Need and scope of global partnership on public health research

BACKGROUND:A large and growing body of "big data" is generated by internet search engines, such as Google. Because people often search for information about public health and medical issues, researchers may be able to use search engine data to monitor and predict public health problems, such as HIV. We sought to assess the feasibility of using Google search data to analyze and predict new HIV diagnoses cases in the United States. METHODS AND FINDINGS:From 2007 to 2014, we collected search volume data on HIV-related Google search keywords across the United States. State-level new HIV diagnoses data were collected from the Centers for Disease Control and Prevention (CDC) and AIDSVu.org. We developed a negative binomial model to predict HIV cases using a subset of significant predictor keywords identified by LASSO. The Google search data were combined with state-level HIV case reports provided by the CDC. We use historical data to train the model and predict new HIV diagnoses from 2011 to 2014, with an average R2 value of 0.99 between predicted versus actual cases, and average root-mean-square error (RMSE) of 108.75. CONCLUSIONS:Results indicate that Google Trends is a feasible tool to predict new cases of HIV at the state level. We discuss the implications of integrating visualization maps and tools based on these models into public health and HIV monitoring and surveillance

Sphalerons and the Electroweak Phase Transition in Models with Higher Scalar Representations

In this work we investigate the sphaleron solution in a $SU(2)\times U(1)_X$ gauge theory, which also encompasses the Standard Model, with higher scalar representation(s) ($J^{(i)},X^{(i)}$). We show that the field profiles describing the sphaleron in higher scalar multiplet, have similar trends like the doublet case with respect to the radial distance. We compute the sphaleron energy and find that it scales linearly with the vacuum expectation value of the scalar field and its slope depends on the representation. We also investigate the effect of $U(1)$ gauge field and find that it is small for the physical value of the mixing angle, $\theta_{W}$ and resembles the case for the doublet. For higher representations, we show that the criterion for strong first order phase transition, $v_{c}/T_{c}>\eta$, is relaxed with respect to the doublet case, i.e. $\eta<1$.Comment: 20 pages, 5 figures & 1 table, published versio

Public-Private-Partnerships for Primary Care in India, Pakistan and Bangladesh: Lessons on Pathways and Drivers

Formalised public-private-partnerships (PPPs) for primary care have proliferated in the mixed health systems of India, Pakistan and Bangladesh, managed and funded by the state. This perspective provides a process-based understanding of pathways adopted by home-grown PPPs and underlying drivers to identify lessons for advancement under Universal Health Coverage (UHC). PPPs have been deployed to respond to local primary care needs ranging from diagnostic screening, maternity services, management of government health centres, mobile clinics to urban primary care systems. Partnerships have evolved to include a diverse range of private partners and more purposeful arrangements, with increase in service volumes, innovations albeit less standardised quality of care. The pathway of PPP instigation, rollout and sustaining in South Asia is based on local starting points by sub-national governments, diffusion of practice across states, common interests and shared bureaucratic coalitions. Success drivers include administrative support beyond the health sector, simplified contractual and payment systems providing operational ease and decision space, and the use of relational management and digital monitoring for resolving issues. However, PPPs are constrained by either too little accountability or excessive accountability in contract design, trust deficits between private and government, and fire-walled PPP implementation creates disconnects from national primary care planning and regulation. Donor supported projectized PPP funding and accompanying rules of business makes PPPs implementation more cumbersome. We conclude that future attention must centrally focus on pathways and drivers to impactfully introduce, scale-up and sustain PPPs in South Asia. Emphasis must be on pathways that build on local simplified ideation, progressive adaptation and allowing contextual diversity under a larger UHC planning architecture, as opposed to centralised one-fit and heavily technocratic initiatives. Success drivers must feature in design of PPP initiatives. Furthermore, we contend that international donor assistance should shift from projectized support for PPPs to building public sector competencies for stewardship, private sector engagement skills as well as the more traditional performance management capacity

Role of Dopamine D2 Receptors in Human Reinforcement Learning

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, while loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically-determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.Neuropsychopharmacology accepted article peview online, 09 April 2014; doi:10.1038/npp.2014.84

The hypomethylating agent Decitabine causes a paradoxical increase in 5-hydroxymethylcytosine in human leukemia cells

The USFDA approved "epigenetic drug", Decitabine, exerts its effect by hypomethylating DNA, demonstrating the pivotal role aberrant genome-wide DNA methylation patterns play in cancer ontology. Using sensitive technologies in a cellular model of Acute Myeloid Leukemia, we demonstrate that while Decitabine reduces the global levels of 5-methylcytosine (5mC), it results in paradoxical increase of 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) levels. Hitherto, the only biological mechanism known to generate 5hmC, 5fC and 5caC, involving oxidation of 5mC by members of Ten-Eleven-Translocation (TET) dioxygenase family, was not observed to undergo any alteration during DAC treatment. Using a multi-compartmental model of DNA methylation, we show that partial selectivity of TET enzymes for hemi-methylated CpG dinucleotides could lead to such alterations in 5hmC content. Furthermore, we investigated the binding of TET1-catalytic domain (CD)-GFP to DNA by Fluorescent Correlation Spectroscopy in live cells and detected the gradual increase of the DNA bound fraction of TET1-CD-GFP after treatment with Decitabine. Our study provides novel insights on the therapeutic activity of DAC in the backdrop of the newly discovered derivatives of 5mC and suggests that 5hmC has the potential to serve as a biomarker for monitoring the clinical success of patients receiving DAC

Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition

Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling

Primary Postnatal Dorsal Root Ganglion Culture from Conventionally Slaughtered Calves

Neurological disorders in ruminants have an important impact on veterinary health, but very few host-specific in vitro models have been established to study diseases affecting the nervous system. Here we describe a primary neuronal dorsal root ganglia (DRG) culture derived from calves after being conventionally slaughtered for food consumption. The study focuses on the in vitro characterization of bovine DRG cell populations by immunofluorescence analysis. The effects of various growth factors on neuron viability, neurite outgrowth and arborisation were evaluated by morphological analysis. Bovine DRG neurons are able to survive for more than 4 weeks in culture. GF supplementation is not required for neuronal survival and neurite outgrowth. However, exogenously added growth factors promote neurite outgrowth. DRG cultures from regularly slaughtered calves represent a promising and sustainable host specific model for the investigation of pain and neurological diseases in bovines

Targeting cancer metabolism: a therapeutic window opens

Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.Burroughs Wellcome FundSmith Family FoundationStarr Cancer ConsortiumDamon Runyon Cancer Research FoundationNational Institutes of Health (U.S.

Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements

Cilia are multi-functional organelles that are constructed using intraflagellar transport (IFT) of cargo to and from their tip. It is widely held that the retrograde IFT motor, dynein-2, must be controlled in order to reach the ciliary tip and then unleashed to power the return journey. However, the mechanism is unknown. Here, we systematically define the mechanochemistry of human dynein-2 motors as monomers, dimers, and multi-motor assemblies with kinesin-II. Combining these data with insights from single-particle electron microscopy, we discover that dynein-2 dimers are intrinsically autoinhibited. Inhibition is mediated by trapping dynein-2’s mechanical “linker” and “stalk” domains within a novel motor-motor interface. We find that linker-mediated inhibition enables efficient transport of dynein-2 by kinesin-II in vitro. These results suggest a conserved mechanism for autoregulation among dimeric dyneins, which is exploited as a switch for dynein-2’s recycling activity during IFT

The effectiveness of a government-sponsored health protection scheme in reducing financial risks for the below-poverty-line population in Bangladesh

Data availability: The data underlying this article will be shared on reasonable request to the corresponding author.Supplementary data are available online at: https://academic.oup.com/heapol/article/39/3/281/7483763#supplementary-data .The Government of Bangladesh is piloting a non-contributory health protection scheme called Shasthyo Surokhsha Karmasuchi (SSK) to increase access to quality essential healthcare services for the below-poverty-line (BPL) population. This paper assesses the effect of the SSK scheme on out-of-pocket expenditure (OOPE) for healthcare, catastrophic health expenditure (CHE) and economic impoverishment of the enrolled population. A comparative cross-sectional study was conducted in Tangail District, where the SSK was implemented. From August 2019 to March 2020, a total of 2315 BPL households (HHs) (1170 intervention and 1145 comparison) that had at least one individual with inpatient care experience in the last 12 months were surveyed. A household is said to have incurred CHE if their OOPE for healthcare exceeds the total (or non-food) HH’s expenditure threshold. Multiple regression analysis was performed using OOPE, incidence of CHE and impoverishment as dependent variables and SSK membership status, actual BPL status and benefits use status as the main explanatory variables. Overall, the OOPE was significantly lower (P < 0.01) in the intervention areas (Bangladeshi Taka (BDT) 23 366) compared with the comparison areas (BDT 24 757). Regression analysis revealed that the OOPE, CHE incidence at threshold of 10% of total expenditure and 40% of non-food expenditure and impoverishment were 33% (P < 0.01), 46% (P < 0.01), 42% (P < 0.01) and 30% (P < 0.01) lower, respectively, in the intervention areas than in the comparison areas. Additionally, HHs that utilized SSK benefits experienced even lower OOPE by 92% (P < 0.01), CHE incidence at 10% and 40% threshold levels by 72% (P < 0.01) and 59% (P < 0.01), respectively, and impoverishment by 27% at 10% level of significance. These findings demonstrated the significant positive effect of the SSK in reducing financial burdens associated with healthcare utilization among the enrolled HHs. This illustrates the importance of the nationwide scaling up of the scheme in Bangladesh to reduce the undue financial risk of healthcare utilization for those in poverty.United States Agency for International Development (USAID) under the terms of its Research for Decision Makers activity, cooperative agreement no. AID-388-A-17-00006