Programmed death-1 (PD-1) defines a transient and dysfunctional oligoclonal T cell population in acute homeostatic proliferation

The host responds to lymphopenic environments by acute homeostatic proliferation, which is a cytokine- and endogenous peptide-driven expansion of lymphocytes that restores the numbers and diversity of T cells. It is unknown how these homeostatically proliferating (HP) cells are ultimately controlled. Using a system where lymphocytic choriomeningitis virus–immune C57BL/6 splenocytes were transferred into lymphopenic T cell–deficient hosts and allowed to reconstitute the environment, we defined the following three populations of T cells: slowly dividing Ly6C+ cells, which contained bona fide virus-specific memory cells, and more rapidly dividing Ly6C− cells segregating into programmed death (PD)-1+ and PD-1− fractions. The PD-1+ HP cell population, which peaked in frequency at day 21, was dysfunctional in that it failed to produce interferon γ or tumor necrosis factor α on T cell receptor (TCR) stimulation, had down-regulated expression of interleukin (IL)-7Rα, IL-15Rβ, and Bcl-2, and reacted with Annexin V, which is indicative of a preapoptotic state. The PD-1+ HP cells, in contrast to other HP cell fractions, displayed highly skewed TCR repertoires, which is indicative of oligoclonal expansion; these skewed repertoires and the PD-1+ population disappeared by day 70 from the host, presumably because of apoptosis. These results suggest that PD-1 may play a negative regulatory role to control rapidly proliferating and potentially pathogenic autoreactive CD8+ T cells during homeostatic reconstitution of lymphopenic environments

Children's Medicines in Tanzania: A National Survey of Administration Practices and Preferences.

The dearth of age-appropriate formulations of many medicines for children poses a major challenge to pediatric therapeutic practice, adherence, and health care delivery worldwide. We provide information on current administration practices of pediatric medicines and describe key stakeholder preferences for new formulation characteristics. We surveyed children aged 6-12 years, parents/caregivers over age 18 with children under age 12, and healthcare workers in 10 regions of Tanzania to determine current pediatric medicine prescription and administration practices as well as preferences for new formulations. Analyses were stratified by setting, pediatric age group, parent/caregiver education, and healthcare worker cadre. Complete data were available for 206 children, 202 parents/caregivers, and 202 healthcare workers. Swallowing oral solid dosage forms whole or crushing/dissolving them and mixing with water were the two most frequently reported methods of administration. Children frequently reported disliking medication taste, and many had vomited doses. Healthcare workers reported medicine availability most significantly influences prescribing practices. Most parents/caregivers and children prefer sweet-tasting medicine. Parents/caregivers and healthcare workers prefer oral liquid dosage forms for young children, and had similar thresholds for the maximum number of oral solid dosage forms children at different ages can take. There are many impediments to acceptable and accurate administration of medicines to children. Current practices are associated with poor tolerability and the potential for under- or over-dosing. Children, parents/caregivers, and healthcare workers in Tanzania have clear preferences for tastes and formulations, which should inform the development, manufacturing, and marketing of pediatric medications for resource-limited settings

Managing healthcare budgets in times of austerity: the role of program budgeting and marginal analysis

Given limited resources, priority setting or choice making will remain a reality at all levels of publicly funded healthcare across countries for many years to come. The pressures may well be even more acute as the impact of the economic crisis of 2008 continues to play out but, even as economies begin to turn around, resources within healthcare will be limited, thus some form of rationing will be required. Over the last few decades, research on healthcare priority setting has focused on methods of implementation as well as on the development of approaches related to fairness and legitimacy and on more technical aspects of decision making including the use of multi-criteria decision analysis. Recently, research has led to better understanding of evaluating priority setting activity including defining ‘success’ and articulating key elements for high performance. This body of research, however, often goes untapped by those charged with making challenging decisions and as such, in line with prevailing public sector incentives, decisions are often reliant on historical allocation patterns and/or political negotiation. These archaic and ineffective approaches not only lead to poor decisions in terms of value for money but further do not reflect basic ethical conditions that can lead to fairness in the decision-making process. The purpose of this paper is to outline a comprehensive approach to priority setting and resource allocation that has been used in different contexts across countries. This will provide decision makers with a single point of access for a basic understanding of relevant tools when faced with having to make difficult decisions about what healthcare services to fund and what not to fund. The paper also addresses several key issues related to priority setting including how health technology assessments can be used, how performance can be improved at a practical level, and what ongoing resource management practice should look like. In terms of future research, one of the most important areas of priority setting that needs further attention is how best to engage public members

Effect of novel technology-enabled multidimensional physical activity feedback in primary care patients at risk of chronic disease – the MIPACT study: A randomised controlled trial

© 2020 The Author(s). Background: Technological progress has enabled the provision of personalised feedback across multiple dimensions of physical activity that are important for health. Whether this multidimensional approach supports physical activity behaviour change has not yet been examined. Our objective was to examine the effectiveness of a novel digital system and app that provided multidimensional physical activity feedback combined with health trainer support in primary care patients identified as at risk of chronic disease. Methods: MIPACT was a parallel-group, randomised controlled trial that recruited patients at medium (≥10 and minimum clinically important difference, MCID). However, there was profound physical activity multidimensionality, and only a small proportion (5%) of patients had consistently low physical activity across all dimensions. Conclusion: In patients at risk of cardiovascular disease and/or type II diabetes, MIPACT did not increase mean physical activity. Using a sophisticated multidimensional digital approach revealed enormous heterogeneity in baseline physical activity in primary care patients, and practitioners may need to screen for low physical activity across dimensions rather than rely on disease-risk algorithms that are heavily influenced by age. Trial registration: This trial is registered with the ISRCTN registry (ISRCTN18008011; registration date 31 July 2013)

Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone

A warm Jet in a cold ocean

Unprecedented quantities of heat are entering the Pacific sector of the Arctic Ocean through Bering Strait, particularly during summer months. Though some heat is lost to the atmosphere during autumn cooling, a significant fraction of the incoming warm, salty water subducts (dives beneath) below a cooler fresher layer of near-surface water, subsequently extending hundreds of kilometers into the Beaufort Gyre. Upward turbulent mixing of these sub-surface pockets of heat is likely accelerating sea ice melt in the region. This Pacific-origin water brings both heat and unique biogeochemical properties, contributing to a changing Arctic ecosystem. However, our ability to understand or forecast the role of this incoming water mass has been hampered by lack of understanding of the physical processes controlling subduction and evolution of this this warm water. Crucially, the processes seen here occur at small horizontal scales not resolved by regional forecast models or climate simulations; new parameterizations must be developed that accurately represent the physics. Here we present novel high resolution observations showing the detailed process of subduction and initial evolution of warm Pacific-origin water in the southern Beaufort Gyre

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Multidimensional individualised Physical ACTivity (Mi-PACT) - a technology-enabled intervention to promote physical activity in primary care: Study protocol for a randomised controlled trial

© 2015 Peacock et al. Background: Low physical activity is a major public health problem. New cost-effective approaches that stimulate meaningful long-term changes in physical activity are required, especially within primary care settings. It is becoming clear that there are various dimensions to physical activity with independent health benefits. Advances in technology mean that it is now possible to generate multidimensional physical activity 'profiles' that provide a more complete representation of physical activity and offer a variety of options that can be tailored to the individual. Mi-PACT is a randomised controlled trial designed to examine whether personalised multidimensional physical activity feedback and self-monitoring alongside trainer-supportive sessions increases physical activity and improves health outcomes in at-risk men and women. Methods/Design: We aim to recruit 216 patients from within primary care aged 40 to 70years and at medium or high risk of cardiovascular disease and/or type II diabetes mellitus. Adopting an unequal allocation ratio (intervention: control) of 2:1, participants will be randomised to one of two groups, usual care or the intervention. The control group will receive usual care from their general practitioner (GP) and standardised messages about physical activity for health. The intervention group will receive physical activity monitors and access to a web-based platform for a 3-month period to enable self-monitoring and the provision of personalised feedback regarding the multidimensional nature of physical activity. In addition, this technology-enabled feedback will be discussed with participants on 5 occasions during supportive one-to-one coaching sessions across the 3-month intervention. The primary outcome measure is physical activity, which will be directly assessed using activity monitors for a 7-day period at baseline, post intervention and at 12months. Secondary measures (at these time-points) include weight loss, fat mass, and markers of metabolic control, motivation and well-being. Discussion: Results from this study will provide insight into the effects of integrated physical activity profiling and self-monitoring combined with in-person support on physical activity and health outcomes in patients at risk of future chronic disease. Trial registration:ISRCTN18008011Trial registration date: 31 July 201

Molecular Investigations of a Locally Acquired Case of Melioidosis in Southern AZ, USA

Melioidosis is caused by Burkholderia pseudomallei, a Gram-negative bacillus, primarily found in soils in Southeast Asia and northern Australia. A recent case of melioidosis in non-endemic Arizona was determined to be the result of locally acquired infection, as the patient had no travel history to endemic regions and no previous history of disease. Diagnosis of the case was confirmed through multiple microbiologic and molecular techniques. To enhance the epidemiological analysis, we conducted several molecular genotyping procedures, including multi-locus sequence typing, SNP-profiling, and whole genome sequence typing. Each technique has different molecular epidemiologic advantages, all of which provided evidence that the infecting strain was most similar to those found in Southeast Asia, possibly originating in, or around, Malaysia. Advancements in new typing technologies provide genotyping resolution not previously available to public health investigators, allowing for more accurate source identification