Autonomous quantum machines and the finite sized Quasi-Ideal clock

Processes such as quantum computation, or the evolution of quantum cellular automata are typically described by a unitary operation implemented by an external observer. In particular, an interaction is generally turned on for a precise amount of time, using a classical clock. A fully quantum mechanical description of such a device would include a quantum description of the clock whose state is generally disturbed because of the back-reaction on it. Such a description is needed if we wish to consider finite sized autonomous quantum machines requiring no external control. The extent of the back-reaction has implications on how small the device can be, on the length of time the device can run, and is required if we want to understand what a fully quantum mechanical treatment of an observer would look like. Here, we consider the implementation of a unitary by a finite sized device which we call the "Quasi-Ideal clock", and show that the back-reaction on it can be made exponentially small in the device's dimension with only a linear increase in energy. As a result, an autonomous quantum machine need only be of modest size and or energy. We are also able to solve a long-standing open problem by using a finite sized quantum clock to approximate the continuous evolution of an Idealised clock. The result has implications on the equivalence of different paradigms of quantum thermodynamics, some which allow external control and some which only allow autonomous thermal machines.Comment: Main text: 9 + 53 pages. V4: Close to the published version, J. Annales Henri Poincar\'e (2018) [Communicated by David P\'erez-Garc\'ia

Meta-analytic Evidence for the Plurality of Mechanisms in Transdiagnostic Structural MRI Studies of Hallucination Status

Background: Hallucinations are transmodal and transdiagnostic phenomena, occurring across sensory modalities and presenting in psychiatric, neurodegenerative, neurological, and non-clinical populations. Despite their cross-category occurrence, little empirical work has directly compared between-group neural correlates of hallucinations. Methods: We performed whole-brain voxelwise meta-analyses of hallucination status across diagnoses using anisotropic effect-size seed-based d mapping (AES-SDM), and conducted a comprehensive systematic review in PubMed and Web of Science until May 2018 on other structural correlates of hallucinations, including cortical thickness and gyrification. Findings: 3214 abstracts were identified. Patients with psychiatric disorders and hallucinations (eight studies) exhibited reduced gray matter (GM) in the left insula, right inferior frontal gyrus, left anterior cingulate/paracingulate gyrus, left middle temporal gyrus, and increased in the bilateral fusiform gyrus, while patients with neurodegenerative disorders with hallucinations (eight studies) showed GM decreases in the left lingual gyrus, right supramarginal gyrus/parietal operculum, left parahippocampal gyrus, left fusiform gyrus, right thalamus, and right lateral occipital gyrus. Group differences between psychiatric and neurodegenerative hallucination meta-analyses were formally confirmed using Monte Carlo randomizations to determine statistical significance, and a jackknife sensitivity analysis established the reproducibility of results across nearly all study combinations. For other structural measures (28 studies), the most consistent findings associated with hallucination status were reduced cortical thickness in temporal gyri in schizophrenia and altered hippocampal volume in Parkinson's disease and dementia. Additionally, increased severity of hallucinations in schizophrenia correlated with GM reductions within the left superior temporal gyrus, right middle temporal gyrus, bilateral supramarginal and angular gyri. Interpretation: Distinct patterns of neuroanatomical alteration characterize hallucination status in patients with psychiatric and neurodegenerative diseases, suggesting a plurality of anatomical signatures. This approach has implications for treatment, theoretical frameworks, and generates refutable predictions for hallucinations in other diseases and their occurrence within the general population. Funding: None.The authors are supported by the following funding sources: Gates Cambridge (CPER); Wellcome Trust (JBR, 103838; CO, 200181/Z/15/Z); National Health and Medical Research Council Neil Hamilton Fairley Fellowship (CO, 1091310); Wellcome Trust Collaborative award (JRG), and a joint award from the Medical Research Council and the Wellcome Trust (JSS)

Twelve tips for integrating massive open online course content into classroom teaching

Massive open online courses (MOOCs) are a novel and emerging mode of online learning. They offer the advantages of online learning and provide content including short video lectures, digital readings, interactive assignments, discussion fora, and quizzes. Besides stand-alone use, universities are also trying to integrate MOOC content into the regular curriculum creating blended learning programs. In this 12 tips article, we aim to provide guidelines for readers to integrate MOOC content from their own or from other institutions into regular classroom teaching based on the literature and our own experiences. We provide advice on how to select the right content, how to assess its quality and usefulness, and how to actually create a blend within your existing course

Potential Cost-Effectiveness of Universal Access to Modern Contraceptives in Uganda

<div><h3>Background</h3><p>Over two thirds of women who need contraception in Uganda lack access to modern effective methods. This study was conducted to estimate the potential cost-effectiveness of achieving universal access to modern contraceptives in Uganda by implementing a hypothetical new contraceptive program (NCP) from both societal and governmental (Ministry of Health (MoH)) perspectives.</p> <h3>Methodology/Principal Findings</h3><p>A Markov model was developed to compare the NCP to the status quo or current contraceptive program (CCP). The model followed a hypothetical cohort of 15-year old girls over a lifetime horizon. Data were obtained from the Uganda National Demographic and Health Survey and from published and unpublished sources. Costs, life expectancy, disability-adjusted life expectancy, pregnancies, fertility and incremental cost-effectiveness measured as cost per life-year (LY) gained, cost per disability-adjusted life-year (DALY) averted, cost per pregnancy averted and cost per unit of fertility reduction were calculated. Univariate and probabilistic sensitivity analyses were performed to examine the robustness of results. Mean discounted life expectancy and disability-adjusted life expectancy (DALE) were higher under the NCP vs. CCP (28.74 vs. 28.65 years and 27.38 vs. 27.01 respectively). Mean pregnancies and live births per woman were lower under the NCP (9.51 vs. 7.90 and 6.92 vs. 5.79 respectively). Mean lifetime societal costs per woman were lower for the NCP from the societal perspective ($1,949 vs.$1,987) and the MoH perspective ($636 vs.$685). In the incremental analysis, the NCP dominated the CCP, i.e. it was both less costly and more effective. The results were robust to univariate and probabilistic sensitivity analysis.</p> <h3>Conclusion/Significance</h3><p>Universal access to modern contraceptives in Uganda appears to be highly cost-effective. Increasing contraceptive coverage should be considered among Uganda's public health priorities.</p> </div

Cost Effectiveness of a Pharmacy-Only Refill Program in a Large Urban HIV/AIDS Clinic in Uganda

HIV/AIDS clinics in Uganda and other low-income countries face increasing numbers of patients and workforce shortages. We performed a cost-effectiveness analysis comparing a Pharmacy-only Refill Program (PRP), a form of task-shifting, to the Standard of Care (SOC) at a large HIV/AIDS clinic in Uganda, the Infectious Diseases Institute (IDI). The PRP was started to reduce workforce shortages and optimize patient care by substituting pharmacy visits for SOC involving monthly physician visits for accessing antiretroviral medicines.We used a retrospective cohort analysis to compare the effectiveness of the PRP compared to SOC. Effectiveness was defined as Favorable Immune Response (FIR), measured as having a CD4 lymphocyte count of over 500 cells/µl at follow-up. We used multivariate logistic regression to assess the difference in FIR between patients in the PRP and SOC. We incorporated estimates of effectiveness into an incremental cost-effectiveness analysis performed from a limited societal perspective. We estimated costs from previous studies at IDI and conducted univariate and probabilistic sensitivity analyses. We identified 829 patients, 578 in the PRP and 251 in SOC. After 12.8 months (PRP) and 15.1 months (SOC) of follow-up, 18.9% of patients had a FIR, 18.6% in the PRP and 19.6% in SOC. There was a non-significant 9% decrease in the odds of having a FIR for PRP compared to SOC after adjusting for other variables (OR 0.93, 95% CI 0.55-1.58). The PRP was less costly than the SOC (US$520 vs. 655 annually, respectively). The incremental cost-effectiveness ratio comparing PRP to SOC was US$ 13,500 per FIR. PRP remained cost-effective at univariate and probabilistic sensitivity analysis.The PRP is more cost-effective than the standard of care. Similar task-shifting programs might help large HIV/AIDS clinics in Uganda and other low-income countries to cope with increasing numbers of patients seeking care

Evaluation of Cynomolgus Macaque (Macaca fascicularis) Endogenous Retrovirus Expression Following Simian Immunodeficiency Virus Infection

Human endogenous retrovirus type K (HERV-K) transcripts are upregulated in the plasma of HIV-infected individuals and have been considered as targets for an HIV vaccine. We evaluated cynomolgus macaque endogenous retrovirus (CyERV) mRNA expression by RT-qPCR in PBMCs isolated from a cohort of animals previously utilized in a live attenuated SIV vaccine trial. CyERV env transcript levels decreased following vaccination (control and vaccine groups) and CyERV env and gag mRNA expression was decreased following acute SIV-infection, whereas during chronic SIV infection, CyERV transcript levels were indistinguishable from baseline. Reduced susceptibility to initial SIV infection, as measured by the number of SIV challenges required for infection, was associated with increased CyERV transcript levels in PBMCs. In vitro analysis revealed that SIV infection of purified CD4+ T-cells did not alter CyERV gene expression. This study represents the first evaluation of ERV expression in cynomolgus macaques following SIV infection, in an effort to assess the utility of cynomolgus macaques as an animal model to evaluate ERVs as a target for an HIV/SIV vaccine. This non-human primate model system does not recapitulate what has been observed to date in the plasma of HIV-infected humans suggesting that further investigation at the cellular level is required to elucidate the impact of HIV/SIV infection on endogenous retrovirus expression

Mechanism of the Interaction between the Intrinsically Disordered C-Terminus of the Pro-Apoptotic ARTS Protein and the Bir3 Domain of XIAP

ARTS (Sept4_i2) is a mitochondrial pro-apoptotic protein that functions as a tumor suppressor. Its expression is significantly reduced in leukemia and lymphoma patients. ARTS binds and inhibits XIAP (X-linked Inhibitor of Apoptosis protein) by interacting with its Bir3 domain. ARTS promotes degradation of XIAP through the proteasome pathway. By doing so, ARTS removes XIAP inhibition of caspases and enables apoptosis to proceed. ARTS contains 27 unique residues in its C-terminal domain (CTD, residues 248–274) which are important for XIAP binding. Here we characterized the molecular details of this interaction. Biophysical and computational methods were used to show that the ARTS CTD is intrinsically disordered under physiological conditions. Direct binding of ARTS CTD to Bir3 was demonstrated using NMR and fluorescence spectroscopy. The Bir3 interacting region in ARTS CTD was mapped to ARTS residues 266–274, which are the nine C-terminal residues in the protein. Alanine scan of ARTS 266–274 showed the importance of several residues for Bir3 binding, with His268 and Cys273 contributing the most. Adding a reducing agent prevented binding to Bir3. A dimer of ARTS 266–274 formed by oxidation of the Cys residues into a disulfide bond bound with similar affinity and was probably required for the interaction with Bir3. The detailed analysis of the ARTS – Bir3 interaction provides the basis for setting it as a target for anti cancer drug design: It will enable the development of compounds that mimic ARTS CTD, remove IAPs inhibition of caspases, and thereby induce apoptosis

Use and efficacy of bone morphogenetic proteins in fracture healing

Signal transduction in aging related disease