National contributions to climate change due to historical emissions of carbon dioxide, methane, and nitrous oxide since 1850.

Anthropogenic emissions of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) have made significant contributions to global warming since the pre-industrial period and are therefore targeted in international climate policy. There is substantial interest in tracking and apportioning national contributions to climate change and informing equitable commitments to decarbonisation. Here, we introduce a new dataset of national contributions to global warming caused by historical emissions of carbon dioxide, methane, and nitrous oxide during the years 1851-2021, which are consistent with the latest findings of the IPCC. We calculate the global mean surface temperature response to historical emissions of the three gases, including recent refinements which account for the short atmospheric lifetime of CH4. We report national contributions to global warming resulting from emissions of each gas, including a disaggregation to fossil and land use sectors. This dataset will be updated annually as national emissions datasets are updated.

Comorbidities and clinical outcomes in adult- and juvenile-onset Huntington's disease: a study of linked Swedish National Registries (2002-2019).

BACKGROUND: Huntington's disease (HD) is a rare, neurodegenerative disease and its complex motor, cognitive and psychiatric symptoms exert a lifelong clinical burden on both patients and their families. OBJECTIVE: To describe the clinical burden and natural history of HD. METHODS: This longitudinal cohort study used data from the linked Swedish national registries to describe the occurrence of comorbidities (acute and chronic), symptomatic treatments and mortality in an incident cohort of individuals who either received the first diagnosis of HD above (adult onset HD; AoHD) or below (juvenile-onset HD; JoHD) 20 years of age, compared with a matched cohort without HD from the general population. Disease burden of all individuals alive in Sweden was described during a single calendar year (2018), including the occurrence of key symptoms, treatments and hospitalizations. RESULTS: The prevalence of HD in 2018 was approximately 10.2 per 100,000. Of 1492 individuals with a diagnosis of HD during 2002 and 2018, 1447 had AoHD and 45 had JoHD. Individuals with AoHD suffered a higher incidence of obsessive-compulsive disorder, acute psychotic episodes, pneumonia, constipation and fractures compared with matched controls. Individuals with JoHD had higher incidence rates of epilepsy, constipation and acute respiratory symptoms. Median time to all-cause mortality in AoHD was 12.1 years from diagnosis. Patients alive with HD in Sweden in 2018 displayed a pattern of increased clinical burden for a number of years since diagnosis. CONCLUSIONS: This study demonstrates the significant and progressive clinical burden in individuals with HD and presents novel insights into the natural history of JoHD.

Patient and public involvement and engagement with cardiac arrest survivors.

Background: Patient and public involvement and engagement (PPIE) with cardiac arrest survivors is an essential component of research to strengthen development, design, delivery and dissemination to ensure research priorities are in the public interest and patient friendly. Cardiac arrest survivors and their relatives were engaged in PPIE to help develop the methods of a research study that aims to reduce individual and care process variation during paramedic-led resuscitation. Methods: This research methodology paper represents the views of seven PPIE representatives and the authors. PPIE representatives included five cardiac arrest survivors and two relatives. Content for the paper was generated by discussion using audio or video call. Notes were taken by the author which included direct quotations generated by the PPIE process. Results: The PPIE representatives considered research surrounding the decisions made by paramedics to be important. From their first-hand experiences, survivors and their relatives felt that a future research study should focus on patient survival. The decision-making of paramedics was identified as most important to explore. Quality of life before the cardiac arrest was considered important as this may help to inform best-interest decisions. The neurologic recovery of patients was important; however, rehabilitation may be extensive and therefore unachievable within the study timeframe. Relatives highlighted that while incorporating their views during resuscitation was important, gaining consent for research participation was not appropriate. Conclusion: PPIE added value and helped to develop a future study to reduce variation in the resuscitation decisions made by paramedics. The group identified what is important to survivors and their relatives and the factors they would like paramedics to consider when making a resuscitation decision. By identifying these factors, the PPIE process has helped to drive the research methods where both quantitative and qualitative designs would be appropriate. Issues in gaining research consent during resuscitation were highlighted.

Forest expansion dominates China's land carbon sink since 1980.

Carbon budget accounting relies heavily on Food and Agriculture Organization land-use data reported by governments. Here we develop a new land-use and cover-change database for China, finding that differing historical survey methods biased China's reported data causing large errors in Food and Agriculture Organization databases. Land ecosystem model simulations driven with the new data reveal a strong carbon sink of 8.9 ± 0.8 Pg carbon from 1980 to 2019 in China, which was not captured in Food and Agriculture Organization data-based estimations due to biased land-use and cover-change signals. The land-use and cover-change in China, characterized by a rapid forest expansion from 1980 to 2019, contributed to nearly 44% of the national terrestrial carbon sink. In contrast, climate changes (22.3%), increasing nitrogen deposition (12.9%), and rising carbon dioxide (8.1%) are less important contributors. This indicates that previous studies have greatly underestimated the impact of land-use and cover-change on the terrestrial carbon balance of China. This study underlines the importance of reliable land-use and cover-change databases in global carbon budget accounting.

The global potential for increased storage of carbon on land.

Constraining the climate crisis requires urgent action to reduce anthropogenic emissions while simultaneously removing carbon dioxide from the atmosphere. Improved information about the maximum magnitude and spatial distribution of opportunities for additional land-based removals of CO2 is needed to guide on-the-ground decision-making about where to implement climate change mitigation strategies. Here, we present a globally consistent spatial dataset (approximately 500-m resolution) of current, potential, and unrealized potential carbon storage in woody plant biomass and soil organic matter. We also provide a framework for prioritizing actions related to the restoration, management, and maintenance of woody carbon stocks and associated soils. By comparing current to potential carbon storage, while excluding areas critical to food production and human habitation, we find 287 petagrams (PgC) of unrealized potential storage opportunity, of which 78% (224 PgC) is in biomass and 22% (63 PgC) is in soil. Improved management of existing forests may offer nearly three-fourths (206 PgC) of the total unrealized potential, with the majority (71%) concentrated in tropical ecosystems. However, climate change is a source of considerable uncertainty. While additional research is needed to understand the impact of natural disturbances and biophysical feedbacks, we project that the potential for additional carbon storage in woody biomass will increase (+17%) by 2050 despite projected decreases (−12%) in the tropics. Our results establish an absolute reference point and conceptual framework for national and jurisdictional prioritization of locations and actions to increase land-based carbon storage.

New land-use-change emissions indicate a declining CO2 airborne fraction.

About half of the anthropogenic CO2 emissions remain in the atmosphere and half are taken up by the land and ocean1. If the carbon uptake by land and ocean sinks becomes less efficient, for example, owing to warming oceans2 or thawing permafrost3, a larger fraction of anthropogenic emissions will remain in the atmosphere, accelerating climate change. Changes in the efficiency of the carbon sinks can be estimated indirectly by analysing trends in the airborne fraction, that is, the ratio between the atmospheric growth rate and anthropogenic emissions of CO2 (refs. 4-10). However, current studies yield conflicting results about trends in the airborne fraction, with emissions related to land use and land cover change (LULCC) contributing the largest source of uncertainty7,11,12. Here we construct a LULCC emissions dataset using visibility data in key deforestation zones. These visibility observations are a proxy for fire emissions13,14, which are - in turn - related to LULCC15,16. Although indirect, this provides a long-term consistent dataset of LULCC emissions, showing that tropical deforestation emissions increased substantially (0.16 Pg C decade-1) since the start of CO2 concentration measurements in 1958. So far, these emissions were thought to be relatively stable, leading to an increasing airborne fraction4,5. Our results, however, indicate that the CO2 airborne fraction has decreased by 0.014 ± 0.010 decade-1 since 1959. This suggests that the combined land-ocean sink has been able to grow at least as fast as anthropogenic emissions.

Divinylpyrimidine reagents generate antibody-drug conjugates with excellent in vivo efficacy and tolerability.

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.

Comorbidity Trajectories Associated With Alzheimer's Disease: A Matched Case-Control Study in a United States Claims Database.

Background: Trajectories of comorbidities among individuals at risk of Alzheimer's disease (AD) may differ from those aging without AD clinical syndrome. Therefore, characterizing the comorbidity burden and pattern associated with AD risk may facilitate earlier detection, enable timely intervention, and help slow the rate of cognitive and functional decline in AD. This case-control study was performed to compare the prevalence of comorbidities between AD cases and controls during the 5 years prior to diagnosis (or index date for controls); and to identify comorbidities with a differential time-dependent prevalence trajectory during the 5 years prior to AD diagnosis. Methods: Incident AD cases and individually matched controls were identified in a United States claims database between January 1, 2000 and December 31, 2016. AD status and comorbidities were defined based on the presence of diagnosis codes in administrative claims records. Generalized estimating equations were used to assess evidence of changes over time and between AD and controls. A principal component analysis and hierarchical clustering was performed to identify groups of AD-related comorbidities with respect to prevalence changes over time (or trajectory), and differences between AD and controls. Results: Data from 186,064 individuals in the IBM MarketScan Commercial Claims and Medicare Supplementary databases were analyzed (93,032 AD cases and 93,032 non-AD controls). In total, there were 177 comorbidities with a ≥ 5% prevalence. Five main clusters of comorbidities were identified. Clusters differed between AD cases and controls in the overall magnitude of association with AD, in their diverging time trajectories, and in comorbidity prevalence. Three clusters contained comorbidities that notably increased in frequency over time in AD cases but not in controls during the 5-year period before AD diagnosis. Comorbidities in these clusters were related to the early signs and/or symptoms of AD, psychiatric and mood disorders, cerebrovascular disease, history of hazard and injuries, and metabolic, cardiovascular, and respiratory complaints. Conclusion: We demonstrated a greater comorbidity burden among those who later developed AD vs. controls, and identified comorbidity clusters that could distinguish these two groups. Further investigation of comorbidity burden is warranted to facilitate early detection of individuals at risk of developing AD.

Modeling Manifest Huntington's Disease Prevalence Using Diagnosed Incidence and Survival Time.

INTRODUCTION: Understanding the epidemiology of Huntington's disease (HD) is key to assessing disease burden and the healthcare resources required to meet patients' needs. We aimed to develop and validate a model to estimate the diagnosed prevalence of manifest HD by the Shoulson-Fahn stage. METHODS: A literature review identified epidemiological data from Brazil, Canada, France, Germany, Italy, Spain, the UK, and the USA. Data on staging distribution at diagnosis, progression, and mortality were derived from Enroll-HD. Newly diagnosed patients with manifest HD were simulated by applying annual diagnosed incidence rates to the total population in each country, each year from 1950 onwards. The number of diagnosed prevalent patients from the previous year who remained in each stage was estimated in line with the probability of death or progression. Diagnosed prevalence in 2020 was estimated as the sum of simulated patients, from all the incident cohorts, still alive. RESULTS: The model estimates that in 2020, there were 66,787 individuals diagnosed with HD in the 8 included countries, of whom 62-63% were in Shoulson-Fahn stages 1 and 2 (with less severely limited functional capacity than those in stages 3-5). Diagnosed prevalence is estimated to be 8.2-9.0 per 100,000 in the USA, Canada, and the 5 included European countries and 3.5 per 100,000 in Brazil. CONCLUSION: The modeled estimates generally accord with the previously published data. This analysis contributes to better understanding of the epidemiology of HD and highlights areas of uncertainty.

Risperidone versus aripiprazole fracture risk in children and adolescents with autism spectrum disorders.

Risperidone and aripiprazole, commonly used antipsychotics in children with autism spectrum disorder (ASD), have previously been associated with elevated fracture risk in other populations. The aim of this study was to evaluate and compare the risk of fracture among children with ASD using risperidone or aripiprazole. This was a retrospective, propensity-score matched cohort study, set between January 2013 and December 2018. We used the MarketScan Medicaid insurance data, which covers multiple states of the United States. We included ASD children aged 2-18 years, who were new users of aripiprazole or risperidone and with no prior history of antipsychotic use or fractures. The main exposure was the continued use of aripiprazole or risperidone. The incidence rates of any fracture during follow-up were evaluated, and the risk between aripiprazole and risperidone was compared via Cox-proportional hazard models. Results were stratified by age, sex, duration of exposure and fracture site. In total, 3312 patients (78% male; mean [SD] age 11.0 [3.7] years) were identified for each cohort. Over the full duration of follow-up, fracture incidence rates per 1000 patient-years were 23.2 for risperidone and 38.4 for aripiprazole (hazard ratio and 95% confidence interval: 0.60 [0.44-0.83]). Risks were similar between cohorts throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. Extremity fractures drove most of the increased risk, with the biggest differences in lower leg and ankle fractures. Differences widened for children aged 10 years or younger (HR [95% CI]: 0.47 [0.30-0.74]). In conclusion, compared to aripiprazole, risperidone was associated with 40% lower risk of fracture. Further analysis on the mechanism and long-term bone health of antipsychotic-treated children with ASD is warranted. LAY SUMMARY: We compared the risk of bone fractures among 6624 children with autism spectrum disorder (ASD), half of whom used risperidone and half of whom used aripiprazole. Taking other factors into account, risks were similar between the two groups throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. The biggest differences were in lower leg and ankle fractures. Overall, compared with aripiprazole, risperidone was associated with 40% lower risk of fracture.

Ranking the Predictive Power of Clinical and Biological Features Associated With Disease Progression in Huntington's Disease.

Huntington's disease (HD) is characterised by a triad of cognitive, behavioural, and motor symptoms which lead to functional decline and loss of independence. With potential disease-modifying therapies in development, there is interest in accurately measuring HD progression and characterising prognostic variables to improve efficiency of clinical trials. Using the large, prospective Enroll-HD cohort, we investigated the relative contribution and ranking of potential prognostic variables in patients with manifest HD. A random forest regression model was trained to predict change of clinical outcomes based on the variables, which were ranked based on their contribution to the prediction. The highest-ranked variables included novel predictors of progression-being accompanied at clinical visit, cognitive impairment, age at diagnosis and tetrabenazine or antipsychotics use-in addition to established predictors, cytosine adenine guanine (CAG) repeat length and CAG-age product. The novel prognostic variables improved the ability of the model to predict clinical outcomes and may be candidates for statistical control in HD clinical studies.

Evaluating nature-based solutions for climate mitigation and conservation requires comprehensive carbon accounting.

Nature-based solutions (NbS) can address climate change, biodiversity loss, human well-being and their interactions in an integrated way. A major barrier to achieving this is the lack of comprehensiveness in current carbon accounting which has focused on flows rather than stocks of carbon and led to perverse outcomes. We propose a new comprehensive approach to carbon accounting based on the whole carbon cycle, covering both stocks and flows, and linking changes due to human activities with responses in the biosphere and atmosphere. We identify enhancements to accounting, namely; inclusion of all carbon reservoirs, changes in their condition and stability, disaggregated flows, and coverage of all land areas. This comprehensive approach recognises that both carbon stocks (as storage) and carbon flows (as sequestration) contribute to the ecosystem service of global climate regulation. In contrast, current ecosystem services measurement and accounting commonly use only carbon sequestration measured as net flows, while greenhouse gas inventories use flows from sources to sinks. This flow-based accounting has incentivised planting and maintaining young forests with high carbon uptake rates, resulting, perversely, in failing to reveal the greater mitigation benefit from protecting larger, more stable and resilient carbon stocks in natural forests. We demonstrate the benefits of carbon storage and sequestration for climate mitigation, in theory as ecosystem services within an ecosystem accounting framework, and in practice using field data that reveals differences in results between accounting for stocks or flows. Our proposed holistic and comprehensive carbon accounting makes transparent the benefits, trade-offs and shortcomings of NbS actions for climate mitigation and sustainability outcomes. Adopting this approach is imperative for revision of ecosystem accounting systems under the System of Environmental-Economic Accounting and contributing to evidence-based decision-making for international conventions on climate (UNFCCC), biodiversity (CBD) and sustainability (SDGs).

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease.

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

Mapping carbon accumulation potential from global natural forest regrowth.

To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide1,2. Regrowing natural forests is a prominent strategy for capturing additional carbon3, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates2,3. To assess why and where rates differ, here we compile 13,112 georeferenced measurements of carbon accumulation. Climatic factors explain variation in rates better than land-use history, so we combine the field measurements with 66 environmental covariate layers to create a global, one-kilometre-resolution map of potential aboveground carbon accumulation rates for the first 30 years of natural forest regrowth. This map shows over 100-fold variation in rates across the globe, and indicates that default rates from the Intergovernmental Panel on Climate Change (IPCC)4,5 may underestimate aboveground carbon accumulation rates by 32 per cent on average and do not capture eight-fold variation within ecozones. Conversely, we conclude that maximum climate mitigation potential from natural forest regrowth is 11 per cent lower than previously reported3 owing to the use of overly high rates for the location of potential new forest. Although our data compilation includes more studies and sites than previous efforts, our results depend on data availability, which is concentrated in ten countries, and data quality, which varies across studies. However, the plots cover most of the environmental conditions across the areas for which we predicted carbon accumulation rates (except for northern Africa and northeast Asia). We therefore provide a robust and globally consistent tool for assessing natural forest regrowth as a climate mitigation strategy.

Contribution of land use to the interannual variability of the land carbon cycle.

Understanding the driving mechanisms of the interannual variability (IAV) of the net land carbon balance (Snet) is important to predict future climate-carbon cycle feedbacks. Past studies showed that the IAV of Snet was correlated with tropical climate variation and controlled by semiarid vegetation. But today's land ecosystems are also under extensive human land use and management. Here, we report a previously hidden role of land use in driving the IAV of Snet by using an improved biosphere model. We found that managed land accounted for 30-45% of the IAV of Snet over 1959-2015, while the contribution of intact land is reduced by more than half compared with previous assessments of the global carbon budget. Given the importance of land use in modulating future land climate-carbon cycle feedbacks, climate mitigation efforts should strive to reduce land-use emissions and enhance the climate resilience of carbon sinks over managed land.

Terrestrial fluxes of carbon in GCP carbon budgets.

The Global Carbon Project (GCP) has published global carbon budgets annually since 2007 (Canadell et al. [2007], Proc Natl Acad Sci USA, 104, 18866-18870; Raupach et al. [2007], Proc Natl Acad Sci USA, 104, 10288-10293). There are many scientists involved, but the terrestrial fluxes that appear in the budgets are not well understood by ecologists and biogeochemists outside of that community. The purpose of this paper is to make the terrestrial fluxes of carbon in those budgets more accessible to a broader community. The GCP budget is composed of annual perturbations from pre-industrial conditions, driven by addition of carbon to the system from combustion of fossil fuels and by transfers of carbon from land to the atmosphere as a result of land use. The budget includes a term for each of the major fluxes of carbon (fossil fuels, oceans, land) as well as the rate of carbon accumulation in the atmosphere. Land is represented by two terms: one resulting from direct anthropogenic effects (Land Use, Land-Use Change, and Forestry or land management) and one resulting from indirect anthropogenic (e.g., CO2 , climate change) and natural effects. Each of these two net terrestrial fluxes of carbon, in turn, is composed of opposing gross emissions and removals (e.g., deforestation and forest regrowth). Although the GCP budgets have focused on the two net terrestrial fluxes, they have paid little attention to the gross components, which are important for a number of reasons, including understanding the potential for land management to remove CO2 from the atmosphere and understanding the processes responsible for the sink for carbon on land. In contrast to the net fluxes of carbon, which are constrained by the global carbon budget, the gross fluxes are largely unconstrained, suggesting that there is more uncertainty than commonly believed about how terrestrial carbon emissions will respond to future fossil fuel emissions and a changing climate.

Psychostimulants/Atomoxetine and Serious Cardiovascular Events in Children with ADHD or Autism Spectrum Disorder.

BACKGROUND: Psychostimulants and atomoxetine have been shown to increase blood pressure, heart rate, and QT interval in children and adolescents; however, based on current literature, it is unclear if these "attention-deficit/hyperactivity disorder (ADHD) medications" are also associated with serious cardiovascular (SCV) events. We addressed this question in commonly exposed groups of children and adolescents with either ADHD or autism spectrum disorder (ASD). METHODS: Using commercial (years 2000-2016) and Medicaid (years 2012-2016) administrative claims data from the United States (US), we conducted two case-control studies, nested within respective cohorts of ADHD and ASD children aged 3-18 years. We defined cases by a composite outcome of stroke, myocardial infarction, or serious cardiac arrhythmia. For each case, we matched ten controls on age, sex, and insurance type. We conducted conditional logistic regression models to test associations between SCV outcomes and a primary exposure definition of current ADHD medication use. Additionally, we controlled for resource use, cardiovascular and psychiatric comorbidities, and use of medications in a variety of sensitivity analyses. RESULTS: We identified 2,240,774 children for the ADHD cohort and 326,221 children for the ASD cohort. For ADHD, 33.9% of cases (63 of 186) versus 32.2% of controls (598 of 1860) were exposed, which yielded an odds ratio (OR) and 95% confidence interval (CI) of 1.08 (0.78-1.49). For ASD, 12.5% of cases (6 of 48) versus 22.1% of controls (106 of 480) were exposed [OR 0.49 (0.20-1.20)]. Covariate-adjusted results and results for individual outcomes and other exposure definitions were consistent with no increased risk of SCV events. CONCLUSION: Using large US claims data, we found no evidence of increased SCV risk in children and adolescents with ADHD or ASD exposed to ADHD medications.