The effect of dose-interval on antibody response to mRNA COVID-19 vaccines: a prospective cohort study.

Background: Vaccination against COVID-19 is highly effective in preventing severe disease and hospitalization, but primary COVID mRNA vaccination schedules often differed from those recommended by the manufacturers due to supply chain issues. We investigated the impact of delaying the second dose on antibody responses to COVID mRNA-vaccines in a prospective cohort of health-care workers in Quebec. Methods: We recruited participants from the McGill University Health Centre who provided serum or participant-collected dried blood samples (DBS) at 28-days, 3 months, and 6 months post-second dose and at 28-days after a third dose. IgG antibodies to SARS-CoV2 spike (S), the receptor-binding domain (RBD), nucleocapsid (N) and neutralizing antibodies to the ancestral strain were assessed by enzyme-linked immunosorbent assay (ELISA). We examined associations between long (≤89 days) versus short (<89 days) between-dose intervals and antibody response through multivariable mixed-effects models adjusted for age, sex, prior covid infection status, time since vaccine dose, and assay batch. Findings: The cohort included 328 participants who received up to three vaccine doses (>80% Pfizer-BioNTech). Weighted averages of the serum (n=744) and DBS (n=216) cohort results from the multivariable models showed that IgG anti-S was 31% higher (95% CI: 12% to 53%) and IgG anti-RBD was 37% higher (95% CI: 14% to 65%) in the long vs. short interval participants, across all time points. Interpretation: Our study indicates that extending the covid primary series between-dose interval beyond 89 days (approximately 3 months) provides stronger antibody responses than intervals less than 89 days. Our demonstration of a more robust antibody response with a longer between dose interval is reassuring as logistical and supply challenges are navigated in low-resource settings.

Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Ranking Decision-Making Criteria for Early Adoption of Innovative Surgical Technologies.

Importance: There is no decision-making framework in the early-adoption stage of novel surgical technologies, putting the quality of health care and resource allocation of the health care system at risk. Objective: To investigate relevant weighted criteria that decision-makers may use to make an informed decision for the early adoption of innovative surgical technologies. Design, Setting, and Participants: This multi-institutional decision analytical modeling study used a mixed-methods multicriteria decision analysis (MCDA) and had 2 phases. First, a panel of 12 experts validated decision criteria in the literature and identified additional criteria. Second, 33 Canadian experts prioritized the main criteria (domains) using the composition pairwise-comparison weight-elicitation method (analytical hierarchy process model) and ranked their subcriteria using the direct-ranking elicitation method (Likert scale). Data were analyzed, and response consistency was estimated using the consistency ratio. Analysis of variance was used to assess for significant differences between expert responses. The MCDA was conducted at McGill University between 2021 and 2023. Data were collected nationally by inviting experts in Canada. Main Outcome and Measure: Criteria domain weights and subcriteria rankings. Priority vectors, which are priority scores analyzed and prioritized from expert responses, were used to rank criteria domains and subcriteria for decision-making on adopting new innovative surgical technologies. Results: A total of 45 experts (33 male [73.3%] and 12 female [26.7%]) were invited with different levels of education (22 experts with MD or equivalent, 13 experts with master's degree, and 12 experts with PhD degree) and years of experience (4 experts with <10, 12 experts with 11-20, 18 experts with 21-30, and 11 experts with >30 years). Surgeon experts (23 individuals) were from all surgical disciplines, and nonsurgeon experts (22 individuals) were administrative officers in surgical device procurement, health technology assessment experts, and hospital directors. A total of 7 domains and 44 subcriteria were identified. The MCDA model found that clinical outcomes had the highest priority vector, at 0.429, followed by patients and public relevance (0.135). Hospital-specific criteria (priority vector, 0.099), technology-specific criteria (priority vector, 0.092), and physician-specific criteria (priority vector, 0.087) were the next most highly ranked. The lowest priority vectors were for economic criteria, at 0.083, and finally policies and procedures, at 0.075. There was consensus in the responses (consistency ratio = 0.006), and there were no statistically significant differences between expert responses. Conclusions and relevance: This study weighted priority criteria domains in importance and established ranked subcriteria for decision-making of early adoption of surgical technologies. Putting these criteria into a framework may help surgeons and decision-makers make informed decisions for the early adoption of new surgical technologies.

A Framework for Aiding the Translation of Scientific Evidence into Policy: The Experience of a Hospital-Based Technology Assessment Unit.

OBJECTIVES: Very few practical frameworks exist to guide the formulation of recommendations at hospital-based health technology assessment (HTA) units. The objectives of our study were: (i) to identify decision criteria specific to the context of hospital-based health technologies and interventions, (ii) to estimate the extent to which the expert community agrees on the importance of the identified criteria, (iii) to incorporate the identified criteria into a decision-aid tool, and (iv) to illustrate the application of a prototype decision-aid tool. METHODS: Relevant decision criteria were identified using existing frameworks for HTA recommendations, our past experience, a literature search, and feedback from a survey of diverse stakeholders. RESULTS: Based on the survey results, twenty-three decision criteria were incorporated into the final framework. We defined an approach that eschewed a scoring system, but instead relied on a visual means for arriving at a final recommendation, by juxtaposing the importance rating for each criterion against the results of the health technology assessment. For a technology to be approved, a majority of criteria considered important should also have received favorable findings. CONCLUSIONS: We created a simple and practical decision-aid tool that incorporates all decision criteria relevant to a hospital-based HTA unit. With its ease of use and accessibility, our tool renders the subjective decision-making process more structured and transparent.

Risk of Miscarriage in Women Receiving Antidepressants in Early Pregnancy, Correcting for Induced Abortions.

BACKGROUND: Earlier studies on the association between antidepressant use and miscarriage have obtained conflicting results after accounting for the role of depression, and none have taken into account the high risk of induced abortions in women using antidepressants. METHODS: We identified 41,964 pregnant women delivering between 1998 and 2002 using Quebec's health administration databases. We compared women prescribed antidepressants in the first trimester and with a recorded diagnosis of depression before pregnancy to (1) women with neither antidepressant use nor a depression diagnosis before or during pregnancy; (2) women with a depression diagnosis before pregnancy, but no antidepressants prescribed in the first trimester; and (3) women prescribed hypothyroid medication in the first trimester, but not antidepressants. We used log binomial regression to assess the adjusted relative risk of miscarriage, corrected for induced abortion risk. RESULTS: The miscarriage risk uncorrected for induced abortions was 16%, 10%, and 9% for depressed women exposed to antidepressants; unexposed depressed women; and unexposed, nondepressed women, respectively. These decreased to 11%, 8%, and 7% after correction for induced abortions. In multivariable analysis, the corrected risk of miscarriage relative to unexposed, nondepressed women was 1.3 (1.1-1.5) for antidepressant-exposed women and 1.1 (1.0-1.2) for unexposed depressed women. The miscarriage relative risk for antidepressant users compared with unexposed depressed women was thus 1.2 (1.0-1.4). CONCLUSIONS: Antidepressant use in the first trimester is associated with an increased risk of miscarriage when compared with either nondepressed or depressed unexposed women, even after accounting for induced abortions.

Smoking in preeclamptic women is associated with higher birthweight for gestational age and lower soluble fms-like tyrosine kinase-1 levels: a nested case control study.

BACKGROUND: Smoking paradoxically increases the risk of small-for-gestational-age (SGA) birth but protects against preeclampsia. Some studies have reported a "U-shaped" distribution of fetal growth in preeclamptic pregnancies, but reasons for this are unknown. We investigated whether cigarette smoking interacts with preeclampsia to affect fetal growth, and compared levels of soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating anti-angiogenic protein, in preeclamptic smokers and non-smokers. METHODS: From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia (cases) and 443 controls. Smoking exposure was assessed by self-report and maternal hair nicotine levels. Fetal growth was assessed as z-score of birthweight for gestational age (BWGA). sFlt-1 was measured in plasma samples collected at the 24-26-week visit. RESULTS: In linear regression, smoking and preeclampsia were each associated with lower BWGA z-scores (ß = -0.29; p = 0.008, and ß = -0.67; p < 0.0001), but positive interaction was observed between smoking and preeclampsia (ß = +0.86; p = 0.0008) such that smoking decreased z-score by -0.29 in controls but increased it by +0.57 in preeclampsia cases. Results were robust to substituting log hair nicotine for self-reported smoking and after adjustment for confounding variables. Mean sFlt-1 levels were lower in cases with hair nicotine levels above vs. below the median (660.4 pg/ml vs. 903.5 pg/ml; p = 0.0054). CONCLUSIONS: Maternal smoking seems to protect against preeclampsia-associated fetal growth restriction and may account, at least partly, for the U-shaped pattern of fetal growth described in preeclamptic pregnancies. Smoking may exert this effect by reducing levels of the anti-angiogenic protein sFlt-1.

Childhood family psychosocial environment and coronary heart disease risk.

OBJECTIVE: Little is known about whether the childhood family psychosocial environment affects coronary heart disease (CHD). Study objectives were to evaluate associations of childhood family psychosocial environment (termed "risky families"; characterized by cold, unaffectionate interactions, conflict, aggression, neglect, and/or low nurturance) with calculated risk for CHD. METHODS: Study participants included 3554 participants of the Coronary Artery Risk Development in Young Adults Study, aged 33 to 45 years. Childhood family psychosocial environment was measured using a risky family questionnaire via self-report. Ten-year CHD risk was calculated using the validated Framingham risk algorithm. RESULTS: In a multivariable-adjusted regression analysis adjusted for age, race/ethnicity, and childhood socioeconomic position, a 1-unit (range, 0-21) increase in risky family score was associated with 1.0% (95% confidence interval = 0.4%-1.7%) and 1.0% (95% confidence interval = 0.2%-1.8%) higher CHD risk in women and men, respectively. Multiple mediation analyses suggested significant indirect effects of education, income, depressive symptomatology, and anger-out expression in women and education in men, indicating that these may be mediating mechanisms between childhood psychosocial environment and CHD risk. Of the modifiable Framingham algorithm components, smoking (in women and men) and high-density lipoprotein (in women) were the factors most strongly associated with risky family score. CONCLUSIONS: Childhood family psychosocial environment was positively associated with the calculated 10-year CHD risk. Mechanisms may include the potential negative impact of childhood family psychosocial environment on later-life socioeconomic position (e.g., education in men and women) and/or psychosocial functioning (e.g., depression and anger-out expression in women), which may in turn lead to higher CHD risk, particularly through smoking (in men and women) and low level of high-density lipoprotein cholesterol (in women).

Hair biomarkers as measures of maternal tobacco smoke exposure and predictors of fetal growth.

INTRODUCTION: Most biomarker studies of the effects of maternal smoking on fetal growth have been based on a single blood or urinary cotinine value, which is inadequate in capturing maternal tobacco exposure over the entire pregnancy. We used hair biomarkers to compare the associations of maternal self-reported smoking, hair nicotine, and hair cotinine with birth weight for gestational age (BW for GA) among active and passive smokers during pregnancy. METHODS: We collected maternal hair in the immediate postpartum period and measured nicotine and cotinine concentrations averaged over the pregnancy in 444 term controls drawn from 5,337 participants in a multicenter nested case-control study of preterm birth. BW for GA Z-score and small for gestational age (SGA) were based on Canadian population-based standards. RESULTS: The addition of hair nicotine to multiple linear regression models containing self-reported active smoking, hair cotinine, or both explained significantly more variance in the BW for GA Z-score (p = .01, .03 and .04, respectively). Similarly, women with hair nicotine, but not cotinine, at or above the median value had a significant increase in the risk of SGA birth (odds ratio: 3.07, 95% CI: 1.25-7.52). No significant association was observed between maternal passive smoking and BW for GA based on hair biomarkers. CONCLUSIONS: Hair nicotine is a better predictor of reductions in BW for GA than either hair cotinine or self-report. Our negative results for passive smoking suggest that previously reported small but significant effects may be explained by misclassification of active smokers as passive smokers based on self-report.

Life-course socioeconomic position and type 2 diabetes mellitus: The Framingham Offspring Study.

Evidence is lacking on whether the duration and timing of low socioeconomic position (SEP) across a person's life course may be associated with incidence of type 2 diabetes mellitus (T2D). The authors' objectives were to investigate associations between cumulative SEP and the incidence of T2D in the Framingham Offspring Study (n = 1,893; 52% women; mean baseline age = 34 years). Pooled logistic regression analyses demonstrated that age-adjusted cumulative SEP was associated with T2D in women (for low vs. high cumulative SEP, odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.08, 3.42). Age-adjusted analyses for young-adulthood SEP (7.85 for ≤12 vs. >16 years of education, OR = 2.84, 95% CI: 1.03), active professional life SEP (for laborer vs. professional/executive/supervisory/technical occupations, OR = 2.40, 95% CI: 1.05, 5.47), and social-mobility frameworks (for declining life-course SEP, OR = 2.99, 95% CI: 1.39, 6.44; for stable low vs. stable high life-course SEP, OR = 1.85, 95% CI: 1.02, 3.35) all demonstrated associations between low SEP and T2D incidence in women. No association was observed between childhood SEP and T2D in women for father's education (some high school or less vs. any postsecondary education, OR = 1.26, 95% CI: 0.72, 2.22). In men, there was little evidence of associations between life-course SEP and T2D incidence. These findings suggest that cumulative SEP is inversely associated with incidence of T2D in women, and that this association may be primarily due to the women's educational levels and occupations.

Life course socioeconomic position is associated with inflammatory markers: the Framingham Offspring Study.

Associations between life course socioeconomic position (SEP) and novel biological risk markers for coronary heart disease such as inflammatory markers are not well understood. Most studies demonstrate inverse associations of life course SEP with C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen, however little is known about associations between life course SEP and other inflammatory markers including intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor II (TNFR2), lipoprotein phospholipase A2 (Lp-PLA2) activity, monocyte chemoattractant protein-1 (MCP-1) or P-selectin. The objectives of this analysis were to determine whether three life course SEP frameworks ("accumulation of risk", "social mobility" and "sensitive periods") are associated with the aforementioned inflammatory markers. We examined 1413 Framingham Offspring Study participants (mean age 61.2+/-8.6 years, 54% women), using multivariable regression analyses. In age- and sex-adjusted regression analyses, cumulative SEP ("accumulation of risk" SEP framework), for low vs. high SEP, was inversely associated with CRP, IL-6, ICAM-1, TNFR2, Lp-PLA2 activity, MCP-1 and fibrinogen. We found that there were few consistent trends between social mobility trajectories and most inflammatory markers. Own educational attainment was inversely associated with 7 of 8 studied inflammatory markers, while father's education, father's occupation and own occupation were inversely associated with 4, 5 and 4 inflammatory markers, respectively, in age- and sex-adjusted analyses. The strengths of association between SEP and inflammatory markers were typically substantially accounted for by CHD risk markers (smoking, body mass index, systolic blood pressure, total:HDL cholesterol ratio, fasting glucose, medications, depressive symptomatology) suggesting these may be important mechanisms that explain associations between SEP and the studied inflammatory markers.

Quality of parental emotional care and calculated risk for coronary heart disease.

OBJECTIVE: To evaluate associations between perceived quality of parental emotional care and calculated 10-year risk for coronary heart disease (CHD). Little is understood about the role of parental emotional care in contributing to the risk for CHD. METHODS: The study sample was composed of 267 participants from the New England Family Study. Quality of parental emotional care was measured, using a validated short version of the Parental Bonding Instrument (PBI) as the average care scores for both parents (range = 0-12), with higher scores indicating greater care. Ten-year CHD risk was calculated, using the validated Framingham Risk Algorithm that incorporates the following prevalent CHD risk factors: age, sex, diabetes, smoking, total cholesterol, high-density lipoprotein cholesterol, and blood pressure. Multiple linear regression assessed associations of PBI with calculated CHD risk after adjusting for childhood socioeconomic status, depressive symptomatology, educational attainment, and body mass index. RESULTS: Among females, a 1-unit increase in the parental emotional care score resulted in a 4.6% (p = .004) decrease in the 10-year CHD risk score, after adjusting for covariates. There was no association between parental emotional care score and calculated CHD risk score in males (p = .22). CONCLUSION: Quality of parental emotional care was inversely associated with calculated 10-year CHD risk in females, and not males. Although the gender differences need further investigation and these findings require replication, these results suggest that the early childhood psychosocial environment may confer risk for CHD in adulthood.

Associations between childhood socioeconomic position and adulthood obesity.

Childhood socioeconomic position (SEP) is inversely associated with cardiovascular disease and all-cause mortality. Obesity in adulthood may be a biologic mechanism. Objectives were to systematically review literature published between 1998 and 2008 that examined associations of childhood SEP with adulthood obesity. Five databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science) were searched for studies from any country, in any language. Forty-eight publications based on 30 studies were identified. In age-adjusted analyses, inverse associations were found between childhood SEP and adulthood obesity in 70% (14 of 20) of studies in females and 27% (4 of 15) in males. In studies of females showing inverse associations between childhood SEP and adulthood obesity, typical effect sizes in age-adjusted analyses for the difference in body mass index between the highest and lowest SEP were 1.0-2.0 kg/m(2); for males, effect sizes were typically 0.2-0.5 kg/m(2). Analyses adjusted for age and adult SEP showed inverse associations in 47% (8 of 17) of studies in females and 14% (2 of 14) of studies in males. When other covariates were additionally adjusted for, inverse associations were found in 4 of 12 studies in females and 2 of 8 studies in males; effect sizes were typically reduced compared with analyses adjusted for age only. In summary, the findings suggest that childhood SEP is inversely related to adulthood obesity in females and not associated in males after adjustment for age. Adulthood SEP and other obesity risk factors may be the mechanisms responsible for the observed associations between childhood SEP and adulthood obesity.

Life-course socioeconomic position and incidence of coronary heart disease: the Framingham Offspring Study.

Cumulative exposure to socioeconomic disadvantage across the life course may be inversely associated with coronary heart disease (CHD); the mechanisms are not fully clear. An objective of this study was to determine whether cumulative life-course socioeconomic position (SEP) is associated with CHD incidence in a well-characterized US cohort that had directly assessed childhood and adulthood measures of SEP and prospectively measured CHD incidence. Furthermore, analyses aimed to evaluate whether adjustment for CHD risk factors reduces the association between cumulative life-course SEP and CHD. The authors examined 1,835 subjects who participated in the Framingham Heart Study Offspring Cohort from 1971 through 2003 (mean age, 35.0 years; 52.4% women). Childhood SEP was measured as father's education; adulthood SEP was assessed as own education and occupation. CHD incidence included myocardial infarction, coronary insufficiency, and coronary death. Cox proportional hazards analyses indicated that cumulative SEP was associated with incident CHD after adjustment for age and sex (hazard ratio = 1.82, 95% confidence interval: 1.17, 2.85 for low vs. high cumulative SEP score). Adjustment for CHD risk factors reduced that magnitude of association (hazard ratio = 1.29, 95% confidence interval: 0.78, 2.13). These findings underscore the potential importance of CHD prevention and treatment efforts for those whose backgrounds include low SEP throughout life.