A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression

Brain cellular heterogeneity may bias cell type specific DNA methylation patterns, influencing findings in psychiatric epigenetic studies. We performed fluorescence activated cell sorting (FACS) of neuronal nuclei and Illumina HM450 DNA methylation profiling in post mortem frontal cortex of 29 major depression and 29 matched controls. We identify genomic features and ontologies enriched for cell type specific epigenetic variation. Using the top cell epigenotype specific (CETS) marks, we generated a publically available R package, “CETS,” capable of quantifying neuronal proportions and generating in silico neuronal profiles from DNA methylation data. We demonstrate a significant overlap in major depression DNA methylation associations between FACS separated and CETS model generated neuronal profiles relative to bulk profiles. CETS derived neuronal proportions correlated significantly with age in the frontal cortex and cerebellum and accounted for epigenetic variation between brain regions. CETS based control of cellular heterogeneity will enable more robust hypothesis testing in the brain

Country-level cost-effectiveness thresholds : initial estimates and the need for further research

Objectives: Cost-effectiveness analysis (CEA) can guide policymakers in resource allocation decisions. CEA assesses whether the health gains offered by an intervention are large enough relative to any additional costs to warrant adoption. Where there are constraints on the healthcare system’s budget or ability to increase expenditures, additional costs imposed by interventions have an ‘opportunity cost’ in terms of the health foregone as other interventions cannot be provided. Cost-effectiveness thresholds (CETs) are typically used to assess whether an intervention is worthwhile and should reflect health opportunity cost. However, CETs used by some decision makers - such as the World Health Organization (WHO) suggested CETs of 1-3 times gross domestic product per capita (GDP pc) - do not. This study estimates CETs based on opportunity cost for a wide range of countries. Methods: We estimate CETs based upon recent empirical estimates of opportunity cost (from the English NHS), estimates of the relationship between country GDP pc and the value of a statistical life, and a series of explicit assumptions. Results: CETs for Malawi (the lowest income country in the world), Cambodia (borderline low/low-middle income), El Salvador (borderline low-middle/upper-middle) and Kazakhstan (borderline high-middle/high) are estimated to be $3-116 (1-51$44-518 (4-51%), $422-1,967 (11-51$4,485-8,018 (32-59%); respectively. Conclusions: To date opportunity cost-based CETs for low/middle income countries have not been available. Although uncertainty exists in the underlying assumptions, these estimates can provide a useful input to inform resource allocation decisions and suggest that routinely used CETs have been too high

Country-level cost-effectiveness thresholds : initial estimates and the need for further research

Objectives: Cost-effectiveness analysis (CEA) can guide policymakers in resource allocation decisions. CEA assesses whether the health gains offered by an intervention are large enough relative to any additional costs to warrant adoption. Where there are constraints on the healthcare system’s budget or ability to increase expenditures, additional costs imposed by interventions have an ‘opportunity cost’ in terms of the health foregone as other interventions cannot be provided. Cost-effectiveness thresholds (CETs) are typically used to assess whether an intervention is worthwhile and should reflect health opportunity cost. However, CETs used by some decision makers - such as the World Health Organization (WHO) suggested CETs of 1-3 times gross domestic product per capita (GDP pc) - do not. This study estimates CETs based on opportunity cost for a wide range of countries. Methods: We estimate CETs based upon recent empirical estimates of opportunity cost (from the English NHS), estimates of the relationship between country GDP pc and the value of a statistical life, and a series of explicit assumptions. Results: CETs for Malawi (the lowest income country in the world), Cambodia (borderline low/low-middle income), El Salvador (borderline low-middle/upper-middle) and Kazakhstan (borderline high-middle/high) are estimated to be $3-116 (1-51$44-518 (4-51%), $422-1,967 (11-51$4,485-8,018 (32-59%); respectively. Conclusions: To date opportunity cost-based CETs for low/middle income countries have not been available. Although uncertainty exists in the underlying assumptions, these estimates can provide a useful input to inform resource allocation decisions and suggest that routinely used CETs have been too high

The Contribution of Community-based Health Planning and Services (CHPS) to Community Sustainability and Health in the Upper West Region of Ghana

Ghana introduced Community-based Health Planning and Services (CHPS) to improve poor health in rural areas. Research in the Upper West Region (UWR) has found poor health is related to degrading social fabric. Recent research suggests the existence of health services in rural, developed contexts increases community sustainability and can be understood through the capitals framework. This study applies the framework to understand the contribution of CHPS to community sustainability and health in the UWR. The region lacks reliable ambulance services; in response, communities have adopted Community-initiated Emergency Transport Services (CETS). The study uses the existence of CETS as a measure of sustainability and gathers details on why some communities have sustained CETS while others have not. Key informant interviews (7), focus groups (12), and in-depth interviews (25) were conducted in 6 communities. Findings suggest CHPS influences health and sustainability through reinforcement of social capital, changes to human capital, and economic gains, and community mobilization is suggested as an important influence on adoption and sustainment of CETS. The study demonstrates the benefits of CHPS as improving social fabric, and reveals novel details surrounding CETS. Key Words: Community Health, Community Sustainability, Rural Health, Capitals Framework, Ghan

Digital Quantum Simulation of the Statistical Mechanics of a Frustrated Magnet

Many interesting problems in physics, chemistry, and computer science are equivalent to problems of interacting spins. However, most of these problems require computational resources that are out of reach by classical computers. A promising solution to overcome this challenge is to exploit the laws of quantum mechanics to perform simulation. Several "analog" quantum simulations of interacting spin systems have been realized experimentally. However, relying on adiabatic techniques, these simulations are limited to preparing ground states only. Here we report the first experimental results on a "digital" quantum simulation on thermal states; we simulated a three-spin frustrated magnet, a building block of spin ice, with an NMR quantum information processor, and we are able to explore the phase diagram of the system at any simulated temperature and external field. These results serve as a guide for identifying the challenges for performing quantum simulation on physical systems at finite temperatures, and pave the way towards large scale experimental simulations of open quantum systems in condensed matter physics and chemistry.Comment: 7 pages for the main text plus 6 pages for the supplementary material

Barriers and Facilitators to Use of a Clinical Evidence Technology in the Management of Skin Problems in Primary Care: Insights from Mixed Methods

Objective: Few studies have examined the impact of a single clinical evidence technology (CET) on provider practice or patient outcomes from the provider’s perspective. A previous cluster-randomized controlled trial with patient-reported data tested the effectiveness of a CET (i.e., VisualDx) in improving skin problem outcomes but found no significant effect. The objectives of this follow-up study were to identify barriers and facilitators to the use of the CET from the perspective of primary care providers (PCPs) and to identify reasons why the CET did not affect outcomes in the trial. Methods: Using a convergent mixed methods design, PCPs completed a post-trial survey and participated in interviews about using the CET for the management of patients’ skin problems. Data from both methods were integrated. Results: PCPs found the CET somewhat easy to use but only occasionally useful. Less experienced PCPs used the CET more frequently. Data from interviews revealed barriers and facilitators at four steps of evidence-based practice: clinical question recognition, information acquisition, appraisal of relevance, and application with patients. Facilitators included uncertainty in dermatology, intention for use, convenience of access, diagnosis and treatment support, and patient communication. Barriers included confidence in dermatology, preference for other sources, interface difficulties, presence of irrelevant information, and lack of decision impact. Conclusion: PCPs found the CET useful for diagnosis, treatment support, and patient communication. However, the barriers of interface difficulties, irrelevant search results, and preferred use of other sources limited its positive impact on patient skin problem management

Simulation of Classical Thermal States on a Quantum Computer: A Transfer Matrix Approach

We present a hybrid quantum-classical algorithm to simulate thermal states of a classical Hamiltonians on a quantum computer. Our scheme employs a sequence of locally controlled rotations, building up the desired state by adding qubits one at a time. We identify a class of classical models for which our method is efficient and avoids potential exponential overheads encountered by Grover-like or quantum Metropolis schemes. Our algorithm also gives an exponential advantage for 2D Ising models with magnetic field on a square lattice, compared with the previously known Zalka's algorithm.Comment: 5 pages, 3 figures; (new in version 2: added new figure, title changed, rearranged paragraphs

Effect of a Clinical Evidence Technology on Patient Skin Disease Outcomes in Primary Care: A Cluster-Randomized Controlled Trial

Objective: Providers’ use of clinical evidence technologies (CETs) improves their diagnosis and treatment decisions. Despite these benefits, few studies have evaluated the impact of CETs on patient outcomes. Investigators evaluated the effect of one CET, VisualDx, on skin problem outcomes in primary care. Methods: The cluster-randomized controlled pragmatic trial was set in outpatient clinics at an academic medical center in the Northeast. Participants were Primary Care Providers (PCPs) and adult patients seen for skin problems. The intervention was VisualDx as used by PCPs. Outcomes were patient-reported time from index clinic visit to problem resolution, and the number of follow-up visits to any provider for the same problem. PCPs assigned to intervention agreed to use VisualDx as their primary evidence source for skin problems. Control group PCPs agreed not to use VisualDx. Investigators collected outcome data from patients by phone at 30 day intervals. Cox proportional hazards models assessed time to resolution. Wilcoxon-rank sum tests and logistic regression compared return appointments. Results: Thirty-two PCPs and 433 patients participated. In proportional hazards modelling adjusted for provider clusters, the days from index visit to skin problem resolution were similar in both groups (HR 0.92; CI 0.70, 1.21 P= 0.54). Patient follow-up appointments did not differ significantly between groups (OR 1.26 95% CI 0.94, 1.70 P =0.29). Conclusion: This pragmatic trial tested the effectiveness of VisualDx on patient reported skin disease outcomes in a generalizable clinical setting. There was no difference in skin problem resolution or number of follow-up visits when PCPs used VisualDx

CUP: Comprehensive User-Space Protection for C/C++

Memory corruption vulnerabilities in C/C++ applications enable attackers to execute code, change data, and leak information. Current memory sanitizers do no provide comprehensive coverage of a program's data. In particular, existing tools focus primarily on heap allocations with limited support for stack allocations and globals. Additionally, existing tools focus on the main executable with limited support for system libraries. Further, they suffer from both false positives and false negatives. We present Comprehensive User-Space Protection for C/C++, CUP, an LLVM sanitizer that provides complete spatial and probabilistic temporal memory safety for C/C++ program on 64-bit architectures (with a prototype implementation for x86_64). CUP uses a hybrid metadata scheme that supports all program data including globals, heap, or stack and maintains the ABI. Compared to existing approaches with the NIST Juliet test suite, CUP reduces false negatives by 10x (0.1%) compared to the state of the art LLVM sanitizers, and produces no false positives. CUP instruments all user-space code, including libc and other system libraries, removing them from the trusted code base