Archaeological investigations along the Ruby Pipeline.

405 pages : illustrations (some color), maps ; 26 cm.The Ruby Pipeline originates in Opal, Wyoming, travels westward across Utah and Nevada, and terminates in Malin, Oregon. Almost 360 miles of the line is in Nevada, where it crosses through some of the most remote, sparsely populated land in the lower 48 states. Despite the remote nature of this corridor, it has produced a rich archaeological record reflecting a dynamic history of land-use pattern changes over a period of at least 13,000 years. Archaeological excavations were conducted at 578 prehistoric sites prior to construction of the pipeline. The sites were distributed across four ecological regions, including (from west to east): the High Rock Country, Upper Lahontan Basin, Upper Humboldt Plains, and Thousand Springs Valley. First evidence of human occupation dates to the Paleoindian (14,500-12,800 cal b.p.) and Paleoarchaic (12,800-7800 cal b.p.) periods, when people spent most of their time in the High Rock Country where important economic resources reached their highest densities. Paleoindian findings are limited to a series of Great Basin Concave Base projectile points and small obsidian flaked stone concentrations. Paleoarchaic sites are much more common, and tend to be represented by Great Basin Stemmed projectile points, bifaces, and a limited number of other flaked stone tools. Most of these assemblages reflect small groups of hunters refurbishing their tool kits as they traveled through the area. An important exception to this pattern was found at Five Mile Flat along the west end of pluvial Lake Parman where two significant habitation sites dating to 11,180 cal b.p. were discovered. One of these sites includes a house floor, which is the oldest ever found in the Great Basin. Despite the warm-dry conditions that characterized much of the middle Holocene, it appears that human populations nearly doubled during the Post-Mazama Period (7800-5700 cal b.p.). Most activity remained concentrated in the High Rock Country, but evidence for occupation begins to trickle out into the Upper Lahontan Basin and Upper Humboldt Plains regions as well. Most of the artifact assemblages remain rather narrow, often composed of Northern Side-notched and Humboldt Concave Base points, bifaces, and debitage, and reflect use of the region by mobile groups of hunters. Major changes took place with the arrival of the Early Archaic (5700-3800 cal b.p.) and continued forward into the Middle Archaic Period (3800-1300 cal b.p.). Early Archaic projectile points are largely represented by Humboldt and Gatecliff forms. It appears that population densities increased almost fourfold from the preceding interval, and all four regions experienced significant occupation for the first time. Simultaneous to this population increase and dispersal, a full complement of site types began to emerge, with large-scale residential areas becoming significant for the first time. This trend continued forward into the Middle Archaic Period where the relative frequency of residential sites almost doubled compared with the Early Archaic interval. Plant macrofossil and archaeofaunal assemblages also become more abundant and diversified at this time, probably marking a broadening of the diet breadth. This general trajectory extends into the Late Archaic (1300-600 cal b.p.) and Terminal Prehistoric periods, as people continued to expand into a wider range of habitats. This was particularly case for the latter interval, as the habitat preferences that made sense for over 12,000 years were upended, with population densities highest in the Upper Humboldt Plains and Thousand Springs Valley. This reorientation corresponds to the arrival of Numic speaking populations, especially the Western Shoshone who appear to have reached northern Nevada much earlier than the Northern Paiute, and is probably linked to a greater emphasis on small-seeded plants that are abundantly present in their territory. Although low ranked compared to many other foods, with the proper technology and work organization, small seeds could support higher population densities than was the case earlier in time. Finally, the discovery of obsidian in multiple Terminal Prehistoric sites from sources located much further away than any other time in the past may signal the earliest use of horses in northern Nevada

Self-Administered Mindfulness Interventions Reduce Stress in a Large, Randomized Controlled Multi-Site Study

Mindfulness witnessed a substantial popularity surge in the past decade, especially as digitally self-administered interventions became available at relatively low costs. Yet, it is uncertain whether they effectively help reduce stress. In a preregistered (OSF https://doi.org/10.17605/OSF.IO/UF4JZ; retrospective registration at ClinicalTrials.gov NCT06308744) multi-site study (nsites = 37, nparticipants = 2,239, 70.4% women, Mage = 22.4, s.d.age = 10.1, all fluent English speakers), we experimentally tested whether four single, standalone mindfulness exercises effectively reduced stress, using Bayesian mixed-effects models. All exercises proved to be more efficacious than the active control. We observed a mean difference of 0.27 (d = −0.56; 95% confidence interval, −0.43 to −0.69) between the control condition (M = 1.95, s.d. = 0.50) and the condition with the largest stress reduction (body scan: M = 1.68, s.d. = 0.46). Our findings suggest that mindfulness may be beneficial for reducing self-reported short-term stress for English speakers from higher-income countries

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

A novel Alzheimer disease locus located near the gene encoding tau protein

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4- (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significansignificantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10-7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P<1.3x10-8), frontal cortex (P<1.3x10-9), and temporal cortex (P<1.2x10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10-6) and temporal cortex (P=2.6x10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

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

The Effects of Dietary Flaxseed on Cardiac Arrhythmias and Claudication in Patients with Peripheral Arterial Disease

Patients with peripheral artery disease (PAD) are at increased risk for cardiovascular events and higher susceptibility for cardiac arrhythmias may be involved. The objectives of this double blinded, randomized controlled FLAX-PAD trial were to determine whether daily consumption of a diet supplemented with 30g of milled flaxseed (or placebo) over one year by PAD patients has effects on the prevalence of cardiac arrhythmias and exercise capacity. Cardiac arrhythmias were assessed on a cardiac stress test and at rest. At baseline, the PAD patients had a high incidence of cardiac arrhythmias (48% in the flaxseed group and 32% in the placebo group). After 1 year, the presence of cardiac arrhythmias in the flaxseed group decreased by 2% and increased by 12% in the placebo group (P>0.05). Electrocardiographic variables (P, PR, QRS, QT, QTc) did not change in either group during the trial. Patients from both groups improved initial and absolute claudication distances but the intergroup difference was also not statistically significant. In summary, the prevalence of cardiac arrhythmias and physical capacity trended in a positive direction for patients ingesting flaxseed but either a larger sample size or a longer intervention with flaxseed may be required to show statistically significant differences.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Waste Form Release Data Package for the 2005 Integrated Disposal Facility Performance Assessment

This data package documents the experimentally derived input data on the representative waste glasses; LAWA44, LAWB45, and LAWC22. This data will be used for Subsurface Transport Over Reactive Multi-phases (STORM) simulations of the Integrated Disposal Facility (IDF) for immobilized low-activity waste (ILAW). The STORM code will be used to provide the near-field radionuclide release source term for a performance assessment to be issued in July 2005. Documented in this data package are data related to 1) kinetic rate law parameters for glass dissolution, 2) alkali (Na+)-hydrogen (H+) ion exchange rate, 3) chemical reaction network of secondary phases that form in accelerated weathering tests, and 4) thermodynamic equilibrium constants assigned to these secondary phases. The kinetic rate law and Na+-H+ ion exchange rate were determined from single-pass flow-through experiments. Pressurized unsaturated flow (PUF) and product consistency (PCT) tests where used for accelerated weathering or aging of the glasses in order to determine a chemical reaction network of secondary phases that form. The majority of the thermodynamic data used in this data package were extracted from the thermody-namic database package shipped with the geochemical code EQ3/6, version 8.0. Because of the expected importance of 129I release from secondary waste streams being sent to IDF from various thermal treatment processes, parameter estimates for diffusional release and solubility-controlled release from cementitious waste forms were estimated from the available literature