Reversed Holocene temperature-moisture relationship in the Horn of Africa.

Anthropogenic climate change is predicted to severely impact the global hydrological cycle1, particularly in tropical regions where agriculture-based economies depend on monsoon rainfall2. In the Horn of Africa, more frequent drought conditions in recent decades3,4 contrast with climate models projecting precipitation to increase with rising temperature5. Here we use organic geochemical climate-proxy data from the sediment record of Lake Chala (Kenya and Tanzania) to probe the stability of the link between hydroclimate and temperature over approximately the past 75,000 years, hence encompassing a sufficiently wide range of temperatures to test the 'dry gets drier, wet gets wetter' paradigm6 of anthropogenic climate change in the time domain. We show that the positive relationship between effective moisture and temperature in easternmost Africa during the cooler last glacial period shifted to negative around the onset of the Holocene 11,700 years ago, when the atmospheric carbon dioxide concentration exceeded 250 parts per million and mean annual temperature approached modern-day values. Thus, at that time, the budget between monsoonal precipitation and continental evaporation7 crossed a tipping point such that the positive influence of temperature on evaporation became greater than its positive influence on precipitation. Our results imply that under continued anthropogenic warming, the Horn of Africa will probably experience further drying, and they highlight the need for improved simulation of both dynamic and thermodynamic processes in the tropical hydrological cycle.

Airway topicalization in pediatric anesthesia: An international cross-sectional study.

BACKGROUND: There is no national or international consensus or guideline on recommended dosing of lidocaine for airway topicalization in children. Doses quoted in the literature vary substantially. AIMS: The primary aim of the study was to ascertain current international dosing practices (mg.kg-1 and concentration of solution) for lidocaine airway topicalization in children. The secondary aims included examining aftercare instructions for those receiving lidocaine airway topicalization and instances of local anesthetic systemic toxicity secondary to the use of lidocaine for airway topicalization in pediatric patients. METHODS: This cross-sectional study consisted of 11-20 questions across three domains-population demographics, clinical practice, and local anesthetic systemic toxicity. It adhered to the consensus-based checklist for reporting of survey studies. Responses were collected over 14 weeks using a combination of probability (cluster and simple random) and nonprobability (purposive, convenience and snowball) sampling. Data were analyzed based on the response rate per question with proportions expressed as percentages and nonparametric data expressed as median (interquartile range [range]) in an effort to minimize nonresponse error. No weighting of items or propensity scoring was applied. RESULTS: After initial exclusions, 1501 participants from 69 countries, across six continents, were included. Consultant anesthetists or those with an equivalent level of experience accounted for 1262/1501 (84.1%) of responses. Results showed heterogeneity in dosing and timing regimens and evidence that dosing may contribute to adverse outcomes. The maximum dose reported by participants who use lidocaine for airway topicalization as part of their normal practice was 5 mg.kg-1 (4-6 mg.kg-1 [0.5-50]) median (interquartile range [range]) over 2 h (1-4 h [0-30]). CONCLUSION: The results support the need for further research and consensus in this area, in order to provide safe provision of lidocaine airway topicalization in children. It is hoped the results of this study can support future collaborative work in this area.

Searching for Heavy Dark Matter near the Planck Mass with XENON1T.

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from multiply interacting massive particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This Letter places strong constraints on spin-independent interactions of dark matter particles with a mass between 1×10^{12} and 2×10^{17} GeV/c^{2}. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross sections for dark matter particles with masses close to the Planck scale.

First Dark Matter Search Results from the LUX-ZEPLIN (LZ) Experiment.

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.

First Dark Matter Search with Nuclear Recoils from the XENONnT Experiment.

We report on the first search for nuclear recoils from dark matter in the form of weakly interacting massive particles (WIMPs) with the XENONnT experiment, which is based on a two-phase time projection chamber with a sensitive liquid xenon mass of 5.9 ton. During the (1.09±0.03) ton yr exposure used for this search, the intrinsic ^{85}Kr and ^{222}Rn concentrations in the liquid target are reduced to unprecedentedly low levels, giving an electronic recoil background rate of (15.8±1.3) events/ton yr keV in the region of interest. A blind analysis of nuclear recoil events with energies between 3.3 and 60.5 keV finds no significant excess. This leads to a minimum upper limit on the spin-independent WIMP-nucleon cross section of 2.58×10^{-47} cm^{2} for a WIMP mass of 28 GeV/c^{2} at 90% confidence level. Limits for spin-dependent interactions are also provided. Both the limit and the sensitivity for the full range of WIMP masses analyzed here improve on previous results obtained with the XENON1T experiment for the same exposure.

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Search for New Physics in Electronic Recoil Data from XENONnT.

We report on a blinded analysis of low-energy electronic recoil data from the first science run of the XENONnT dark matter experiment. Novel subsystems and the increased 5.9 ton liquid xenon target reduced the background in the (1, 30) keV search region to (15.8±1.3) events/(ton×year×keV), the lowest ever achieved in a dark matter detector and ∼5 times lower than in XENON1T. With an exposure of 1.16 ton-years, we observe no excess above background and set stringent new limits on solar axions, an enhanced neutrino magnetic moment, and bosonic dark matter.

Biobehavioral organization shapes the immune epigenome in infant rhesus Macaques (Macaca mulatta).

How individuals respond to and cope with stress is linked with their health and well-being. It is presumed that early stress responsiveness helps shape the health of the developing organism, but the relationship between stress responsiveness and early immune function during development is not well-known. We hypothesized that stress responsiveness may shape epigenetic regulation of immune genes in infancy. We investigated whether aspects of behavioral responsiveness and hypothalamic-pituitary adrenal stress-response were associated with epigenome-wide immune cell DNA methylation patterns in 154 infant rhesus monkeys (3-4 months old). Infants' behavioral and physiological responses were collected during a standardized biobehavioral assessment, which included temporary relocation and separation from their mother and social group. Genome-wide DNA methylation was quantified using restricted representation bisulfite sequencing (RRBS) from blood DNA collected 2-hours post-separation. Epigenome-wide analyses were conducted using simple regression, multiple regression controlling for immune cell counts, and permutation regression, all corrected for false discovery rate. Across the variables analyzed, there were 20,368 unique sites (in 9,040 genes) at which methylation was significantly associated with at least one behavioral responsiveness or cortisol measure across the three analyses. There were significant associations in 442 genes in the Immune System Process ontology category, and 94 genes in the Inflammation mediated by chemokine and cytokine signaling gene pathway. Out of 35 candidate genes that were selected for further investigation, there were 13 genes with at least one site at which methylation was significantly associated with behavioral responsiveness or cortisol, including two intron sites in the glucocorticoid receptor gene, at which methylation was negatively correlated with emotional behavior the day following the social separation (Day 2 Emotionality; ß = -0.39, q < 0.001) and cortisol response following a relocation stressor (Sample 1; ß = -0.33, q < 0.001). We conclude that biobehavioral stress responsiveness may correlate with the developing epigenome, and that DNA methylation of immune cells may be a mechanism by which patterns of stress response affect health and immune functioning.

Interleukin-2 receptor-α proximal promoter hypomethylation is associated with multiple sclerosis.

Genetic studies have demonstrated association between single-nucleotide polymorphisms within the IL2RA (interleukin-2 receptor α-subunit) gene and risk of developing multiple sclerosis (MS); however, these variants do not have obvious functional consequences. DNA methylation is a source of genetic variation that could impact on autoimmune disease risk. We investigated DNA methylation of the IL2RA promoter in genomic DNA obtained from peripheral blood mononuclear cells and neural tissue using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A differential methylation profile of IL2RA was identified, suggesting that IL2RA expression was regulated by DNA methylation. We extended our analysis of DNA methylation to peripheral blood mononuclear cell (PBMC) of MS cases and controls using MALDI-TOF and Illumina HumanMethylation450 arrays. Analyses of CpG sites within the proximal promoter of IL2RA in PBMC showed no differences between MS cases and controls despite an increase in IL2RA expression. In contrast, we inferred significant DNA methylation differences specific to particular leukocyte subtypes in MS cases compared with controls by deconvolution of the array data. The decrease in methylation in patients correlated with an increase in IL2RA expression in T cells from MS cases in comparison with controls. Our data suggest that differential methylation of the IL2RA promoter in T cells could be an important pathogenic mechanism in MS.

The epidemiology and global burden of autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASDs) are persistent disabling neurodevelopmental disorders clinically evident from early childhood. For the first time, the burden of ASDs has been estimated for the Global Burden of Disease Study 2010 (GBD 2010). The aims of this study were to develop global and regional prevalence models and estimate the global burden of disease of ASDs. METHOD: A systematic review was conducted for epidemiological data (prevalence, incidence, remission and mortality risk) of autistic disorder and other ASDs. Data were pooled using a Bayesian meta-regression approach while adjusting for between-study variance to derive prevalence models. Burden was calculated in terms of years lived with disability (YLDs) and disability-adjusted life-years (DALYs), which are reported here by world region for 1990 and 2010. RESULTS: In 2010 there were an estimated 52 million cases of ASDs, equating to a prevalence of 7.6 per 1000 or one in 132 persons. After accounting for methodological variations, there was no clear evidence of a change in prevalence for autistic disorder or other ASDs between 1990 and 2010. Worldwide, there was little regional variation in the prevalence of ASDs. Globally, autistic disorders accounted for more than 58 DALYs per 100 000 population and other ASDs accounted for 53 DALYs per 100 000. CONCLUSIONS: ASDs account for substantial health loss across the lifespan. Understanding the burden of ASDs is essential for effective policy making. An accurate epidemiological description of ASDs is needed to inform public health policy and to plan for education, housing and financial support services.

Development of UK guidance on the management of erectile dysfunction resulting from radical radiotherapy and androgen deprivation therapy for prostate cancer.

AIM: To develop a management strategy (rehabilitation programme) for erectile dysfunction (ED) after radiotherapy (RT) or androgen deprivation therapy (ADT) for prostate cancer that is suitable for use in a UK NHS healthcare context. METHODS: PubMed literature searches of ED management in this patient group together with a survey of 28 experts in the management of treatment-induced ED from across the UK were conducted. RESULTS: Data from 19 articles and completed questionnaires were collated. The findings discussed in this article confirm that RT/ADT for prostate cancer can significantly impair erectile function. While many men achieve erections through PDE5-I use, others need combined management incorporating exercise and lifestyle modifications, psychosexual counselling and other erectile aids. This article offers a comprehensive treatment algorithm to manage patients with ED associated with RT/ADT. CONCLUSION: Based on published research literature and survey analysis, recommendations are proposed for the standardisation of management strategies employed for ED after RT/ADT. In addition to implementing the algorithm, understanding the rationale for the type and timing of ED management strategies is crucial for clinicians, men and their partners.

Louis Pasteur's beer of revenge.

Although by the mid-nineteenth century evidence existed for an association between micoorganisms and disease, it was the combined efforts of Louis Pasteur and Robert Koch that created the germ theory of disease--the theory that specific microbes cause specific diseases. Surprisingly, the relationship between the two founders of microbiology and immunology was far from friendly.

The global burden of anxiety disorders in 2010.

BACKGROUND: Despite their high prevalence, the global burden of anxiety disorders has never been calculated comprehensively. The new Global Burden of Disease (GBD) study has estimated burden due to morbidity and mortality caused by any anxiety disorder. METHOD: Prevalence was estimated using Bayesian meta-regression informed by data identified in a systematic review. Years of life lived with disability (YLDs) were calculated by multiplying prevalent cases by an average disability weight based on severity proportions (mild, moderate and severe). Disability-adjusted life years (DALYs) were then calculated and age standardized using global standard population figures. Estimates were also made for additional suicide mortality attributable to anxiety disorders. Findings are presented for YLDs, DALYs and attributable burden due to suicide for 21 world regions in 1990 and 2010. RESULTS: Anxiety disorders were the sixth leading cause of disability, in terms of YLDs, in both high-income (HI) and low- and middle-income (LMI) countries. Globally, anxiety disorders accounted for 390 DALYs per 100,000 persons [95% uncertainty interval (UI) 191-371 DALYs per 100,000] in 2010, with no discernible change observed over time. Females accounted for about 65% of the DALYs caused by anxiety disorders, with the highest burden in both males and females experienced by those aged between 15 and 34 years. Although there was regional variation in prevalence, the overlap between uncertainty estimates means that substantive differences in burden between populations could not be identified. CONCLUSIONS: Anxiety disorders are chronic, disabling conditions that are distributed across the globe. Future estimates of burden could be further improved by obtaining more representative data on severity state proportions.

Pharmacokinetics of intravenously and trans-dermally administered fluralaner in healthy laying shaver hens: fluralaner in chickens.

Ectoparasite infestations negatively affect both backyard and commercial chicken flocks in the United States. Fluralaner is an isoxazoline shown to be efficacious in treating mite and bed bug infestations in poultry. Fluralaner is approved to treat fleas and ticks in dogs and cats in the United States and to treat mite infestations of chickens in Europe and Australia; however, the use of fluralaner in poultry is not yet approved in the United States. This study aimed to investigate the plasma fluralaner pharmacokinetic profile of intravenous and transdermal routes and apparent bioavailability of fluralaner administered trans-dermally in healthy shaver hens. A total of 12 individually housed healthy shaver hens received a single dose of either intravenous technical grade fluralaner at 0.5 mg/kg, or transdermal fluralaner (Bravecto (fluralaner transdermal solution) for dogs, 280 mg/mL, Merck Animal Health) at mean 58.7 mg/kg. Plasma from each hen was collected from the jugular, ulnar, or medial metatarsal vein at multiple intervals. Fluralaner concentrations in plasma were determined using Ultra Performance Liquid Chromatography with Mass Spectrometry (UPLC/MS). Noncompartmental analysis revealed that the geometric mean elimination half-life for intravenous and transdermal routes were 80.5 and 179.6 h, respectively. The geometric mean apparent bioavailability of transdermal routes was estimated as 3.4%. Prolonged fluralaner concentration in plasma above minimum inhibitory concentration of bed bugs following the single dose was observed in healthy shaver hens for both routes. It is important to understand the pharmacokinetic profile could be useful in determining the appropriate treatment strategy.

Residue, distribution and depletion of fluralaner in egg following a single intravenous and transdermal administration in healthy shaver hens: fluralaner residue in egg.

The demand for the use of fluralaner in an extra label manner is increasing due to lack of efficacious treatment to combat mites and bed bugs in the poultry industry in the United States. Fluralaner residue data in eggs is lacking and residues might cause risks to human health. The present study aimed to determine the depletion profiles of fluralaner in eggs and estimate the drug withdrawal interval in whole eggs by adopting the US Food and Drug administration tolerance limit method with single intravenous (0.5 mg/kg) or transdermal administration (average 58.7 mg/kg) in healthy shaver hens. Hens were treated intravenously or trans-dermally with fluralaner. The eggs were collected daily for 28 d for intravenous treated and for 40 d from the transdermal route group. Fluralaner concentrations in yolk and albumen were determined by mass spectrometry. The greater percentage of fluralaner was observed in yolk when compared to the albumen for both administration routes. Noncompartmental analysis was used to calculate the pharmacokinetic parameters in yolk, albumen and whole egg. The longest apparent half-life confirmed in yolk was 3.7 d for intravenous and 14.3 d for the transdermal route. The withdrawal intervals in whole egg for fluralaner following the intravenous and transdermal administration were 7 d and 81 d, respectively, with maximum residue limits (1.3 µg/g) at 13 d and 171 d, respectively, based on the limit of quantification (0.4 µg/g) from the analytical assay reported by EMA and APVMA.

Global prevalence of anxiety disorders: a systematic review and meta-regression.

BACKGROUND: The literature describing the global prevalence of anxiety disorders is highly variable. A systematic review and meta-regression were undertaken to estimate the prevalence of anxiety disorders and to identify factors that may influence these estimates. The findings will inform the new Global Burden of Disease study. Method A systematic review identified prevalence studies of anxiety disorders published between 1980 and 2009. Electronic databases, reference lists, review articles and monographs were searched and experts then contacted to identify missing studies. Substantive and methodological factors associated with inter-study variability were identified through meta-regression analyses and the global prevalence of anxiety disorders was calculated adjusting for study methodology. RESULTS: The prevalence of anxiety disorders was obtained from 87 studies across 44 countries. Estimates of current prevalence ranged between 0.9% and 28.3% and past-year prevalence between 2.4% and 29.8%. Substantive factors including gender, age, culture, conflict and economic status, and urbanicity accounted for the greatest proportion of variability. Methodological factors in the final multivariate model (prevalence period, number of disorders and diagnostic instrument) explained an additional 13% of variance between studies. The global current prevalence of anxiety disorders adjusted for methodological differences was 7.3% (4.8-10.9%) and ranged from 5.3% (3.5-8.1%) in African cultures to 10.4% (7.0-15.5%) in Euro/Anglo cultures. CONCLUSIONS: Anxiety disorders are common and the substantive and methodological factors identified here explain much of the variability in prevalence estimates. Specific attention should be paid to cultural differences in responses to survey instruments for anxiety disorders.

Estimating remission from untreated major depression: a systematic review and meta-analysis.

BACKGROUND: Few studies have examined spontaneous remission from major depression. This study investigated the proportion of prevalent cases of untreated major depression that will remit without treatment in a year, and whether remission rates vary by disorder severity. METHOD: Wait-list controlled trials and observational cohort studies published up to 2010 with data describing remission from untreated depression at ≤ 2-year follow-up were identified. Remission was defined as rescinded diagnoses or below threshold scores on standardized symptom measures. Nineteen studies were included in a regression model predicting the probability of 12-month remission from untreated depression, using logit transformed remission proportion as the dependent variable. Covariates included age, gender, study type and diagnostic measure. RESULTS: Wait-listed compared to primary-care samples, studies with longer follow-up duration and older adult compared to adult samples were associated with lower probability of remission. Child and adolescent samples were associated with higher probability of remission. Based on adult samples recruited from primary-care settings, the model estimated that 23% of prevalent cases of untreated depression will remit within 3 months, 32% within 6 months and 53% within 12 months. CONCLUSIONS: It is undesirable to expect 100% treatment coverage for depression, given many will remit before access to services is feasible. Data were drawn from consenting wait-list and primary-care samples, which potentially over-represented mild-to-moderate cases of depression. Considering reported rates of spontaneous remission, a short untreated period seems defensible for this subpopulation, where judged appropriate by the clinician. Conclusions may not apply to individuals with more severe depression.

Global variation in the prevalence and incidence of major depressive disorder: a systematic review of the epidemiological literature.

BACKGROUND: Summarizing the epidemiology of major depressive disorder (MDD) at a global level is complicated by significant heterogeneity in the data. The aim of this study is to present a global summary of the prevalence and incidence of MDD, accounting for sources of bias, and dealing with heterogeneity. Findings are informing MDD burden quantification in the Global Burden of Disease (GBD) 2010 Study. METHOD: A systematic review of prevalence and incidence of MDD was undertaken. Electronic databases Medline, PsycINFO and EMBASE were searched. Community-representative studies adhering to suitable diagnostic nomenclature were included. A meta-regression was conducted to explore sources of heterogeneity in prevalence and guide the stratification of data in a meta-analysis. RESULTS: The literature search identified 116 prevalence and four incidence studies. Prevalence period, sex, year of study, depression subtype, survey instrument, age and region were significant determinants of prevalence, explaining 57.7% of the variability between studies. The global point prevalence of MDD, adjusting for methodological differences, was 4.7% (4.4-5.0%). The pooled annual incidence was 3.0% (2.4-3.8%), clearly at odds with the pooled prevalence estimates and the previously reported average duration of 30 weeks for an episode of MDD. CONCLUSIONS: Our findings provide a comprehensive and up-to-date profile of the prevalence of MDD globally. Region and study methodology influenced the prevalence of MDD. This needs to be considered in the GBD 2010 study and in investigations into the ecological determinants of MDD. Good-quality estimates from low-/middle-income countries were sparse. More accurate data on incidence are also required.

Indication of reactor ν(e) disappearance in the Double Chooz experiment.

The Double Chooz experiment presents an indication of reactor electron antineutrino disappearance consistent with neutrino oscillations. An observed-to-predicted ratio of events of 0.944±0.016(stat)±0.040(syst) was obtained in 101 days of running at the Chooz nuclear power plant in France, with two 4.25 GW(th) reactors. The results were obtained from a single 10 m(3) fiducial volume detector located 1050 m from the two reactor cores. The reactor antineutrino flux prediction used the Bugey4 flux measurement after correction for differences in core composition. The deficit can be interpreted as an indication of a nonzero value of the still unmeasured neutrino mixing parameter sin(2)2θ(13). Analyzing both the rate of the prompt positrons and their energy spectrum, we find sin(2)2θ(13)=0.086±0.041(stat)±0.030(syst), or, at 90% C.L., 0.017