If a safety aid is present, there must be danger: the paradoxical effects of hand sanitizer during a contamination exposure task

Perceptions of danger often arise in the context of feared threat cues, but individuals also rely on other heuristics that lead them to infer danger in ambiguous situations. For example, individuals may interpret their own anxiety or safety-seeking behaviors as indicators of threat. Another potential source of danger information is the mere availability of safety aids in the environment. Although assumed to be helpful, safety aids might paradoxically elicit, rather than alleviate, anxiety. The present study was designed to assess the degree to which concern-relevant safety aids exacerbate distress. Participants (N = 71) completed several self-report measures and engaged in a contamination-related behavioral avoidance task (BAT) in the presence or absence of a 2L hand sanitizer dispenser. Results showed that participants higher in trait contamination aversion and in the presence of hand sanitizer endorsed greater inferences of danger, hypervigilance, peak BAT anxiety and disgust, BAT avoidance, and urges to wash following the BAT. Theoretical and clinical implications of the paradoxical inference of danger from the presence of safety aids are discussed

Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Kirsch and colleagues show that, in antidepressant trials, there is a greater difference in efficacy between drug and placebo amongst more severely depressed patients. However, this difference seems to result from a poorer response to placebo amongst more depressed patients

Assessment of obsessive-compulsive symptom dimensions: development and evaluation

Although several measures of obsessive-compulsive (OC) symptoms exist, most are limited in that they are not consistent with the most recent empirical findings on the nature and dimensional structure of obsessions and compulsions. In the present research, the authors developed and evaluated a measure called the Dimensional Obsessive-Compulsive Scale (DOCS) to address limitations of existing OC symptom measures. The DOCS is a 20-item measure that assesses the four dimensions of OC symptoms most reliably replicated in previous structural research. Factorial validity of the DOCS was supported by exploratory and confirmatory factor analyses of 3 samples, including individuals with OC disorder, those with other anxiety disorders, and nonclinical individuals. Scores on the DOCS displayed good performance on indices of reliability and validity, as well as sensitivity to treatment and diagnostic sensitivity, and hold promise as a measure of OC symptoms in clinical and research settings

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

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

Anxiety sensitivity dimensions and prediction of fearful responding to interoceptive exposure exercises

Includes bibliographical references (pages [70]-76)Anxiety sensitivity (AS), the tendency to fear one's own anxiety symptoms based on beliefs about their harmful consequences, reliably predicts fearful responding to a variety of tasks that produce strong interoceptive (i.e., somatic) sensations. Consistent with the idea that panic may result from the interaction between fears of specific anxiety symptoms and the experience of congruent anxiety symptoms, panic induction studies have consistently found that fears of the anxiety symptoms produced by a particular panic induction task are the strongest predictor of fearful responding to that task. These studies suggest that the predictive ability of AS in panic induction studies can be significantly enhanced by measuring the construct at the multidimensional level, and that fears of specific types of anxiety symptoms might provide a more powerful explanatory model for predicting emotional responding to aversive stimuli. The goal of the present study was to examine the ability four AS dimensions assessed by the Anxiety Sensitivity Index - Revised to predict fearful responding to four interoceptive exposure exercises in a nonclinical sample. Seventy-two undergraduate participants completed measures of AS, anxiety symptoms, trait anxiety, and panic attack history. Participants then engaged in four exercises: (1) shaking their head quickly from side to side for 90 seconds, (2) running in place for 120 seconds, (3) breathing through a thin coffee straw for as long as possible over two consecutive trials, and (4) reading a prepared speech out loud into a video camera about feeling anxious while experiencing publicly observable anxiety reactions. Each exercise elicited a pattern of fearful responding that was generally consistent with theoretical expectations. Global AS was significantly and uniquely associated with fearful responding to each exercise with the exception of reading the speech, even after controlling for trait anxiety and panic attack history. State anxiety was the strongest predictor of fear, and AS did not account for unique variance in fear after controlling for state anxiety. Contrary to prediction, AS dimensions did not demonstrate an interpretable pattern of predicting fearful responding to the exercises. The results are discussed in terms of cognitive theories of panic, and limitations of the present study and directions for future research are addressed.Ph.D. (Doctor of Philosophy

The ethics of exposure therapy for anxiety disorders

Exposure-based cognitive-behavioral therapy (CBT) is the most empirically supported psychological treatment for the anxiety disorders. However, few therapists provide exposure therapy to their clients. Although the poor dissemination of exposure-based treatments may be partially attributable to a shortage of suitably trained therapists, exposure therapy also suffers from a public relations problem among practitioners who believe it to be intolerable, unsafe, and unethical. This chapter provides an overview of ethical issues and considerations relevant to the use of exposure therapy. It is argued that exposure therapy may be delivered in an ethical, tolerable, and safe manner by therapists who take reasonable steps to create a professional context. Specific strategies for avoiding potential ethical conflicts in the use of exposure-based treatments are discussed