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Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1β, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia.

Southeast (SE) Asia is located in a transitional zone where hydroclimate is controlled by both the Indian and East Asian summer monsoon branches. Recent proxy-based studies and climate models suggest that the hydroclimate of SE Asia may be out of phase with neighboring regions, such as India and China. However, we lack sufficient proxy records to verify this postulation or to identify spatial and temporal variations. This study reconstructs both past temperatures and effective moisture in Central Vietnam during Marine Isotope Stage 3 (approximately 50,00 to 30,000 years BP) to determine how these two climate variables relate in the past. Terrestrial temperatures and precipitation are reconstructed using biomarkers (branched glycerol dialkyl glycerol tetraethers, brGDGT) and compound-specific isotope analyses (carbon and hydrogen-isotopic values of leaf wax n-acids, δ13Cwax, and δDwax) from a buried peat deposit in the Central Highlands of Vietnam. The brGDGTs-derived annual temperatures range from 22.9 to 26.2°C and show a warming trend coincident with a weakening of summer insolation. A coincident and gradual enrichment of δ13Cwax from 47 to 33 kyr BP suggests a transition from C3 to C4 vegetation dominance. Such a response could signal an overall decrease in precipitation or a shift in the seasonality of precipitation. The δDwax data, however, do not indicate an overall drying trend, which supports the idea that a shift in the seasonality of rainfall, along with higher annual temperatures, is driving the vegetation change. In addition, the δDwax records may exhibit a trend opposite to a site in Thailand. We argue that the isotopic variability in the precipitation of Central Vietnam reflects the shift in moisture sources along with the shift in seasonality. In this case, an increase in amount of precipitation derived from the South China Sea in winter months is marked by rain enriched in δ2H-which could also be interpreted as a decrease in precipitation. The increase in rainfall during winter monsoon months (e.g. winter) in the Central Highlands of Vietnam does not appear to reach Thailand. We recommend that the precipitation proxies should be applied with knowledge of regional climate context and argue that better geographic representation of monsoonal climates is necessary to fully understand and model this critical climate system.

Paleoclimate records from lakes of the southwestern USA have been limited by a lack of independent paleothermometers, resulting in conflicting characterizations of millennial-scale variability in temperature and moisture. Here a novel method called Brillouin thermometry is applied to halite-bearing dry intervals of the late Pleistocene/Holocene (45–0 ka) core record of Searles Lake, California. Halite from the sediment-water interface records lake bottom temperatures during dry, high salinity periods. Analysis of modern saline lakes of various chemistries, depths, climate zones, and mixing regimes shows that: 1) average bottom water temperature is approximately equal to mean annual air temperature, and 2) annual range of bottom water temperature is inversely proportional to lake depth. Brillouin temperatures for eight halite intervals 30.6 ka to 8.5 ka range from 11.8 ± 3.6 to 22.4 ± 3.2 °C. Bottom water temperature variability indicates paleolake depths of ~10 m during halite precipitation. Brillouin thermometric results are then assessed in comparison with two additional temperature proxy records from the same Searles Lake sediment core: 1) branched glycerol dialkyl glycerol tetraethers (brGDGTs) extracted from wet mud intervals, and 2) thermodynamic constraints from evaporite minerals and mineral sequences. Temperatures from brGDGTs for mud intervals 44.7 ka to 3.6 ka range from 13.4 ± 2.8 to 23.9 ± 3.0 °C. Comparisons of Brillouin/brGDGT temperatures with predicted equilibrium temperatures of salt crystallization indicate intervals where seasonal temperature variability forced the dissolution and/or recrystallization of existing temperature-sensitive evaporites. The multiproxy temperature record of Searles Lake agrees with other regional records at glacial/interglacial timescales but displays a wider degree of millennial-scale variability, with temperatures during the last glacial ranging from 8.3 °C below modern mean annual temperatures to 3.8 °C above.

Glycerol dialkyl glycerol tetraethers (GDGTs), including both the archaeal isoprenoid GDGTs (isoGDGTs) and the bacterial branched GDGTs (brGDGTs), have been used in paleoclimate studies to reconstruct temperature in marine and terrestrial archives. However, GDGTs are present in many different types of environments, with relative abundances that strongly depend on the depositional setting. This suggests that GDGT distributions can be used more broadly to infer paleoenvironments in the geological past. In this study, we analyzed 1153 samples from a variety of modern sedimentary settings for both isoGDGT and brGDGTs. We used machine learning on the GDGT relative abundances from this dataset to relate the lipid distributions to the physical and chemical characteristics of the depositional settings. We observe a robust relationship between the depositional environment and the lipid distribution profiles of our samples. This dataset was used to train and test the Branched and Isoprenoid GDGT Machine learning Classification algorithm (BIGMaC), which identifies the environment a sample comes from based on the distribution of GDGTs with high accuracy. We tested the model on the sedimentary record from the Giraffe kimberlite pipe, an Eocene maar in subantarctic Canada, and found that the BIGMaC reconstruction agrees with independent stratigraphic information, provides new information about the paleoenvironment of this site, and helps improve paleotemperature reconstruction. In cases where paleoenvironments are unknown or are changing, BIGMaC can be applied in concert with other proxies to generate more refined paleoclimatic records.

Paleoclimate data assimilation (DA) is a novel tool for reconstructing past climates that directly integrates proxy records with climate model output. Despite the potential for DA to expand the scope of quantitative paleoclimatology, these methods remain difficult to implement in practice due to the multi-faceted requirements and data handling necessary for DA reconstructions, the diversity of DA methods, and the need for computationally efficient algorithms. Here, we present DASH, a MATLAB toolbox designed to facilitate paleoclimate DA analyses. DASH provides command line and scripting tools that implement common tasks in DA workflows. The toolbox is highly modular and is not built around any specific analysis, and thus DASH supports paleoclimate DA for a wide variety of time periods, spatial regions, proxy networks, and algorithms. DASH includes tools for integrating and cataloguing data stored in disparate formats, building state vector ensembles, and running proxy (system) forward models. The toolbox also provides optimized algorithms for implementing ensemble Kalman filters, particle filters, and optimal sensor analyses with variable and modular parameters. This paper reviews the key components of the DASH toolbox and presents examples illustrating DASH's use for paleoclimate DA applications.

PURPOSE: In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research. METHODS: We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization). RESULTS: Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms. CONCLUSIONS: We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies.

Southwestern North America, like many subtropical regions, is predicted to become drier in response to anthropogenic warming. However, during the Pliocene, when carbon dioxide was above pre-industrial levels, multiple lines of evidence suggest that southwestern North America was much wetter. While existing explanations for a wet Pliocene invoke increases in winter rain, recent modeling studies hypothesize that summer rain may have also played an important role. Here, we present the first direct evidence for an intensified Pliocene monsoon in southwestern North America using leaf wax hydrogen isotopes. These new records provide evidence that the Pliocene featured an intensified and expanded North American Monsoon. Using proxies and isotope-enabled model simulations, we show that monsoon intensification is linked to amplified warming on the southern California margin relative to the tropical Pacific. This mechanism has clear relevance for understanding present-day monsoon variations, since we show that intervals of amplified subtropical warming on the California margin, as are seen during modern California margin heat waves, are associated with a stronger monsoon. Since marine heat waves are predicted to increase in frequency, the future may bring intervals of `Pliocene-like' rainfall that co-exist with intensifying megadrought in southwestern North America, with implications for ecosystems, human infrastructure, and water resources

In this poster, I will present plans to complete a PlioMIP2 simulation at high resolution (HR) in the fully-coupled Community Earth System Model (CESM). This simulation is part of the NCAR Accelerated Scientific Discovery PaleoWeather project and also includes HR simulations of the Early Eocene Climatic Optimum, with CO2 reconstructed to be much higher than today’s, and the Last Glacial Maximum with much lower CO2. CESM is being configured with a resolution of 0.25° for the atmosphere and land, and 0.1° for the ocean and sea ice. This set of fully-coupled paleo-HR climate simulations for past greenhouse and icehouse climates will study the drivers that govern the characteristics of extreme weather events in both atmosphere and ocean under altered climate states. Potential applications include diagnosing changes in atmospheric synoptic features like mesoscale convective systems, tropical cyclones, monsoons, and atmospheric rivers, of coastal upwelling zones, and for their impacts on past regional precipitation patterns. In addition, the paleo-HR simulations will better resolve the landscape of topographies and coasts. Both are critical for accurate comparison with the paleoclimate record since most of the terrestrial and marine paleo-observations come from basins surrounded by mountains and near-shore locations. The paleo-HR simulations will complement the preindustrial, historical and RCP8.5 future simulations available from the iHESP project (https://ihesp.tamu.edu/), resulting in HR simulations to investigate the dynamics that connect past and future climate changes.

Cloud and convective parameterizations strongly influence uncertainties in equilibrium climate sensitivity (ECS). We provide a proof-of-concept study to constrain these parameterizations in a perturbed parameter ensemble of the atmosphere-only version of the Goddard Institute for Space Studies (GISS) Model E2.1 simulations by evaluating model biases in the present-day runs using multiple satellite climatologies and by comparing simulated δ18O of precipitation (δ18Op), known to be sensitive to parameterization schemes, with a global database of speleothem δ18O records covering the Last Glacial Maximum (LGM), mid-Holocene (MH) and pre-industrial (PI) periods. Relative to modern interannual variability, paleoclimate simulations show greater sensitivity to parameter changes, allowing for an evaluation of model uncertainties over a broader range of climate forcing and the identification of parts of the world that are parameter sensitive. Certain simulations reproduced absolute δ18Op values across all time periods, along with LGM and MH δ18Op anomalies relative to the PI, better than the default parameterization. No single set of parameterizations worked well in all climate states, likely due to the non-stationarity of cloud feedbacks under varying boundary conditions. Future work that involves varying multiple parameter sets simultaneously with coupled ocean feedbacks will likely provide improved constraints on cloud and convective parameterizations.

Climate changes across the last 24,000 years provide key insights into Earth system responses to external forcing. Climate model simulations and proxy data have independently allowed for study of this crucial interval; however, they have at times yielded disparate conclusions. Here, we leverage both types of information using paleoclimate data assimilation to produce the first observationally constrained, full-field reanalysis of surface temperature change spanning the Last Glacial Maximum to present. We demonstrate that temperature variability across the last 24 kyr was linked to two modes: radiative forcing from ice sheets and greenhouse gases; and a superposition of changes in thermohaline circulation and seasonal insolation. In contrast with previous proxy-based reconstructions our reanalysis results show that global mean temperatures warmed between the early and middle Holocene and were stable thereafter. When compared with recent temperature changes, our reanalysis indicates that both the rate and magnitude of modern observed warming are unprecedented relative to the changes of the last 24 kyr.

Branched glycerol dialkyl glycerol tetraethers (brGDGTs) in lake sediments are increasingly being used to reconstruct past temperatures. However, recent studies suggest that brGDGT distributions and concentrations vary with lake size and environmental conditions such as seasonality and its effects on water column temperature and chemistry. To test their use as a paleothermometer in high-altitude environments of mid-latitude North America, we analyzed brGDGT distributions in lake surface sediments across a range of lake depths and elevations in the Rocky Mountains of Wyoming and Colorado. Our results suggest that brGDGT distributions and the MBT’5Me index correlate with water column temperatures, which are sensitive to both lake water depth and air temperatures. Based on these relationships, we developed a calibration to mean summer air temperatures using a Bayesian regression model that incorporates the MBT’5Me index and lake water depth. We applied our calibration to lake sediments from Lower Paintrock Lake in northern Wyoming to test its use as a paleothermometer. Reconstructed temperature trends are consistent with pollen-inferred temperatures at the same site and with known regional climate history, demonstrating that our calibration can be successfully applied to infer temperatures in high-altitude environments of mid-latitude North America.

Research Objectives To describe potential effects of a novel Cranial Movement Therapy (CMT) on long-lasting post-Traumatic Brain Injury (TBI) symptoms. Design Case report. Setting Specialized private practice on concussion and TBI. Participants A 57-year-old female with sustaining post-TBI symptoms for 2 years, with a new incident 2 weeks prior to initial visit. Interventions A novel technique of CMT was originally developed to improve post-TBI symptoms by potential restoration of the cranial bones’ position and optimization of CSF and blood flow. This approach consists of a detailed history of the mechanism of injury, systematic evaluation including palpation, assessment, and manipulation of the cranial bones, cervical spine and surrounding musculature. Each session, symmetry, mobility, and tonicity of cranial structures and soft tissues were assessed. Treatment protocol consisted of 5 consecutive sets of proposed CMT technique on the palate and other osseous cranial structures found with deficits, of 1 session every 20 minutes, over the course of 4 days with added home-based cognitive training program. Follow-up was repeated for 2 months post-initial treatment. Main Outcome Measures Primary outcomes were severity of headache and cognitive dysfunction on a 0-10 scale and frequency of occurrence. Results Following receiving CMT, the participant reported 80% decrease in headache severity (5/10 to 1/10) and complete resolution (100% decrease) of cognitive dysfunction (6/10 to 0/10) at the conclusion of treatment on day 4 with no recurrence after 2 months of follow up. Conclusions This case report successfully documented a significant reduction in severity and frequency of headaches, complete elimination of cognitive difficulties following application of this novel CMT technique in a patient experiencing long-lasting post-TBI symptoms. Findings warrant future randomized controlled investigation of this approach in the treatment of patients with post-TBI symptoms. Author(s) Disclosures Primary authors (CS) who has originally developed this novel technique foresees potential financial conflict of interest since he is the CEO/owner of the facility this case is treated. All other authors declare that they have no relevant financial or non-financial competing interests to report.

The early Eocene (56 to 48 million years ago) is inferred to have been the most recent time that Earth's atmospheric CO2 concentrations exceeded 1000 ppm. Global mean temperatures were also substantially warmer than present day. As such, study of early Eocene climate provides insight into how a super-warm Earth system behaves and offers an opportunity to evaluate climate models under conditions of high greenhouse gas forcing. The Deep Time Model Intercomparison Project (DeepMIP) is a systematic model-model and model-data intercomparison of three early Paleogne time slices: latest Paleocene, Paleocene-Eocene thermal maximum and early Eocene climatic optimum. A previous article outlined the model experimental design for climate model simulations. In this article, we outline the methodologies to be used for the compilation and analysis of climate proxy data, primarily proxies for temperature and CO2. This paper establishes the protocols for a concerted and coordinated effort to compile the climate proxy records across a wide geographic range. The resulting climate atlas will be used to constrain and evaluate climate models for the three selected time intervals, and provide insights into the mechanisms that control these warm climate states. We provide version 0.1 of this database, in anticipation that this will be expanded in subsequent publications.