#35 - Enamel isotopes reveal late Pleistocene ecosystem dynamics in southeastern North America

The end of the late Pleistocene (~10,000 years ago) witnessed the extinction of over seventy percent of North America’s megafaunal genera. Although this pattern has been extensively investigated, its causal mechanisms remain elusive. Much of this difficulty is related to the spatial and temporal discontinuity of sites dating to the period leading up to the extinctions. Due to its removal from glacial conditions, southeastern North America provides a unique window into ecosystem dynamics just prior to human arrival in the region. In this study, we present new stable carbon and oxygen isotope data from Mammuthus columbiand Bison latifronsteeth collected from a well-dated Last Glacial Maximum (~20,000 rcybp) locality called Clark Quarry in coastal Georgia, USA. We compare these data to those from similarly aged (middle and late Rancholabrean) localities from Florida and demonstrate the presence of a vegetation gradient with elevated levels of C3vegetation at higher latitudes. We hypothesize that this pattern may have contributed to previously described migratory patterns of mastodon (Mammut) populations in southeastern North America. Serially-sampled δ13C and δ18O values suggest that Clark Quarry Mammuthus and Bison changed their diet seasonally with the incorporation of elevated quantities of C4vegetation during warmer periods. Our data indicate more exaggerated seasonal dietary variability in these taxa at Clark Quarry relative to those collected from the interglacial locality of Waccasassa River in Florida, providing additional evidence for the significant influence of glacial dynamics in structuring North American ecosystems

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

28. Spatial variation in white-tailed deer morphology across southeastern North America

Morphological variation across space in large mammal species can provide insights into their overall ecology and evolutionary history. However, these analyses are frequently limited by the availability of high-resolution morphological data from a large number of individuals over a wide spatial scale. In this study, we compiled morphological data (\u3e700,000 individuals; \u3e600 localities) spanning two decades collected from white-tailed deer (Odocoileus virginiana) across Georgia, Virginia, South Carolina, North Carolina and Tennessee. We use these data to investigate spatial heterogeneity in the morphological characteristics (e.g., body weight, total antler spread, antler diameter) of this species across southeastern North America. Preliminary analysis indicates 1) significant variation in body size across the space considered here, and 2) the potential of this large data set to provide unprecedented insights into the ecology and biogeography of this important species. Finally, the patterns identified here could serve as a model for evaluating extinct mammal herbivores in the paleontological record of this region. Future analysis will incorporate morphological data from additional localities outside of southeastern North America

Enamel isotopes reveal late Pleistocene ecosystem dynamics in southeastern North America

The end of the late Pleistocene (∼10,000 years ago) witnessed the extinction of over seventy percent of North America\u27s megafaunal genera. Although this pattern has been extensively investigated, its causal mechanisms remain elusive. Much of this difficulty is related to the spatial and temporal discontinuity of sites dating to the period leading up to the extinctions. In this study, we present new stable carbon and oxygen isotope data from Mammuthus columbi and Bison latifrons teeth collected from a well-dated Last Glacial Maximum (∼20,000 rcybp) locality called Clark Quarry in coastal Georgia, USA. This site lies in direct proximity to where Sir Charles Lyell collected the type specimen of M. columbi in 1846 and therefore is of added historical significance. We compare these data to those from similarly aged (Sangamonian interglacial and Wisconsin glacial intervals) localities from Florida and demonstrate the presence of a vegetation gradient with elevated levels of C3 vegetation at higher latitudes. Serially-sampled δ13C and δ18O values suggest that Clark Quarry Mammuthus and Bison changed their diet seasonally with the incorporation of elevated quantities of C4 vegetation during warmer periods. Our data indicate more exaggerated seasonal dietary variability in these taxa at Clark Quarry relative to those collected from the Sangamonian interglacial locality of Waccasassa River in Florida, providing additional evidence for the significant influence of glacial dynamics in structuring North American ecosystems. These high-resolution ecological patterns should be incorporated into hypotheses focused on extinction dynamics in southeastern North America and more broadly