbetapir F18) scans were obtained on a GE Discovery ST‐16PET/CT scanner at baseline and 52‐weeks. MIMNuero software was used to standardize the PET images to the whole cerebellum and calculate tracer standard uptake value ratios (SUVR) in 6 ROIs. One‐year regional SUVR delta scores were calculated. We constructed ordinary least squares regression models to assess HGD’s relationship with continuous regional delta SUVR scores controlling for age, sex, and intervention group assignment. Statistical analyses were performed using R (v. 3.6.2; R Foundation, Vienna, Austria). Statistical significance was set at p &lt; 0.05.ResultsThe participants were 68% female with a mean age of 71.1 ± 5.2 years. In the precuneus, higher intake of the derived HGD pattern (β=0.23, p=0.02), sugar (β=0.24, p=0.01), and total carbohydrate (β=0.22, p=0.03) correlated with more amyloid accumulation. Higher reported intake of carbohydrate as a percentage of total energy was related to more amyloid accumulation in the inferior medial frontal gyrus (β=0.20, p=0.04), posterior cingulate gyrus (β=0.20, p=0.04), precuneus (β=0.21, p=0.04), and superior parietal lobule (β=0.21, p=0.03).ConclusionThe results of this study corroborate our previous findings and suggest a physiological role for HGD in amyloid pathology prior to onset of AD‐related symptoms.

Effect of comprehensive, individualized, person‐centered management on antidepressant usage in advanced Alzheimer’s persons in a 28‐week, randomized, controlled trial

AbstractBackgroundWe published results of a clinician‐blind, parallel‐group study of Comprehensive, Individualized, Person‐Centered Management (CI‐PCM) in moderate‐to‐severe, community‐residing, Alzheimer’s persons (Reisberg…Kenowsky, Dement Geriatr Cogn Disord, 2017). CI‐PCM intervention subjects (n=10) showed 967% greater global improvement than subjects randomized to Usual Community Care (UCC, n=10). Behavioral Pathology in Alzheimer’s Disease‐Frequency Weighted (BEHAVE‐AD‐FW) total scores showed significant benefit in the intervention group at week 28 (p&lt;0.05). Kettunen asserts, (Eur J Clin Pharmacol, 2018), “Among persons with AD, antidepressants are used for treatment of BPSD…their effectiveness in this indication is modest.” Casey states, (Pharmacy &amp; Therapeutics, 2015), “Antidepressants…are widely used in dementia for depressed mood, anxiety, agitation, and apathy.” Bui recommends, (Cochrane for Clinicians, American Family Practice, 2012), “…antidepressants should be used [in patients with dementia] only if all other nonpharmacologic interventions for neuropsychiatric symptoms are unsuccessful.” Herein, we examine the effect of the CIPCM program on antidepressant usage and the Behavioral and Psychological Symptoms of Dementia (BPSD) as measured with the BEHAVE‐AD‐FW.MethodInvestigators blinded to treatment group assignment reviewed subject charts (N=20), for antidepressant usage, and BEHAVE‐AD‐FW total and category F scores, which measure tearfulness and depressed mood. Costs of antidepressant usage, and BEHAVE‐AD‐FW total, and category F scores for each group were compared.ResultThere were no significant differences in antidepressant usage or BEHAVE‐AD‐FW total or category F scores between groups at baseline. At all study visits, 50% of subjects in each group took antidepressants. At week 28, community physicians prescribed CI‐PCM subjects less or the same dose of antidepressants, and prescribed comparator subjects the same or greater doses, and additional antidepressants. BEHAVE‐AD‐FW category F scores for UCC comparators were persistently elevated and worsened by week 28, whereas, CI‐PCM group scores improved to zero, indicating no depressive symptoms.ConclusionFor CI‐PCM subjects, total BPSD symptomatology declined significantly (p&lt;0.05), antidepressant usage declined, and tearfulness and depressed mood resolved, by week 28. In contrast, UCC subjects increased antidepressant usage, paid 4.42 times more for antidepressants, and had worsening of behavioral disturbances and depressive symptoms. CI‐PCM is an effective nonpharmacologic intervention that reduces antidepressant usage in advanced AD persons with BPSD.

Pointer‐ZZZ: Sleep ancillary to U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk of Alzheimer's disease

AbstractBackgroundNon‐pharmacological approaches that target modifiable risks through lifestyle interventions provide the most promising evidence to delay disease. In older adults, chronic sleep disturbances marked by sleep‐disordered breathing (SDB) and sleep fragmentation are associated with impaired hippocampal functioning, increased beta‐amyloid burden, and greater Alzheimer’s risk. These and other sleep abnormalities are associated with reduced vascular health. Although some evidence suggests that diet, exercise, and cardiovascular risk reduction can improve sleep and improved sleep benefits cognition in older adults, these effects have not been confirmed in a rigorous clinical trial.MethodsThe U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), funded by the Alzheimer’s Association, was launched in the Fall of 2018. It is investigating whether lifestyle interventions ‐ Self‐Guided (SG) versus a Structured (STR) lifestyle intervention ‐ influence cognitive trajectories over 2 years in 2000 older cognitively normal adults (aged 60‐79 yrs) who are at increased risk for cognitive decline, Alzheimer’s disease and other dementias. The NIH‐funded POINTER‐zzz ancillary study adds in‐home objective sleep assessments for 700 participants to examine the effects of lifestyle modification and cardiovascular risk management on sleep disturbances that are linked to cognitive decline and Alzheimer’s disease and that may improve with U.S. POINTER interventions.ResultsPOINTER‐zzz methods and study design will be presented, which will permit over 2000 objective sleep assessments to be completed over 2 years. These assessments will provide extensive oximetry and actigraphy data for analysis by lifestyle intervention group assignment. Sleep data will be examined relative to intervention effects on cognition and other parent trial and ancillary study outcomes, including MRI and amyloid/tau PET brain imaging. POINTER‐zzz leverages resources provided by the parent trial and other funded ancillary studies, and by well‐established collaborations with sleep experts.ConclusionsPOINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep abnormalities that are linked to cognitive decline and Alzheimer’s in a well‐characterized, diverse cohort of at‐risk older adults. The study may identify an effective strategy for improving sleep that could have important consequences for reduced risk of Alzheimer’s disease and related dementias.

Postintervention Effects of Varying Treatment Arms on Glycemic Failure and β-Cell Function in the TODAY Trial.

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that glycemic failure rates were significantly lower in youth randomized to metformin plus rosiglitazone treatment than in youth randomized to metformin alone or metformin plus intensive lifestyle intervention. At the end of the study, rosiglitazone was permanently discontinued, and routine diabetes care resumed. Herein, we report postintervention glycemic failure rates in TODAY participants over an additional 36 months of follow-up for the three original treatment arms and describe insulin sensitivity and β-cell function outcomes. A total of 699 participants were randomized during TODAY, of whom 572 enrolled in the TODAY2 observational follow-up. Glycemic failure was defined as HbA1c ≥8% over a 6-month period, inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation during TODAY, or sustained HbA1c ≥8% over two consecutive visits during TODAY2. Oral glucose tolerance tests were conducted, and insulin sensitivity, insulinogenic index, and oral disposition index were calculated. During the 36 months of TODAY2, glycemic failure rates did not differ among participants by original treatment group assignment. Insulin sensitivity and β-cell function deteriorated rapidly during the 36 months of TODAY2 routine diabetes care but did not differ by treatment group assignment. The added benefit of preventing glycemic failure by using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation. More work is needed to address this rapid progression to avoid long-term diabetes complications.

Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial

Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection. This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49. Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7-28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4]; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1]; difference in least-squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug. Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation. Ablynx, a Sanofi Company.

Elective Labor Induction at 39 Weeks of Gestation Compared With Expectant Management: Factors Associated With Adverse Outcomes in Low-Risk Nulliparous Women.

To evaluate characteristics associated with adverse outcomes in low-risk nulliparous women randomized to elective labor induction at 39 weeks of gestation or expectant management. We conducted a secondary analysis of women randomized during the 38th week to induction at 39 weeks of gestation or expectant management. Deliveries before 39 weeks of gestation and those not adherent to study protocol or with fetal anomalies were excluded. A composite of adverse outcomes (perinatal death or severe neonatal complications), third- or fourth-degree lacerations, and postpartum hemorrhage were evaluated. Log binomial regression models estimated relative risks and 95% CIs for associations of outcomes with patient characteristics including randomly assigned treatment group. Interactions between patient characteristics and treatment group were tested. Of 6,096 women with outcome data, 5,007 (82.1%) met criteria for inclusion in this analysis. Frequency of the perinatal composite was 252 (5.0%), 166 (3.3%) for third- or fourth-degree perineal laceration, and 237 (4.7%) for postpartum hemorrhage. In multivariable analysis, intended labor induction at 39 weeks of gestation was associated with a reduced perinatal composite outcome (4.1% vs 6.0%; adjusted relative risk [aRR] 0.71; 95% CI 0.55-0.90), whereas increasing body mass index (BMI) was associated with an increased perinatal composite outcome (aRR 1.04/unit increase; 95% CI 1.02-1.05). Decreased risk of third- or fourth-degree perineal laceration was observed with increasing BMI (aRR 0.96/unit increase; 95% CI 0.93-0.98) and in Black women compared with White women (1.2% vs 3.9%; aRR 0.34; 95% CI 0.19-0.60). Increased risk of postpartum hemorrhage was observed in Hispanic women compared with White women (6.3% vs 4.0%; aRR 1.64; 95% CI 1.18-2.29). Patient characteristics associated with adverse outcomes were similar between treatment groups (P for interaction >.05). Compared with expectant management, intended induction at 39 weeks of gestation was associated with reduced risk of adverse perinatal outcome. Patient characteristics associated with adverse outcomes were few and similar between groups. ClinicalTrials.gov, NCT01990612.