Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

SummaryWe have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

International audienceAutism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs

Care and communication between health professionals and patients affected by severe or chronic illness in community care settings: a qualitative study of care at the end of life

Background: Advance care planning (ACP) enables patients to consider, discuss and, if they wish, document their wishes and preferences for future care, including decisions to refuse treatment, in the event that they lose capacity to make decisions for themselves. ACP is a key component of UK health policy to improve the experience of death and dying for patients and their families. There is limited evidence about how patients and health professionals understand ACP, or when and how this is initiated. It is evident that many people find discussion of and planning for end of life care difficult, and tend to avoid the topic. Aim: To investigate how patients, their relatives and health professionals initiate and experience discussion of ACP and the outcomes of advance discussions in shaping care at the end of life. Design and data collection: Qualitative study with two workstreams: (1) interviews with 37 health professionals (general practitioners, specialist nurses and community nurses) about their experiences of ACP; and (2) longitudinal case studies of 21 patients with 6-month follow-up. Cases included a patient and, where possible, a nominated key relative and/or health professional as well as a review of medical records. Complete case triads were obtained for 11 patients. Four cases comprised the patient alone, where respondents were unable or unwilling to nominate either a family member or a professional carer they wished to include in the study. Patients were identified as likely to be within the last 6 months of life. Ninety-seven interviews were completed in total. Setting: General practices and community care settings in the East Midlands of England. Findings: The study found ACP to be uncommon and focused primarily on specific documented tasks involving decisions about preferred place of death and cardiopulmonary resuscitation, supporting earlier research. There was no evidence of ACP in nearly half (9 of 21) of patient cases. Professionals reported ACP discussions to be challenging. It was difficult to recognise when patients had entered the last year of life, or to identify their readiness to consider future planning. Patients often did not wish to do so before they had become gravely ill. Consequently, ACP discussions tended to be reactive, rather than pre-emptive, occurring in response to critical events or evidence of marked deterioration. ACP discussions intersected two parallel strands of planning: professional organisation and co-ordination of care; and the practical and emotional preparatory work that patients and families undertook to prepare themselves for death. Reference to ACP as a means of guiding decisions for patients who had lost capacity was rare. Conclusions: Advance care planning remains uncommon, is often limited to documentation of a few key decisions, is reported to be challenging by many health professionals, is not welcomed by a substantial number of patients and tends to be postponed until death is clearly imminent. Current implementation largely ignores the purpose of ACP as a means of extending personal autonomy in the event of lost capacity. Future work: Attention should be paid to public attitudes to death and dying (including those of culturally diverse and ethnic minority groups), place of death, resuscitation and the value of anticipatory planning. In addition the experiences and needs of two under-researched groups should be explored: the frail elderly, including those who manage complex comorbid conditions, unrecognised as vulnerable cases; and those patients affected by stigmatised conditions, such as substance abuse or serious mental illness who fail to engage constructively with services and are not recognised as suitable referrals for palliative and end of life care. Funding: The National Institute for Health Research Health Services and Delivery Research programme

Measurement of ϒ production in pp collisions at √s = 2.76 TeV

The production of ϒ(1S), ϒ(2S) and ϒ(3S) mesons decaying into the dimuon final state is studied with the LHCb detector using a data sample corresponding to an integrated luminosity of 3.3 pb−1 collected in proton–proton collisions at a centre-of-mass energy of √s = 2.76 TeV. The differential production cross-sections times dimuon branching fractions are measured as functions of the ϒ transverse momentum and rapidity, over the ranges pT < 15 GeV/c and 2.0 < y < 4.5. The total cross-sections in this kinematic region, assuming unpolarised production, are measured to be σ (pp → ϒ(1S)X) × B ϒ(1S)→μ+μ− = 1.111 ± 0.043 ± 0.044 nb, σ (pp → ϒ(2S)X) × B ϒ(2S)→μ+μ− = 0.264 ± 0.023 ± 0.011 nb, σ (pp → ϒ(3S)X) × B ϒ(3S)→μ+μ− = 0.159 ± 0.020 ± 0.007 nb, where the first uncertainty is statistical and the second systematic

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Multiobjective optimization of aerospace structures /

"This report presents the multiobjective optimization methodology suitable to the preliminary design of large scale aircraft structures. The algorithm is based on generalized compound scaling techniques to reach the intersection of multiple functions. Multiobjective functions are treated similar to the behavior constraints by generating pseudo targets on objectives. This algorithm is very efficient due to the fact that it does not solve many single objective optimization problems in reaching the Pareto set. The Pareto set gives several optimum solutions, and the designer has to use additional decision criteria in selecting the best design. In this work a reliability index based concept is used as the decision criterion. System reliability of the Pareto designs is calculated due to the random nature of material properties, fabrication tolerances, and service loads, where the random parameters influencing the design appear through their mean and covariance values."--Report documentation page.Cover title.Final report for period: January 1990 - December 1991.""July 1992.""WL-TR-92-3052."Includes bibliographical references (pages 114-120).Ch. 1. Introduction. -- Ch. 2. Finite element formulation. -- Ch. 3. Sensitivity analysis. -- Ch. 4. Optimization algorithm. -- Ch. 5. Numerical results and discussions. --Ch. 6. Conclusions."This report presents the multiobjective optimization methodology suitable to the preliminary design of large scale aircraft structures. The algorithm is based on generalized compound scaling techniques to reach the intersection of multiple functions. Multiobjective functions are treated similar to the behavior constraints by generating pseudo targets on objectives. This algorithm is very efficient due to the fact that it does not solve many single objective optimization problems in reaching the Pareto set. The Pareto set gives several optimum solutions, and the designer has to use additional decision criteria in selecting the best design. In this work a reliability index based concept is used as the decision criterion. System reliability of the Pareto designs is calculated due to the random nature of material properties, fabrication tolerances, and service loads, where the random parameters influencing the design appear through their mean and covariance values."--Report documentation page.Research supported by the United States Air Force Flight Dynamics Directorate, and performed by the Department of Mechanical and Materials Engineering, Wright State University, Dayton,Ohio, under contact no.Mode of access: Internet