Disentangling Temporal and Rate Codes in the Primate Somatosensory Cortex.

Millisecond-scale temporal spiking patterns encode sensory information in the periphery, but their role in the neocortex remains controversial. The sense of touch provides a window into temporal coding because tactile neurons often exhibit precise, repeatable, and informative temporal spiking patterns. In the somatosensory cortex (S1), responses to skin vibrations exhibit phase locking that faithfully carries information about vibratory frequency. However, the respective roles of spike timing and rate in frequency coding are confounded because vibratory frequency shapes both the timing and rates of responses. To disentangle the contributions of these two neural features, we measured S1 responses as rhesus macaques performed frequency discrimination tasks in which differences in frequency were accompanied by orthogonal variations in amplitude. We assessed the degree to which the strength and timing of responses could account for animal performance. First, we showed that animals can discriminate frequency, but their performance is biased by amplitude variations. Second, rate-based representations of frequency are susceptible to changes in amplitude but in ways that are inconsistent with the animals' behavioral biases, calling into question a rate-based neural code for frequency. In contrast, timing-based representations are highly informative about frequency but impervious to changes in amplitude, which is also inconsistent with the animals' behavior. We account for the animals' behavior with a model wherein frequency coding relies on a temporal code, but frequency judgments are biased by perceived magnitude. We conclude that information about vibratory frequency is not encoded in S1 firing rates but primarily in temporal patterning on millisecond timescales.

Effects of CB1R inverse agonist, INV-202, in patients with features of metabolic syndrome. A randomized, placebo-controlled, double-blind phase 1b study.

AIMS: To evaluate the clinical safety, tolerability, and pharmacokinetic and pharmacodynamic profile of the novel cannabinoid receptor-1 (CB1R) inverse agonist, INV-202, in adults with features of metabolic syndrome. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, placebo-controlled, 28-day repeat-dose (INV-202 [25 mg] or placebo, once-daily oral tablet), parallel-group study in 37 participants aged 18 to 65 years (46% female, mean age 55 years, glycated haemoglobin 5.7% [39 mmol/mol], body mass index [BMI] 38.1 kg/m2 ) with features of metabolic syndrome and glucose intolerance. An oral glucose tolerance test (OGTT) was performed at baseline and at the end of the study. Lipid profiles, weight, waist circumference and biomarkers were assessed weekly. Statistical comparisons were performed post hoc. RESULTS: INV-202 was well tolerated with no serious or severe treatment-emergent adverse events; the most common events related to known effects of CB1R blockade in the gastrointestinal tract. INV-202 produced a significant mean weight loss of 3.5 kg (3.3% compared with placebo participants who gained a mean 0.6 kg [0.5%]). INV-202 also exhibited significant reductions in waist circumference and BMI (P ≤ 0.03). There was no significant difference in OGTT 0- to 3-hour area under the curve for INV-202 versus placebo: least squares mean 29.38 versus 30.25 h*mmol/L, with an INV-202: placebo ratio of 97.1% (95% confidence interval 90.2, 105.6; P = 0.43). CONCLUSIONS: INV-202 was well tolerated, producing a signal for rapid weight loss with improvements in other metabolic syndrome markers in this population. These findings support further exploration and long-term assessment of cardiometabolic effects.

Ventral pallidum regulates the default mode network, controlling transitions between internally and externally guided behavior.

Daily life requires transitions between performance of well-practiced, automatized behaviors reliant upon internalized representations and behaviors requiring external focus. Such transitions involve differential activation of the default mode network (DMN), a group of brain areas associated with inward focus. We asked how optogenetic modulation of the ventral pallidum (VP), a subcortical DMN node, impacts task switching between internally to externally guided lever-pressing behavior in the rat. Excitation of the VP dramatically compromised acquisition of an auditory discrimination task, trapping animals in a DMN state of automatized internally focused behavior and impairing their ability to direct attention to external sensory stimuli. VP inhibition, on the other hand, facilitated task acquisition, expediting escape from the DMN brain state, thereby allowing rats to incorporate the contingency changes associated with the auditory stimuli. We suggest that VP, instant by instant, regulates the DMN and plays a deterministic role in transitions between internally and externally guided behaviors.

Amazonian birds in more dynamic habitats have less population genetic structure and higher gene flow.

Understanding the factors that govern variation in genetic structure across species is key to the study of speciation and population genetics. Genetic structure has been linked to several aspects of life history, such as foraging strategy, habitat association, migration distance, and dispersal ability, all of which might influence dispersal and gene flow. Comparative studies of population genetic data from species with differing life histories provide opportunities to tease apart the role of dispersal in shaping gene flow and population genetic structure. Here, we examine population genetic data from sets of bird species specialized on a series of Amazonian habitat types hypothesized to filter for species with dramatically different dispersal abilities: stable upland forest, dynamic floodplain forest, and highly dynamic riverine islands. Using genome-wide markers, we show that habitat type has a significant effect on population genetic structure, with species in upland forest, floodplain forest, and riverine islands exhibiting progressively lower levels of structure. Although morphological traits used as proxies for individual-level dispersal ability did not explain this pattern, population genetic measures of gene flow are elevated in species from more dynamic riverine habitats. Our results suggest that the habitat in which a species occurs drives the degree of population genetic structuring via its impact on long-term fluctuations in levels of gene flow, with species in highly dynamic habitats having particularly elevated gene flow. These differences in genetic variation across taxa specialized in distinct habitats may lead to disparate responses to environmental change or habitat-specific diversification dynamics over evolutionary time scales.

A compreensão dos fatores que governam a variação da estrutura genética entre as espécies é fundamental para o estudo da especiação e da genética das populações. A estrutura genética tem sido ligada a vários aspectos da história da vida, tais como estratégia de forrageio, associação ao habitat, distância de migração e capacidade de dispersão, os quais poderiam influenciar a dispersão e o fluxo gênico. Estudos comparativos usando espécies que diferem nas suas histórias de vida oferecem uma oportunidade para desvendar o papel da dispersão no estabelecimento do fluxo gênico e da estrutura genética da população. Aqui examinamos dados genéticos populacionais de diversas espécies de aves com diferentes capacidades de dispersão especializadas em três habitats amazônicos, incluindo florestas de terra-firme, florestas de várzea e ilhas fluviais, cujos ambientes ripários são altamente dinâmicos. Utilizando dados genômicos que incluem milhares de loci, mostramos que o tipo de habitat tem um efeito significativo na estruturação genética das populações; espécies de florestas de terra-firme, florestas de várzea e ilhas fluviais exibem níveis de estruturação progressivamente menores. Embora os traços morfológicos frequentemente usados como indicadores da capacidade de dispersão a nível individual não expliquem este padrão, as medidas genéticas populacionais de fluxo gênico são altas em espécies associadas a habitats ribeirinhos mais dinâmicos. Nossos resultados sugerem que o habitat no qual uma espécie é encontrada determina o grau de estruturação genética da população através de seu impacto nas flutuações de longo prazo do fluxo gênico, com espécies em habitats altamente dinâmicos tendo um fluxo gênico particularmente alto. As diferenças na variação genética dos táxons especializados em diferentes habitats podem resultar em respostas díspares às mesmas mudanças ambientais, ou dinâmicas de diversificação específicas a um determinado habitat ao longo de escalas de tempo evolutivas.

Comprender los factores que rigen la variación de la estructura genética entre especies es clave para el estudio de la especiación y la genética de poblaciones. La estructura genética se ha relacionado con varios aspectos de la historia vital, como la estrategia de búsqueda de alimento, la asociación de hábitats, la distancia de migración y la capacidad de dispersión, factores todos ellos que podrían influir en la dispersión y el flujo genético. Los estudios comparativos de datos genéticos poblacionales de especies con historias vitales diferentes ofrecen la oportunidad de desentrañar el papel de la dispersión en la conformación del flujo genético y la estructura genética poblacional. En este trabajo examinamos los datos genéticos de poblaciones de especies de aves especializadas en una serie de hábitats amazónicos que, según la hipótesis, filtran especies con capacidades de dispersión radicalmente diferentes: bosques estables de tierras altas, bosques dinámicos de llanuras aluviales e islas fluviales altamente dinámicas. Utilizando marcadores genómicos, demostramos que el tipo de hábitat tiene un efecto significativo en la estructura genética de la población, y que las especies de los bosques de tierras altas, los bosques inundables y las islas fluviales presentan niveles de estructura progresivamente más bajos. Aunque los rasgos morfológicos utilizados como indicadores de la capacidad de dispersión individual no explican este patrón, las medidas genéticas poblacionales del flujo genético son más elevadas en las especies de hábitats fluviales más dinámicos. Nuestros resultados sugieren que el hábitat en el que se encuentra una especie determina el grado de estructuración genética de la población a través de su impacto en las fluctuaciones a largo plazo de los niveles de flujo genético, siendo las especies de hábitats muy dinámicos las que presentan un flujo genético particularmente elevado. Estas diferencias en la variación genética entre taxones especializados en hábitats distintos pueden dar lugar a respuestas dispares al cambio ambiental o a dinámicas de diversificación específicas del hbitat a lo largo de escalas temporales evolutivas.

Comprehensive review of the use of hydrogel spacers prior to radiation therapy for prostate cancer.

OBJECTIVES: To provide a comprehensive narrative review of the published data on the impact of hydrogel spacers on rectal dosimetry and toxicity and to outline the practicalities of inserting hydrogel spacers. RESULTS: A growing body of evidence suggests that the administration of hydrogel spacers is safe and is associated with limited peri-operative morbidity. The impact on rectal dosimetry has been clearly established and use of hydrogel spacers is associated with reduced rectal morbidity. These results have been corroborated by several Phase II and III clinical trials and subsequent meta-analysis. There are several areas for future research, including the role of hydrogel spacers in prostate stereotactic beam radiotherapy and post-radiotherapy local recurrence. CONCLUSIONS: Hydrogel spacers provide a low-morbidity method to potential reduce rectal toxicity after radiation therapy in men with prostate cancer. Data outlining sexual function and oncological outcomes are limited to date. Future studies, currently being conducted, may provide further clarification of the role of hydrogel spacers in prostate cancer management.

The utility of machine learning algorithms for the prediction of patient-reported outcome measures following primary hip and knee total joint arthroplasty.

BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly used as quality benchmark in total hip and knee arthroplasty (THA; TKA) due to bundled payment systems that aim to provide a patient-centered, value-based treatment approach. However, there is a paucity of predictive tools for postoperative PROMs. Therefore, this study aimed to develop and validate machine learning models for the prediction of numerous patient-reported outcome measures following primary hip and knee total joint arthroplasty. METHODS: A total of 4526 consecutive patients (2137 THA; 2389 TKA) who underwent primary hip and knee total joint arthroplasty and completed both pre- and postoperative PROM scores was evaluated in this study. The following PROM scores were included for analysis: HOOS-PS, KOOS-PS, Physical Function SF10A, PROMIS SF Physical and PROMIS SF Mental. Patient charts were manually reviewed to identify patient demographics and surgical variables associated with postoperative PROM scores. Four machine learning algorithms were developed to predict postoperative PROMs following hip and knee total joint arthroplasty. Model assessment was performed through discrimination, calibration and decision curve analysis. RESULTS: The factors most significantly associated with the prediction of postoperative PROMs include preoperative PROM scores, Charlson Comorbidity Index, American Society of Anaesthesiology score, insurance status, age, length of hospital stay, body mass index and ethnicity. The four machine learning models all achieved excellent performance across discrimination (AUC > 0.83), calibration and decision curve analysis. CONCLUSION: This study developed machine learning models for the prediction of patient-reported outcome measures at 1-year following primary hip and knee total joint arthroplasty. The study findings show excellent performance on discrimination, calibration and decision curve analysis for all four machine learning models, highlighting the potential of these models in clinical practice to inform patients prior to surgery regarding their expectations of postoperative functional outcomes following primary hip and knee total joint arthroplasty. LEVEL OF EVIDENCE: Level III, case control retrospective analysis.

A molecular and ecological study of Macracanthorhynchus ingens (von Linstow, 1879) (Acanthocephala: Archiacanthocephala), in its paratenic and definitive hosts in southeastern Mexico and the Eastern USA.

The acanthocephalan Macracanthorhynchus ingens (von Linstow 1879) (Acanthocephala: Archiacanthocephala) is a parasite that infects the gut of carnivores (racoons, coyotes, wolves, foxes, badgers, skunks, opossum, mink and bears) as an adult and the body cavity of lizards, snakes, and frogs as a cystacanth in the Americas. In this study, adults and cystacanths of M. ingens from southeastern Mexico and southern Florida, USA, were identified morphologically by having a cylindrical proboscis armed with 6 rows of hooks each with 6 hooks. Hologenophores were used to sequence the small (SSU) and large (LSU) subunits of ribosomal DNA and cytochrome c oxidase subunit 1 (cox 1) from mitochondrial DNA. Phylogenetic analysis of the new SSU and LSU sequences of M. ingens placed them in a clade with other sequences available in GenBank identified as M. ingens. The cox 1 tree showed that the nine new sequences and six previously published sequences of M. ingens from the USA form a clade with other sequences previously identified as M. ingens from GenBank. The intraspecific genetic divergence among isolates from the Americas ranged from 0 to 2%, and in combination with the phylogenetic trees confirmed that the isolates belonged to the same species. The cox 1 haplotype network inferred with 15 sequences revealed 10 haplotypes separated from each other by a few substitutions. Rio Grande Leopard Frogs and Vaillant´s Frogs harbored cystacanths with low prevalence, 28% and 37% respectively, in Mexico. Brown Basilisks, an invasive lizard in Florida, USA, had high values of prevalence, 92% and 93% in males and females, respectively. Females harbored more cystacanths than males (0-39 vs 0-21) for unknown reasons that may, however, be related to ecological differences.

Earth history and the passerine superradiation.

Avian diversification has been influenced by global climate change, plate tectonic movements, and mass extinction events. However, the impact of these factors on the diversification of the hyperdiverse perching birds (passerines) is unclear because family level relationships are unresolved and the timing of splitting events among lineages is uncertain. We analyzed DNA data from 4,060 nuclear loci and 137 passerine families using concatenation and coalescent approaches to infer a comprehensive phylogenetic hypothesis that clarifies relationships among all passerine families. Then, we calibrated this phylogeny using 13 fossils to examine the effects of different events in Earth history on the timing and rate of passerine diversification. Our analyses reconcile passerine diversification with the fossil and geological records; suggest that passerines originated on the Australian landmass ∼47 Ma; and show that subsequent dispersal and diversification of passerines was affected by a number of climatological and geological events, such as Oligocene glaciation and inundation of the New Zealand landmass. Although passerine diversification rates fluctuated throughout the Cenozoic, we find no link between the rate of passerine diversification and Cenozoic global temperature, and our analyses show that the increases in passerine diversification rate we observe are disconnected from the colonization of new continents. Taken together, these results suggest more complex mechanisms than temperature change or ecological opportunity have controlled macroscale patterns of passerine speciation.

Neural network models accurately predict discharge disposition after revision total knee arthroplasty?

PURPOSE: Based on the rising incidence of revision total knee arthroplasty (TKA), bundled payment models may be applied to revision TKA in the near future. Facility discharge represents a significant cost factor for those bundled payment models; however, accurately predicting discharge disposition remains a clinical challenge. The purpose of this study was to develop and validate artificial intelligence algorithms to predict discharge disposition following revision total knee arthroplasty. METHODS: A retrospective review of electronic patient records was conducted to identify patients who underwent revision total knee arthroplasty. Discharge disposition was defined as either home discharge or non-home discharge, which included rehabilitation and skilled nursing facilities. Four artificial intelligence algorithms were developed to predict this outcome and were assessed by discrimination, calibration and decision curve analysis. RESULTS: A total of 2228 patients underwent revision TKA, of which 1405 patients (63.1%) were discharged home, whereas 823 patients (36.9%) were discharged to a non-home facility. The strongest predictors for non-home discharge following revision TKA were American Society of Anesthesiologist (ASA) score, Medicare insurance type and revision surgery for peri-prosthetic joint infection, non-white ethnicity and social status (living alone). The best performing artificial intelligence algorithm was the neural network model which achieved excellent performance across discrimination (AUC = 0.87), calibration and decision curve analysis. CONCLUSION: This study developed four artificial intelligence algorithms for the prediction of non-home discharge disposition for patients following revision total knee arthroplasty. The study findings show excellent performance on discrimination, calibration and decision curve analysis for all four candidate algorithms. Therefore, these models have the potential to guide preoperative patient counselling and improve the value (clinical and functional outcomes divided by costs) of revision total knee arthroplasty patients. LEVEL OF EVIDENCE: IV.

Machine learning algorithms predict extended postoperative opioid use in primary total knee arthroplasty.

PURPOSE: Adequate postoperative pain control following total knee arthroplasty (TKA) is required to achieve optimal patient recovery. However, the postoperative recovery may lead to an unnaturally extended opioid use, which has been associated with adverse outcomes. This study hypothesizes that machine learning models can accurately predict extended opioid use following primary TKA. METHODS: A total of 8873 consecutive patients that underwent primary TKA were evaluated, including 643 patients (7.2%) with extended postoperative opioid use (> 90 days). Electronic patient records were manually reviewed to identify patient demographics and surgical variables associated with prolonged postoperative opioid use. Five machine learning algorithms were developed, encompassing the breadth of state-of-the-art machine learning algorithms available in the literature, to predict extended opioid use following primary TKA, and these models were assessed by discrimination, calibration, and decision curve analysis. RESULTS: The strongest predictors for prolonged opioid prescription following primary TKA were preoperative opioid duration (100% importance; p < 0.01), drug abuse (54% importance; p < 0.01), and depression (47% importance; p < 0.01). The five machine learning models all achieved excellent performance across discrimination (AUC > 0.83), calibration, and decision curve analysis. Higher net benefits for all machine learning models were demonstrated, when compared to the default strategies of changing management for all patients or no patients. CONCLUSION: The study findings show excellent model performance for the prediction of extended postoperative opioid use following primary total knee arthroplasty, highlighting the potential of these models to assist in preoperatively identifying at risk patients, and allowing the implementation of individualized peri-operative counselling and pain management strategies to mitigate complications associated with prolonged opioid use. LEVEL OF EVIDENCE: IV.

Outcome of revision surgery for adverse local tissue reactions in patients with recalled total hip arthroplasty.

INTRODUCTION: Recalls of total hip arthroplasty (THA) implants, including metal-on-metal (MoM) THA and dual taper stems, due to increased risk of adverse local tissue reaction (ALTR), represent a challenge for both surgeons and patients. This study aims to analyze the revision surgery outcomes for ALTR in patients with recalled THA implants. METHODS: A total of 118 consecutive patients who underwent revision surgery due to ALTR with recalled THA were analyzed. Sub-group analysis was performed for recalled MoM THAs, head-neck modular stems, and dual taper neck-stems. RESULTS: At a mean follow-up of 6.6 years, the complication and reoperation rates of the recalled THAs were 32.2% and 25.4% respectively. The most common post-revision complication was dislocation (16%). Revision of modular taper corrosion THA and high-grade intraoperative tissue damage were risk factors associated with post-revision complications. CONCLUSION: This study reports high complication and reoperation rates of recalled THAs at mid-term follow-up. The high revision surgery complication rates in both groups suggest the importance of a systematic evaluation of all THA patients with at-risk implants. LEVEL OF EVIDENCE: Level III, case control retrospective analysis.

The demography of extinction in eastern North American birds.

Species are being lost at an unprecedented rate during the Anthropocene. Progress has been made in clarifying how species traits influence their propensity to go extinct, but the role historical demography plays in species loss or persistence is unclear. In eastern North America, five charismatic landbirds went extinct last century, and the causes of their extinctions have been heavily debated. Although these extinctions are most often attributed to post-colonial human activity, other factors such as declining ancestral populations prior to European colonization could have made these species particularly susceptible. We used population genomic data from these extinct birds and compared them with those from four codistributed extant species. We found extinct species harboured lower genetic diversity and effective population sizes than extant species, but both extinct and non-extinct birds had similar demographic histories of population expansion. These demographic patterns are consistent with population size changes associated with glacial-interglacial cycles. The lack of support for overall population declines during the Pleistocene corroborates the view that, although species that went extinct may have been vulnerable due to low diversity or small population size, their disappearance was driven by human activities in the Anthropocene.

Comparison of Sampling Methods for International Normalized Ratio Monitoring in Haemodialysis Patients (INRHaemo Study).

BACKGROUND: Haemorrhagic and thrombotic complications are common in dialysis patients on warfarin; thus, accurate international normalized ratio (INR) monitoring is critical. For expediency and patient comfort, blood sampling from the haemodialysis access or circuit is commonly performed. Point-of-care (POC) INR machines allow both peripheral vein preservation and rapid results, yet are not validated in the haemodialysis population. METHODS: A prospective cohort study in haemodialysis patients taking warfarin was undertaken. Three paired samples were drawn over a single session: peripheral blood INR, POC INR, and dialysis INR. Agreement using Bland-Altman analysis and correlation coefficients between the peripheral blood INR, haemodialysis INR, and POC INR were calculated. Inappropriate dosing decisions based on haemodialysis or POC INR were quantified. RESULTS: Amongst 34 patients, agreement between the dialysis INR and peripheral blood INR was high, with the haemodialysis INR differing from the peripheral INR by <±0.2, 85.2% of the time. Correlation between the 2 methods was high (r = 0.914; p < 0.001). POC INR differed from peripheral INR values by <±0.2, 67.6% of the time, with less agreement at higher INR values. Dosing decisions were incongruent between the dialysis and peripheral INR in 6%, whilst the POC and peripheral INR disagreed in 26%. CONCLUSIONS: There was good agreement and correlation between the peripheral blood, haemodialysis access/circuit, and POC INR values. POC INR was less reliable at higher values, and dosing decisions differed from the peripheral INR in a quarter of cases.

The Political Economy of Health: Revisiting Its Marxian Origins to Address 21st-Century Health Inequalities.

The "political economy of health" is concerned with how political and economic domains interact and shape individual and population health outcomes. However, the term is variously defined in the public health, medical, and social science literatures.This could result in confusion about the term and its associated tradition, thereby constituting a barrier to its application in public health research and practice.To address these issues, I survey the political economy of health tradition, clarify its specifically Marxian theoretical legacy, and discuss its relevance to understanding and addressing public health issues. I conclude by discussing the benefits of employing critical theories of race and racism with Marxian political economy to better understand the roles of class exploitation and racial oppression in epidemiological patterning.

Impact of Implementing an Academic Detailing Program on Opioid-Benzodiazepine Co-Prescribing Trends at the U.S. Department of Veterans Affairs.

OBJECTIVES: To assess the process and outcomes of academic detailing to enhance the Opioid Safety Initiative and the Psychotropic Drug Safety Initiative to reduce co-prescribing of opioid-benzodiazepine combinations in veterans. METHODS: A retrospective cohort design was conducted to evaluate the impact of implementing an academic detailing program on opioid-benzodiazepine co-prescribing between October 2014 through March 2019 at the U.S. Department of Veterans Affairs (VA). The primary outcome was the monthly prevalence of veterans (number per 1,000 population) who were co-prescribed opioid-benzodiazepine combination. Process measure was evaluated using implementation reach (proportion of providers who received academic detailing). Station-level analysis was performed using a linear fixed effects regression model to evaluate the rate of change in the prevalence of veterans co-prescribed opioid-benzodiazepine. RESULTS: Altogether 130 VA stations was included for analysis; 119 stations implemented opioid-related or benzodiazepine-related academic detailing, and 11 stations did not. Stations that had implemented academic detailing had a 33% greater monthly reduction on the opioid-benzodiazepine co-prescribing prevalence compared to stations that did not implement academic detailing (P = .036). In the linear fixed effects regression model, stations that were expected to have 100% of providers exposed to academic detailing were statistically associated with a greater decrease in the monthly prevalence of Veterans co-prescribed opioid-benzodiazepine by 4.9 veterans per 1,000 population (P < .001) compared to stations with 0% of providers exposed to academic detailing. CONCLUSIONS: Stations that implemented academic detailing and had a higher proportion of providers who were exposed to opioid- or benzodiazepine-related academic detailing had a significant decrease in the monthly prevalence of Veterans co-prescribed opioid-benzodiazepine combinations.

Basal forebrain contributes to default mode network regulation.

The default mode network (DMN) is a collection of cortical brain regions that is active during states of rest or quiet wakefulness in humans and other mammalian species. A pertinent characteristic of the DMN is a suppression of local field potential gamma activity during cognitive task performance as well as during engagement with external sensory stimuli. Conversely, gamma activity is elevated in the DMN during rest. Here, we document that the rat basal forebrain (BF) exhibits the same pattern of responses, namely pronounced gamma oscillations during quiet wakefulness in the home cage and suppression of this activity during active exploration of an unfamiliar environment. We show that gamma oscillations are localized to the BF and that gamma-band activity in the BF has a directional influence on a hub of the rat DMN, the anterior cingulate cortex, during DMN-dominated brain states. The BF is well known as an ascending, activating, neuromodulatory system involved in wake-sleep regulation, memory formation, and regulation of sensory information processing. Our findings suggest a hitherto undocumented role of the BF as a subcortical node of the DMN, which we speculate may be important for switching between internally and externally directed brain states. We discuss potential BF projection circuits that could underlie its role in DMN regulation and highlight that certain BF nuclei may provide potential target regions for up- or down-regulation of DMN activity that might prove useful for treatment of DMN dysfunction in conditions such as epilepsy or major depressive disorder.

Synthesis and Antibody Binding Studies of Schistosome-Derived Oligo-α-(1-2)-l-Fucosides.

Schistosomiasis is caused by blood-dwelling parasitic trematodes of the genus Schistosoma and is classified by the WHO as the second most socioeconomically devastating parasitic disease, second only to malaria. Schistosoma expresses a complex array of glycans as part of glycoproteins and glycolipids that can be targeted by both the adaptive and the innate part of the immune system. Some of these glycans can be used for diagnostic purposes. A subgroup of schistosome glycans is decorated with unique α-(1-2)-fucosides and it has been shown that these often multi-fucosylated fragments are prime targets for antibodies generated during infection. Since these α-(1-2)-fucosides cannot be obtained in sufficient purity from biological sources, we set out to develop an effective route of synthesis towards α-(1-2)-oligofucosides of varying length. Here we describe the exploration of two different approaches, starting from either end of the fucose chains. The oligosaccharides have been attached to gold nanoparticles and used in an enzyme-linked immunosorbent assay ELISA and a microarray format to probe antibody binding. We show that binding to the oligofucosides of antibodies in sera of infected people depends on the length of the oligofucose chains, with the largest glycans showing most binding.

Investigating the utility of traditional and genomic multi-locus datasets to resolve relationships in Lipaugus and Tijuca (Cotingidae).

Rapid diversification limits our ability to resolve evolutionary relationships and examine diversification history, as in the case of the Neotropical cotingas. Here we present an analysis with complete taxon sampling for the cotinga genera Lipaugus and Tijuca, which include some of the most range-restricted (e.g., T. condita) and also the most widespread and familiar (e.g., L. vociferans) forest birds in the Neotropics. We used two datasets: (1) Sanger sequencing data sampled from eight loci in 34 individuals across all described taxa and (2) sequence capture data linked to 1,079 ultraconserved elements and conserved exons sampled from one or two individuals per species. Phylogenies estimated from the Sanger sequencing data failed to resolve three nodes, but the sequence capture data produced a well-supported tree. Lipaugus and Tijuca formed a single, highly supported clade, but Tijuca species were not sister and were embedded within Lipaugus. A dated phylogeny confirmed Lipaugus and Tijuca diversified rapidly in the Miocene. Our study provides a detailed evolutionary hypothesis for Lipaugus and Tijuca and demonstrates that increasing genomic sampling can prove instrumental in resolving the evolutionary history of recent radiations.

Phylogeography of montane dragons could shed light on the history of forests and diversification processes on Sumatra.

Biogeographical evidence, both, for and against the "regional endemism paradigm" hypothesis has been uncovered across the Greater Sunda Region (Sundaland) of Southeast Asia. Additionally, there are competing hypotheses regarding how Pleistocene forests may have impacted biological patterns and processes in Sumatra. Using montane agamid lizards from Sumatra, we derived and analyzed a phylogenetic dataset, genetic divergence estimates, and contemporary distributional patterns among species. We tested whether (1) Sumatra's highland Draconinae diversification fits the regional endemism paradigm hypothesis and (2) Draconinae phylogeography provides biological evidence for Pleistocene forest extent at various points in history. Our results suggest in situ diversification was the main driver behind montane Draconinae lizard diversification in Sumatra, rejecting the "regional endemism paradigm". Contemporary distribution of endemic species and their genetic relationships may potentially provide biologicalevidence for determining more precise elevational lower limits of montane forests during the Pleistocene epoch. Our data suggests montane forests did not retreat more than 700-750 m during glacial maxima because lower retreating forests would have become interconnected, allowing for widespread dispersal, exchange of gene flow and sympatric distributions contemporarily. To the contrary, our divergence estimates show that cloud forest dragons have been isolated for millions of years, suggesting there may have been a continuous disconnect between some areas, predating the Pleistocene. There may also be other ecological and evolutionary factors that impacted Draconinae distributions, such as competition, making this an excellent system for testing questions regarding montane biogeography. Additionally, we provide the first phylogeny for a wide range of Sundaland agamid species and identify some biogeographic pressures that may have triggered montane Draconinae diversification in Sumatra.

Opioid Prescribing and Opioid Risk Mitigation Strategies in the Veterans Health Administration.

INTRODUCTION: The Veterans Health Administration (VHA) has taken a multifaceted approach to addressing opioid safety and promoting system-wide opioid stewardship. AIM: To provide a comprehensive evaluation of current opioid prescribing practices and implementation of risk mitigation strategies in VHA. SETTING: VHA is the largest integrated health care system in the United States. PROGRAM DESCRIPTION: VHA prescribing data in conjunction with implementation of opioid risk mitigation strategies are routinely tracked and reviewed by VHA's Pharmacy Benefits Management Services (including Academic Detailing Service) and the Pain Management Program Office. Additional data are derived from the Partnered Evidence-Based Policy Resource Center (PEPReC) and from a 2019 survey of interdisciplinary pain management teams at VHA facilities. Prescribing data are reported quarterly until first quarter fiscal year 2020 (Q1FY2020), ending December 31, 2019. PROGRAM EVALUATION: VHA opioid dispensing peaked in 2012 with 679,376 Veterans receiving an opioid prescription, and when including tramadol, in 2013 with 869,956 Veterans. Since 2012, the number of Veterans dispensed an opioid decreased 56% and co-prescribed opioid/benzodiazepine decreased 83%. Veterans with high-dose opioids (≥ 100 mg morphine equivalent daily dose) decreased 77%. In Q1FY2020, among Veterans on long-term opioid therapy (LTOT), 91.1% had written informed consent, 90.8% had a urine drug screen, and 89.0% had a prescription drug monitoring program query. Naloxone was issued to 217,469 Veterans and resulted in > 1,000 documented overdose reversals. In 2019, interdisciplinary pain management teams were fully designated at 68%, partially designated at 28%, and not available at 4% of 140 VA parent facilities. Fifty percent of Veterans on opioids at very high risk for overdose/suicide received interdisciplinary team reviews. IMPLICATIONS: VHA clinicians have greatly reduced their volume of opioid prescribing for pain management and expanded implementation of opioid risk mitigation strategies. IMPACTS: VHA's integrated health care system provides a model for opioid stewardship and interdisciplinary pain care.