Lifting Universal Masking in Schools - Covid-19 Incidence among Students and Staff.

BACKGROUND: In February 2022, Massachusetts rescinded a statewide universal masking policy in public schools, and many Massachusetts school districts lifted masking requirements during the subsequent weeks. In the greater Boston area, only two school districts - the Boston and neighboring Chelsea districts - sustained masking requirements through June 2022. The staggered lifting of masking requirements provided an opportunity to examine the effect of universal masking policies on the incidence of coronavirus disease 2019 (Covid-19) in schools. METHODS: We used a difference-in-differences analysis for staggered policy implementation to compare the incidence of Covid-19 among students and staff in school districts in the greater Boston area that lifted masking requirements with the incidence in districts that sustained masking requirements during the 2021-2022 school year. Characteristics of the school districts were also compared. RESULTS: Before the statewide masking policy was rescinded, trends in the incidence of Covid-19 were similar across school districts. During the 15 weeks after the statewide masking policy was rescinded, the lifting of masking requirements was associated with an additional 44.9 cases per 1000 students and staff (95% confidence interval, 32.6 to 57.1), which corresponded to an estimated 11,901 cases and to 29.4% of the cases in all districts during that time. Districts that chose to sustain masking requirements longer tended to have school buildings that were older and in worse condition and to have more students per classroom than districts that chose to lift masking requirements earlier. In addition, these districts had higher percentages of low-income students, students with disabilities, and students who were English-language learners, as well as higher percentages of Black and Latinx students and staff. Our results support universal masking as an important strategy for reducing Covid-19 incidence in schools and loss of in-person school days. As such, we believe that universal masking may be especially useful for mitigating effects of structural racism in schools, including potential deepening of educational inequities. CONCLUSIONS: Among school districts in the greater Boston area, the lifting of masking requirements was associated with an additional 44.9 Covid-19 cases per 1000 students and staff during the 15 weeks after the statewide masking policy was rescinded.

Do Polymorphisms Predict Hypnotherapy Response in Children With Functional Abdominal Pain Disorders: An Explorative Study.

Genetic variations, in specific COMT , OPRM1 , and MAO-A polymorphisms, have been associated with hypnotizability in adults. The aim of this exploratory study was to investigate whether these polymorphisms are also associated with response to hypnotherapy (HT) in children. Patients (8-18 years, n = 260) diagnosed with a functional abdominal pain disorder (FAPD) from a previous trial assessing HT efficacy were approached for participation and 144 agreed to collect a buccal sample. Primary aim was to explore the association between COMT , OPRM1 , and MAO-A polymorphisms with treatment success (TS) after 3-month HT. Additionally, associations between these polymorphisms and adequate relief, anxiety, depression, quality of life, somatization, hypnotic susceptibility, expectations, pain beliefs, and coping strategies were evaluated. Participants with different variations of COMT , MAO-A , and OPRM1 achieved similar TS levels ( P > 0.05). No associations were found between these polymorphisms and secondary outcomes. This suggest that in pediatric patients with FAPDs, COMT , OPRM1 , and MAO-A polymorphisms do not predict HT response.

Genetic variation at the coronary artery disease risk locus GUCY1A3 modifies cardiovascular disease prevention effects of aspirin.

AIMS: Efficacy of aspirin in primary prevention of cardiovascular disease (CVD) may be influenced by a common allele in guanylate cyclase GUCY1A3, which has been shown to modify platelet function and increase CVD risk. METHODS AND RESULTS: We investigated whether homozygotes of the GUCY1A3 rs7692387 risk (G) allele benefited from aspirin in two long-term, randomized placebo-controlled trials of aspirin in primary CVD prevention: the Women's Genome Health Study (WGHS, N = 23 294) and a myocardial infarction (MI, N = 550) and stroke (N = 382) case-control set from the Physician's Health Study (PHS, N = 22 071). Bleeding risk was evaluated in the WGHS. In the placebo group of the WGHS, the GUCY1A3 risk (G) allele was confirmed to increase CVD risk [hazard ratio 1.38; 95% confidence interval (CI) 1.08-1.78; P = 0.01]. Random-effects meta-analysis of the WGHS and PHS revealed that aspirin reduced CVD events among risk allele homozygotes [G/G: odds ratio (OR) 0.79; 95% CI 0.65-0.97; P = 0.03] but increased CVD events among non-risk allele carriers (e.g. G/A: OR 1.39; 95% CI 1.03-1.87; P = 0.03) thus implying an interaction between genotype stratum and aspirin intake (Pinteraction = 0.01). Bleeding associated with aspirin increased in all genotype groups, with higher risks in heterozygotes. CONCLUSION: In two randomized placebo-controlled trials in the setting of primary prevention, aspirin reduced the incidence of CVD events in individuals homozygous for the GUCY1A3 risk (G) allele, whereas heterozygote individuals had more events when taking aspirin.

The Association Between C-Reactive Protein and Postoperative Delirium Differs by Catechol-O-Methyltransferase Genotype.

OBJECTIVE: Catechol-O-methyltransferase (COMT), a key enzyme in degrading catecholamines associated with the stress response, may influence susceptibility to delirium. Individuals with the COMT (rs4680) Val/Val genotype (designated "warriors") withstand the onset of neuropsychiatric disorders and cognitive decline, whereas individuals with Met/Met and Val/Met genotypes ("nonwarriors") are more susceptible to these conditions. We evaluated whether COMT genotype modifies the established association between acute phase reactant (stress marker) C-reactive protein (CRP) and postoperative delirium. METHODS: This was a prospective cohort study conducted at two academic medical centers. The study involved 547 patients aged 70 or older undergoing major noncardiac surgery. We collected blood, extracted DNA, and performed COMT genotyping using allele-specific polymerase chain reaction assays, considering warriors versus nonwarriors. High plasma CRP, measured on postoperative day 2 using enzyme-linked immunosorbent assay, was defined by the highest sample-based quartile (≥234.12 mg/L). Delirium was determined using the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and race/ethnicity, stratified by COMT genotype, to determine whether the association between CRP and delirium differed by COMT. RESULTS: Prevalence of COMT warriors was 26%, and postoperative delirium occurred in 23%. Among COMT warriors, high CRP was not associated with delirium (relative risk [RR] 1.0, 95% confidence interval [CI] 0.4-2.6). In contrast, among nonwarriors, we found the expected relationship of high CRP and delirium (RR 1.5, 95% CI 1.1-2.2). CONCLUSION: COMT warriors may be protected against the increased risk of delirium associated with high CRP on postoperative day 2. With further confirmation, COMT genotype may help target interventions for delirium prevention in the vulnerable nonwarrior group.

Open-label placebo reduces fatigue in cancer survivors: a randomized trial.

PURPOSE: Cancer-related fatigue (CRF) is a common and challenging late effect for many cancer survivors. Clinical trials demonstrate robust placebo effects on CRF in blinded trials. Recently, open-label placebo (OLP) has been shown to improve a variety of symptoms in other populations. We conducted a randomized controlled trial to investigate the effect of OLP on CRF in cancer survivors, and to explore biologic and psychological correlates of placebo efficacy. METHODS: Forty cancer survivors (92.5% female; mean age 47.3 years) were randomized to OLP or no treatment control. OLP participants were prescribed two placebo tablets twice daily, for 3 weeks. All participants completed assessments at Baseline, Day 8, and Day 22. The primary endpoint was change in CRF (FACIT-F), and secondary outcomes included exercise frequency, mood, and quality of life. We examined whether personality characteristics or a genetic variation important in dopamine catabolism (catechol-O-methyltransferase; COMT) affected the placebo response. RESULTS: The OLP group reported significantly improved CRF at both Day 8 (p = 0.005) and Day 22 (p = .02), while the control group did not (ps > .05). CRF improvement differed by COMT genotype, but was not associated with personality characteristics. Marginal improvements were noted in the placebo group for some secondary outcomes (exercise frequency and quality of life), but not in the control group. CONCLUSIONS: Results demonstrate that even when administered openly, placebos improve CRF in cancer survivors and dopaminergic systems may be associated with this response. This novel research has meaningful implications for the use of OLP in symptom management for cancer survivors.

The Effect of Anesthetic Choice (Sevoflurane Versus Desflurane) and Neuromuscular Management on Speed of Airway Reflex Recovery.

BACKGROUND: Nonintubated patients receiving sevoflurane have slower protective airway reflex recovery after anesthesia compared with patients receiving desflurane. We asked whether this difference would remain significant among intubated patients receiving rocuronium or whether the impact of variable neuromuscular recovery would predominate and thus minimize differences between anesthetics. METHODS: After obtaining written informed consent, patients were randomly assigned to receive sevoflurane (n = 41) or desflurane (n = 40), with neuromuscular monitoring by quantitative train-of-four (TOF) method using accelerometry. Intubation was facilitated by administration of 1 mg/kg rocuronium. Neuromuscular block was produced, with the goal of maintaining 10% to 15% of baseline function. After surgery, neostigmine 70 µg/kg + glycopyrrolate 14 µg/kg was administered. When TOF ratio reached ≥ 0.7, anesthetic was discontinued and fresh gas flow was raised to 15 L/m. The time of first response to command was noted, after which patients were given a 20-mL water swallowing test at 2, 6, 14, 22, 30, and 60 minutes. The following average time intervals were compared between the 2 intervention groups: anesthetic discontinuation to first response to command (T1); first response to command to first successful passing of swallow test (T2); and anesthetic discontinuation to first successful passing of swallow test (T3). We also compared the rates of successful swallow tests at 2 minutes after first response to command in the 2 groups, first categorizing as failures all those who were unable to take the test at 2 minutes, and then excluding 10 patients unable to take the test at this time for reasons other than somnolence (n = 10). RESULTS: Patients receiving desflurane passed the swallowing test at shorter time intervals after first response to command than did patients receiving sevoflurane (Wilcoxon-Mann-Whitney odds = 1.60; 95% confidence interval [CI], 1.01-2.69; P = 0.054). Two minutes after the first response to command, among all 81 patients, the chance of passing the swallowing test was higher after desflurane compared with sevoflurane anesthesia (relative risk = 1.6; 95% CI, 1.0-2.5; P = 0.04). Of the 71 patients (as above), we observed a significantly higher chance of passing at 2 minutes after first response to command (relative risk = 1.8; 95% CI, 1.2-2.7; P = 0.006) in patients receiving desflurane (25/33) compared with those receiving sevoflurane (16/38). In 18 of 81 and 16 of 71 patients, the neuromuscular monitoring and reversal protocols were not followed (neostigmine underdosed, extubation at TOF <0.7, or reliance on tactile as opposed to quantitative TOF measurement). In both the total cohort and the subset of 71, neuromuscular protocol adherence increased the chance of passing the swallow test, independent of anesthetic assignment in multivariable logistic regression (P = 0.02 and P = 0.006, respectively), demonstrating significant effect on airway reflex recovery independent of chosen anesthetic. CONCLUSIONS: Compared with sevoflurane, desflurane allowed faster recovery of airway reflexes after anesthesia in intubated patients. Clinical management of neuromuscular block, including full reversal and the use of quantitative TOF, affects airway reflex recovery-an effect that may be at least as profound as the choice of potent inhaled anesthetic.

The Burmese python genome reveals the molecular basis for extreme adaptation in snakes.

Snakes possess many extreme morphological and physiological adaptations. Identification of the molecular basis of these traits can provide novel understanding for vertebrate biology and medicine. Here, we study snake biology using the genome sequence of the Burmese python (Python molurus bivittatus), a model of extreme physiological and metabolic adaptation. We compare the python and king cobra genomes along with genomic samples from other snakes and perform transcriptome analysis to gain insights into the extreme phenotypes of the python. We discovered rapid and massive transcriptional responses in multiple organ systems that occur on feeding and coordinate major changes in organ size and function. Intriguingly, the homologs of these genes in humans are associated with metabolism, development, and pathology. We also found that many snake metabolic genes have undergone positive selection, which together with the rapid evolution of mitochondrial proteins, provides evidence for extensive adaptive redesign of snake metabolic pathways. Additional evidence for molecular adaptation and gene family expansions and contractions is associated with major physiological and phenotypic adaptations in snakes; genes involved are related to cell cycle, development, lungs, eyes, heart, intestine, and skeletal structure, including GRB2-associated binding protein 1, SSH, WNT16, and bone morphogenetic protein 7. Finally, changes in repetitive DNA content, guanine-cytosine isochore structure, and nucleotide substitution rates indicate major shifts in the structure and evolution of snake genomes compared with other amniotes. Phenotypic and physiological novelty in snakes seems to be driven by system-wide coordination of protein adaptation, gene expression, and changes in the structure of the genome.

Polymorphisms in catechol-O-methyltransferase modify treatment effects of aspirin on risk of cardiovascular disease.

OBJECTIVE: Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. APPROACH AND RESULTS: We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05-3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83-2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar. CONCLUSIONS: Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome.

Background: Irritable bowel syndrome (IBS) is a highly prevalent chronic pain disorder with multiple underlying mechanisms and few treatments that have been demonstrated to be effective in placebo controlled trials. One potential reason may be the use of composite outcomes, such as the IBS Symptom Severity Scale (IBS-SSS) which includes descriptive items related to pain frequency and pain intensity as well as bowel dysfunction and bloating. We investigated if different features of IBS pain have distinct genetic associations and if these may be moderated by sex hormones. Participants and Setting: Adult outpatients with moderately severe IBS (>175 on IBS-SSS) enrolled in a clinical trial reported IBS-SSS at baseline and after 6 weeks of therapy. Methods: Fixed effects modeling was used to test the effect of COMT rs4680 genotype to change in pain severity (rated 0-100) and pain frequency (defined as number of days with pain in the past 10 days) from baseline to week 6 with IBS treatment. Parallel exploratory genome-wide association studies (GWAS) were also performed to identify single nucleotide polymorphisms (SNPs) associated with change in pain severity or pain frequency across all participants. Results: A total of 212 participants (74% female) were included. The COMT rs4680 met allele was associated with decreased pain severity over the course of the trial in gene dosage models [beta(SE) -5.9 (2.6), P = 0.028]. Exploratory GWAS for change in pain frequency identified 5 SNPs in close proximity on chromosome 18 near L3MBTL4 which reached genome-wide significance (all P < 5.0E-8). This effect was not mediated by changing estradiol levels. There was also a region of chromosome 7 with 24 SNPs of genome-wide suggestive significance for change in pain severity (all P < 1.0E-5). Conclusions: Previously reported association between COMT rs4680 genotype and treatment response as measured by IBS-SSS is related to pain severity, but not pain frequency. We also identified new candidate genes associated with changes in IBS pain severity (SNX13) and pain frequency (L3MBTL4) in response to treatment. Further studies are needed to understand these associations and genetic determinants of different components of IBS-SSS. ClinicalTrials.gov, Identifier: NCT0280224.

What Do Placebo and Nocebo Effects Have to Do With Health Equity? The Hidden Toll of Nocebo Effects on Racial and Ethnic Minority Patients in Clinical Care.

A placebo effect is a positive clinical response to non-specific elements of treatment with a sham or inert replica of a drug, device, or surgical intervention. There is considerable evidence that placebo effects are driven by expectation of benefit from the intervention. Expectation is shaped by a patient's past experience, observations of the experience of others, and written, verbal, or non-verbal information communicated during treatment. Not surprisingly, expectation in the clinical setting is strongly influenced by the attitude, affect, and communication style of the healthcare provider. While positive expectations can produce beneficial effects, negative information and experiences can lead to negative expectations, and consequently negative or nocebo effects. Key components identified and studied in the placebo and nocebo literature intersect with factors identified as barriers to quality care in the clinical setting for Black patients and other patients of color, including poor patient-clinician communication, medical mistrust, and perceived discrimination. Thus, in the context of discrimination and bias, the absence of placebo and presence of nocebo-generating influences in clinical settings could potentially reinforce racial and ethnic inequities in clinical outcomes and care. Healthcare inequities have consequences that ripple through the medical system, strengthening adverse short- and long-term outcomes. Here, we examine the potential for the presence of nocebo effects and absence of placebo effects to play a role in contributing to negative outcomes related to unequal treatment in the clinical encounter.

Historical Controls in Randomized Clinical Trials: Opportunities and Challenges.

Randomized control trials (RCTs) with placebo are the gold standard for determining efficacy of novel pharmaceutical treatments. Since their inception, over 75 years ago, researchers have amassed a large body of underutilized data on outcomes in the placebo control arms of these trials. Although rare disease indications have used these historical placebo data as synthetic controls to reduce burden on patients and accelerate drug discovery, broad use of historical controls is in its infancy. Large-scale historical placebo data could be leveraged to benefit both drug developers and patients if warehoused and made more available to guide trial design and analysis. Here, we examine challenges in utilizing historical controls related to heterogeneity in trial design, outcome ascertainment, patient characteristics, and unmeasured pharmacogenomic effects. We then discuss the advantages and disadvantages of current approaches and propose a path forward to broader use of historical controls in RCTs.

Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome.

Background and Aims: Irritable bowel syndrome (IBS), a functional pain disorder of gut-brain interactions, is characterized by a high placebo response in randomized clinical trials (RCTs). Catechol-O-methyltransferase (COMT) rs4680, which encodes high-activity (val) or low-activity (met) enzyme variants, was previously associated with placebo response to sham-acupuncture in an IBS RCT. Examining COMT effects and identifying novel genomic factors that influence response to placebo pills is critical to identifying underlying mechanisms and predicting and managing placebos in RCTs. Methods: Participants with IBS (N = 188) were randomized to three placebo-related interventions, namely, double-blind placebo (DBP), open-label placebo (OLP), or simply trial enrollment without placebo treatment [no placebo (i.e., no pill) treatment control (NPC)], for 6 weeks. COMT rs4680, gene-set, and genome-wide suggestive (p < 10-5) loci effects on irritable bowel symptom severity score (IBS-SSS) across all participants were examined. Results: Participants with IBS homozygous for rs4680 met (met/met) had the greatest improvement across all arms, with significantly greater improvement compared to val/val in DBP (beta (SE), -89.4 (42.3); p = 0.04). Twelve genome-wide suggestive loci formed a gene regulatory network highly connected to EGR1, a transcription factor involved in placebo-related processes of learning, memory, and response to stress and reward. EGR1 gene expression in peripheral blood mononuclear cells (PBMC) was significantly reduced at the endpoint across all treatment arms (log fold-change, -0.15; p = 0.02). Gene-set enrichment analysis returned three genome-wide significant ontology terms (GO:0032968, GO:0070934, and GO:0070937) linked to transcription regulation and GO:0003918 associated with DNA topoisomerase regulation. Conclusion: These results suggest common molecular mechanisms in response to varying forms of placebo that may inform personalized IBS treatment and placebo response prediction. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT0280224.

NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review.

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.

Assessment of Placebo Response in Objective and Subjective Outcome Measures in Rheumatoid Arthritis Clinical Trials.

Importance: Large placebo responses in randomized clinical trials may keep effective medication from reaching the market. Primary outcome measures of clinical trials have shifted from patient-reported to objective outcomes, partly because response to randomized placebo treatment is thought to be greater in subjective compared with objective outcomes. However, a direct comparison of placebo response in subjective and objective outcomes in the same patient population is missing. Objective: To assess whether subjective patient-reported (pain severity) and objective inflammation (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]) outcomes differ in placebo response. Design, Setting, and Participants: The placebo arms of 5 double-blind, randomized, placebo-controlled clinical trials were included in this cross-sectional study. These trials were conducted internationally for 24 weeks or longer between 2005 and 2009. All patients with rheumatoid arthritis randomized to placebo (N = 788) were included. Analysis of data from these trials was conducted from March 27 to December 31, 2019. Intervention: Placebo injection. Main Outcomes and Measures: The difference (with 95% CIs) from baseline at week 12 and week 24 on a 0- to 100-mm visual analog scale to evaluate the severity of pain, CRP level, and ESR. Results: Of the 788 patients included in the analysis, 644 were women (82%); mean (SD) age was 51 (13) years. There was a statistically significant decrease in patient-reported pain intensity (week 12: -14 mm; 95% CI, -12 to -16 mm and week 24: -20 mm; 95% CI, -16 to -22 mm). Similarly, significant decreases were noted in the CRP level (week 12: -0.51 mg/dL; 95% CI, -0.47 to -0.56 mg/dL and week 24: -1.16 mg/dL; 95% CI, -1.03 to -1.30 mg/dL) and ESR (week 12: -11 mm/h; 95% CI, -10 to 12 mm/h and week 24: -25 mm/h; 95% CI, -12 to -26 mm/h) (all P < .001). Conclusions and Relevance: The findings of this study suggest that improvements in clinical outcomes among participants randomized to placebo were not limited to subjective outcomes. Even if these findings could largely demonstrate a regression to the mean, they should be considered for future trial design, as unexpected favorable placebo responses may result in a well-designed trial becoming underpowered to detect the treatment difference needed in clinical drug development.

Self-reported health without clinically measurable benefits among adult users of multivitamin and multimineral supplements: a cross-sectional study.

OBJECTIVE: Multiple clinical trials fail to identify clinically measurable health benefits of daily multivitamin and multimineral (MVM) consumption in the general adult population. Understanding the determinants of widespread use of MVMs may guide efforts to better educate the public about effective nutritional practices. The objective of this study was to compare self-reported and clinically measurable health outcomes among MVM users and non-users in a large, nationally representative adult civilian non-institutionalised population in the USA surveyed on the use of complementary health practices. DESIGN: Cross-sectional analysis of the effect of MVM consumption on self-reported overall health and clinically measurable health outcomes. PARTICIPANTS: Adult MVM users and non-users from the 2012 National Health Interview Survey (n=21 603). PRIMARY AND SECONDARY OUTCOME MEASURES: Five psychological, physical, and functional health outcomes: (1) self-rated health status, (2) needing help with routine needs, (3) history of 10 chronic diseases, (4) presence of 19 health conditions in the past 12 months, and (5) Kessler 6-Item (K6) Psychological Distress Scale to measure non-specific psychological distress in the past month. RESULTS: Among 4933 adult MVM users and 16 670 adult non-users, MVM users self-reported 30% better overall health than non-users (adjusted OR 1.31; 95% CI 1.17 to 1.46; false discovery rate adjusted p<0.001). There were no differences between MVM users and non-users in history of 10 chronic diseases, number of present health conditions, severity of current psychological distress on the K6 Scale and rates of needing help with daily activities. No effect modification was observed after stratification by sex, education, and race. CONCLUSIONS: MVM users self-reported better overall health despite no apparent differences in clinically measurable health outcomes. These results suggest that widespread use of multivitamins in adults may be a result of individuals' positive expectation that multivitamin use leads to better health outcomes or a self-selection bias in which MVM users intrinsically harbour more positive views regarding their health.

Drug-Placebo Additivity in Randomized Clinical Trials.

In randomized clinical trials (RCTs), it is assumed that nonspecific effects beyond action of pharmacological agents are roughly equivalent in drug and placebo treatment groups. Hence, since the inception of RCTs, drug efficacy is determined by comparing outcomes in active to those in placebo control arms. However, quantitation of efficacy is based on an unproven assumption, that drug and placebo responses are always additive. Response to treatment in RCTs can be differentially influenced by the perturbing effects of patient expectations, side effects, and pharmacogenomic interactions in both drug and placebo arms. Ability to control for these effects requires understanding of when and where they arise, how to mitigate, analyze, and even leverage their impact. Here, we examine three factors that influence additivity: expectation, side effects, and pharmacogenomics. Furthermore, to provide novel insights into nonadditivity and solutions for managing it, we introduce systems pharmacogenomics, a network approach to integrating and analyzing the effects of the numerous interacting perturbations to which a patient is exposed in RCTs.

Systems pharmacogenomics - gene, disease, drug and placebo interactions: a case study in COMT.

Disease, drugs and the placebos used as comparators are inextricably linked in the methodology of the double-blind, randomized controlled trial. Nonetheless, pharmacogenomics, the study of how individuals respond to drugs based on genetic substrate, focuses primarily on the link between genes and drugs, while the link between genes and disease is often overlooked and the link between genes and placebos is largely ignored. Herein, we use the example of the enzyme catechol-O-methyltransferase to examine the hypothesis that genes can function as pharmacogenomic hubs across system-wide regulatory processes that, if perturbed in andomized controlled trials, can have primary and combinatorial effects on drug and placebo responses.

Correction: Catechol-O-Methyltransferase moderates effect of stress mindset on affect and cognition.

[This corrects the article DOI: 10.1371/journal.pone.0195883.].