Computational phenotyping of two-person interactions reveals differential neural response to depth-of-thought.

Reciprocating exchange with other humans requires individuals to infer the intentions of their partners. Despite the importance of this ability in healthy cognition and its impact in disease, the dimensions employed and computations involved in such inferences are not clear. We used a computational theory-of-mind model to classify styles of interaction in 195 pairs of subjects playing a multi-round economic exchange game. This classification produces an estimate of a subject's depth-of-thought in the game (low, medium, high), a parameter that governs the richness of the models they build of their partner. Subjects in each category showed distinct neural correlates of learning signals associated with different depths-of-thought. The model also detected differences in depth-of-thought between two groups of healthy subjects: one playing patients with psychiatric disease and the other playing healthy controls. The neural response categories identified by this computational characterization of theory-of-mind may yield objective biomarkers useful in the identification and characterization of pathologies that perturb the capacity to model and interact with other humans

Le territoire, générateur d’inégalités face aux cancers

Agir efficacement contre les inégalités géographiques face aux cancers implique une meilleure compréhension du processus aboutissant à ces inégalités. Une méthodologie interdisciplinaire, traitant conjointement les multiples dimensions par lesquelles le territoire impacte la santé et retraçant l’évolution pronostique des patients, permettrait de répondre à ce besoin. La cohorte EMS, retraçant la prise en charge de patients atteints de sarcomes (cancers rares) en Rhône-Alpes, a été analysée suivant ces principes méthodologiques. L’analyse de 15 variables géographiques ayant une influence sur la santé a permis de distinguer six types de territoires rhônalpins. Cette typologie a ensuite été croisée avec les données de la cohorte EMS pour étudier les pertes de chances propres à chaque type de territoire. La surmortalité des pôles urbains est liée à l’incidence plus importante des sarcomes, quand celle des quartiers populaires et des espaces ruraux s’expliquent davantage par des pertes de chances de survie au cours de la prise en charge.Cancers inequalities in France are among the highest in developed countries and these gaps seem to be growing in the last decades. Territorial inequalities of cancers are analyzed by mapping, which showed higher mortality rates in the North-East Regions of France. At the local scale, standardized mortality rates are two times higher in some areas in the North as other areas in the South-East. Epidemiological studies, mostly based on multilevel analysis, evidence the impact of physical environment, deprivation or health care access on health outcomes. But to identify contextual effects are not sufficient to understand how cancer inequalities are built and how patient’s life context contributes to this process. As epidemiological approach is splitting contextual effects according to health outcomes, geographical approach may have to explain how these contextual effects lead to cancer inequalities, by using territorial typology to summarize these contextual effects. Comparing health outcomes according to this territorial classification may help to understand territory’s ability to generate health inequalities. Several stages across the cancer continuum are implied in the building of the cancer inequalities. This medical process has to be reconstructed to determine whether mortality inequalities are generated by a higher incidence or a lower survival. Moreover, lower survival may be linked to the worse prognosis of patients at diagnosis or to the lower quality of management according to cancer care facilities. Evolution of patients’ prognosis may be reconstructed, thanks to clinical data, in order to identify the most influent steps during this medical process. As a result, to understand the way geographical inequalities of cancers are building requires a multidisciplinary methodology, considering the territory’s contribution as a whole and using longitudinal clinical data. But to reconstitute this medical process is quite difficult actually because few longitudinal and exhaustive data are available. The EMS cohort represents an opportunity to test and discuss this methodological approach. This cohort includes all sarcoma (rare cancer) patients diagnosed in 2005 and 2006, in the Rhône-Alpes Region, and collects clinical data from the diagnosis to the patient follow-up. For this geographical analysis of the EMS cohort, we used a territorial typology generated thanks to multivariate analysis of 15 geographical variables known for their impact on health. Strong differences are noticed in terms of environment exposures, deprivation and health care access between the six types of territory (metropolitan neighborhoods, working-class neighborhoods, urban districts, residential areas, periurban areas, rural areas). This typology seems to be relevant to study geographical inequalities because it enables to distinguish populations which are not exposed to the same risks through their life context. A logistic regression including stage, age and histological subtype, as clinical factors influencing prognosis, estimates the patients’ prognosis at diagnosis. This prognosis score seems to be quite predictive because only 7% of “good prognosis” patients will be dead five years later, whereas this five years death rate raises to 80% for the worse prognosis patients. Analysis of geographical inequalities for sarcoma patients in the Rhône-Alpes Region shows the diversity of situations leading to inequalities of mortality. Indeed, the higher mortality in three types of territories has to be attributed to three different processes. In the case of the urban hub, this high mortality is linked to the higher incidence of sarcoma, as survival rate for patients of these districts is very close to the regional average. As incidence and prognosis risk in the working-class neighborhoods are quite similar to the regional average, higher mortality is due to the loss of survival odds in the course of treatments, probably because of a less optimal management. Despite the second lower incidence among the six types of territories, the worse prognosis of patients (more late-stage diagnosis) and the loss of survival odds during cancer management explained the high mortality rated in the rural areas. Thanks to the EMS cohort’s analysis, we assess the potential of a multidisciplinary methodology studying the territory’s ability to generate geographical inequalities of cancers. Territorial typology, produced without health outcomes data, may be used for every health studies as a synthetic index of the territory and also evidence strong inequalities of health according to people’s life contexts. As public policies struggle to be successful on this issue, to identify key events in the medical process leading to cancer inequalities may improve the territorialization and the efficiency of these policies. Territories with high risk before diagnosis would be focused on prevention and early diagnosis, whereas those more disadvantage during the management would lean towards cancer care quality, access to hospitals and cancer expertise and patient compliance

Global health partnerships: building multi-national collaborations to achieve lasting improvements in maternal and neonatal health

Abstract Background In response to health care challenges worldwide, extensive funding has been channeled to the world’s most vulnerable health systems. Funding alone is not sufficient to address the complex issues and challenges plaguing these health systems. To see lasting improvement in maternal and infant health outcomes in the developing world, a global commitment to the sharing of knowledge and resources through international partnerships is critical. But partnerships that merely introduce western medical techniques and protocols to low resource settings, without heeding the local contexts, are misguided and unsustainable. Forming partnerships with mutual respect, shared vision, and collaborative effort is needed to ensure that all parties, irrespective of whether they belong to resource rich or resource poor settings, learn from each other so that meaningful and sustained system strengthening can take place. Methods In this paper, we describe the partnership building model of an international NGO, Kybele, which is committed to achieving childbirth safety through sustained partnerships in low resource settings. The Kybele model adapts generic stages of successful partnerships documented in the literature to four principles relevant to Kybele’s work. A multiple-case study approach is used to demonstrate how the model is applied in different country settings. Results The four principle of Kybele’s partnership model are robust drivers of successful partnerships in diverse country settings. Conclusions Much has been written about the need for multi-country partnerships to achieve sustainable outcomes in global health, but few papers in the literature describe how this has been achieved in practice. A strong champion, support and engagement of stakeholders, co-creation of solutions with partners, and involvement of partners in the delivery of solutions are all requirements for successful and sustained partnerships

Conservative versus liberal oxygenation targets in critically ill children: the randomised multiple-centre pilot Oxy-PICU trial

BACKGROUND: Oxygen saturation monitoring for children receiving respiratory support is standard worldwide. No randomised clinical trials have compared peripheral oxygen saturation (SpO_{2}) targets for critically ill children. The harm of interventions to raise SpO_{2} to > 94% may exceed their benefits. METHODS: We undertook an open, parallel-group randomised trial of children > 38 weeks completed gestation and  94%) or a conservative oxygenation group (SpO_{2} = 88–92% inclusive). Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between-group separation of SpO_{2} and safety. The Oxy-PICU trial was registered before recruitment: ClinicalTrials.gov identifier NCT03040570. RESULTS: A total of 159 children met the inclusion criteria, of whom 119 (75%) were randomised between April and July 2017, representing a rate of 10 patients per month per site. The mean time to randomisation from first contact with an intensive care team was 1.9 (SD 2.2) h. Consent to continue in the study was obtained in 107 cases (90%); the children’s parents/legal representatives were supportive of the consent process. The median (interquartile range, IQR) of time-weighted individual mean SpO_{2} was 94.9% (92.6–97.1) in the conservative oxygenation group and 97.5% (96.2–98.4) in the liberal group [difference 2.7%, 95% confidence interval (95% CI) 1.3–4.0%, p < 0.001]. Median (IQR) time-weighted individual mean FiO_{2} was 0.28 (0.24–0.37) in the conservative group and 0.37 (0.30–0.42) in the liberal group (difference 0.08, 95% CI 0.03–0.13, p < 0.001). There were no significant between-group differences in length of stay, duration of organ support or mortality. Two prespecified serious adverse events (cardiac arrests) occurred, both in the liberal oxygenation group. CONCLUSION: A definitive clinical trial of peripheral oxygen saturation targets is feasible in critically ill children

Development of high-throughput methods to screen disease caused by Rhizoctonia solani AG 2-1 in oilseed rape

Background: Rhizoctonia solani (Kühn) is a soil-borne, necrotrophic fungus causing damping off, root rot and stem canker in many cultivated plants worldwide. Oilseed rape (OSR, Brassica napus) is the primary host for anastomosis group (AG) 2-1 of R. solani causing pre- and post-emergence damping-off resulting in death of seedlings and impaired crop establishment. Presently, there are no known resistant OSR genotypes and the main methods for disease control are fungicide seed treatments and cultural practices. The identification of sources of resistance for crop breeding is essential for sustainable management of the disease. However, a high-throughput, reliable screening method for resistance traits is required. The aim of this work was to develop a low cost, rapid screening method for disease phenotyping and identification of resistance traits. Results: Four growth systems were developed and tested: (1) nutrient media plates, (2) compost trays, (3) light expanded clay aggregate (LECA) trays, and (4) a hydroponic pouch and wick system. Seedlings were inoculated with virulent AG 2-1 to cause damping-off disease and grown for a period of 4–10 days. Visual disease assessments were carried out or disease was estimated through image analysis using ImageJ. Conclusion: Inoculation of LECA was the most suitable method for phenotyping disease caused by R. solani AG 2-1 as it enabled the detection of differences in disease severity among OSR genotypes within a short time period whilst allowing measurements to be conducted on whole plants. This system is expected to facilitate identification of resistant germplasm

Prioritizing single-nucleotide variations that potentially regulate alternative splicing

Recent evidence suggests that many complex diseases are caused by genetic variations that play regulatory roles in controlling gene expression. Most genetic studies focus on nonsynonymous variations that can alter the amino acid composition of a protein and are therefore believed to have the highest impact on phenotype. Synonymous variations, however, can also play important roles in disease pathogenesis by regulating pre-mRNA processing and translational control. In this study, we systematically survey the effects of single-nucleotide variations (SNVs) on binding affinity of RNA-binding proteins (RBPs). Among the 10,113 synonymous SNVs identified in 697 individuals in the 1,000 Genomes Project and distributed by Genetic Analysis Workshop 17 (GAW17), we identified 182 variations located in alternatively spliced exons that can significantly change the binding affinity of nine RBPs whose binding preferences on 7-mer RNA sequences were previously reported. We found that the minor allele frequencies of these variations are similar to those of nonsynonymous SNVs, suggesting that they are in fact functional. We propose a workflow to identify phenotype-associated regulatory SNVs that might affect alternative splicing from exome-sequencing-derived genetic variations. Based on the affecting SNVs on the quantitative traits simulated in GAW17, we further identified two and four functional SNVs that are predicted to be involved in alternative splicing regulation in traits Q1 and Q2, respectively

Renal cell cancer without a renal primary

Renal cell carcinoma has been increasing in incidence over the past two decades. Men are affected more than women and metastatic disease at presentation occurs in up to one third of patients. Metastasis can occur to virtually any organ, and involvement of multiple organs is not uncommon. To date, no reports have been found of metastatic disease without a renal primary. We present a case of renal cell cancer initially presenting as a subcutaneous mass with subsequent pancreatic and parotid gland metastases in absence of a primary renal source

Rivastigmine Lowers Aβ and Increases sAPPα Levels, Which Parallel Elevated Synaptic Markers and Metabolic Activity in Degenerating Primary Rat Neurons

Overproduction of amyloid-β (Aβ) protein in the brain has been hypothesized as the primary toxic insult that, via numerous mechanisms, produces cognitive deficits in Alzheimer's disease (AD). Cholinesterase inhibition is a primary strategy for treatment of AD, and specific compounds of this class have previously been demonstrated to influence Aβ precursor protein (APP) processing and Aβ production. However, little information is available on the effects of rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, on APP processing. As this drug is currently used to treat AD, characterization of its various activities is important to optimize its clinical utility. We have previously shown that rivastigmine can preserve or enhance neuronal and synaptic terminal markers in degenerating primary embryonic cerebrocortical cultures. Given previous reports on the effects of APP and Aβ on synapses, regulation of APP processing represents a plausible mechanism for the synaptic effects of rivastigmine. To test this hypothesis, we treated degenerating primary cultures with rivastigmine and measured secreted APP (sAPP) and Aβ. Rivastigmine treatment increased metabolic activity in these cultured cells, and elevated APP secretion. Analysis of the two major forms of APP secreted by these cultures, attributed to neurons or glia based on molecular weight showed that rivastigmine treatment significantly increased neuronal relative to glial secreted APP. Furthermore, rivastigmine treatment increased α-secretase cleaved sAPPα and decreased Aβ secretion, suggesting a therapeutic mechanism wherein rivastigmine alters the relative activities of the secretase pathways. Assessment of sAPP levels in rodent CSF following once daily rivastigmine administration for 21 days confirmed that elevated levels of APP in cell culture translated in vivo. Taken together, rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the α-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.