Showing papers by "University of Cambridge published in 2022"

Brain charts for the human lifespan

Abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Recent Advances in Design of Electrocatalysts for High‐Current‐Density Water Splitting

Abstract: Electrochemical water splitting technology for producing "green hydrogen" is important for the global mission of carbon neutrality. Electrocatalysts with decent performance at high current densities play a central role in the industrial implementation of this technology. This field has advanced immensely in recent years, as witnessed by many types of catalysts designed and synthesized toward industriallyrelevant current densities (>200 mA cm-2 ). By discussing recent advances in this field, several key aspects are summarized that affect the catalytic performance for high-current-density electrocatalysis, including dimensionality of catalysts, surface chemistry, electron transport path, morphology, and catalyst-electrolyte interplay. The multiscale design strategy that considers these aspects comprehensively for developing high-current-density electrocatalysts are highlighted. The perspectives on the future directions in this emerging field are also put forward.

Clonal dynamics of haematopoiesis across the human lifespan

Abstract: Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

Using deep learning to annotate the protein universe

Abstract: Understanding the relationship between amino acid sequence and protein function is a long-standing challenge with far-reaching scientific and translational implications. State-of-the-art alignment-based techniques cannot predict function for one-third of microbial protein sequences, hampering our ability to exploit data from diverse organisms. Here, we train deep learning models to accurately predict functional annotations for unaligned amino acid sequences across rigorous benchmark assessments built from the 17,929 families of the protein families database Pfam. The models infer known patterns of evolutionary substitutions and learn representations that accurately cluster sequences from unseen families. Combining deep models with existing methods significantly improves remote homology detection, suggesting that the deep models learn complementary information. This approach extends the coverage of Pfam by >9.5%, exceeding additions made over the last decade, and predicts function for 360 human reference proteome proteins with no previous Pfam annotation. These results suggest that deep learning models will be a core component of future protein annotation tools. A deep learning model predicts protein functional annotations for unaligned amino acid sequences.

Traumatic brain injury: progress and challenges in prevention, clinical care, and research

Abstract: Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research. In LMICs, the occurrence of TBI is driven by road traffic incidents, often involving vulnerable road users such as motorcyclists and pedestrians. In HICs, most TBI is caused by falls, particularly in older people (aged ≥65 years), who often have comorbidities. Risk factors such as frailty and alcohol misuse provide opportunities for targeted prevention actions. Little evidence exists to inform treatment of older patients, who have been commonly excluded from past clinical trials—consequently, appropriate evidence is urgently required. Although increasing age is associated with worse outcomes from TBI, age should not dictate limitations in therapy. However, patients injured by low-energy falls (who are mostly older people) are about 50% less likely to receive critical care or emergency interventions, compared with those injured by high-energy mechanisms, such as road traffic incidents. Mild TBI, defined as a Glasgow Coma sum score of 13–15, comprises most of the TBI cases (over 90%) presenting to hospital. Around 50% of adult patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health by 6 months after their injury. Fewer than 10% of patients discharged after presenting to an emergency department for TBI in Europe currently receive follow-up. Structured follow-up after mild TBI should be considered good practice, and urgent research is needed to identify which patients with mild TBI are at risk for incomplete recovery. The selection of patients for CT is an important triage decision in mild TBI since it allows early identification of lesions that can trigger hospital admission or life-saving surgery. Current decision making for deciding on CT is inefficient, with 90–95% of scanned patients showing no intracranial injury but being subjected to radiation risks. InTBIR studies have shown that measurement of blood-based biomarkers adds value to previously proposed clinical decision rules, holding the potential to improve efficiency while reducing radiation exposure. Increased concentrations of biomarkers in the blood of patients with a normal presentation CT scan suggest structural brain damage, which is seen on MR scanning in up to 30% of patients with mild TBI. Advanced MRI, including diffusion tensor imaging and volumetric analyses, can identify additional injuries not detectable by visual inspection of standard clinical MR images. Thus, the absence of CT abnormalities does not exclude structural damage—an observation relevant to litigation procedures, to management of mild TBI, and when CT scans are insufficient to explain the severity of the clinical condition. Although blood-based protein biomarkers have been shown to have important roles in the evaluation of TBI, most available assays are for research use only. To date, there is only one vendor of such assays with regulatory clearance in Europe and the USA with an indication to rule out the need for CT imaging for patients with suspected TBI. Regulatory clearance is provided for a combination of biomarkers, although evidence is accumulating that a single biomarker can perform as well as a combination. Additional biomarkers and more clinical-use platforms are on the horizon, but cross-platform harmonisation of results is needed. Health-care efficiency would benefit from diversity in providers. In the intensive care setting, automated analysis of blood pressure and intracranial pressure with calculation of derived parameters can help individualise management of TBI. Interest in the identification of subgroups of patients who might benefit more from some specific therapeutic approaches than others represents a welcome shift towards precision medicine. Comparative-effectiveness research to identify best practice has delivered on expectations for providing evidence in support of best practices, both in adult and paediatric patients with TBI. Progress has also been made in improving outcome assessment after TBI. Key instruments have been translated into up to 20 languages and linguistically validated, and are now internationally available for clinical and research use. TBI affects multiple domains of functioning, and outcomes are affected by personal characteristics and life-course events, consistent with a multifactorial bio-psycho-socio-ecological model of TBI, as presented in the US National Academies of Sciences, Engineering, and Medicine (NASEM) 2022 report. Multidimensional assessment is desirable and might be best based on measurement of global functional impairment. More work is required to develop and implement recommendations for multidimensional assessment. Prediction of outcome is relevant to patients and their families, and can facilitate the benchmarking of quality of care. InTBIR studies have identified new building blocks (eg, blood biomarkers and quantitative CT analysis) to refine existing prognostic models. Further improvement in prognostication could come from MRI, genetics, and the integration of dynamic changes in patient status after presentation. Neurotrauma researchers traditionally seek translation of their research findings through publications, clinical guidelines, and industry collaborations. However, to effectively impact clinical care and outcome, interactions are also needed with research funders, regulators, and policy makers, and partnership with patient organisations. Such interactions are increasingly taking place, with exemplars including interactions with the All Party Parliamentary Group on Acquired Brain Injury in the UK, the production of the NASEM report in the USA, and interactions with the US Food and Drug Administration. More interactions should be encouraged, and future discussions with regulators should include debates around consent from patients with acute mental incapacity and data sharing. Data sharing is strongly advocated by funding agencies. From January 2023, the US National Institutes of Health will require upload of research data into public repositories, but the EU requires data controllers to safeguard data security and privacy regulation. The tension between open data-sharing and adherence to privacy regulation could be resolved by cross-dataset analyses on federated platforms, with the data remaining at their original safe location. Tools already exist for conventional statistical analyses on federated platforms, however federated machine learning requires further development. Support for further development of federated platforms, and neuroinformatics more generally, should be a priority. This update to the 2017 Commission presents new insights and challenges across a range of topics around TBI: epidemiology and prevention (section 1); system of care (section 2); clinical management (section 3); characterisation of TBI (section 4); outcome assessment (section 5); prognosis (Section 6); and new directions for acquiring and implementing evidence (section 7). Table 1 summarises key messages from this Commission and proposes recommendations for the way forward to advance research and clinical management of TBI.Table 1Key messages and recommendationsKey messagesRecommendationsSection 1Worldwide, TBI is a leading cause of injury-related death and disability, with devastating effects on patients and their familiesContinue concerted efforts to address this vast global health problem and focus on better prevention, improved access to care, and promotion of clinical research to improve treatment standardsSection 1More than 90% of patients presenting to hospital with TBI have so-called mild TBI (GCS 13–15), but evidence to inform treatment of patients with mild TBI is scarceIncrease public health interest and establish a research focus on mild TBISection 1In HICs, older patients (≥65 years) who are mostly injured by falls account for 30–40% of hospital admissions for TBI. Frailty and alcohol abuse contribute to falls causing TBI in older peopleTarget fall prevention for older citizens in HICsSections 1, 2People in LMICs are disproportionately affected by TBI, with most injuries caused by road traffic incidents. Substantial disparities in care exist, with little infrastructure available for emergency pre-hospital care and very little access to post-acute careDeliver on implementation of road safety goals, described in WHO's Decade for Action on Road Safety plan launched in 2021. Improve emergency pre-hospital care and develop an infrastructure for post-acute careSection 2Disparities in care also exist in HICs and relate to: older people injured by low-energy mechanisms (falls); access to rehabilitation for patients with moderate to severe TBI (GCS ≤12); and follow-up in patients with mild TBIAddress disparities through close collaboration between policymakers and clinicians; Approaches to consider include: critical appraisal of triage tools used in emergency settings; involvement of rehabilitation services at an early stage of the in-hospital treatment for TBI; and establishment of structured follow-up after mild TBI as good practiceSections 2, 4Use of blood-based biomarkers is on the verge of a breakthrough for diagnostic and prognostic use in TBI, but few assay platforms have been approved for clinical use and substantial variability exists between platformsStimulate the development, validation, and approval of clinical-use platforms, and facilitate cross-platform harmonisation of biomarker assaysSection 3Older patients often have co-morbidities, but very little evidence exists to inform their treatmentStimulate a research focus on older patients with TBISection 3Access to rehabilitation services is inconsistent and no protocols for treating long-term problems existImprove access to rehabilitation services and develop evidence-based treatments for long-term problems—including fatigue, and cognitive and behavioural changesSection 4Substantial advances have been made towards individualised management with improved characterisation and understanding of disease processes in TBI, but physicians are not yet sufficiently able to match therapies to subgroups of patientsStimulate research to identify subgroups of patients who would be most likely to benefit from specific interventionsSection 5Around 50% of patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health and wellbeing by 6 months after injuryImplement care pathways to ensure structured follow-up of patients with mild TBI, and stimulate research to identify patients with mild TBI at high risk for incomplete recovery, which would allow timely evaluation and treatmentSection 5Outcome in women after TBI is poorer than in menFacilitate research to help explain this sex and gender difference and inform intervention strategiesSection 6Prognostic models have been developed and extensively validated for moderate and severe TBI. No well-validated models exist for mild TBI, nor do models exist that are applicable across all ranges of TBI severityInitiatives should be stimulated to develop models applicable across the range of TBI severity. Availability of such models would constitute a huge step forward and facilitate implementation into clinical practiceSection 6Quality indicators developed for TBI are restricted to the ICU setting and are not yet ready for translation into practiceResearch should be stimulated to refine, validate, and implement quality indicators for TBISection 7Costs of data curation and deep harmonisation in preparation for sharing research data are underestimated and can amount to up to 20% of a study budgetFor completed studies, mechanisms should be developed to facilitate maintenance of the data and to provide guidance to external researchers wishing to analyse the data. For new studies, inclusion of an appropriate budget to prepare data for sharing should be foreseen in the grant awardSection 7TBI is often characterised by both an acute mental incapacity of patients to provide informed consent for participation in research and an emergency situation. Although GDPR recognises the issue of absence of capacity to provide consent, no provisions are included that are relevant to patients with an acute absence of capacity or to emergency situationsDevelop better regulatory guidance. Consider mandating that researchers obtain objective proof of mental capacity of the study participant, who might have been temporarily mentally incapacitated, before requesting informed consent.Section 7Data sharing and analyses across different datasets do not necessarily require data transfer and can be done on a federated platform. Use of a federated platform facilitates broad use of data and reduces the risks for violation of data security and privacy regulationSupport is required for the development of platforms for federated analysis, particularly for development and implementation of machine-learning techniques on such platformsTBI=traumatic brain injury. HICs=high-income countries. LMICs=low-income and middle-income countries. GCS=Glasgow Coma sum score. ICU=intensive care unit. GDPR=general data protection regulation. Open table in a new tab TBI=traumatic brain injury. HICs=high-income countries. LMICs=low-income and middle-income countries. GCS=Glasgow Coma sum score. ICU=intensive care unit. GDPR=general data protection regulation. The first Lancet Neurology Commission on traumatic brain injury (TBI),1Maas AIR Menon DK Adelson PD et al.Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research.Lancet Neurol. 2017; 16: 987-1048Summary Full Text Full Text PDF PubMed Scopus (938) Google Scholar published in 2017, provided a comprehensive resource for subsequent research, clinical care, and policy development. The Commission did more than just collate data; it provided an integrated picture of TBI in 2017, identified gaps in knowledge, and presented recommendations to improve clinical care and research from the perspectives of policymakers, clinicians, and researchers. This resource provided the foundation for a substantial body of subsequent research, informed the strategies of major funding organisations (such as the EU and the US National Institutes of Health [NIH]), and was used to brief legislators and inform policy.2Menon DK Bryant C Time for change in acquired brain injury.Lancet Neurol. 2019; 18: 28Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar The 2017 Commission documented that TBI was estimated to remain one of the top three causes of injury-related death and disability up to 2030. Overall, 50 million–60 million people have a TBI each year, costing the global economy around US$400 billion annually. Of all common neurological disorders, TBI has the highest incidence and poses a substantial public health burden (figure 1). In Europe, more than 2 million people are admitted to hospital each year because of TBI, and about 82 000 die.3Majdan M Plancikova D Brazinova A et al.Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis.Lancet Public Health. 2016; 1: e76-e83Summary Full Text Full Text PDF PubMed Scopus (213) Google Scholar Care for all severities of TBI was noted to be inconsistent across centres, regions, and countries, both for acute and post-acute care. The 2017 Commission recognised that the substantial between-centre variability in treatment and outcome in TBI offered unique opportunities for comparative-effectiveness research to improve the strength of evidence. Methods for diagnosis and classification of patients with TBI were noted to be insufficient to permit targeting of current and new therapies to the needs of individual patients. The Commission underlined the need for multidimensional outcome constructs that quantify the overall burden of disability from TBI, to guide improved clinical management, and to support high-quality research. Since publication of the 2017 Commission, much has changed in the field of TBI. Studies have provided new data on epidemiology and casemix of TBI in the hospital setting, and new insights regarding the effects of systems of care on TBI management and outcome. Clinical care has been informed by the results of a substantial body of research since that Commission, much of which was supported by the International TBI Research (InTBIR) initiative, a coalition of major funding bodies that came together in 2011 to support neurotrauma research.4Bell MJ Kochanek PM International traumatic brain injury research: an annus mirabilis?.Lancet Neurol. 2019; 18: 904-905Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Tosetti P Hicks RR Theriault E Phillips A Koroshetz W Draghia-Akli R Toward an international initiative for traumatic brain injury research.J Neurotrauma. 2013; 30: 1211-1222Crossref PubMed Scopus (61) Google Scholar Although there have been advances in the characterisation of TBI with the use of advanced neuroimaging, blood biomarkers, and genomics, these advances have not yet been fully translated into clinical care. However, there is increasing evidence that these advances will facilitate identification of patients with TBI who share specific disease mechanisms, treatment response characteristics, or prognosis, thus providing a basis for individualised management. Progress has also occurred in the prediction and characterisation of outcome following TBI, and although these advances are still being developed in research settings, their clinical application will likely occur over the next few years. Challenges remain, particularly in low-income and middle-income countries (LMICs), relating to prevention of TBI, access to care, and provision of clinical guidelines that can be implemented in resource-limited contexts. It is also crucial that we ensure equitable integration of researchers from LMICs in neurotrauma research. Disparities in care provision have also been identified in high-income countries (HICs). In the research context, developments both within the TBI field and insights into novel approaches to trial design from the COVID-19 pandemic have highlighted exciting new approaches and opportunities for generating evidence to support clinical care. Many of these new approaches are dependent on collaborative research and data-sharing, a process that can be constrained by regulatory requirements and facilitated by novel data analysis techniques. This 2022 update on the Commission for TBI describes advances along with attendant challenges and opportunities, and provides a staging post in ongoing efforts to improve clinical care and outcomes. The first Lancet Neurology Commission on TBI1Maas AIR Menon DK Adelson PD et al.Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research.Lancet Neurol. 2017; 16: 987-1048Summary Full Text Full Text PDF PubMed Scopus (938) Google Scholar highlighted the huge public health burden posed by TBI. Reported population-based incidence rates in New Zealand and North America were between 811 and 979 per 100 000 people per year and hospital discharge rates in the EU were 287·2 per 100 000 people per year, with substantial variation between Member States. We highlighted how methodological variations confound comparisons of TBI epidemiology patterns between regions, countries, and continents, and emphasised the need for standardised epidemiological monitoring and international consensus on definitions and approaches. Since then, the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study has provided estimates of global TBI incidence rates using a standardised approach.6James SL Theadom A Ellenbogen RG et al.Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2019; 18: 56-87Summary Full Text Full Text PDF PubMed Scopus (561) Google Scholar CENTER-TBI and TRACK-TBI—two large-scale, real-world observational studies on TBI of all severities—have provided insight into TBI-related disability and characteristics of patients currently presenting to hospital. The COVID-19 pandemic has had clear effects on both TBI incidence and presenting causes of injury. In this section, we discuss these new findings on the incidence, mechanisms, and burden of TBI. We additionally focus on four subpopulations of increasing relevance: older people, children and adolescents, criminal offenders, and sports participants, also highlighting specific targets for prevention and ongoing prevention initiatives. The age-adjusted incidence of all severities of TBI from epidemiological population-based studies published between 2015 and 2020 ranged between 476 per 100 000 individuals in South Korea7Kim H-K Leigh J-H Lee YS et al.Decreasing incidence and mortality in traumatic brain injury in Korea, 2008–2017: a population-based longitudinal study.Int J Environ Res Public Health. 2020; 17: 6197Crossref Scopus (4) Google Scholar to 787 per 100 000 individuals in the USA.8Taylor CA Bell JM Breiding MJ Xu L Traumatic brain injury-related emergency department visits, hospitalizations, and deaths—United States, 2007 and 2013.MMWR Surveill Summ. 2017; 66: 1-16Crossref PubMed Scopus (1139) Google Scholar However, these incidence studies might still underestimate the true extent of the problem. A Canadian study of concussion9Langer L Levy C Bayley M Increasing incidence of concussion: true epidemic or better recognition?.J Head Trauma Rehabil. 2020; 35: E60-E66Crossref PubMed Scopus (45) Google Scholar (a subset of mild TBI) revealed a higher annual incidence rate of 1153 per 100 000 individuals. Small regional or single-centre studies reported a decrease in TBI incidence during periods of COVID-19 lockdowns, reflecting decreased mobility, reduced participation in sports and recreational activities, and possibly reluctance to seek medical treatment for milder injuries.10Lester A Leach P Zaben M The impact of the COVID-19 pandemic on traumatic brain injury management: lessons learned over the first year.World Neurosurg. 2021; 156: 28-32Crossref PubMed Scopus (2) Google Scholar, 11Reitzle L Schmidt C Färber F et al.Perceived access to health care services and relevance of telemedicine during the COVID-19 pandemic in Germany.Int J Environ Res Public Health. 2021; 18: 7661Crossref PubMed Scopus (7) Google Scholar A few cohort studies reported12Figueroa JM Boddu J Kader M et al.The effects of lockdown during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on neurotrauma-related hospital admissions.World Neurosurg. 2021; 146: e1-e5Crossref PubMed Scopus (15) Google Scholar, 13Lãzãrescu AM Benichi S Blauwblomme T et al.Abusive head trauma in infants during the COVID-19 pandemic in the Paris metropolitan area.JAMA Netw Open. 2022; 5: e2226182Crossref PubMed Scopus (1) Google Scholar an increase in suspected head trauma in children and gunshot wounds to the head. Although there has been an increase in intimate partner violence during the pandemic,14Viero A Barbara G Montisci M Kustermann K Cattaneo C Violence against women in the COVID-19 pandemic: a review of the literature and a call for shared strategies to tackle health and social emergencies.Forensic Sci Int. 2021; 319: 110650Crossref PubMed Scopus (56) Google Scholar, 15Brink J Cullen P Beek K Peters SAE Intimate partner violence during the COVID-19 pandemic in Western and Southern European countries.Eur J Public Health. 2021; 31: 1058-1063Crossref PubMed Scopus (8) Google Scholar there are no specific data on TBI in this context. For the pre-COVID-19 era, GBD reported a worldwide age-standardised TBI incidence of 369 per 100 000 people (95% CI 331–412) in 2016.6James SL Theadom A Ellenbogen RG et al.Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2019; 18: 56-87Summary Full Text Full Text PDF PubMed Scopus (561) Google Scholar Updated rates for 2019 are 346 per 100 000 people (298–401).16Global Health Data Exchange.https://ghdx.healthdata.org/gbd-results-toolDate accessed: August 9, 2022Google Scholar These rates are lower than previously reported in population-based studies and closer to those reported for hospital admissions. A likely explanation is that GBD mainly accesses data from hospital presentations and uses an indirect approach to capturing TBI incidence involving identification of external causes of injury and linking the nature of the most severe injury to the external cause. Therefore, TBI might not be captured in cases with severe extracranial injuries. Assessing temporal trends and national variations in TBI incidence is complex and confounded by methodological diversity. We previously found a ten-fold difference in the reported incidence of hospital admissions for TBI between countries in Europe,3Majdan M Plancikova D Brazinova A et al.Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis.Lancet Public Health. 2016; 1: e76-e83Summary Full Text Full Text PDF PubMed Scopus (213) Google Scholar probably reflecting nation-specific differences in data capture and reporting methods. A major strength of the GBD approach is that it uses a standardised approach across all global regions and calculates age-adjusted incidence rates, enabling cross-country comparisons. Nevertheless, GBD also reported substantial between-country differences in incidence rates. A common denominator in both approaches is the use of hospital International Classification of Diseases (ICD) injury coding for data extraction. Inconsistencies within and between hospitals in ICD coding might be a main cause of the large variations observed. These considerations highlight a crucial need to standardise conduct and reporting of incidence studies. The main injury mechanisms causing TBI are falls, road traffic incidents, and violence. GBD reported that, overall, their relative contributions have remained stable between 1990 and 2019, with falls being the most common cause (52% in 1990 and 54% in 2019). These average numbers might, however, mask shifts within regions. Global modelling suggests that the incidence of TBI in LMICs is significantly higher than in HICs,6James SL Theadom A Ellenbogen RG et al.Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2019; 18: 56-87Summary Full Text Full Text PDF PubMed Scopus (561) Google Scholar, 17Dewan MC Rattani A Gupta S et al.Estimating the global incidence of traumatic brain injury.J Neurosurg. 2018; 130: 1-18PubMed Google Scholar and is mainly driven by road traffic collisions, particularly those involving motorcyclists. These findings were confirmed in the Global Neurotrauma Outcomes Study,18Clark D Joannides A Adeleye AO et al.Casemix, management, and mortality of patients receiving emergency neurosurgery for traumatic brain injury in the Global Neurotrauma Outcomes Study: a prospective observational cohort study.Lancet Neurol. 2022; 21: 438-449Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar showing a clear relationship between the mechanism of injury and the UN's Human Development Index (a composite index of life expectancy, education, and per person income indicators, which is used to rank countries into four tiers of human development: low, medium, high, and very high; figure 2). By contrast with findings in LMICs, the CENTER-TBI registry,19Lecky FE Otesile O Marincowitz C et al.The burden of traumatic brain injury from low-energy falls among patients from 18 countries in the CENTER-TBI registry: a comparative cohort study.PLoS Med. 2021; 18: e1003761Crossref PubMed Scopus (2) Google Scholar which mainly collected data from HICs, reported that 12 127 (56%) of 21 681 patients with TBI were injured by falls, of whom 71% had a low-energy (ground-level) fall. Compared with 13 059 patients injured by high-energy transfer, those injured through low-energy falls were older (median 74 years [IQR 56–84] vs 42 years [25–60]), and more often female (50% [95% CI 48–51] vs 32% [31–34]). The CENTER-TBI Core study20Steyerberg EW Wiegers E Sewalt C et al.Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study.Lancet Neurol. 2019; 18: 923-934Su

Room-temperature optically detected magnetic resonance of single defects in hexagonal boron nitride

Abstract: Optically addressable spins in materials are important platforms for quantum technologies, such as repeaters and sensors. Identification of such systems in two-dimensional (2d) layered materials offers advantages over their bulk counterparts, as their reduced dimensionality enables more feasible on-chip integration into devices. Here, we report optically detected magnetic resonance (ODMR) from previously identified carbon-related defects in 2d hexagonal boron nitride (hBN). We show that single-defect ODMR contrast can be as strong as 6% and displays a magnetic-field dependence with both positive or negative sign per defect. This bipolarity can shed light into low contrast reported recently for ensemble ODMR measurements for these defects. Further, the ODMR lineshape comprises a doublet resonance, suggesting either low zero-field splitting or hyperfine coupling. Our results offer a promising route towards realising a room-temperature spin-photon quantum interface in hexagonal boron nitride.

Fast, Slow, Early, Late: Quenching Massive Galaxies at z ∼ 0.8

Abstract: We investigate the stellar populations for a sample of 161 massive, mainly quiescent galaxies at $\langle z_{\rm obs} \rangle=0.8$ with deep Keck/DEIMOS rest-frame optical spectroscopy (HALO7D survey). With the fully Bayesian framework Prospector, we simultaneously fit the spectroscopic and photometric data with an advanced physical model (including non-parametric star-formation histories, emission lines, variable dust attenuation law, and dust and AGN emission) together with an uncertainty and outlier model. We show that both spectroscopy and photometry are needed to break the dust-age-metallicity degeneracy. We find a large diversity of star-formation histories: although the most massive ($M_{\star}>2\times10^{11}~M_{\odot}$) galaxies formed the earliest (formation redshift of $z_{\rm f}\approx5-10$ with a short star-formation timescale of $\tau_{\rm SF}\lesssim1~\mathrm{Gyr}$), lower-mass galaxies have a wide range of formation redshifts, leading to only a weak trend of $z_{\rm f}$ with $M_{\star}$. Interestingly, several low-mass galaxies with have formation redshifts of $z_{\rm f}\approx5-8$. Star-forming galaxies evolve about the star-forming main sequence, crossing the ridgeline several times in their past. Quiescent galaxies show a wide range and continuous distribution of quenching timescales ($\tau_{\rm quench}\approx0-5~\mathrm{Gyr}$) with a median of $\langle\tau_{\rm quench}\rangle=1.0_{-0.9}^{+0.8}~\mathrm{Gyr}$ and of quenching epochs of $z_{\rm quench}\approx0.8-5.0$ ($\langle z_{\rm quench}\rangle=1.3_{-0.4}^{+0.7}$). This large diversity of quenching timescales and epochs points toward a combination of internal and external quenching mechanisms. In our sample, rejuvenation and "late bloomers" are uncommon. In summary, our analysis supports the "grow & quench" framework and is consistent with a wide and continuously-populated diversity of quenching timescales.

How Reproducible are Surface Areas Calculated from the BET Equation?

Abstract: Porosity and surface area analysis play a prominent role in modern materials science. At the heart of this sits the Brunauer-Emmett-Teller (BET) theory, which has been a remarkably successful contribution to the field of materials science. The BET method was developed in the 1930s for open surfaces but is now the most widely used metric for the estimation of surface areas of micro- and mesoporous materials. Despite its widespread use, the calculation of BET surface areas causes a spread in reported areas, resulting in reproducibility problems in both academia and industry. To prove this, for this analysis, 18 already-measured raw adsorption isotherms were provided to sixty-one labs, who were asked to calculate the corresponding BET areas. This round-robin exercise resulted in a wide range of values. Here, the reproducibility of BET area determination from identical isotherms is demonstrated to be a largely ignored issue, raising critical concerns over the reliability of reported BET areas. To solve this major issue, a new computational approach to accurately and systematically determine the BET area of nanoporous materials is developed. The software, called "BET surface identification" (BETSI), expands on the well-known Rouquerol criteria and makes an unambiguous BET area assignment possible.

On the Stellar Populations of Galaxies at z = 9–11: The Growth of Metals and Stellar Mass at Early Times

Abstract: We present a detailed stellar population analysis of 11 bright ($H<26.6$) galaxies at $z=9-11$ (three spectroscopically confirmed) to constrain the chemical enrichment and growth of stellar mass of early galaxies. We use the flexible Bayesian spectral energy distribution (SED) fitting code Prospector with a range of star-formation histories (SFHs), a flexible dust attenuation law and a self-consistent modeling of emission lines. This approach allows us to assess how different priors affect our results, and how well we can break degeneracies between dust attenuation, stellar ages, metallicity and emission lines using data which probe only the rest-frame ultraviolet to optical wavelengths. We measure a median observed ultraviolet spectral slope $\beta=-1.87_{-0.43}^{+0.35}$ for relatively massive star-forming galaxies ($9<\log(M_{\star}/M_{\odot})<10$), consistent with no change from $z=4$ to $z=9-10$ at these stellar masses, implying rapid enrichment. Our SED-fitting results are consistent with a star-forming main sequence with sub-linear slope ($0.7\pm0.2$) and specific star-formation rates of $3-10~\mathrm{Gyr}^{-1}$. However, the stellar ages and SFHs are less well constrained. Using different SFH priors, we cannot distinguish between median mass-weighted ages of $\sim50-150$ Myr, which corresponds to 50\% formation redshifts of $z_{50}\sim10-12$ at $z\sim9$ and is of the order of the dynamical timescales of these systems. Importantly, the models with different SFH priors are able to fit the data equally well. We conclude that the current observational data cannot tightly constrain the mass-buildup timescales of these $z=9-11$ galaxies, with our results consistent with SFHs implying both a shallow and steep increase of the cosmic SFR density with time at $z>10$.

The impact of the coronavirus lockdown on mental health: evidence from the United States

Abstract: Abstract The coronavirus outbreak has caused significant disruptions to people’s lives. We exploit variation in lockdown measures across states to document the impact of stay-at-home orders on mental health using real-time survey data in the United States. We find that the lockdown measures lowered mental health by 0.083 standard deviations. This large negative effect is entirely driven by women. As a result of the lockdown measures, the existing gender gap in mental health has increased by 61%. The negative effect on women’s mental health cannot be explained by an increase in financial worries or caring responsibilities.

Thermal comfort in hospital buildings – A literature review

Abstract: Hospital buildings are required to secure a variety of indoor environments according to the diverse requirements of patients and staff. Among these requirements, thermal comfort is an important design criterion for indoor environmental quality that affects patients' healing processes and the wellbeing of medical staff. The patients’ thermal comfort is given priority due to their medical conditions and impaired immune systems. Thermal comfort and related contexts have been well-covered in many research articles; however, the number of review articles is limited. This article aims to conduct a holistic and critical review of existing studies offering insights on future research trends (180 articles were analyzed). The key research themes are identified using scientometric analysis. Focus is on influencing factors, field-surveys, improving measures and energy saving related to thermal comfort. The primary outcome concludes that ventilation systems play a key role in maintaining acceptable, thermally-comfortable conditions for patients and medical staff. It is also found that acceptable thermal comfort is highly case-dependent and varies substantially based on the health condition of the patient as well as the type and level of staff activities. The measures currently mentioned to minimize energy consumption are also discussed. Some interesting issues, including the inaccuracy arising from the use of predicted mean vote (PMV) and the impact of gender, age, and related factors on thermal comfort, have been noted. This review provides insights into the design and assessment of hospital thermal environments.

Genetic associations of protein-coding variants in human disease

Abstract: Abstract Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes 1 . Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.

VQE method: a short survey and recent developments

Abstract: Abstract The variational quantum eigensolver (VQE) is a method that uses a hybrid quantum-classical computational approach to find eigenvalues of a Hamiltonian. VQE has been proposed as an alternative to fully quantum algorithms such as quantum phase estimation (QPE) because fully quantum algorithms require quantum hardware that will not be accessible in the near future. VQE has been successfully applied to solve the electronic Schrödinger equation for a variety of small molecules. However, the scalability of this method is limited by two factors: the complexity of the quantum circuits and the complexity of the classical optimization problem. Both of these factors are affected by the choice of the variational ansatz used to represent the trial wave function. Hence, the construction of an efficient ansatz is an active area of research. Put another way, modern quantum computers are not capable of executing deep quantum circuits produced by using currently available ansatzes for problems that map onto more than several qubits. In this review, we present recent developments in the field of designing efficient ansatzes that fall into two categories—chemistry–inspired and hardware–efficient—that produce quantum circuits that are easier to run on modern hardware. We discuss the shortfalls of ansatzes originally formulated for VQE simulations, how they are addressed in more sophisticated methods, and the potential ways for further improvements.

Chiral self-assembly of cellulose nanocrystals is driven by crystallite bundles

Abstract: Abstract The transfer of chirality across length-scales is an intriguing and universal natural phenomenon. However, connecting the properties of individual building blocks to the emergent features of their resulting large-scale structure remains a challenge. In this work, we investigate the origins of mesophase chirality in cellulose nanocrystal suspensions, whose self-assembly into chiral photonic films has attracted significant interest. By correlating the ensemble behaviour in suspensions and films with a quantitative morphological analysis of the individual nanoparticles, we reveal an inverse relationship between the cholesteric pitch and the abundance of laterally-bound composite particles. These ‘bundles’ thus act as colloidal chiral dopants, analogous to those used in molecular liquid crystals, providing the missing link in the hierarchical transfer of chirality from the molecular to the colloidal scale.

A review of molecular representation in the age of machine learning

Abstract: Research in chemistry increasingly requires interdisciplinary work prompted by, among other things, advances in computing, machine learning, and artificial intelligence. Everyone working with molecules, whether chemist or not, needs an understanding of the representation of molecules in a machine-readable format, as this is central to computational chemistry. Four classes of representations are introduced: string, connection table, feature-based, and computer-learned representations. Three of the most significant representations are simplified molecular-input line-entry system (SMILES), International Chemical Identifier (InChI), and the MDL molfile, of which SMILES was the first to successfully be used in conjunction with a variational autoencoder (VAE) to yield a continuous representation of molecules. This is noteworthy because a continuous representation allows for efficient navigation of the immensely large chemical space of possible molecules. Since 2018, when the first model of this type was published, considerable effort has been put into developing novel and improved methodologies. Most, if not all, researchers in the community make their work easily accessible on GitHub, though discussion of computation time and domain of applicability is often overlooked. Herein, we present questions for consideration in future work which we believe will make chemical VAEs even more accessible. This article is categorized under: Data Science > Chemoinformatics

Population level physical activity before and during the first national COVID-19 lockdown: A nationally representative repeat cross-sectional study of 5 years of Active Lives data in England

Abstract: Summary Background To limit the spread of COVID-19 in March 2020, the population of England was instructed to stay home, leaving only for essential shopping, health-care, work, or exercise. The impact on population activity behaviours is not clear. We describe changes in duration and types of activity undertaken by adults ≥16 years in England between March and May 2016-19 and 2020, by socio-demographic strata. Methods Using nationally representative data collected between November 2015 and May 2020 by the Sport England Active Lives Surveys (n=726,257) we assessed trends in amount and type of non-occupational moderate-to-vigorous physical activity. Using data from n=74,430 mid-April to mid-May respondents, we then estimated the odds ratios of reporting any activity in the four-week recall period in 2020 compared to 2016-19. Gamma regressions estimated the mean ratios (MR) of duration amongst those reporting any activity in 2020 compared to 2016-19. Findings Population activity declined substantially after the restrictions were introduced. Compared to 2016-19 levels, the odds of reporting any activity in 2020 were 30% lower (95% confidence interval (CI) 26-34%). The largest declines were amongst non-white ethnicities, the youngest and oldest age groups, and the unemployed; no socio-demographic subgroup had higher odds. Amongst those undertaking activity, weekly duration was similar in the two periods (MR 0.99, 95%CI (0.96-1.01%)). The odds of participating in walking for leisure and gardening were 11% (6-16%) and 15% (9-21%) higher, respectively, whereas the odds for team and racket sport and walking for travel participation were 76% (73-79%) and 66% (64-68%) lower, respectively. Interpretation Restrictions introduced in Spring 2020 likely reduced physical activity levels in England. The magnitude of the declines were not uniform by demographic groups or by activity type, which future policies should consider. Funding TS, KW, SJS, and SB are supported by UK Medical Research Council [grant numbers MC_UU_00006/4 and MC_UU_12015/3] and SB is supported by the NIHR Biomedical Research Centre in Cambridge (IS-BRC-1215-20014).

Genetic correlates of phenotypic heterogeneity in autism

Abstract: The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.

PD-L1–PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection

Abstract: Phenotypic and transcriptional profiling of regulatory T (Treg) cells at homeostasis reveals that T cell receptor activation promotes Treg cells with an effector phenotype (eTreg) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eTreg cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced Treg cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in Treg cells prevents loss of eTreg cells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells: eTreg cells and increased levels of interleukin-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eTreg cell expression of PD-1 acts as a sensor to rapidly tune the pool of eTreg cells at homeostasis and during inflammatory processes.