Assessing patient, physician, and practice characteristics predicting the use of low-value services.

OBJECTIVE: To examine characteristics of beneficiaries, physicians, and their practice sites associated with greater use of low-value services (LVS) using LVS measures that reflect current care practices. DATA SOURCES: This study was conducted in the context of a large, nationwide primary care redesign initiative (Comprehensive Primary Care Plus), using Medicare claims data in 2018. STUDY DESIGN: We examined beneficiary-level total counts of LVS based on the existing 31 claims-based measures updated by excluding three services provided with diminishing frequency to Medicare beneficiaries and by replacing these with more recently identified LVS. We estimated hierarchical linear models with an extensive list of beneficiary, physician, and practice site characteristics to examine the contribution of characteristics at each level in predicting greater use of LVS. We also examined the proportion of variation in LVS use attributable to the set of characteristics at each level. DATA COLLECTION/EXTRACTION METHODS: The study included 5,074,642 Medicare fee-for-service beneficiaries attributed to 32,406 primary care physicians in 11,009 primary care practice sites. PRINCIPAL FINDINGS: Patients with disabilities, end-stage renal disease, and those in regions with higher poverty rates receive 10 (standard error [SE] = 3.0), 80 (SE = 14.0), and 10 (SE = 1.0) more LVS per 1000 beneficiaries across all 31 measures combined than patients without such attributes, respectively. Greater physician comprehensiveness and an increase in the number of primary care practitioners at a practice were associated with 40 (SE = 20.0) and 20 (SE = 6.0) fewer LVS per 1000 beneficiaries, respectively. Yet, the explanatory variables we examined only account for 11 percent of the variation in LVS use, with most of the variation (87 percent) being due to unobserved differences at the beneficiary level. CONCLUSIONS: Unexplained residual variation, from underlying patient preferences and behavior of non-primary care providers, could be important determinants of LVS use.

Precipitation, vegetation productivity, and human impacts control home range size of elephants in dryland systems in northern Namibia.

Climatic variability, resource availability, and anthropogenic impacts heavily influence an animal's home range. This makes home range size an effective metric for understanding how variation in environmental factors alter the behavior and spatial distribution of animals. In this study, we estimated home range size of African elephants (Loxodonta africana) across four sites in Namibia, along a gradient of precipitation and human impact, and investigated how these gradients influence the home range size on regional and site scales. Additionally, we estimated the time individuals spent within protected area boundaries. The mean 50% autocorrelated kernel density estimate for home range was 2200 km2 [95% CI:1500-3100 km2]. Regionally, precipitation and vegetation were the strongest predictors of home range size, accounting for a combined 53% of observed variation. However, different environmental covariates explained home range variation at each site. Precipitation predicted most variation (up to 74%) in home range sizes (n = 66) in the drier western sites, while human impacts explained 71% of the variation in home range sizes (n = 10) in Namibia's portion of the Kavango-Zambezi Transfrontier Conservation Area. Elephants in all study areas maintained high fidelity to protected areas, spending an average of 85% of time tracked on protected lands. These results suggest that while most elephant space use in Namibia is driven by natural dynamics, some elephants are experiencing changes in space use due to human modification.

Author Correction: Economic value of protected areas via visitor mental health.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Economic value of protected areas via visitor mental health.

We evaluate methods to calculate the economic value of protected areas derived from the improved mental health of visitors. A conservative global estimate using quality-adjusted life years, a standard measure in health economics, is US$6 trillion p.a. This is an order of magnitude greater than the global value of protected area tourism, and two to three orders greater than global aggregate protected area management agency budgets. Future research should: refine this estimate using more precise methods; consider interactions between health and conservation policies and budgets at national scales; and examine links between personalities and protected area experiences at individual scale.

Differential Roles of the mTOR-STAT3 Signaling in Dermal γδ T Cell Effector Function in Skin Inflammation.

Dermal γδT cells play critical roles in skin homeostasis and inflammation. However, the underlying molecular mechanisms by which these cells are activated have not been fully understood. Here, we show that the mechanistic or mammalian target of rapamycin (mTOR) and STAT3 pathways are activated in dermal γδT cells in response to innate stimuli such as interleukin-1ß (IL-1ß) and IL-23. Although both mTOR complex 1 (mTORC1) and mTORC2 are essential for dermal γδT cell proliferation, mTORC2 deficiency leads to decreased dermal γδT17 cells. It appears that mitochondria-mediated oxidative phosphorylation is critical in this process. Notably, although the STAT3 pathway is critical for dermal Vγ4T17 effector function, it is not required for Vγ6T17 cells. Transcription factor IRF-4 activation promotes dermal γδT cell IL-17 production by linking IL-1ß and IL-23 signaling. The absence of mTORC2 in dermal γδT cells, but not STAT3, ameliorates skin inflammation. Taken together, our results demonstrate that the mTOR-STAT3 signaling differentially regulates dermal γδT cell effector function in skin inflammation.

A Critical Role of the IL-1ß-IL-1R Signaling Pathway in Skin Inflammation and Psoriasis Pathogenesis.

The IL-1 signaling pathway has been shown to play a critical role in the pathogenesis of chronic, autoinflammatory skin diseases such as psoriasis. However, the exact cellular and molecular mechanisms have not been fully understood. Here, we show that IL-1ß is significantly elevated in psoriatic lesional skin and imiquimod-treated mouse skin. In addition, IL-1R signaling appears to correlate with psoriasis disease progression and treatment response. IL-1 signaling in both dermal γδ T cells and other cells such as keratinocytes is essential to an IMQ-induced skin inflammation. IL-1ß induces dermal γδ T cell proliferation and IL-17 production in mice. In addition, IL-1ß stimulates keratinocytes to secrete chemokines that preferentially chemoattract peripheral CD27- CCR6+IL-17 capable of producing γδ T cells (γδT17). Further studies showed that endogenous IL-1ß secretion is regulated by skin commensals to maintain dermal γδT17 homeostasis in mice. Mouse skin associated with Corynebacterium species, bacteria enriched in human psoriatic lesional skin, has increased IL-1ß and dermal γδT17 cell expansion. Thus, the IL-1ß-IL-1R signaling pathway may contribute to skin inflammation and psoriasis pathogenesis via the direct regulation of dermal IL-17-producing cells and stimulation of keratinocytes for amplifying inflammatory cascade.

Patient and provider perspectives on shared decision making: a systematic review of the peer-reviewed literature.

For comparative effectiveness research to be effective, patients and providers must collaborate in shared decision making (SDM) to make evidence-based clinical decisions that align with patient preferences. We conducted a systematic review to examine patient and provider attitudes toward and engagement in SDM in the USA. Searches in PubMed and PsycINFO identified 1585 articles published between July 2006 and December 2016, of which 290 were screened in for coding and analysis. We found that patients and providers have generally positive attitudes toward SDM, but actual engagement in SDM behavior is lagging. Translation of positive attitudes into behavior could be achieved through policies that support key SDM processes of sharing evidence, considering patient preferences and discussing the relative advantages of different clinical options.

Innate γδT17 cells play a protective role in DSS-induced colitis via recruitment of Gr-1+CD11b+ myeloid suppressor cells.

Innate γδ T cells play critical roles in mucosal immunity such as regulating intestinal epithelial homeostasis. In addition, γδ T cells are significantly increased in the inflamed mucosa of patients with ulcerative colitis. However, γδ T cells are a heterogeneous population. IL-17-producing versus IFNγ-producing γδ T cells play differential roles in different disease settings. Therefore, dissecting the exact role of different subsets of γδ T cells in colitis is essential for understanding colitis immunopathogenesis. In the current study, we found that TCR δ-deficient mice had a more severe dextran sodium sulfate (DSS)-induced colitis that was reduced upon reconstitution of γδT17 cells but not IFNγ-producing γδ T cells. Immunophenotyping of the cellular infiltrate upon DSS-induced colitis showed a reduced infiltration of Gr-1+CD11b+ myeloid cells into the sites of inflammation in mice lacking γδT17 cells. Further experiments demonstrated that IL-17, IL-18, and chemokine CXCL5 were critical in Gr-1+CD11b+ myeloid cell recruitment. In vitro T cell suppressive assay indicated that this Gr-1+CD11b+ population was immunosuppressive. Depletion of Gr-1+CD11b+ myeloid cells resulted in an increase severity of DSS-induced colitis. Our study elucidates a new immune pathway involving γδT17-dependent recruitment of Gr-1+CD11b+ myeloid cells to the site of colitis inflammation important in the protection of colitis initiation and progression.

Microbiota-activated CD103+ DCs stemming from microbiota adaptation specifically drive γδT17 proliferation and activation.

BACKGROUND: IL-17-producing γδT cells (γδT17) promote autoinflammatory diseases and cancers. Yet, γδT17 peripheral regulation has not been thoroughly explored especially in the context of microbiota-host interaction. The potent antigen-presenting CD103+ dendritic cell (DC) is a key immune player in close contact with both γδT17 cells and microbiota. This study presents a novel cellular network among microbiota, CD103+ DCs, and γδT17 cells. METHODS: Immunophenotyping of IL-17r-/- mice and IL-17r-/- IRF8-/- mice were performed by ex vivo immunostaining and flow cytometric analysis. We observed striking microbiome differences in the oral cavity and gut of IL-17r-/- mice by sequencing 16S rRNA gene (v1-v3 region) and analyzed using QIIME 1.9.0 software platform. Principal coordinate analysis of unweighted UniFrac distance matrix showed differential clustering for WT and IL-17r-/- mice. RESULTS: We found drastic homeostatic expansion of γδT17 in all major tissues, most prominently in cervical lymph nodes (cLNs) with monoclonal expansion of Vγ6 γδT17 in IL-17r-/- mice. Ki-67 staining and in vitro CFSE assays showed cellular proliferation due to cell-to-cell contact stimulation with microbiota-activated CD103+ DCs. A newly developed double knockout mice model for IL-17r and CD103+ DCs (IL-17r-/-IRF8-/-) showed a specific reduction in Vγ6 γδT17. Vγ6 γδT17 expansion is inhibited in germ-free mice and antibiotic-treated specific pathogen-free (SPF) mice. Microbiota transfer using cohousing of IL-17r-/- mice with wildtype mice induces γδT17 expansion in the wildtype mice with increased activated CD103+ DCs in cLNs. However, microbiota transfer using fecal transplant through oral gavage to bypass the oral cavity showed no difference in colon or systemic γδT17 expansion. CONCLUSIONS: These findings reveal for the first time that γδT17 cells are regulated by microbiota dysbiosis through cell-to-cell contact with activated CD103+ DCs leading to drastic systemic, monoclonal expansion. Microbiota dysbiosis, as indicated by drastic bacterial population changes at the phylum and genus levels especially in the oral cavity, was discovered in mice lacking IL-17r. This network could be very important in regulating both microbiota and immune players. This critical regulatory pathway for γδT17 could play a major role in IL-17-driven inflammatory diseases and needs further investigation to determine specific targets for future therapeutic intervention.

Space Use and Movement of a Neotropical Top Predator: The Endangered Jaguar.

Accurately estimating home range and understanding movement behavior can provide important information on ecological processes. Advances in data collection and analysis have improved our ability to estimate home range and movement parameters, both of which have the potential to impact species conservation. Fitting continuous-time movement model to data and incorporating the autocorrelated kernel density estimator (AKDE), we investigated range residency of forty-four jaguars fit with GPS collars across five biomes in Brazil and Argentina. We assessed home range and movement parameters of range resident animals and compared AKDE estimates with kernel density estimates (KDE). We accounted for differential space use and movement among individuals, sex, region, and habitat quality. Thirty-three (80%) of collared jaguars were range resident. Home range estimates using AKDE were 1.02 to 4.80 times larger than KDE estimates that did not consider autocorrelation. Males exhibited larger home ranges, more directional movement paths, and a trend towards larger distances traveled per day. Jaguars with the largest home ranges occupied the Atlantic Forest, a biome with high levels of deforestation and high human population density. Our results fill a gap in the knowledge of the species' ecology with an aim towards better conservation of this endangered/critically endangered carnivore-the top predator in the Neotropics.

Uncovering periodic patterns of space use in animal tracking data with periodograms, including a new algorithm for the Lomb-Scargle periodogram and improved randomization tests.

BACKGROUND: Periodicity in activity level (rest/activity cycles) is ubiquitous in nature, but whether and how these periodicities translate into periodic patterns of space use by animals is much less documented. Here we introduce an analytical protocol based on the Lomb-Scargle periodogram (LSP) to facilitate exploration of animal tracking datasets for periodic patterns. The LSP accommodates missing observations and variation in the sampling intervals of the location time series. RESULTS: We describe a new, fast algorithm to compute the LSP. The gain in speed compared to other R implementations of the LSP makes it tractable to analyze long datasets (>10(6) records). We also give a detailed primer on periodicity analysis, focusing on the specificities of movement data. In particular, we warn against the risk of flawed inference when the sampling schedule creates artefactual periodicities and we introduce a new statistical test of periodicity that accommodates temporally autocorrelated background noise. Applying our LSP-based analytical protocol to tracking data from three species revealed that an ungulate exhibited periodicity in its movement speed but not in its locations, that a central place-foraging seabird tracked moon phase, and that the movements of a range-resident canid included a daily patrolling component that was initially masked by the stochasticity of the movements. CONCLUSION: The new, fast algorithm tailored for movement data analysis and now available in the R-package ctmm makes the LSP a convenient exploratory tool to detect periodic patterns in animal movement data.

Maximum-entropy description of animal movement.

We introduce a class of maximum-entropy states that naturally includes within it all of the major continuous-time stochastic processes that have been applied to animal movement, including Brownian motion, Ornstein-Uhlenbeck motion, integrated Ornstein-Uhlenbeck motion, a recently discovered hybrid of the previous models, and a new model that describes central-place foraging. We are also able to predict a further hierarchy of new models that will emerge as data quality improves to better resolve the underlying continuity of animal movement. Finally, we also show that Langevin equations must obey a fluctuation-dissipation theorem to generate processes that fall from this class of maximum-entropy distributions when the constraints are purely kinematic.

How far to go? Determinants of migration distance in land mammals.

Animal migration is a global phenomenon, but few studies have examined the substantial within- and between-species variation in migration distances. We built a global database of 94 land migrations of large mammalian herbivore populations ranging from 10 to 1638 km. We examined how resource availability, spatial scale of resource variability and body size affect migration distance among populations. Resource availability measured as normalised difference vegetation index had a strong negative effect, predicting a tenfold difference in migration distances between low- and high-resource areas and explaining 23% of the variation in migration distances. We found a weak, positive effect of the spatial scale of resource variability but no effect of body size. Resource-poor environments are known to increase the size of mammalian home ranges and territories. Here, we demonstrate that for migratory populations as well, animals living in resource-poor environments travel farther to fulfil their resource needs.

Differential developmental requirement and peripheral regulation for dermal Vγ4 and Vγ6T17 cells in health and inflammation.

Dermal IL-17-producing γδT cells have a critical role in skin inflammation. However, their development and peripheral regulation have not been fully elucidated. Here we demonstrate that dermal γδT cells develop from the embryonic thymus and undergo homeostatic proliferation after birth with diversified TCR repertoire. Vγ6T cells are bona fide resident, but precursors of dermal Vγ4T cells may require extrathymic environment for imprinting skin-homing properties. Thymic Vγ6T cells are more competitive than Vγ4 for dermal γδT cell reconstitution and TCRδ(-/-) mice reconstituted with Vγ6 develop psoriasis-like inflammation after IMQ-application. Although both IL-23 and IL-1ß promote Vγ4 and Vγ6 proliferation, Vγ4 are the main source of IL-17 production that requires IL-1 signalling. Mice with deficiency of IL-1RI signalling have significantly decreased skin inflammation. These studies reveal a differential developmental requirement and peripheral regulation for dermal Vγ6 and Vγ4 γδT cells, implying a new mechanism that may be involved in skin inflammation.

From fine-scale foraging to home ranges: a semivariance approach to identifying movement modes across spatiotemporal scales.

Understanding animal movement is a key challenge in ecology and conservation biology. Relocation data often represent a complex mixture of different movement behaviors, and reliably decomposing this mix into its component parts is an unresolved problem in movement ecology. Traditional approaches, such as composite random walk models, require that the timescales characterizing the movement are all similar to the usually arbitrary data-sampling rate. Movement behaviors such as long-distance searching and fine-scale foraging, however, are often intermixed but operate on vastly different spatial and temporal scales. An approach that integrates the full sweep of movement behaviors across scales is currently lacking. Here we show how the semivariance function (SVF) of a stochastic movement process can both identify multiple movement modes and solve the sampling rate problem. We express a broad range of continuous-space, continuous-time stochastic movement models in terms of their SVFs, connect them to relocation data via variogram regression, and compare them using standard model selection techniques. We illustrate our approach using Mongolian gazelle relocation data and show that gazelle movement is characterized by ballistic foraging movements on a 6-h timescale, fast diffusive searching with a 10-week timescale, and asymptotic diffusion over longer timescales.

Human polymorphonuclear neutrophils specifically recognize and kill cancerous cells.

Polymorphonuclear neutrophils (PMNs), the main effectors of the innate immune system, have rarely been considered as an anticancer therapeutic tool. However, recent investigations using animal models and preliminary clinical studies have highlighted the potential antitumor efficacy of PMNs. In the current study, we find that PMNs from some healthy donors naturally have potent cancer-killing activity against 4 different human cancer cell lines. The killing activity appears to be cancer cell-specific since PMNs did not kill primary normal epithelial cells or an immortalized breast epithelial cell line. Transfecting the immortalized mammary cells with plasmids expressing activated forms of the rat sarcoma viral oncogene homolog (Ras) and teratocarcinoma oncogene 21 (TC21) oncogenes was sufficient to provoke aggressive attack by PMNs. However, transfection with activated Ras-related C3 botulinum toxin substrate (Rac1) was ineffective, suggesting specificity in PMN-targeting of neoplastic cells. Furthermore, PMNs from lung cancer patients were also found to exhibit relatively poor cancer-killing activity compared to the cytolytic activity of the average healthy donor. Taken together, our results suggest that PMN-based treatment regimens may represent a paradigm shift in cancer immunotherapy that may be easily introduced into the clinic to benefit a subset of patients with PMN-vulnerable tumors.

Dermal γδ T cells--a new player in the pathogenesis of psoriasis.

Psoriasis is considered as a T-cell driven chronic inflammatory skin disease. Both T helper (Th) 1 and Th17 cells have been demonstrated to participate in psoriasis pathogenesis. Recently, a new subset of γδ T cells residing in the dermis has been identified. Dermal γδ T cells are the major source of interleukin (IL)-17 in the skin upon IL-23 stimulation. More importantly, they are also shown to be involved in psoriasis development. In this review, we focus on this newly discovered cell population both in mice and human, particularly discussing its role in the pathogenesis of psoriasis. The biologic therapeutics targeting dermal γδ T cell and its related molecules in the treatment of psoriasis are also included.