Early Detection of Poor Adherers to Statins: Applying Individualized Surveillance to Pay for Performance

Background: Medication nonadherence costs $300 billion annually in the US. Medicare Advantage plans have a financial incentive to increase medication adherence among members because the Centers for Medicare and Medicaid Services (CMS) now awards substantive bonus payments to such plans, based in part on population adherence to chronic medications. We sought to build an individualized surveillance model that detects early which beneficiaries will fall below the CMS adherence threshold. Methods: This was a retrospective study of over 210,000 beneficiaries initiating statins, in a database of private insurance claims, from 2008-2011. A logistic regression model was constructed to use statin adherence from initiation to day 90 to predict beneficiaries who would not meet the CMS measure of proportion of days covered 0.8 or above, from day 91 to 365. The model controlled for 15 additional characteristics. In a sensitivity analysis, we varied the number of days of adherence data used for prediction. Results: Lower adherence in the first 90 days was the strongest predictor of one-year nonadherence, with an odds ratio of 25.0 (95% confidence interval 23.7-26.5) for poor adherence at one year. The model had an area under the receiver operating characteristic curve of 0.80. Sensitivity analysis revealed that predictions of comparable accuracy could be made only 40 days after statin initiation. When members with 30-day supplies for their first statin fill had predictions made at 40 days, and members with 90-day supplies for their first fill had predictions made at 100 days, poor adherence could be predicted with 86% positive predictive value. Conclusions: To preserve their Medicare Star ratings, plan managers should identify or develop effective programs to improve adherence. An individualized surveillance approach can be used to target members who would most benefit, recognizing the tradeoff between improved model performance over time and the advantage of earlier detection

Knowledge-based instantiation of full atomic detail into coarse-grain RNA 3D structural models

Motivation: The recent development of methods for modeling RNA 3D structures using coarse-grain approaches creates a need to bridge low- and high-resolution modeling methods. Although they contain topological information, coarse-grain models lack atomic detail, which limits their utility for some applications

Incidence of type 2 diabetes in people with a history of hospitalisation for major mental illness in Scotland 2001-2015: a retrospective cohort study

Objective: To determine the incidence of type 2 diabetes in people with a history of hospitalization for major mental illness versus no mental illness in Scotland by time period and sociodemographics. Research Design and Methods: We used national Scottish population-based records to create cohorts with a hospital record of schizophrenia, bipolar disorder, or depression or no mental illness and to ascertain diabetes incidence. We used quasi-Poisson regression models including age, sex, time period, and area-based deprivation to estimate incidence and relative risks (RRs) of diabetes by mental illness status. Estimates are illustrated for people aged 60 years and in the middle deprivation quintile in 2015. Results: We identified 254,136 diabetes cases during 2001–2015. Diabetes incidence in 2015 was 1.5- to 2.5-fold higher in people with versus without a major mental disorder, with the gap having slightly increased over time. RRs of diabetes incidence were greater among women than men for schizophrenia (RR 2.40 [95% CI 2.01, 2.85] and 1.63 [1.38, 1.94]), respectively) and depression (RR 2.10 [1.86, 2.36] and 1.62 [1.43, 1.82]) but similar for bipolar disorder (RR 1.65 [1.35, 2.02] and 1.50 [1.22, 1.84]). Absolute and relative differences in diabetes incidence associated with mental illness increased with increasing deprivation. Conclusions: Disparities in diabetes incidence between people with and without major mental illness appear to be widening. Major mental illness has a greater effect on diabetes risk in women and people living in more deprived areas, which has implications for intervention strategies to reduce diabetes risk in this vulnerable population

Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration

The loss of cone photoreceptors that mediate daylight vision represents a leading cause of blindness, for which cell replacement by transplantation offers a promising treatment strategy. Here, we characterize cone differentiation in retinas derived from mouse embryonic stem cells (mESCs). Similar to in vivo development, a temporal pattern of progenitor marker expression is followed by the differentiation of early thyroid hormone receptor β2-positive precursors and, subsequently, photoreceptors exhibiting cone-specific phototransduction-related proteins. We establish that stage-specific inhibition of the Notch pathway increases cone cell differentiation, while retinoic acid signaling regulates cone maturation, comparable with their actions in vivo. MESC-derived cones can be isolated in large numbers and transplanted into adult mouse eyes, showing capacity to survive and mature in the subretinal space of Aipl1−/− mice, a model of end-stage retinal degeneration. Together, this work identifies a robust, renewable cell source for cone replacement by purified cell suspension transplantation

The structural basis of rubisco phase separation in the pyrenoid

Approximately one-third of global CO2 fixation occurs in a phase-separated algal organelle called the pyrenoid. The existing data suggest that the pyrenoid forms by the phase separation of the CO2-fixing enzyme Rubisco with a linker protein; however, the molecular interactions underlying this phase separation remain unknown. Here we present the structural basis of the interactions between Rubisco and its intrinsically disordered linker protein Essential Pyrenoid Component 1 (EPYC1) in the model alga Chlamydomonas reinhardtii. We find that EPYC1 consists of five evenly spaced Rubisco-binding regions that share sequence similarity. Single-particle cryo-electron microscopy of these regions in complex with Rubisco indicates that each Rubisco holoenzyme has eight binding sites for EPYC1, one on each Rubisco small subunit. Interface mutations disrupt binding, phase separation and pyrenoid formation. Cryo-electron tomography supports a model in which EPYC1 and Rubisco form a codependent multivalent network of specific low-affinity bonds, giving the matrix liquid-like properties. Our results advance the structural and functional understanding of the phase separation underlying the pyrenoid, an organelle that plays a fundamental role in the global carbon cycle

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

A Review of Interventions to Reduce Mechanical Restraint and Seclusion among Adult Psychiatric Inpatients

Objective: This review examines nature and effectiveness of interventions to reduce the use of mechanical restraint and seclusion among adult psychiatric inpatients. Method: Electronic searches were conducted to locate post-1960 empirical studies of restraint and seclusion reduction in English. A total of 36 studies were identified, mostly from the USA. Analysis was conducted using a structured data extraction tool. Results: The majority of studies reported reduced levels or mechanical restraint and/or seclusion, but the standard of evidence was poor. There were no randomised trials. Most were retrospective studies of official records before and after the intervention was introduced, with varying follow-up periods. The interventions were diverse, but tended to include one or more of the following: new restraint and/or seclusion policies, staffing changes, staff training, review procedures and crisis management initiatives. The research was unable to address which of these elements was most effective. There was also evidence that some improved outcomes were achieved by substituting restraint or seclusion for each other or for alternatives forms of containment (medication in particular). Nurses’ attitudes, skills and approach to patient care were absent from the literature. Conclusions: Interventions probably can reduce the use of restraint and seclusion, but better designed research is required to demonstrate their effectiveness conclusively. More attention should also be paid to understanding how interventions work, particularly from the perspective of nursing staff. This is essential to the successful implementation of restraint and seclusion interventions across different psychiatric settings and treatment populations

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Genome-Wide Association Data Reveal a Global Map of Genetic Interactions among Protein Complexes

This work demonstrates how gene association studies can be analyzed to map a global landscape of genetic interactions among protein complexes and pathways. Despite the immense potential of gene association studies, they have been challenging to analyze because most traits are complex, involving the combined effect of mutations at many different genes. Due to lack of statistical power, only the strongest single markers are typically identified. Here, we present an integrative approach that greatly increases power through marker clustering and projection of marker interactions within and across protein complexes. Applied to a recent gene association study in yeast, this approach identifies 2,023 genetic interactions which map to 208 functional interactions among protein complexes. We show that such interactions are analogous to interactions derived through reverse genetic screens and that they provide coverage in areas not yet tested by reverse genetic analysis. This work has the potential to transform gene association studies, by elevating the analysis from the level of individual markers to global maps of genetic interactions. As proof of principle, we use synthetic genetic screens to confirm numerous novel genetic interactions for the INO80 chromatin remodeling complex

Emergence and spread of SARS-CoV-2 lineage B.1.620 with variant of concern-like mutations and deletions

Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Delta, Y144Delta, and LLA241/243Delta. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers