The biopsychosocial model of stress in adolescence: self-awareness of performance versus stress reactivity

Extensive research among adults supports the biopsychosocial (BPS) model of challenge and threat, which describes relationships among stress appraisals, physiological stress reactivity, and performance; however, no previous studies have examined these relationships in adolescents. Perceptions of stressors as well as physiological reactivity to stress increase during adolescence, highlighting the importance of understanding the relationships among stress appraisals, physiological reactivity, and performance during this developmental period. In this study, 79 adolescent participants reported on stress appraisals before and after a Trier Social Stress Test in which they performed a speech task. Physiological stress reactivity was defined by changes in cardiac output and total peripheral resistance from a baseline rest period to the speech task, and performance on the speech was coded using an objective rating system. We observed in adolescents only two relationships found in past adult research on the BPS model variables: (1) pre-task stress appraisal predicted post-task stress appraisal and (2) performance predicted post-task stress appraisal. Physiological reactivity during the speech was unrelated to pre- and post-task stress appraisals and to performance. We conclude that the lack of association between post-task stress appraisal and physiological stress reactivity suggests that adolescents might have low self-awareness of physiological emotional arousal. Our findings further suggest that adolescent stress appraisals are based largely on their performance during stressful situations. Developmental implications of this potential lack of awareness of one’s physiological and emotional state during adolescence are discussed.Psycholog

Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource

Objective: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn’s disease (CD), including their impact on need for surgery. Design: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). Conclusion: Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Prevalence, Correlates, and Treatment of Lifetime Suicidal Behavior Among Adolescents: Results From the National Comorbidity Survey Replication Adolescent Supplement

Context Although suicide is the third leading cause of death among US adolescents, little is known about the prevalence, correlates, or treatment of its immediate precursors, adolescent suicidal behaviors (ie, suicide ideation, plans, and attempts). Objectives To estimate the lifetime prevalence of suicidal behaviors among US adolescents and the associations of retrospectively reported, temporally primary DSM-IV disorders with the subsequent onset of suicidal behaviors. Design Dual-frame national sample of adolescents from the National Comorbidity Survey Replication Adolescent Supplement. Setting Face-to-face household interviews with adolescents and questionnaires for parents. Participants A total of 6483 adolescents 13 to 18 years of age and their parents. Main Outcome Measures Lifetime suicide ideation, plans, and attempts. Results The estimated lifetime prevalences of suicide ideation, plans, and attempts among the respondents are 12.1%, 4.0%, and 4.1%, respectively. The vast majority of adolescents with these behaviors meet lifetime criteria for at least one DSM-IV mental disorder assessed in the survey. Most temporally primary (based on retrospective age-of-onset reports) fear/anger, distress, disruptive behavior, and substance disorders significantly predict elevated odds of subsequent suicidal behaviors in bivariate models. The most consistently significant associations of these disorders are with suicide ideation, although a number of disorders are also predictors of plans and both planned and unplanned attempts among ideators. Most suicidal adolescents (>80%) receive some form of mental health treatment. In most cases (>55%), treatment starts prior to onset of suicidal behaviors but fails to prevent these behaviors from occurring. Conclusions Suicidal behaviors are common among US adolescents, with rates that approach those of adults. The vast majority of youth with suicidal behaviors have preexisting mental disorders. The disorders most powerfully predicting ideation, though, are different from those most powerfully predicting conditional transitions from ideation to plans and attempts. These differences suggest that distinct prediction and prevention strategies are needed for ideation, plans among ideators, planned attempts, and unplanned attempts

Suicide Among Soldiers: A Review of Psychosocial Risk and Protective Factors

Suicide is difficult to predict and prevent and remains a leading cause of death worldwide. Although soldiers historically have had a suicide rate well below that of the general population, the suicide rate among members of the U.S. Army has increased markedly over the past several years and now exceeds that of the general population. This paper reviews psychosocial factors known to be associated with the increased risk of suicidal behavior in general and describes how some of these factors may be especially important in understanding suicide among soldiers. Moving forward, the prevention of suicide requires additional research aimed at: (a) better describing when, where, and among whom suicidal behavior occurs, (b) using exploratory studies to discover new risk and protective factors, (c) developing new methods of predicting suicidal behavior that synthesize information about modifiable risk and protective factors from multiple domains, and (d) understanding the mechanisms and pathways through which suicidal behavior develops. Although the scope and severity of this problem is daunting, the increasing attention and dedication to this issue by the Armed Forces, scientists, and society provide hope for our ability to better predict and prevent these tragic outcomes in the future.Psycholog

Parent psychopathology and offspring mental disorders: results from the WHO World Mental Health Surveys

Background Associations between specific parent and offspring mental disorders are likely to have been overestimated in studies that have failed to control for parent comorbidity. Aims To examine the associations of parent with respondent disorders. Method Data come from the World Health Organization (WHO) World Mental Health Surveys (n = 51 507). Respondent disorders were assessed with the Composite International Diagnostic Interview and parent disorders with informant-based Family History Research Diagnostic Criteria interviews. Results Although virtually all parent disorders examined (major depressive, generalised anxiety, panic, substance and antisocial behaviour disorders and suicidality) were significantly associated with offspring disorders in multivariate analyses, little specificity was found. Comorbid parent disorders had significant sub-additive associations with offspring disorders. Population-attributable risk proportions for parent disorders were 12.4% across all offspring disorders, generally higher in high- and upper-middle-than low-/lower-middle-income countries, and consistently higher for behaviour (11.0-19.9%) than other (7.1-14.0%) disorders. Conclusions Parent psychopathology is a robust non-specific predictor associated with a substantial proportion of offspring disorders.Analysis GroupAnalysis GroupBristolMyers SquibbBristol-Myers SquibbEli Lilly CompanyEli Lilly CompanyEPIQEPI-QGlaxoSmithKlineGlaxoSmithKlineJohnson & Johnson PharmaceuticalsJohnson & Johnson PharmaceuticalsOrtho-McNeil Janssen Scientific AffairsOrthoMcNeil Janssen Scientific AffairsPfizerPfizerSanofiAventis GroupeSanofi-Aventis GroupeShire USShire USUnited States National Institute of Mental Health [R01MH070884, R01MH093612]United States National Institute of Mental HealthNIMHNIMH [HHSN271200700030C]John D. and Catherine T. MacArthur FoundationJohn D. and Catherine T. MacArthur FoundationPfizer FoundationPfizer FoundationUS Public Health ServiceUS Public Health Service [R13-MH066849, R01-MH069864, R01 DA016558]Fogarty International Center [FIRCA R03-TW006481]Fogarty International CenterPan American Health Organization (PAHO)Pan American Health Organization (PAHO)Eli Lilly & Company FoundationEli Lilly & Company FoundationOrthoMcNeil PharmaceuticalOrtho-McNeil PharmaceuticalShireShireState of Sao Paulo Research Foundation (FAPESP)State of Sao Paulo Research Foundation (FAPESP) [03/00204-3]Ministry of HealthMinistry of HealthNational Center for Public Health ProtectionNational Center for Public Health ProtectionShenzhen Bureau of HealthShenzhen Bureau of HealthShenzhen Bureau of Science, Technology, and InformationShenzhen Bureau of Science, Technology, and InformationMinistry of Social ProtectionMinistry of Social ProtectionEuropean CommissionEuropean Commission [QLG5-1999-01042, SANCO 20041231]Piedmont Region (Italy)Piedmont Region (Italy)Fondo de Investigacion Sanitaria, Institut de Salud Carlos III, Spain [FIS 00/0028]Fondo de Investigacion Sanitaria, Institut de Salud Carlos III, SpainMinisterio de Ciencia y Tecnologia, Spain [SAF 2000-158-CE]Ministerio de Ciencia y Tecnologia, SpainDepartament de Salut, Generalitat de Catalunya, Spain, Institut de Salud Carlos IIIDepartament de Salut, Generalitat de Catalunya, Spain, Institut de Salud Carlos III [CIBER CB06/02/0046, RETICS RD06/0011 REM-TAP]Government of IndiaGovernment of IndiaWHOWHOUnited Nations Development Group (UNDG)United Nations Development Group (UNDG)Japan Ministry of Health, Labour and WelfareJapan Ministry of Health, Labour and Welfare [H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013]Lebanese Ministry of Public HealthLebanese Ministry of Public HealthWHO (Lebanon)WHO (Lebanon)National Institute of Health/Fogarty International CenterNational Institute of Health/Fogarty International Center [R03 TW006481-01]Janssen CilagJanssen CilagEli LillyEli LillyAstraZenecaAstraZenecaHikma PharmHikma PharmNovartisNovartisNational Institute of Psychiatry Ramon de la Fuente [INPRFMDIES 4280]National Institute of Psychiatry Ramon de la FuenteNational Council on Science and TechnologyNational Council on Science and Technology [CONACyT-G30544-H]WHO (Geneva)WHO (Geneva)WHO (Nigeria)WHO (Nigeria)Federal Ministry of Health, Abuja, NigeriaFederal Ministry of Health, Abuja, NigeriaHealth & Social Care Research & Development Division of the Public Health AgencyHealth & Social Care Research & Development Division of the Public Health AgencyChampalimaud FoundationChampalimaud FoundationGulbenkian FoundationGulbenkian FoundationFoundation for Science and Technology (FCT)Foundation for Science and Technology (FCT)US National Institute of Mental Health [R01-MH059575, RO1-MH61905]US National Institute of Mental HealthNational Institute of Drug AbuseNational Institute of Drug AbuseSouth African Department of HealthSouth African Department of HealthUniversity of Michiganuniversity of MichiganNational Institute of Mental Health [U01-MH60220]National Institute of Mental HealthRobert Wood Johnson FoundationRobert Wood Johnson Foundation [044708