Decay and Decoupling of heavy Right-handed Majorana Neutrinos in the L-R model

Heavy right-handed neutrinos are of current interest. The interactions and decay of such neutrinos determine their decoupling epoch during the evolution of the universe. This in turn affects various observable features like the energy density, nucleosynthesis, CMBR spectrum, galaxy formation, and baryogenesis. Here, we consider reduction of right-handed electron-type Majorana neutrinos, in the left-right symmetric model, by the WR+ - WR- channel and the channel originating from an anomaly, involving the SU(2)R gauge group, as well as decay of such neutrinos. We study the reduction of these neutrinos for different ranges of left-right model parameters, and find that, if the neutrino mass exceeds the right-handed gauge boson mass, then the neutrinos never decouple for realistic values of the parameters, but, rather, decay in equilibrium. Because there is no out-of-equilibrium decay, no mass bounds can be set for the neutrinos.Comment: Latex, 16 pages, No figures. Some additions in the text and references. Conclusions unaffected. To appear in Eur. Phys. J.

Novel Likelihood Ratio Tests for Screening Gene‐Gene and Gene‐Environment Interactions With Unbalanced Repeated‐Measures Data

There has been extensive literature on modeling gene‐gene interaction (GGI) and gene‐environment interaction (GEI) in case‐control studies with limited literature on statistical methods for GGI and GEI in longitudinal cohort studies. We borrow ideas from the classical two‐way analysis of variance literature to address the issue of robust modeling of interactions in repeated‐measures studies. While classical interaction models proposed by Tukey and Mandel have interaction structures as a function of main effects, a newer class of models, additive main effects and multiplicative interaction (AMMI) models, do not have similar restrictive assumptions on the interaction structure. AMMI entails a singular value decomposition of the cell residual matrix after fitting the additive main effects and has been shown to perform well across various interaction structures. We consider these models for testing GGI and GEI from two perspectives: likelihood ratio test based on cell means and a regression‐based approach using individual observations. Simulation results indicate that both approaches for AMMI models lead to valid tests in terms of maintaining the type I error rate, with the regression approach having better power properties. The performance of these models was evaluated across different interaction structures and 12 common epistasis patterns. In summary, AMMI model is robust with respect to misspecified interaction structure and is a useful screening tool for interaction even in the absence of main effects. We use the proposed methods to examine the interplay between the hemochromatosis gene and cumulative lead exposure on pulse pressure in the Normative Aging Study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99643/1/gepi21744-sup-0001-si.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99643/2/gepi21744.pd

Amyloid-dependent and amyloid-independent effects of Tau in individuals without dementia

Objective: To investigate the relationship between the topography of amyloid-β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. Methods: We evaluated 154 individuals who were assessed with amyloid-β PET with [18F]AZD4694, tau-PET with [18F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid-β PET with [18F]Florbetapir, tau-PET with [18F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel-wise linear regressions between amyloid-PET, tau-PET, and their interaction with cognitive function, correcting for age, sex, and years of education. Results: In both cohorts, we observed that tau-PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR-SoB) scores independently of local amyloid-PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau-PET and clinical function were dependent on local amyloid-PET (FWE corrected at p < 0.001). Interpretation: In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid-β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid-β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau’s relationship with cognitive dysfunction was dependent on local amyloid-β concentrations. Our results provide evidence that amyloid-β in Alzheimer’s disease influences cognition by potentiating the deleterious effects of tau pathology

A three-range approach enhances the prognostic utility of CSF biomarkers in Alzheimer's disease

Introduction: Alzheimer's disease consensus recommends biomarker dichotomization, a practice with well-described clinical strengths and methodological limitations. Although neuroimaging studies have explored alternative biomarker interpretation strategies, a formally defined three-range approach and its prognostic impact remains under-explored for cerebrospinal fluid (CSF) biomarkers. Methods: With two-graph receiver-operating characteristics based on different reference schemes, we derived three-range cut-points for CSF Elecsys biomarkers. According to baseline CSF status, we assessed the prognostic utility of this in predicting risk of clinical progression and longitudinal trajectories of cognitive decline and amyloid–beta (Aβ) positron emission tomography (PET) accumulation in non-demented individuals (Alzheimer's Disease Neuroimaging Initiative [ADNI]; n = 1246). In all analyses, we compared herein-derived three-range CSF cut-points to previously described binary ones. Results: In our main longitudinal analyses, we highlight CSF p-tau181/Aβ1-42 three-range cut-points derived based on the cognitively normal Aβ-PET negative versus dementia Aβ-PET positive reference scheme for best depicting a prognostically relevant biomarker abnormality range. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization and a clearly abnormal group at higher risk for cognitive decline, with power analyses suggesting the latter group as potential trial enrichment candidates. Furthermore, we demonstrate that individuals with intermediate-range CSF status have similar rates of Aβ deposition to those in the clearly abnormal group. Discussion: The proposed approach can refine clinico-biological prognostic assessment and potentially enhance trial recruitment, as it captures faster biomarker-related cognitive decline in comparison to binary cut-points. Although this approach has implications for trial recruitment and observational studies, further discussion is needed regarding clinical practice applications

Impact of a personalised, digital, HIV self-testing app-based program on linkages and new infections in the township populations of South Africa.

INTRODUCTION: Implementation data for digital unsupervised HIV self-testing (HIVST) are sparse. We evaluated the impact of an app-based, personalised, oral HIVST program offered by healthcare workers in Western Cape, South Africa. METHODS: In a quasirandomised study (n=3095), we recruited consenting adults with undiagnosed HIV infection from township clinics. To the HIVST arm participants (n=1535), we offered a choice of an offsite (home, office or kiosk based), unsupervised digital HIVST program (n=962), or an onsite, clinic-based, supervised digital HIVST program (n=573) with 24/7 linkages services.With propensity score analyses, we compared outcomes (ie, linkages, new HIV infections and test referrals) with conventional HIV testing (ConvHT) arm participants (n=1560), recruited randomly from geographically separated clinics. RESULTS: In both arms, participants were young (HIVST vs ConvHT) (mean age: 28.2 years vs 29.2 years), female (65.0% vs 76.0%) and had monthly income <3000 rand (80.8% vs 75%).Participants chose unsupervised HIVST (62.7%) versus supervised HIVST and reported multiple sex partners (10.88% vs 8.7%), exposure to sex workers (1.4% vs 0.2%) and fewer comorbidities (0.9% vs 1.9%). Almost all HIVST participants were linked (unsupervised HIVST (99.7%), supervised HIVST (99.8%) vs ConvHT (98.5%)) (adj RR 1.012; 95% CI 1.005 to 1.018) with new HIV infections: overall HIVST (9%); supervised HIVST (10.9%) and unsupervised HIVST (7.6%) versus ConvHT (6.79%) (adj RR 1.305; 95% CI 1.023 to 1.665); test referrals: 16.7% HIVST versus 3.1% ConvHT (adj RR 5.435; 95% CI 4.024 to 7.340). CONCLUSIONS: Our flexible, personalised, app-based HIVST program, offered by healthcare workers, successfully linked almost all HIV self-testers, detected new infections and increased referrals to self-test. Data are relevant for digital HIVST initiatives worldwide