Disclosing genetic risk for Alzheimer’s dementia to individuals with mild cognitive impairment

IntroductionThe safety of predicting conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia using apolipoprotein E (APOE) genotyping is unknown.MethodsWe randomized 114 individuals with MCI to receive estimates of 3‐year risk of conversion to AD dementia informed by APOE genotyping (disclosure arm) or not (non‐disclosure arm) in a non‐inferiority clinical trial. Primary outcomes were anxiety and depression scores. Secondary outcomes included other psychological measures.ResultsUpper confidence limits for randomization arm differences were 2.3 on the State Trait Anxiety Index and 0.5 on the Geriatric Depression Scale, below non‐inferiority margins of 3.3 and 1.0. Moreover, mean scores were lower in the disclosure arm than non‐disclosure arm for test‐related positive impact (difference: ‐1.9, indicating more positive feelings) and AD concern (difference: ‐0.3).DiscussionProviding genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154645/1/trc212002_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154645/2/trc212002.pd

Viscoelastic Testing and Coagulopathy of Traumatic Brain Injury

A unique coagulopathy often manifests following traumatic brain injury, leading the clinician down a difficult decision path on appropriate prophylaxis and therapy. Conventional coagulation assays—such as prothrombin time, partial thromboplastin time, and international normalized ratio—have historically been utilized to assess hemostasis and guide treatment following traumatic brain injury. However, these plasma-based assays alone often lack the sensitivity to diagnose and adequately treat coagulopathy associated with traumatic brain injury. Here, we review the whole blood coagulation assays termed viscoelastic tests and their use in traumatic brain injury. Modified viscoelastic tests with platelet function assays have helped elucidate the underlying pathophysiology and guide clinical decisions in a goal-directed fashion. Platelet dysfunction appears to underlie most coagulopathies in this patient population, particularly at the adenosine diphosphate and/or arachidonic acid receptors. Future research will focus not only on the utility of viscoelastic tests in diagnosing coagulopathy in traumatic brain injury, but also on better defining the use of these tests as evidence-based and/or precision-based tools to improve patient outcomes

Preschool hyperactivity specifically elevates long-term mental health risks more strongly in males than females: a prospective longitudinal study through to young adulthood

Evidence of continuities between preschool hyperactivity and adult mental health problems highlight the potential value of targeting early identification and intervention strategies. However, specific risk factors are currently unclear. This large-scale prospective longitudinal study aimed to identify which hyperactive preschoolers are at greatest long-term risk of poor mental health. One hundred and seventy children (89 females) rated as hyperactive by their parents and 88 non-hyperactive controls (48 females) were identified from a community sample of 4,215 3 year-olds. Baseline data relating to behavioral/emotional problems and background characteristics were collected. Follow-up mental health and functional impairment outcomes were collected between 14 and 25 years of age. At age 3 years, males and females in the hyperactive group had similarly raised levels of hyperactivity and other behavior problems. In adolescence/young adulthood, these individuals showed elevated symptoms of ADHD, conduct disorder, mood disorder, anxiety and autism, as well as functional impairment. Preschool hyperactivity was strongly predictive of poor adolescent/adult outcomes for males across domains with effects being specifically driven by hyperactivity. For females, the effects of preschool hyperactivity were smaller and dropped to non-significant levels when other preschool problems were taken into account. Environmental risk factors also differed between the sexes, although these may also have been mediated by genetic risk. In conclusion, these results demonstrate marked sex differences in preschool predictors of later adolescent/adult mental health problems. Future research should include a measure of preschool inattention as well hyperactivity. The findings highlight the potential value of tailored approaches to early identification strategies

AKT1 polymorphisms are associated with risk for metabolic syndrome

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations

A comparison of the clinical effectiveness and cost of specialised individually-delivered parent training for preschool attention-deficit/hyperactivity disorder and a generic, group-based programme: a multi-centre, randomised controlled trial of the New Forest Parenting Programme versus Incredible Years

Objective: To compare the efficacy and cost of specialised individually-delivered parent training (PT) for preschool children with attention-deficit/ hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). Design: Multi-centre, three-arm parallel group randomised controlled trial. Research Setting: National Health Service Trusts. Participants: Preschool children (33-54 months) fulfilling ADHD research diagnostic criteria. Interventions: New Forest Parenting Programme (NFPP) – 12 week individual, home-delivered ADHD PT programme; Incredible Years (IY) – 12 week group-based, PT programme initially designed for children with behaviour problems. Main outcome measures: Primary outcome - Parent ratings of child’s ADHD symptoms (Swanson, Nolan & Pelham Questionnaire - SNAP-IV). Secondary outcomes - teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post-treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputation). Intervention and other costs were estimated using standardized approaches. Results: NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms (mean difference -0.009 95%CI [-0.191, 0.173], p=0.921) or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms (-0.189 95%CI [-0.380, 0.003], p=0.053). NFPP significantly reduced parent-rated conduct-problems compared to TAU across scales (p-values.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1,591 versus £2,103). Conclusions: Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually-delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches. Funding: National Institute of Health Research. Trial Registration: Trial name: COPPI Trial; ISRCTN39288126

Lessons from mouse chimaera experiments with a reiterated transgene marker:revised marker criteria and a review of chimaera markers

Recent reports of a new generation of ubiquitous transgenic chimaera markers prompted us to consider the criteria used to evaluate new chimaera markers and develop more objective assessment methods. To investigate this experimentally we used several series of fetal and adult chimaeras, carrying an older, multi-copy transgenic marker. We used two additional independent markers and objective, quantitative criteria for cell selection and cell mixing to investigate quantitative and spatial aspects of developmental neutrality. We also suggest how the quantitative analysis we used could be simplified for future use with other markers. As a result, we recommend a five-step procedure for investigators to evaluate new chimaera markers based partly on criteria proposed previously but with a greater emphasis on examining the developmental neutrality of prospective new markers. These five steps comprise (1) review of published information, (2) evaluation of marker detection, (3) genetic crosses to check for effects on viability and growth, (4) comparisons of chimaeras with and without the marker and (5) analysis of chimaeras with both cell populations labelled. Finally, we review a number of different chimaera markers and evaluate them using the extended set of criteria. These comparisons indicate that, although the new generation of ubiquitous fluorescent markers are the best of those currently available and fulfil most of the criteria required of a chimaera marker, further work is required to determine whether they are developmentally neutral. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11248-015-9883-7) contains supplementary material, which is available to authorized users

Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial

Background From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19. Methods TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464). Findings Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62–1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88–2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group. Interpretation Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation

Interleukin-15 And Interleukin-15Rα Snps And Associations With Muscle, Bone, And Predictors Of The Metabolic Syndrome

The aims of this study were to examine associations between two SNPs in the human IL-15 gene and three SNPs in the IL-15Rα gene with predictors of metabolic syndrome and phenotypes in muscle, strength, and bone at baseline and in response to resistance training (RT). Subjects were Caucasians who had not performed RT in the previous year and consisted of a strength cohort (n = 748), volumetric cohort (n = 722), and serum cohort (n = 544). Subjects completed 12 weeks of unilateral RT of the non-dominant arm, using their dominant arm as an untrained control. ANCOVA analyses revealed gender-specific associations with: (1) IL-15 SNP (rs1589241) and cholesterol (p = 0.04), LDL (p = 0.02), the homeostasis model assessment (HOMA; p = 0.03), and BMI (p = 0.002); (2) IL-15 SNP (rs1057972) and the pre- to post-training absolute difference in 1RM strength (p = 0.02), BMI (p = 0.008), and fasting glucose (p = 0.03); (3) IL-15Rα SNP (rs2296135) and baseline total bone volume (p = 0.04) and the pre- to post-training absolute difference in isometric strength (p = 0.01); and 4) IL-15Rα SNP (rs2228059) and serum triglycerides (p = 0.04), baseline whole muscle volume (p = 0.04), baseline cortical bone volume (p = 0.04), and baseline muscle quality (p = 0.04). All associations were consistent in showing a potential involvement of the IL-15 pathway with muscle and bone phenotypes and predictors of metabolic syndrome. © 2008 Elsevier Ltd. All rights reserved

Akt1 Polymorphisms Are Associated With Risk For Metabolic Syndrome

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40-65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p \u3c 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations. © 2010 The Author(s)