Small carbonaceous fossils (SCFs) from the Terreneuvian (lower Cambrian) of Baltica

We describe a new assemblage of small carbonaceous fossils (SCFs) from diagenetically 9 minimally altered clays and siltstones of Terreneuvian age from the Lontova and Voosi formations of 10 Estonia, Lithuania and Russia. This is the first detailed account of an SCF assemblage from the 11 Terreneuvian, and includes a number of previously undocumented Cambrian organisms. Recognisably 12 bilaterian-derived SCFs include abundant protoconodonts (total-group Chaetognatha), and distinctive 13 cuticular spines of scalidophoran worms. Alongside these metazoan remains are a range of protistan-14 grade fossils, including Retiranus balticus gen. et sp. nov., a distinctive funnel-shaped or sheet-like 15 problematicum characterized by terminal or marginal vesicles, and Lontohystrichosphaera grandis 16 gen. et sp. nov., a large (100–550 μm) ornamented vesicular microfossil. Together these data offer a 17 fundamentally enriched view of Terreneuvian life in the epicratonic seas of Baltica, from an episode 18 where records of non-biomineralized life are currently sparse. Even so, the recovered assemblages 19 contain a lower diversity of metazoans than SCF biotas from younger (Stage 4) Baltic successions that 20 represent broadly equivalent environments, echoing the diversification signal recorded in the coeval 21 shelly and trace-fossil records. Close comparison to the biostratigraphic signal from Fortunian small 22 shelly fossils (SSFs) supports a late Fortunian age for most of the Lontova/Voosi succession, rather 23 than a younger (wholly Stage 2) range.NER

Role of Optical Neuromonitoring in Neonatal Encephalopathy—Current State and Recent Advances

Neonatal encephalopathy (NE) in term and near-term infants is a significant global health problem; the worldwide burden of disease remains high despite the introduction of therapeutic hypothermia. Assessment of injury severity and effective management in the neonatal intensive care unit (NICU) relies on multiple monitoring modalities from systemic to brain-specific. Current neuromonitoring tools provide information utilized for seizure management, injury stratification, and prognostication, whilst systemic monitoring ensures multi-organ dysfunction is recognized early and supported wherever needed. The neuromonitoring technologies currently used in NE however, have limitations in either their availability during the active treatment window or their reliability to prognosticate and stratify injury confidently in the early period following insult. There is therefore a real need for a neuromonitoring tool that provides cot side, early and continuous monitoring of brain health which can reliably stratify injury severity, monitor response to current and emerging treatments, and prognosticate outcome. The clinical use of near-infrared spectroscopy (NIRS) technology has increased in recent years. Research studies within this population have also increased, alongside the development of both instrumentation and signal processing techniques. Increasing use of commercially available cerebral oximeters in the NICU, and the introduction of advanced optical measurements using broadband NIRS (BNIRS), frequency domain NIRS (FDNIRS), and diffuse correlation spectroscopy (DCS) have widened the scope by allowing the direct monitoring of oxygen metabolism and cerebral blood flow, both key to understanding pathophysiological changes and predicting outcome in NE. This review discusses the role of optical neuromonitoring in NE and why this modality may provide the next significant piece of the puzzle toward understanding the real time state of the injured newborn brain

Ethnic differences in success at application for consultant posts among United Kingdom physicians from 2011 to 2019: a retrospective cross-sectional observational study

OBJECTIVES: To identify associations between success following application for consultant physician posts and demographic factors. DESIGN: Logistic regression analysis of nationwide survey data. SETTING: United Kingdom (UK) physicians with a recent certificate of completion of training (CCT). PARTICIPANTS: All UK trainee physicians who received a CCT between 2010 and 2019 were surveyed. Respondents were excluded if they had not applied for a consultant post or if application data were incomplete. MAIN OUTCOME MEASURES: The primary outcome measure was success over the entire consultant application process, i.e. shortlisted and offered the post following the first application. Secondary outcomes were: shortlisted following first application and offered a consultant post at first interview. RESULTS: From 7037 CCT holders surveyed, 50.7% responded. While 1198 (59.7%) respondents were white, 760 (37.9%) were from minority ethnic groups and 50 (3.5%) were of unknown ethnicity. Primary medical qualification (PMQ) country was the UK in 75.3% (n = 1512). On multivariable logistic regression analysis the independent negative associations with success were: minority ethnicity (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.43-0.71); p < 0.001) vs. white; PMQ from Europe (OR 0.47, 95% CI 0.28-0.79; p = 0.004) or Asia (OR 0.68, 95% CI 0.49-0.96; p = 0.027) vs. UK PMQ; year of CCT 2012 (OR 0.40, 95% CI 0.24-0.68; p = 0.001), 2013 (OR 0.39, 95% CI 0.23-0.65; p < 0.001), and 2014 (OR 0.26, 95% CI 0.15-0.43; p < 0.001) vs. 2019. Specialties associated with lower success rates included Cardiology, Endocrinology, Genitourinary medicine, Palliative care, Renal and Respiratory, compared to Acute medicine. CONCLUSIONS: Minority ethnic group candidates for consultant physician posts had lower success rates compared to white candidates after correction for important variables including specialty, time from and country of PMQ. This finding requires further evaluation to identify the causes for this variation

Oxygen minimum zones in the early Cambrian ocean

The relationship between the evolution of early animal 26 communities and oceanic oxygen levels remains unclear. In particular, uncertainty persists in reconstructions of redox conditions during the pivotal early Cambrian (541-510 million years ago, Ma), where conflicting datasets from deeper marine settings suggest either ocean anoxia or fully oxygenated conditions. By coupling geochemical palaeoredox proxies with a record of organic-walled fossils from exceptionally well-defined successions of the early Cambrian Baltic Basin, we provide evidence for the early establishment of modern-type oxygen minimum zones (OMZs). Both inner- and outer shelf environments were pervasively oxygenated, whereas mid-depth settings were characterized by spatially oscillating anoxia. As such, conflicting redox signatures recovered from individual sites most likely derive from sampling bias, whereby anoxic conditions represent mid-shelf environments with higher productivity. This picture of a spatially restricted anoxic wedge contrasts with prevailing models of globally stratified oceans, offering a more nuanced and realistic account of the Proterozoic-Phanerozoic ocean transition

The Sec1/Munc18 protein Vps45 regulates cellular levels of its SNARE binding partners Tlg2 and Snc2 in Saccharomyces cerevisiae

Intracellular membrane trafficking pathways must be tightly regulated to ensure proper functioning of all eukaryotic cells. Central to membrane trafficking is the formation of specific SNARE (soluble N-ethylmeleimide-sensitive factor attachment protein receptor) complexes between proteins on opposing lipid bilayers. The Sec1/Munc18 (SM) family of proteins play an essential role in SNARE-mediated membrane fusion, and like the SNAREs are conserved through evolution from yeast to humans. The SM protein Vps45 is required for the formation of yeast endosomal SNARE complexes and is thus essential for traffic through the endosomal system. Here we report that, in addition to its role in regulating SNARE complex assembly, Vps45 regulates cellular levels of its SNARE binding partners: the syntaxin Tlg2 and the v-SNARE Snc2: Cells lacking Vps45 have reduced cellular levels of Tlg2 and Snc2; and elevation of Vps45 levels results in concomitant increases in the levels of both Tlg2 and Snc2. As well as regulating traffic through the endosomal system, the Snc v-SNAREs are also required for exocytosis. Unlike most vps mutants, cells lacking Vps45 display multiple growth phenotypes. Here we report that these can be reversed by selectively restoring Snc2 levels in vps45 mutant cells. Our data indicate that as well as functioning as part of the machinery that controls SNARE complex assembly, Vps45 also plays a key role in determining the levels of its cognate SNARE proteins; another key factor in regulation of membrane traffic

The gravity duals of SO/USp superconformal quivers

We study the gravity duals of SO/USp superconformal quiver gauge theories realized by M5-branes wrapping on a Riemann surface ("G-curve") together with a Z_2-quotient. When the G-curve has no punctures, the gravity solutions are classified by the genus g of the G-curve and the torsion part of the four-form flux G_4. We also find that there is an interesting relation between anomaly contributions from two mysterious theories: T_{SO(2N)} theory with SO(2N)^3 flavor symmetry and \tilde{T}_{SO(2N)} theory with SO(2N) x USp(2N-2)^2 flavor symmetry. The dual gravity solutions for various SO/USp-type tails are also studied.Comment: 27 pages, 13 figures; v2 minor corrections, typos corrected, Figure 13 replaced, references adde

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

What is the optimal duration of human chorionic gonadotrophin surveillance following evacuation of a molar pregnancy? A retrospective analysis on over 20,000 consecutive patients

OBJECTIVE: To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal Human Chorionic Gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines. METHODS: The Charing Cross Hospital Trophoblast Disease Centre database was screened to identify all registered cases of hydatidiform mole (HM) between 1980 and 2009. RESULTS: We identified 20,144 cases of HM, comprising 8,400 CHM, 9,586 PHM, and 2,158 cases of unclassified hydatidiform mole (UHM). Twenty-nine cases (20 CHM, 3 PHM and 6 UHM) developed pGTN after the first normal hCG. For CHM the risk of pGTN at the point of hCG normalisation was 1 in 406, and fell rapidly in the first six months of monitoring. For PHM the risk of pGTN at the point of hCG normalisation was 1 in 3,195. Women with CHM where hCG normalisation occurred beyond 56 days after uterine evacuation of molar tissue were found to have a 3.8-fold higher risk of pGTN. CONCLUSIONS: Our results show that pGTN can occur after hCG normalisation following PHM but the risk is extremely low. Women with CHM have a comparatively higher risk of pGTN after hCG normalisation. Those with CHM where hCG normalises within 56 days represent a group with a lower risk of pGTN. We have revised the current UK hCG surveillance protocol for PHM to a single additional confirmatory normal urine hCG measurement one month after first normalisation. The protocol for CHM remains unchanged

Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank

Background Older age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain whether leucocyte telomere length (LTL), previously proposed as a marker of biological age, is also associated with COVID-19 outcomes. Methods We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006–2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 130 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships. Findings Of 6775 participants in UKB who tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1·17 (95% CI 1·05–1·30; P = 0·004) per 1-SD shorter usual LTL, after adjustment for age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant. Interpretation Shorter LTL is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Further data are needed to determine whether this association reflects causality. Funding UK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation