The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity.

The superficial layers of the medial entorhinal cortex (MEC) are a major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that MEC inputs are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences in the hippocampal theta cycle are particularly dependent on the MEC

Long View (41RB112): Data Recovery of Two Plains Village Period Components in Roberts County, Texas, Volume 1

This archeological data recovery investigation in Roberts County in the northeastern panhandle of Texas was necessitated by the proposed widening of State Highway 70 (CSJ: 0490-04-037) by the Texas Department of Transportation (TxDOT), Amarillo District. This proposed highway rehabilitation program will directly impact a roughly 10 meter (m, 30 ft.) wide north-south section of prehistoric site 41RB112, the Long View site. This site consists of two horizontally distinct Plains Village period occupations shallowly buried along a linear interfluvial ridge between two small tributary creeks to the Canadian River in the midslope of this broad, dissected valley. This site was initially discovered by TxDOT archeologist, Dennis Price in June 2004 during an archeological inventory of the proposed 9.7 kilometer (6 mile) section north of the Canadian River in response to the planned highway rehabilitation program. Based on Mr. Price’s discovery of multiple artifact classes in buried context he recommended this site be assessed for its eligibility for listing on the National Register of Historic Places under criterion d and possible designation as a State Archeological Landmark (SAL) per the requirements of Section 106 of the National Historic Preservation Act (NHPA) and other related legislation. Following the Texas Historical Commissions concurrence with that recommendation, TxDOT through the Environmental (ENV) Affairs Division, contracted to TRC Environmental Corporation (TRC) under an existing Scientific Services Contract No. 57XXSA006 and issued a Work Authorization to TRC of Austin to conduct the site eligibility assessment. During a site visit by TxDOT geoarcheologist James Abbott and TRC archeologist Mike Quigg in February 2005, the site boundaries were expanded to nearly 300 meters (m) along the proposed area of potential effect (APE). Investigative strategies were devised to assess the Long View site. In May 2005, TRC’s archeologists from Austin conducted archeological testing for a NRHP and SAL eligibility assessment investigation at 41RB112. The assessment along the 10-m-wide by 300-m-long APE was accomplished by hand-excavating 28 1-by-1 m units (totaling 16.8 m3), hand-excavating four narrow ca. 30 centimeter (cm) wide trenches (two in each area totaling nearly 32 linear meters), as well as cleaning and inspecting 28 m of existing road cut exposures. These investigations determined that cultural materials clustered at the northern and southern ends (Areas A and C respectively) of the site with nearly 120 m of noncultural bearing deposits (Area B) between the two concentrations. A 4-m-wide mechanically bladed fireguard paralleled the existing fenceline throughout the length of the APE and disturbed much of the near surface materials in that zone. The opposite, eastern side of the highway was investigated through the excavation of six 50-by-50 cm shovel tests, surface, and road cut inspection. Based on the results from the hand-excavations and various collections conducted during the site assessment, it became apparent that the two ends (Areas A and C) of the Long View site in TxDOT’s proposed APE contained well-defined cultural components in the top 50 cmbs. Each end appeared to represent habitation remains from single occupation episodes with potential structures, restricted to a narrow time period of less than 100 years between uncalibrated 630 and 710 B.P. of the Plains Village period. Rodent and natural disturbances had vertically displaced some small cultural objects within the sandy deposits, but the restricted period of occupation to roughly a 100 year period reduces this impact. TRC recommended the site was eligible for listing on the National Register and as a State Landmark. The Texas Historical Commissions concurred with that recommendation, and subsequently the ENV Affairs Division of TxDOT, again contracted to TRC under an existing Scientific Services Contract No. 575XXSA008 and issued a Work Authorization to TRC Austin to perform the mitigation of the proposed impacts. Data recovery investigations were conducted during August through November 2006 along the western side of the existing highway. The previously identified northern-Area A and southern–Area C areas with high concentrations of cultural materials were targeted. These investigations began with a thorough geophysical survey that employed three noninvasive electrical detective instruments across Areas A and C anticipating to detect the locations of subsurface cultural features to target by hand-excavations. Some excavations targeted the detected anomalies, whereas others targeted previously identified features. In the end, hand-excavated blocks were completed in Areas A and C. The excavations totaled 128 m2 in Area A and 93 m2 in Area C for a grand total of 221 m2 or 103.4 m3. In conjunction with the archeological excavations, geoarcheological investigations focused on defining the age and development of the natural Holocene sediments that contained the cultural materials. The geoarcheological assessment included detailed stratigraphic documentation of site and near site deposits, sediment texture characterization, soil thin sections, magnetic susceptibility, multiple chemical analyses (organic, calcium, and phosphorus). Detailed stratigraphic data was also collected at two rare pithouse structures to pursue construction and filling episodes. The excavations yielded significant and diverse cultural assemblages from the two occupations assigned Component A and C. Both components are attributed to the Plains Village period with two discrete occupations dating to uncalibrated 460 to 535 B.P. (cal A.D. 1398 to 1447) in Component A and 530 to 700 B.P. (cal A.D. 1280 to 1437) in Component C. The two assemblages are significant not only in their diversity and quality of materials but also in the information they yielded. This report represents one of the first complete documents to present the entire cultural assemblage from a single site for this time period and region. The total recovered assemblage includes 157 formal chipped and ground stone tools, 226 informal tools, 3,414 pieces of lithic debitage, over 6,400 faunal fragments (1.4 kg), some 1,541 ceramic sherds, 1,790 burned rocks, at least 116 macrobotanical samples that includes 16 maize cobs, two human burials, and remains of a third, juvenile scattered along a previously bladed fireguard, 32 intact cultural features that include two rare pithouses, and other cultural debris related to these two campsites. The human remains and associated artifacts will be repatriated in accord with the requirements of the Native American Graves Protection and Repatriation Act (NAGPRA). A suite of 10 technical analyses directed at mostly the cultural assemblages included; use-wear, phytolith, diatom, petrography, macrobotanical, starch grain, instrumental neutron activation, bison bone isotopes, obsidian sourcing, radiocarbon and optical stimulated dating. This data was used to address 11 specific research questions concerning these Plains Village period occupations. Not only does the cultural debris contribute to our understanding of the time period but the geoarcheological information obtained explains the conditions and how the materials were preserved, and inform us concerning the past depositional environment in this immediate area. The combined information contributes to a significant understanding to a specific part of the Plains Village cultures in the Texas panhandle. Following the acceptance of the final report by the TxDOT and the Texas Historical Commission these cultural materials and all the documentation from the combined investigations will be permanently curated at Texas State University in San Marcos, Texas. The curated materials will provide important data that can be researched by interested parties in the future

Biochar Supplementation in Growing and Finishing Diets

Two metabolism studies were conducted to evaluate the effects of biochar (0, 0.8, or 3% of diet dry matter) on digestibility and methane production in growing and finishing diets. Intake was not affected by biochar inclusion in the growing diet and increased with 0.8% biochar inclusion in the finishing study. Digestibility tended to increase quadratically with biochar inclusion in the growing study while digestibility tended to linearly decrease with biochar inclusion in the finishing study. Methane production (g/d) decreased 10.7% in the growing study and 9.9% in the finishing study with 0.8% biochar compared to no biochar. Methane production was reduced 10.6% and 18.4% in the growing and finishing studies, respectively, when measured as g/lb of intake. Although biochar is not FDA approved for animal feeding, the initial research shows potential as a methane mitigation strategy in both growing and finishing diets

Mapping alterations to the endogenous elemental distribution within the lateral ventricles and choroid plexus in brain disorders using X-ray fluorescence imaging

The choroid plexus and cerebral ventricles are critical structures for the production of cerebral spinal fluid (CSF) and play an important role in regulating ion and metal transport in the brain, however many aspects of its roles in normal physiology and disease states, such as psychiatric illness, remain unknown. The choroid plexus is difficult to examine in vivo, and in situ ex vivo, and as such has typically been examined indirectly with radiolabeled tracers or ex vivo stains, making measurements of the endogenous K+, Cl-, and Ca+ distributions unreliable. In the present study, we directly examined the distribution of endogenous ions and biologically relevant transition metals in the choroid plexus and regions surrounding the ventricles (ventricle wall, cortex, corpus callosum, striatum) using X-ray fluorescence imaging (XFI). We find that the choroid plexus was rich in Cl- and Fe while K+ levels increase further from the ventricle as Cl- levels decrease, consistent with the known role of ion transporters in the choroid plexus CSF production. A polyI:C offspring displayed enlarged ventricles, elevated Cl- surrounding the ventricles, and intraventricular calcifications. These observations fit with clinical findings in patients with schizophrenia and suggest maternal treatment with polyI:C may lead to dysfunctional ion regulation in offspring. This study demonstrates the power of XFI for examining the endogenous elemental distributions of the ventricular system in healthy brain tissue as well as disease models

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Biochar Supplementation in Growing and Finishing Diets

Two metabolism studies were conducted to evaluate the effects of biochar (0, 0.8, or 3% of diet dry matter) on digestibility and methane production in growing and finishing diets. Intake was not affected by biochar inclusion in the growing diet and increased with 0.8% biochar inclusion in the finishing study. Digestibility tended to increase quadratically with biochar inclusion in the growing study while digestibility tended to linearly decrease with biochar inclusion in the finishing study. Methane production (g/d) decreased 10.7% in the growing study and 9.9% in the finishing study with 0.8% biochar compared to no biochar. Methane production was reduced 10.6% and 18.4% in the growing and finishing studies, respectively, when measured as g/lb of intake. Although biochar is not FDA approved for animal feeding, the initial research shows potential as a methane mitigation strategy in both growing and finishing diets

Assessing Planet Nanosatellite Sensors for Ocean Color Usage

An increasing number of commercial nanosatellite-based Earth-observing sensors are providing high-resolution images for much of the coastal ocean region. Traditionally, to improve the accuracy of normalized water-leaving radiance (nLw) estimates, sensor gains are computed using in-orbit vicarious calibration methods. The initial series of Planet nanosatellite sensors were primarily designed for land applications and are missing a second near-infrared band, which is typically used in selecting aerosol models for atmospheric correction over oceanographic regions. This study focuses on the vicarious calibration of Planet sensors and the duplication of its red band for use in both the aerosol model selection process and as input to bio-optical ocean product algorithms. Error measurements show the calibration performed well at the Marine Optical Buoy location near Lanai, Hawaii. Further validation was performed using in situ data from the Aerosol Robotic Network—Ocean Color platform in the northern Adriatic Sea. Bio-optical ocean color products were generated and compared with products from the Visual Infrared Imaging Radiometric Suite sensor. This approach for sensor gain generation and usage proved effective in increasing the accuracy of nLw measurements for bio-optical ocean product algorithms