Publications by authors named "Richard Houghton"

58 Publications

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

Sci Total Environ 2021 May 20;769:144341. Epub 2021 Jan 20.

Griffith Climate Change Response Program, Griffith University, Queensland 4222, Australia.

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).
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http://dx.doi.org/10.1016/j.scitotenv.2020.144341DOI Listing
May 2021

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

Sci Transl Med 2020 12;12(574)

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1B 5EH, UK.

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.
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http://dx.doi.org/10.1126/scitranslmed.abc2888DOI Listing
December 2020

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

Nat Commun 2020 09 24;11(1):4841. Epub 2020 Sep 24.

Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK.

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/m 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.
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http://dx.doi.org/10.1038/s41467-020-18636-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518421PMC
September 2020

Mapping carbon accumulation potential from global natural forest regrowth.

Nature 2020 09 23;585(7826):545-550. Epub 2020 Sep 23.

Conservation International, Arlington, VA, USA.

To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide. Regrowing natural forests is a prominent strategy for capturing additional carbon, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates. 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) 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 reported 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.
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http://dx.doi.org/10.1038/s41586-020-2686-xDOI Listing
September 2020

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

Nat Commun 2020 06 23;11(1):3170. Epub 2020 Jun 23.

Woods Hole Research Center, Falmouth, MA, 02540, USA.

Understanding the driving mechanisms of the interannual variability (IAV) of the net land carbon balance (S) is important to predict future climate-carbon cycle feedbacks. Past studies showed that the IAV of S 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 S by using an improved biosphere model. We found that managed land accounted for 30-45% of the IAV of S 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.
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http://dx.doi.org/10.1038/s41467-020-16953-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311403PMC
June 2020

Terrestrial fluxes of carbon in GCP carbon budgets.

Glob Chang Biol 2020 05 24;26(5):3006-3014. Epub 2020 Mar 24.

Woods Hole Research Center, Falmouth, MA, USA.

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., CO , 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 CO 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.
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http://dx.doi.org/10.1111/gcb.15050DOI Listing
May 2020

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

CNS Drugs 2020 01;34(1):93-101

Personalized Health Care Data Science, Real World Data, F. Hoffmann-La Roche Ltd., Grenzacherstrasse. 124, 4070, Basel, Switzerland.

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.
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http://dx.doi.org/10.1007/s40263-019-00686-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982643PMC
January 2020

Fumarate Metabolic Signature for the Detection of Reed Syndrome in Humans.

Clin Cancer Res 2020 01 21;26(2):391-396. Epub 2019 Oct 21.

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.

Purpose: Inherited pathogenic variants in genes encoding the metabolic enzymes succinate dehydrogenase (SDH) and fumarate hydratase predispose to tumor development through accumulation of oncometabolites (succinate and fumarate, respectively; ref. 1). Noninvasive detection of tumor succinate by proton magnetic resonance spectroscopy (H-MRS) has been reported in SDH-deficient tumors, but the potential utility of this approach in the management of patients with hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome is unknown.

Experimental Design: Magnetic resonance spectroscopy (H-MRS) was performed on three cases and correlated with germline genetic results and tumor IHC when available.

Results: Here, we have demonstrated a proof of principle that H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation .

Conclusions: This study demonstrates that detection of fumarate could be employed as a functional biomarker.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1729DOI Listing
January 2020

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

Lancet 2019 10 6;394(10207):1415-1424. Epub 2019 Sep 6.

The Hatter Cardiovascular Institute, University College London, London, UK. Electronic address:

Background: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months.

Methods: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed.

Findings: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed.

Interpretation: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI.

Funding: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.
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http://dx.doi.org/10.1016/S0140-6736(19)32039-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891239PMC
October 2019

Treatment Patterns in Patients with Incident Parkinson's Disease in the United States.

J Parkinsons Dis 2019 ;9(4):749-759

Product Development Personalized Health Care, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Background: Treatment patterns in Parkinson's disease (PD) have not been extensively studied for nearly two decades. Insurance claims are appropriate for such analysis.

Objective: To understand the standard of care use of symptomatic treatments in new cases of PD and factors associated with treatment choice.

Methods: Retrospective cohort study using claims data from the United States between 2008 and 2016. We used Kaplan-Meier methodology to estimate time to treatment start and switch or add-on therapy and Cox proportional hazards models to identify predictors.

Results: We identified 68,532 patients eligible for treatment pattern analyses. Median time from diagnosis until first treatment was 37 days (95% confidence interval: 36-38). Two distinct patterns of treatment initiation were identified: fast initiators and patients with delayed treatment start (or no recorded treatment). Levodopa therapies were the most commonly prescribed treatment class (52.6%). Increased age was associated with shorter time to start of treatment with levodopa. Younger age was associated with shorter time to initiation of dopamine agonists and other symptomatic treatments. Patients that initiated treatment with levodopa/combinations had the fewest switches/add-ons [30.4%; median time 7.29 (6.71, 8.13) years]. Older patients had fewer switch/add-on therapies, but only in the group that started with levodopa/combination therapy.

Conclusions: Time from diagnosis to treatment start was relatively short, suggesting that PD diagnosis, as reflected in the database, is closely linked to start of symptomatic treatment. Levodopa treatment remains the most common treatment, especially for older patients. Delayed treatment start was associated with increased age and comorbidity.
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http://dx.doi.org/10.3233/JPD-191636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839607PMC
July 2020

Correction to: Psychometric Validation of the Autism Impact Measure (AIM).

J Autism Dev Disord 2019 Jun;49(6):2571

Patient Centered Outcomes Research, Biometrics, Roche Products, Ltd, Falcon Way, Welwyn Garden City, UK.

The article Psychometric Validation of the Autism Impact Measure (AIM), written by Richard Houghton, Brigitta Monz, Kiely Law, Georg Loss, Stephanie Le Scouiller, Frank de Vries and Tom Willgoss was originally published electronically on the publisher's internet portal (currently SpringerLink) on 09 April 2019 without open access.With the author(s)' decision to opt for Open Choice the copyright of the article changed on May 2019 to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
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http://dx.doi.org/10.1007/s10803-019-04076-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546867PMC
June 2019

Psychometric Validation of the Autism Impact Measure (AIM).

J Autism Dev Disord 2019 Jun;49(6):2559-2570

Patient Centered Outcomes Research, Biometrics, Roche Products, Ltd, Falcon Way, Welwyn Garden City, UK.

The Autism impact measure (AIM) is a caregiver-reported questionnaire assessing autism symptom frequency and impact in children, previously shown to have good test-retest reliability, convergent validity and structural validity. This study extended previous work by exploring the AIM's ability to discriminate between 'known-groups' of children, and estimating thresholds for clinically important responses. Data were collected online and electronically on computer and mobile devices; hence, it was also possible to confirm other psychometric properties of the AIM in this format. This study provides confirmatory and additional psychometric validation of the AIM. The AIM offers a valid, quick and inexpensive method for caregivers to report core symptoms of autism spectrum disorder (ASD) including communication deficits, difficulties with social interactions and repetitive behaviors.
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http://dx.doi.org/10.1007/s10803-019-04011-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546866PMC
June 2019

Treatment patterns in children with autism in the United States.

Autism Res 2019 03 10;12(3):517-526. Epub 2019 Jan 10.

Personalized Health Care Data Science, Real World Data, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Children with autism receive different types of non-drug treatments. We aimed to describe caregiver-reported pattern of care and its variability by geography and healthcare coverage in a US-wide sample of children aged 3-17 years. We recruited caregivers from the Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort. Two online questionnaires (non-drug treatment, Autism Impact Measure) were completed in September/October 2017. Primary outcome measures were caregiver-reported types and intensities of treatments (behavioral, developmental/relationship, speech and language (SLT), occupational, psychological, "other"; parent/caregiver training) in the previous 12 months. Main explanatory variables were geography and type of healthcare coverage. We investigated associations between the type/intensity of treatments and geography (metropolitan/nonmetropolitan) or coverage (Medicaid vs privately insured by employer) using regression analysis. Caregivers (n = 5,122) were mainly mothers (92.1%) with mean (SD) age of 39.0 (7.3) years. Mean child age was 9.1 (3.9) years; mostly males (80.0%). Almost all children received at least one intervention (96.0%). Eighty percent received SLT or occupational therapy, while 52.0% received both. Behavioral therapy and SLT were significantly more frequent and more intense in metropolitan than in nonmetropolitan areas. No consistently significant associations were seen between healthcare coverage and frequency or intensity of interventions. At least one barrier such as "waiting list" and "no coverage" was reported by 44.8%. In conclusion, in children sampled from SPARK, we observed differences between metropolitan and nonmetropolitan areas, while we did not find significant differences between those privately insured versus Medicaid. Autism Res 2019, 12: 517-526 © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: The American Academy of Child and Adolescent Psychiatry recommends the use of multiple treatment modalities in autism spectrum disorder (ASD). We wanted to understand what types of treatment children (aged 3-17 years) with ASD receive in the United States, how and where the treatments take place and for how long. We invited caregivers from Simons Foundation Powering Autism Research for Knowledge ("SPARK ," https://sparkforautism.org/) to complete the study questions online. Participants reported on utilization of conventional, non-drug treatments for ASD, including behavioral interventions, developmental/relationship interventions, speech and language therapy (SLT), occupational therapy, psychological therapy, and parent/caregiver training. People that completed the study (n = 5,122) were primarily mothers of the child with ASD (92%); most of the children were boys (80%). The ASD care for the child was mostly coordinating by the mother. Almost all children received at least some type of non-drug therapies (96%), most often SLT and/or occupational therapy, mainly provided in school. Behavioral therapy was most often received in public school in rural areas, while at home in urban areas. We saw less use of behavioral therapy and SLT in rural areas, but overall comparable use between children covered by Medicaid and those covered by private insurance. Almost half the caregivers reported at least one barrier to treatment, such as "waiting list" and "no coverage." More than half said that their child benefited "much" or "very much" from the therapies received. While overall non-drug treatment rates for children with ASD were high in the United States in our study, differences existed depending on where the family lives; not only regarding the type of therapy, but also where it takes place.
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http://dx.doi.org/10.1002/aur.2070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519302PMC
March 2019

Natural climate solutions for the United States.

Sci Adv 2018 11 14;4(11):eaat1869. Epub 2018 Nov 14.

The Nature Conservancy, Arlington, VA 22203, USA.

Limiting climate warming to <2°C requires increased mitigation efforts, including land stewardship, whose potential in the United States is poorly understood. We quantified the potential of natural climate solutions (NCS)-21 conservation, restoration, and improved land management interventions on natural and agricultural lands-to increase carbon storage and avoid greenhouse gas emissions in the United States. We found a maximum potential of 1.2 (0.9 to 1.6) Pg COe year, the equivalent of 21% of current net annual emissions of the United States. At current carbon market prices (USD 10 per Mg COe), 299 Tg COe year could be achieved. NCS would also provide air and water filtration, flood control, soil health, wildlife habitat, and climate resilience benefits.
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http://dx.doi.org/10.1126/sciadv.aat1869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235523PMC
November 2018

Psychiatric Comorbidities and Psychotropic Medication Use in Autism: A Matched Cohort Study with ADHD and General Population Comparator Groups in the United Kingdom.

Autism Res 2018 12 31;11(12):1690-1700. Epub 2018 Oct 31.

Neuroscience, Ophthalmology, and Rare Diseases (NORD), Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd., Basel, Switzerland.

Psychiatric comorbidities and use of psychotropic medications are common among patients with autism spectrum disorder (ASD). However, most previous research used data from the United States (US) and few studies have compared medication use in ASD to control groups, making contextualization of results difficult. In the United Kingdom (UK), general practitioners play a key role in the management of ASD. We conducted a retrospective, cross-sectional study over calendar year 2015, using primary care data from the UK. We identified a prevalent cohort of ASD cases (n = 10,856) and matched control groups of (a) general population (n = 21,712) and (b) attention deficit hyperactivity disorder (ADHD; n = 7,058) on age, sex and region. We described psychiatric comorbidities, psychotropic medications, and healthcare utilization in all three cohorts. Within the ASD cohort, we used multivariable logistic regression models to explore associations between patient characteristics and the outcomes of: any psychotropic medication, polypharmacy, and number of primary care visits. We used conditional logistic regression to compare the ASD and control groups. Psychiatric comorbidities were recorded for 41.5% of ASD patients; 32.3% received psychotropic medication and 9.8% received polypharmacy. Increased age and all psychiatric comorbidities (except conduct disorder) were associated with treatment use. Males were less likely to receive a treatment than females [Odds ratio (OR) 0.74 (0.66-0.83)]. ASD patients were more likely to take psychotropic medications than the general population [OR 4.91 (4.46-5.40)], but less likely compared to ADHD patients [OR 0.40 (0.37-0.44)]. Overall, rates of medication use in the UK were lower than those previously reported in the US. Autism Research 2018, 11: 1690-1700. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We used electronic medical records from the UK, to describe the amount of psychiatric comorbidities, psychotropic medication use and healthcare resource use in ASD. Around one in three people with ASD were prescribed a psychotropic medication, which was more than the general population, but less than for those with ADHD. Increased age, psychiatric comorbidities and female gender were all independently associated with psychotropic medication use. Rates of medication use in the UK were lower than those previously reported in the US.
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http://dx.doi.org/10.1002/aur.2040DOI Listing
December 2018

Where is the residual terrestrial carbon sink?

Glob Chang Biol 2018 08 7;24(8):3277-3279. Epub 2018 Jun 7.

Woods Hole Research Center, Falmouth, Massachusetts, USA.

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http://dx.doi.org/10.1111/gcb.14313DOI Listing
August 2018

The exceptional value of intact forest ecosystems.

Nat Ecol Evol 2018 04 26;2(4):599-610. Epub 2018 Feb 26.

Fenner School of Environment and Society, The Australian National University, Canberra, Australian Capital Territory, Australia.

As the terrestrial human footprint continues to expand, the amount of native forest that is free from significant damaging human activities is in precipitous decline. There is emerging evidence that the remaining intact forest supports an exceptional confluence of globally significant environmental values relative to degraded forests, including imperilled biodiversity, carbon sequestration and storage, water provision, indigenous culture and the maintenance of human health. Here we argue that maintaining and, where possible, restoring the integrity of dwindling intact forests is an urgent priority for current global efforts to halt the ongoing biodiversity crisis, slow rapid climate change and achieve sustainability goals. Retaining the integrity of intact forest ecosystems should be a central component of proactive global and national environmental strategies, alongside current efforts aimed at halting deforestation and promoting reforestation.
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http://dx.doi.org/10.1038/s41559-018-0490-xDOI Listing
April 2018

Natural climate solutions.

Proc Natl Acad Sci U S A 2017 10 16;114(44):11645-11650. Epub 2017 Oct 16.

The Nature Conservancy, Arlington, VA 22203.

Better stewardship of land is needed to achieve the Paris Climate Agreement goal of holding warming to below 2 °C; however, confusion persists about the specific set of land stewardship options available and their mitigation potential. To address this, we identify and quantify "natural climate solutions" (NCS): 20 conservation, restoration, and improved land management actions that increase carbon storage and/or avoid greenhouse gas emissions across global forests, wetlands, grasslands, and agricultural lands. We find that the maximum potential of NCS-when constrained by food security, fiber security, and biodiversity conservation-is 23.8 petagrams of CO equivalent (PgCOe) y (95% CI 20.3-37.4). This is ≥30% higher than prior estimates, which did not include the full range of options and safeguards considered here. About half of this maximum (11.3 PgCOe y) represents cost-effective climate mitigation, assuming the social cost of CO pollution is ≥100 USD MgCOe by 2030. Natural climate solutions can provide 37% of cost-effective CO mitigation needed through 2030 for a >66% chance of holding warming to below 2 °C. One-third of this cost-effective NCS mitigation can be delivered at or below 10 USD MgCO Most NCS actions-if effectively implemented-also offer water filtration, flood buffering, soil health, biodiversity habitat, and enhanced climate resilience. Work remains to better constrain uncertainty of NCS mitigation estimates. Nevertheless, existing knowledge reported here provides a robust basis for immediate global action to improve ecosystem stewardship as a major solution to climate change.
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http://dx.doi.org/10.1073/pnas.1710465114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676916PMC
October 2017

Psychiatric comorbidities and use of psychotropic medications in people with autism spectrum disorder in the United States.

Autism Res 2017 Dec 30;10(12):2037-2047. Epub 2017 Sep 30.

Neuroscience, Ophthalmology, and Rare Diseases (NORD), Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, 4070, Switzerland.

This study investigated psychotropic medication usage in two large, cohorts of people with autism spectrum disorder (ASD) throughout the calendar year 2014. The cohorts referred to individuals with commercial (employer-sponsored) and Medicaid insurance in the United States. We aimed to understand prescribing patterns of such medications across a wide age-range and in the presence/absence of other clinical and non-clinical characteristics, including psychiatric comorbidities. We described the prevalence and length of prescriptions by age, psychiatric comorbidity and overall. We also fitted multivariable logistic regression models to describe the relationship between treatments and subject characteristics simultaneously. Eighty percent of the identified population was male, although gender did not impact the odds of receiving medication. Medication use was strongly associated with age, increasing most rapidly before adulthood; generally plateauing thereafter. All psychiatric comorbidities studied also individually increased the chances of medication use, with epilepsy and ADHD having the highest associations in both the commercial (OR > 7) and Medicaid (OR around 12) cohorts. Those in non-capitated insurance plans, in foster care and white individuals also had increased odds of prescriptions. Overall, slightly more Medicaid enrollees received any psychotropic treatment (commercial: 64%, Medicaid: 69%). Nonetheless in both cohorts, a large proportion of individuals received treatment even without a diagnosis of any other psychiatric comorbidity (commercial: 31%, Medicaid: 33%). In summary, this report sheds new light on the latest patterns of psychiatric comorbidity profile and psycho-pharmacological treatment patterns in ASD Autism Res 2017, 10: 2037-2047. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: this study identified a large number of children and adults in the US with autism spectrum disorder (autism) from employer-sponsored and government funded (Medicaid) health insurance data. Psychotropic medications were used by over two thirds of people, and four in ten people received two medications at the same time. The chances of receiving medication increased for individuals with other psychiatric conditions (e.g., ADHD), and also increased with age.
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http://dx.doi.org/10.1002/aur.1848DOI Listing
December 2017

Negative emissions from stopping deforestation and forest degradation, globally.

Glob Chang Biol 2018 01 22;24(1):350-359. Epub 2017 Sep 22.

Woods Hole Research Center, Falmouth, MA, USA.

Forest growth provides negative emissions of carbon that could help keep the earth's surface temperature from exceeding 2°C, but the global potential is uncertain. Here we use land-use information from the FAO and a bookkeeping model to calculate the potential negative emissions that would result from allowing secondary forests to recover. We find the current gross carbon sink in forests recovering from harvests and abandoned agriculture to be -4.4 PgC/year, globally. The sink represents the potential for negative emissions if positive emissions from deforestation and wood harvest were eliminated. However, the sink is largely offset by emissions from wood products built up over the last century. Accounting for these committed emissions, we estimate that stopping deforestation and allowing secondary forests to grow would yield cumulative negative emissions between 2016 and 2100 of about 120 PgC, globally. Extending the lifetimes of wood products could potentially remove another 10 PgC from the atmosphere, for a total of approximately 130 PgC, or about 13 years of fossil fuel use at today's rate. As an upper limit, the estimate is conservative. It is based largely on past and current practices. But if greater negative emissions are to be realized, they will require an expansion of forest area, greater efficiencies in converting harvested wood to long-lasting products and sources of energy, and novel approaches for sequestering carbon in soils. That is, they will require current management practices to change.
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http://dx.doi.org/10.1111/gcb.13876DOI Listing
January 2018

Fire and deforestation dynamics in Amazonia (1973-2014).

Global Biogeochem Cycles 2017 01 12;31(1):24-38. Epub 2017 Jan 12.

NASA Goddard Institute for Space Studies New York New York USA; Center for Climate Systems Research Columbia University New York New York USA.

Consistent long-term estimates of fire emissions are important to understand the changing role of fire in the global carbon cycle and to assess the relative importance of humans and climate in shaping fire regimes. However, there is limited information on fire emissions from before the satellite era. We show that in the Amazon region, including the Arc of Deforestation and Bolivia, visibility observations derived from weather stations could explain 61% of the variability in satellite-based estimates of bottom-up fire emissions since 1997 and 42% of the variability in satellite-based estimates of total column carbon monoxide concentrations since 2001. This enabled us to reconstruct the fire history of this region since 1973 when visibility information became available. Our estimates indicate that until 1987 relatively few fires occurred in this region and that fire emissions increased rapidly over the 1990s. We found that this pattern agreed reasonably well with forest loss data sets, indicating that although natural fires may occur here, deforestation and degradation were the main cause of fires. Compared to fire emissions estimates based on Food and Agricultural Organization's Global Forest and Resources Assessment data, our estimates were substantially lower up to the 1990s, after which they were more in line. These visibility-based fire emissions data set can help constrain dynamic global vegetation models and atmospheric models with a better representation of the complex fire regime in this region.
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http://dx.doi.org/10.1002/2016GB005445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324547PMC
January 2017

Tropical nighttime warming as a dominant driver of variability in the terrestrial carbon sink.

Proc Natl Acad Sci U S A 2015 Dec 7;112(51):15591-6. Epub 2015 Dec 7.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544;

The terrestrial biosphere is currently a strong carbon (C) sink but may switch to a source in the 21st century as climate-driven losses exceed CO2-driven C gains, thereby accelerating global warming. Although it has long been recognized that tropical climate plays a critical role in regulating interannual climate variability, the causal link between changes in temperature and precipitation and terrestrial processes remains uncertain. Here, we combine atmospheric mass balance, remote sensing-modeled datasets of vegetation C uptake, and climate datasets to characterize the temporal variability of the terrestrial C sink and determine the dominant climate drivers of this variability. We show that the interannual variability of global land C sink has grown by 50-100% over the past 50 y. We further find that interannual land C sink variability is most strongly linked to tropical nighttime warming, likely through respiration. This apparent sensitivity of respiration to nighttime temperatures, which are projected to increase faster than global average temperatures, suggests that C stored in tropical forests may be vulnerable to future warming.
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http://dx.doi.org/10.1073/pnas.1521479112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697419PMC
December 2015

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

Authors:
Martin Hrabě de Angelis George Nicholson Mohammed Selloum Jacqui White Hugh Morgan Ramiro Ramirez-Solis Tania Sorg Sara Wells Helmut Fuchs Martin Fray David J Adams Niels C Adams Thure Adler Antonio Aguilar-Pimentel Dalila Ali-Hadji Gregory Amann Philippe André Sarah Atkins Aurelie Auburtin Abdel Ayadi Julien Becker Lore Becker Elodie Bedu Raffi Bekeredjian Marie-Christine Birling Andrew Blake Joanna Bottomley Mike Bowl Véronique Brault Dirk H Busch James N Bussell Julia Calzada-Wack Heather Cater Marie-France Champy Philippe Charles Claire Chevalier Francesco Chiani Gemma F Codner Roy Combe Roger Cox Emilie Dalloneau André Dierich Armida Di Fenza Brendan Doe Arnaud Duchon Oliver Eickelberg Chris T Esapa Lahcen El Fertak Tanja Feigel Irina Emelyanova Jeanne Estabel Jack Favor Ann Flenniken Alessia Gambadoro Lilian Garrett Hilary Gates Anna-Karin Gerdin George Gkoutos Simon Greenaway Lisa Glasl Patrice Goetz Isabelle Goncalves Da Cruz Alexander Götz Jochen Graw Alain Guimond Wolfgang Hans Geoff Hicks Sabine M Hölter Heinz Höfler John M Hancock Robert Hoehndorf Tertius Hough Richard Houghton Anja Hurt Boris Ivandic Hughes Jacobs Sylvie Jacquot Nora Jones Natasha A Karp Hugo A Katus Sharon Kitchen Tanja Klein-Rodewald Martin Klingenspor Thomas Klopstock Valerie Lalanne Sophie Leblanc Christoph Lengger Elise le Marchand Tonia Ludwig Aline Lux Colin McKerlie Holger Maier Jean-Louis Mandel Susan Marschall Manuel Mark David G Melvin Hamid Meziane Kateryna Micklich Christophe Mittelhauser Laurent Monassier David Moulaert Stéphanie Muller Beatrix Naton Frauke Neff Patrick M Nolan Lauryl Mj Nutter Markus Ollert Guillaume Pavlovic Natalia S Pellegata Emilie Peter Benoit Petit-Demoulière Amanda Pickard Christine Podrini Paul Potter Laurent Pouilly Oliver Puk David Richardson Stephane Rousseau Leticia Quintanilla-Fend Mohamed M Quwailid Ildiko Racz Birgit Rathkolb Fabrice Riet Janet Rossant Michel Roux Jan Rozman Ed Ryder Jennifer Salisbury Luis Santos Karl-Heinz Schäble Evelyn Schiller Anja Schrewe Holger Schulz Ralf Steinkamp Michelle Simon Michelle Stewart Claudia Stöger Tobias Stöger Minxuan Sun David Sunter Lydia Teboul Isabelle Tilly Glauco P Tocchini-Valentini Monica Tost Irina Treise Laurent Vasseur Emilie Velot Daniela Vogt-Weisenhorn Christelle Wagner Alison Walling Bruno Weber Olivia Wendling Henrik Westerberg Monja Willershäuser Eckhard Wolf Anne Wolter Joe Wood Wolfgang Wurst Ali Önder Yildirim Ramona Zeh Andreas Zimmer Annemarie Zimprich Chris Holmes Karen P Steel Yann Herault Valérie Gailus-Durner Ann-Marie Mallon Steve Dm Brown

Nat Genet 2015 Sep 27;47(9):969-978. Epub 2015 Jul 27.

MRC Harwell, Medical Research Council, Harwell, UK.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
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http://dx.doi.org/10.1038/ng.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564951PMC
September 2015

Determination of avibactam and ceftazidime in human plasma samples by LC-MS.

Bioanalysis 2015 ;7(12):1423-34

AstraZeneca, Macclesfield, Cheshire East SK10 2NA, UK.

Aim: Avibactam, a novel non-β-lactam β-lactamase inhibitor co-administrated with the β-lactam antibiotic ceftazidime, is in clinical development. The need to evaluate its PK and PD requires accurate and reliable bioanalytical methods.

Methods: We describe LC-MS/MS methods for the determination of avibactam and ceftazidime in human plasma. Avibactam was extracted using weak anionic exchange solid-phase extraction and analyzed on an amide column. Ceftazidime was extracted using protein precipitation and analyzed on a C18 column. Calibration curves were established over 10-10,000 ng/ml (avibactam) and 43.8-87,000 ng/ml (ceftazidime).

Results & Conclusion: Method validation, cross-validation between three laboratories and incurred sample re-analysis demonstrated method robustness. The methods were successfully applied to multiple clinical studies.
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http://dx.doi.org/10.4155/bio.15.76DOI Listing
April 2016

A naturally occurring variant of the human prion protein completely prevents prion disease.

Nature 2015 Jun 10;522(7557):478-81. Epub 2015 Jun 10.

MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.
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http://dx.doi.org/10.1038/nature14510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486072PMC
June 2015

The Bangladesh Risk of Acute Vascular Events (BRAVE) Study: objectives and design.

Eur J Epidemiol 2015 Jul 1;30(7):577-87. Epub 2015 May 1.

Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK,

During recent decades, Bangladesh has experienced a rapid epidemiological transition from communicable to non-communicable diseases. Coronary heart disease (CHD), with myocardial infarction (MI) as its main manifestation, is a major cause of death in the country. However, there is limited reliable evidence about its determinants in this population. The Bangladesh Risk of Acute Vascular Events (BRAVE) study is an epidemiological bioresource established to examine environmental, genetic, lifestyle and biochemical determinants of CHD among the Bangladeshi population. By early 2015, the ongoing BRAVE study had recruited over 5000 confirmed first-ever MI cases, and over 5000 controls "frequency-matched" by age and sex. For each participant, information has been recorded on demographic factors, lifestyle, socioeconomic, clinical, and anthropometric characteristics. A 12-lead electrocardiogram has been recorded. Biological samples have been collected and stored, including extracted DNA, plasma, serum and whole blood. Additionally, for the 3000 cases and 3000 controls initially recruited, genotyping has been done using the CardioMetabochip+ and the Exome+ arrays. The mean age (standard deviation) of MI cases is 53 (10) years, with 88 % of cases being male and 46 % aged 50 years or younger. The median interval between reported onset of symptoms and hospital admission is 5 h. Initial analyses indicate that Bangladeshis are genetically distinct from major non-South Asian ethnicities, as well as distinct from other South Asian ethnicities. The BRAVE study is well-placed to serve as a powerful resource to investigate current and future hypotheses relating to environmental, biochemical and genetic causes of CHD in an important but under-studied South Asian population.
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http://dx.doi.org/10.1007/s10654-015-0037-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516898PMC
July 2015

Recommendations on incurred sample stability (ISS) by GCC.

Bioanalysis 2014 Sep;6(18):2385-90

Quintiles Bioanalytical & ADME Labs, Ithaca, NY, USA.

The topic of incurred sample stability (ISS) has generated considerable discussion within the bioanalytical community in recent years. The subject was an integral part of the seventh annual Workshop on Recent Issues in Bioanalysis (WRIB) held in Long Beach, CA, USA, in April 2013, and at the Global CRO Council for Bioanalysis (GCC) meeting preceding it. Discussion at both events focused on the use of incurred samples for ISS purposes in light of results from a recent GCC survey completed by member companies. This paper reports the consensus resulting from these discussions and serves as a useful reference for depicting ISS issues and concerns, summarizing the GCC survey results and providing helpful recommendations on ISS in the context of bioanalytical method development and application.
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http://dx.doi.org/10.4155/bio.14.155DOI Listing
September 2014