Archaeological Investigations at the Ikirahak Site Raise Questions Concerning Taltheilei Land Use in Southern Nunavut

We report a new Taltheilei site-type found off the west coast of Hudson Bay in southern Nunavut. The Taltheilei is an archaeological culture that existed in the Barrenlands of the central Canadian Subarctic between 2600 and 300 years ago. Their land use strategies were tethered to the seasonal migrations of the Beverly and Qamanirjuaq caribou herds throughout tundra and forest landscapes. Tundra-based sites are typically interpreted as short-lived summer camps, but our discovery of three unique pit-house sites on the shores of Maguse Lake raises new questions concerning diversity in Taltheilei tundra land use. Architectural, faunal, lithic, and geoarchaeological data recovered from the Ikirahak site (JjKs-7) support the hypothesis that Taltheilei groups were extending their tundra stays into the fall. We report the evidence from four excavated pit-house features. Terraced platforms along the internal perimeters of these houses suggest they were designed for cold season use. The faunal assemblage is dominated by caribou remains. Higher relative frequencies of appendicular elements suggest a focus on secondary butchering. A large fraction of the faunal assemblage is highly fragmented and calcined, which is consistent with heavy processing and the use of bone as an alternative fuel source. Higher frequencies of lithic debris around dwelling floor perimeters are suggestive of maintenance activities. Multi-element concentrations in dwelling and site-wide sediments also show that hearth refuse was dumped outside. These findings seem to reflect longer tundra occupations during fall, a land use strategy that was likely guided by Qamanirjuaq herd behaviour specific to the Maguse Lake area, fall hunting and processing goals, and ecologically couched mobility logistics. As just four pit-houses from one Taltheilei camp have been investigated to date, our understanding of these places within Taltheilei worlds and northern socio-ecologies is currently limited. Further research at Ikirahak, the other Maguse Lake pit-house sites, and at other caribou water crossings on the tundra of the Qamanirjuaq caribou range is needed to support or refute our hypotheses.Nous signalons un nouveau site de type taltheilei trouvé sur la côte ouest de la baie d’Hudson, dans le sud du Nunavut. La culture taltheilei est une culture archéologique qui a existé dans les landes de la zone subarctique centrale canadienne il y a de cela 2600 à 300 ans. Les stratégies d’utilisation des terres de cette culture étaient rattachées aux migrations saisonnières des hardes de caribous de Beverly et de Qamanirjuaq dans la toundra et la forêt. De manière générale, les sites trouvés dans la toundra sont interprétés comme des campements d’été de courte durée. Cependant, notre découverte de trois sites uniques de maisons semi-souterraines sur les rives du lac Maguse soulève de nouvelles questions au sujet de la diversité de l’utilisation de la toundra par les Taltheilei. Les données architecturales, fauniques, lithiques et géoarchéologiques recueillies au site d’Ikirahak soutiennent l’hypothèse selon laquelle les groupements de Taltheilei occupaient la toundra jusqu’à l’automne. Nous signalons des preuves en provenance de quatre aménagements de maisons semi-souterraines. Le long du périmètre interne de ces maisons, les plateformes en terrasses suggèrent qu’elles étaient conçues pour servir pendant la saison froide. Des restes de caribous dominent l’assemblage faunique. Des fréquences relatives plus élevées d’éléments appendiculaires laissent entrevoir que le dépeçage secondaire y occupait une grande place. Une grande fraction de l’assemblage faunique est fortement fragmentée et calcinée, ce qui correspond à une transformation importante et à l’utilisation des os comme source de combustible. Les grandes fréquences de débris lithiques entourant le périmètre des planchers d’habitations suggèrent des activités de maintenance. Les concentrations d’éléments multiples dans les sédiments des habitations et de l’ensemble du site indiquent également que les déchets des âtres étaient jetés à l’extérieur. Ces constatations laissent entrevoir de plus longues occupations de la toundra à l’automne, une stratégie d’utilisation des terres vraisemblablement guidée par le comportement propre à la harde de Qamanirjuaq dans la région du lac Maguse, par la chasse automnale et par les objectifs de transformation, de même que par la logistique de la mobilité en termes écologiques. Puisque seulement quatre maisons semi-souterraines d’un seul campement taltheilei ont été étudiées jusqu’à maintenant, nous comprenons toujours peu de choses au sujet de ces endroits dans le monde des Taltheilei et des socioécologies nordiques. Il y a lieu de pousser les recherches plus loin à Ikirahak, là où se trouvent les autres sites de maisons semi-souterraines du lac Maguse, ainsi qu’à d’autres passages de franchissement de l’eau sur la toundra du parcours des caribous de Qamanirjuaq afin de confirmer ou de réfuter nos hypothèses

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

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

Cetacean occurrence in the Gulf of Alaska from long-term passive acoustic monitoring

Abstract: The Gulf of Alaska is an important habitat for a diverse array of marine mammals, many of which were severely depleted by historical whaling. To study current cetacean distributions in this region, passive acoustic monitoring was used to detect species-specific call types between 2011 and 2015 at five locations spanning the continental shelf, slope, and offshore seamounts. Spatial and temporal detection patterns were examined for nine species to compare differences in behavior and habitat use. Mysticetes showed seasonal increases in calling that indicated possible behavioral shifts between feeding and breeding in blue (Balaenoptera musculus), fin (B. physalus), and humpback (Megaptera novaeangliae) whales, and matched known migration timing of gray whales (Eschrichtius robustus). Interannual changes in blue and fin whale calling may relate to the marine heat wave that began in 2013 and lasted through the end of the monitoring period. Odontocete detections revealed unique spatial distributions, with killer whales (Orcinus orca) most common on the continental shelf and sperm whales (Physeter macrocephalus) most common on the continental slope, where detections occurred year-round. Beaked whales showed both spatial and temporal separation: Baird’s beaked whale (Berardius bairdii) detections were highest at Quinn Seamount in the spring, Cuvier’s (Ziphius cavirostris) at Pratt Seamount in winter, and Stejneger’s (Mesoplodon stejnegeri) on the continental slope in the fall. The year-round presence of many species highlights the ecological importance of the Gulf of Alaska and the spatiotemporal information reported here should inform future conservation efforts

Cetacean occurrence offshore of Washington from long-term passive acoustic monitoring

AbstractA variety of cetacean species inhabit the productive waters offshore of Washington State, USA. Although the general presence of many of these species has been documented in this region, our understanding of fine-scale habitat use is limited. Here, passive acoustic monitoring was used to investigate the spatial and temporal distributions of ten cetacean species at three locations offshore of Washington. Between 2004 and 2013, a total of 2845 days of recordings were collected from sites on the continental shelf and slope, and in a submarine canyon. Acoustic presence was higher for all species at sites farther offshore. Detections were highest during the fall and winter for blue (Balaenoptera musculus), fin (B. physalus), and humpback whales (Megaptera novaeangliae), likely related to reproductive behavior, while minke whales (B. acutorostrata) were only detected on two days. Odontocetes showed temporal separation, with sperm whale (Physeter macrocephalus) detections highest in spring, Risso’s (Grampus griseus) and Pacific white-sided dolphins (Lagenorhynchus obliquidens) highest in summer, and Stejneger’s beaked whales (Mesoplodon stejnegeri), Cuvier’s beaked whales (Ziphius cavirostris), and the BW37V signal type highest in winter or spring. There was interannual variation in detections for most mysticete species, which may be linked to oceanographic conditions: blue and fin whale detections increased during 2007 and 2008, and fin and humpback whale detections increased in 2011. These results inform our understanding of cetacean behavior and habitat use in this region and may aid in the development of conservation strategies suited to the dynamic conditions that drive cetacean distribution

Use It or Lose It: Copyright and Fair Use for Researchers and Scholars

A public forum on Copyright and Fair Use. Panelists included: Adrian Alexander, R.M. and Ida McFarlin Dean of the Library, The University of Tulsa Kevin J. H. Dettmar, W. M. Keck Professor and Chair of English, Pomona College. Sam Halabi, Assistant Professor, The University of Tulsa College of Law Peter Jaszi, Professor and Director of the Glushko-Samuelson Intellectual Property Clinic, Washington College of Law, American University Sean Latham, Pauline Walter Professor of English and Comparative Literature, Editor of the James Joyce Quarterly, The University of Tulsa Brendan O’Neill, Editor, Literature and Cinema Studies, Oxford University Press, New York Kate O’Neill, Professor, University of Washington School of Law Robert Pickering, Applied Associate Professor of Museum Science and Management and Anthropology, Senior Curator of the Gilcrease Museum, The University of Tulsa Tamara Piety, Professor and Associate Dean of Faculty Development, The University of Tulsa College of Law Paul K. Saint-Amour, Associate Professor and Graduate Chair of English, University of Pennsylvania Robert Spoo, Professor and Chapman Distinguished Chair,The University of Tulsa College of Law Laura Stevens, Associate Professor of English and Editor of Tulsa Studies in Women’s Literature, The University of Tuls