Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

ECT and DBS: Depression Treatments and their Perceived Threat to Personal Identity

Major Depressive Disorder (MDD) presents a serious global health concern. Despite improvements in MDD treatment, the rates and overall societal burden of this debilitating disorder continue to increase. Moreover, approximately one third of depressed individuals are resistant to traditional psychotherapeutic and psychopharmacological treatments. The urgency to find alternative treatments has led to further exploration of brain stimulation therapies, such as electroconvulsive therapy (ECT) and deep brain stimulation (DBS). Research demonstrates the potential these therapies have to effectively alleviate depressive symptoms. However, although rare, these treatments can have concerning side effects. These side effects appear to threaten personal identity, raising both clinical and theoretical concerns. In this thesis, I explore nature of MDD from a neurological and phenomenological lens, discuss theoretical understandings of the self, and closely examine how MDD influences patients’ personal identity. Additionally, I provide an in depth explanation of the administration, efficacy, and side effects of ECT and DBS as MDD treatments. Lastly, I make two arguments stemming from clinical and theoretical perspectives. First, from the clinical perspective, it is necessary to continue researching and refining these brain stimulation therapies given compelling evidence of their antidepressant effects. Second, the theoretical perspective is practical in that it can uncover and explain personal identity issues patients face, and can explain how events, such as receiving ECT or DBS, can be incorporated into personal identity. Moreover, the theoretical perspective directs future research and medical practice, and overall demonstrates how potential threats to personal identity can be prevented or at least diminished

Guest Removal and External Pressure Variation Induce Spin Crossover in Halogen-Functionalized 2-D Hofmann Frameworks

The effect of halogen functionalization on the spin crossover (SCO) properties of a family of 2-D Hofmann framework materials, [FePd(CN)(thioX)]·2HO (X = Cl and Br; thioCl = ()-1-(5-chlorothiophen-2-yl)--(4-1,2,4-triazol-4-yl)methanimine) and thioBr = ()-1-(5-bromothiophen-2-yl)--(4-1,2,4-triazol-4-yl)methanimine)), is reported. Inclusion of both the chloro- and bromo-functionalized ligands into the Hofmann-type frameworks ( and ) results in a blocking of spin-state transitions due to internal chemical pressure effects derived by the collective steric bulk of the halogen atoms and guest molecules. Cooperative one-step SCO transitions are revealed by either guest removal or the application of external physical pressure. Notably, removal of solvent water reveals a robust framework scaffold with only marginal variation between the solvated and desolvated structures (as investigated by powder and single crystal X-ray diffraction). Yet, one-step complete SCO transitions are revealed in and with a transition temperature shift between the analogues due to various steric, structural, and electronic considerations. SCO can also be induced in the solvated species, and , with the application of physical pressure, revealing a complete one-step SCO transition above 0.62 GPa (as investigated by magnetic susceptibility and single crystal X-ray diffraction measurements)

Patient, Caregiver, and Decliner Perspectives on Whether to Enroll in Adaptive Deep Brain Stimulation Research.

This research study provides patient and caregiver perspectives as to whether or not to undergo adaptive deep brain stimulation (aDBS) research. A total of 51 interviews were conducted in a multi-site study including patients undergoing aDBS and their respective caregivers along with persons declining aDBS. Reasons highlighted for undergoing aDBS included hopes for symptom alleviation, declining quality of life, desirability of being in research, and altruism. The primary reasons for not undergoing aDBS issues were practical rather than specific to aDBS technology, although some persons highlighted a desire to not be the first to trial the new technology. These themes are discussed in the context of "push" factors wherein any form of surgical intervention is preferable to none and "pull" factors wherein opportunities to contribute to science combine with hopes and/or expectations for the alleviation of symptoms. We highlight the significance of study design in decision making. aDBS is an innovative technology and not a completely new technology. Many participants expressed value in being part of research as an important consideration. We suggest that there are important implications when comparing patient perspectives vs. theoretical perspectives on the choice for or against aDBS. Additionally, it will be important how we communicate with patients especially in reference to the complexity of study design. Ultimately, this study reveals that there are benefits and potential risks when choosing a research study that involves implantation of a medical device

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders