The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The world's major religions' points of viewon end-of-life decisions in the intensive care unit

Objective: Recent research has shown that the religious affiliation of both physicians and patients markedly influences end-of-life decisions in the intensive care unit in the Western world. The world’s major religions’ standings on withholding and withdrawing of therapy, on hastening of the death process when providing pain relief (double effect) and on euthanasia are described. This review also discusses whether nutrition should be provided to patients in a permanent vegetative state, and the issues of brain death and organ donation. Design: The review is based on literature research and a description of the legislature in countries where religious rulings do influence secular law. Results: Not all religions have distinct rulings on all the above-mentioned issues, but it is pointed out that all religions will probably have to develop rulings on these questions. The importance of patient autonomy in the Western (Christian) world is not necessarily an issue among other ethnic and religious groups, and guidelines are presented with methods to uncover and deal with different ethnic and religious views. Conclusion: Many religious groupings are now spread world-wide (most notably Muslims), and with increasing globalization it is important that health-care systems take into account the religious beliefs of a wide variety of ethnic and religious groups when contemplating end-of-life decisions

Relieving suffering or intentionally hastening death: where do you draw the line?

OBJECTIVE: End-of-life practices vary worldwide. The objective was to demonstrate that there is no clear-cut distinction between treatments administered to relieve pain and suffering and those intended to shorten the dying process. DESIGN: Secondary analysis of a prospective, observational study. SETTING: Thirty-seven intensive care units in 17 European countries. PATIENTS: Consecutive patients dying or with any limitation of therapy. INTERVENTIONS: Evaluation of the type of end-of-life category; dates and times of intensive care unit admission, death, or discharge; and decisions to limit therapy, medication, and doses used for active shortening of the dying process and the intent of the doctors prescribing the medication. MEASUREMENTS AND MAIN RESULTS: Limitation of life-sustaining therapy occurred in 3,086 (72.6%) of 4,248 patients, and 94 (2.2%) underwent active shortening of the dying process. Medication for active shortening of the dying process included administration of opiates (morphine to 71 patients) or benzodiazepines (diazepam to 54 patients) alone or in combination. The median dosage for morphine was 25.0 mg/hr and for diazepam 20.8 mg/hr. Doses of opiates and benzodiazepines were no higher than mean doses used with withdrawal in previous studies in 20 of 66 patients and were within the ranges of doses used in all but one patient. Doctors considered that medications for active shortening of the dying process definitely led to the patient's death in 72 patients (77%), probably led to the patient's death in 11 (12%), and were unlikely to have led to death in 11 (12%) patients. CONCLUSIONS: There is a gray area in end-of-life care between treatments administered to relieve pain and suffering and those intended to shorten the dying process

O R I G I N A L Reasons, considerations, difficulties and documentation of end-of-life decisions in European intensive care units: the ETHICUS Study

Abstract Objective: To evaluate physicians' reasoning, considerations and possible difficulties in end-of-life decision-making for patients in European intensive care units (ICUs). Design: A prospective observational study. Setting: Thirty-seven ICUs in 17 European countries. Patients and participants: A total of 3,086 patients for whom an end-of-life decision was taken between January 1999 and June 2000. The dataset excludes patients who died after attempts at cardiopulmonary resuscitation and brain-dead patients. Measurements and results: Physicians indicated which of a pre-determined set of reasons for, considerations in, and difficulties with end-of-life decision-making was germane in each case as it arose. Overall, 2,134 (69%) of the decisions were documented in the medical record, with inter-regional differences in documentation practice. Primary reasons given by physicians for the decision mostly concerned the patient's medical condition (79%), especially unresponsive to therapy (46%), while chronic disease (12%), quality of life (4%), age (2%) and patient or family request (2%) were infrequent. Good medical practice (66%) and best interests (29%) were the commonest primary considerations reported, 272 while resource allocation issues such as cost effectiveness (1%) and need for an ICU bed (0%) were uncommon. Living wills were considered in only 1% of cases. Physicians in central Europe reported no significant difficulty in 81% of cases, while in northern and southern regions there was no difficulty in 92-93% of cases. Conclusions: European ICU physicians do not experience difficulties with end-of-life decisions in most cases. Allocation of limited resources is a minor consideration and autonomous choices by patient or family remain unusual. Inter-regional differences were found

Changes in End-of-Life Practices in European Intensive Care Units From 1999 to 2016

Importance: End-of-life decisions occur daily in intensive care units (ICUs) around the world, and these practices could change over time. Objective: To determine the changes in end-of-life practices in European ICUs after 16 years. Design, Setting, and Participants: Ethicus-2 was a prospective observational study of 22 European ICUs previously included in the Ethicus-1 study (1999-2000). During a self-selected continuous 6-month period at each ICU, consecutive patients who died or had any limitation of life-sustaining therapy from September 2015 until October 2016 were included. Patients were followed up until death or until 2 months after the first treatment limitation decision. Exposures: Comparison between the 1999-2000 cohort vs 2015-2016 cohort. Main Outcomes and Measures: End-of-life outcomes were classified into 5 mutually exclusive categories (withholding of life-prolonging therapy, withdrawing of life-prolonging therapy, active shortening of the dying process, failed cardiopulmonary resuscitation [CPR], brain death). The primary outcome was whether patients received any treatment limitations (withholding or withdrawing of life-prolonging therapy or shortening of the dying process). Outcomes were determined by senior intensivists. Results: Of 13 625 patients admitted to participating ICUs during the 2015-2016 study period, 1785 (13.1%) died or had limitations of life-prolonging therapies and were included in the study. Compared with the patients included in the 1999-2000 cohort (n = 2807), the patients in 2015-2016 cohort were significantly older (median age, 70 years [interquartile range {IQR}, 59-79] vs 67 years [IQR, 54-75]; P < .001) and the proportion of female patients was similar (39.6% vs 38.7%; P = .58). Significantly more treatment limitations occurred in the 2015-2016 cohort compared with the 1999-2000 cohort (1601 [89.7%] vs 1918 [68.3%]; difference, 21.4% [95% CI, 19.2% to 23.6%]; P < .001), with more withholding of life-prolonging therapy (892 [50.0%] vs 1143 [40.7%]; difference, 9.3% [95% CI, 6.4% to 12.3%]; P < .001), more withdrawing of life-prolonging therapy (692 [38.8%] vs 695 [24.8%]; difference, 14.0% [95% CI, 11.2% to 16.8%]; P < .001), less failed CPR (110 [6.2%] vs 628 [22.4%]; difference, -16.2% [95% CI, -18.1% to -14.3%]; P < .001), less brain death (74 [4.1%] vs 261 [9.3%]; difference, -5.2% [95% CI, -6.6% to -3.8%]; P < .001) and less active shortening of the dying process (17 [1.0%] vs 80 [2.9%]; difference, -1.9% [95% CI, -2.7% to -1.1%]; P < .001). Conclusions and Relevance: Among patients who had treatment limitations or died in 22 European ICUs in 2015-2016, compared with data reported from the same ICUs in 1999-2000, limitations in life-prolonging therapies occurred significantly more frequently and death without limitations in life-prolonging therapies occurred significantly less frequently. These findings suggest a shift in end-of-life practices in European ICUs, but the study is limited in that it excluded patients who survived ICU hospitalization without treatment limitations.status: publishe

Changes in End-of-Life Practices in European Intensive Care Units From 1999 to 2016

Key PointsQuestionHave end-of-life practices in European intensive care units (ICUs) changed from 1999-2000 to 2015-2016? FindingsIn this prospective observational study of 1785 patients who had limitations in life-prolonging therapies or died in 22 European ICUs in 2015-2016, compared with data previously reported from the same ICUs in 1999-2000 (2807 patients), treatment limitations (withholding or withdrawing life-sustaining treatment or active shortening of the dying process) occurred significantly more frequently (89.7\% vs 68.3\%), whereas death without any limitations in life-prolonging therapies occurred significantly less frequently (10.3\% vs 31.7\%). MeaningThese findings suggest that end-of-life care practices in European ICUs changed from 1999-2000 to 2015-2016 with more limitations in life-prolonging therapies and fewer deaths without treatment limitations. ImportanceEnd-of-life decisions occur daily in intensive care units (ICUs) around the world, and these practices could change over time. ObjectiveTo determine the changes in end-of-life practices in European ICUs after 16 years. Design, Setting, and ParticipantsEthicus-2 was a prospective observational study of 22 European ICUs previously included in the Ethicus-1 study (1999-2000). During a self-selected continuous 6-month period at each ICU, consecutive patients who died or had any limitation of life-sustaining therapy from September 2015 until October 2016 were included. Patients were followed up until death or until 2 months after the first treatment limitation decision. ExposuresComparison between the 1999-2000 cohort vs 2015-2016 cohort. Main Outcomes and MeasuresEnd-of-life outcomes were classified into 5 mutually exclusive categories (withholding of life-prolonging therapy, withdrawing of life-prolonging therapy, active shortening of the dying process, failed cardiopulmonary resuscitation {[}CPR], brain death). The primary outcome was whether patients received any treatment limitations (withholding or withdrawing of life-prolonging therapy or shortening of the dying process). Outcomes were determined by senior intensivists. ResultsOf 13625 patients admitted to participating ICUs during the 2015-2016 study period, 1785 (13.1\%) died or had limitations of life-prolonging therapies and were included in the study. Compared with the patients included in the 1999-2000 cohort (n=2807), the patients in 2015-2016 cohort were significantly older (median age, 70 years {[}interquartile range \{IQR\}, 59-79] vs 67 years {[}IQR, 54-75]; P&lt;.001) and the proportion of female patients was similar (39.6\% vs 38.7\%; P=.58). Significantly more treatment limitations occurred in the 2015-2016 cohort compared with the 1999-2000 cohort (1601 {[}89.7\%] vs 1918 {[}68.3\%]; difference, 21.4\% {[}95\% CI, 19.2\% to 23.6\%]; P&lt;.001), with more withholding of life-prolonging therapy (892 {[}50.0\%] vs 1143 {[}40.7\%]; difference, 9.3\% {[}95\% CI, 6.4\% to 12.3\%]; P&lt;.001), more withdrawing of life-prolonging therapy (692 {[}38.8\%] vs 695 {[}24.8\%]; difference, 14.0\% {[}95\% CI, 11.2\% to 16.8\%]; P&lt;.001), less failed CPR (110 {[}6.2\%] vs 628 {[}22.4\%]; difference, -16.2\% {[}95\% CI, -18.1\% to -14.3\%]; P&lt;.001), less brain death (74 {[}4.1\%] vs 261 {[}9.3\%]; difference, -5.2\% {[}95\% CI, -6.6\% to -3.8\%]; P&lt;.001) and less active shortening of the dying process (17 {[}1.0\%] vs 80 {[}2.9\%]; difference, -1.9\% {[}95\% CI, -2.7\% to -1.1\%]; P&lt;.001). Conclusions and RelevanceAmong patients who had treatment limitations or died in 22 European ICUs in 2015-2016, compared with data reported from the same ICUs in 1999-2000, limitations in life-prolonging therapies occurred significantly more frequently and death without limitations in life-prolonging therapies occurred significantly less frequently. These findings suggest a shift in end-of-life practices in European ICUs, but the study is limited in that it excluded patients who survived ICU hospitalization without treatment limitations. This study compares changes in end-of-life practices (withholding or withdrawing of life-prolonging therapy, active shortening of the dying process, failed CPR, documentation of brain death) in 22 European ICUs between 1999-2000 and 2015-2016