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Excessive and persistent fear of clusters of holes, also known as trypophobia, has been suggested to reflect cortical hyperexcitability and may be associated with mental health risks. No study, however, has yet examined these associations in representative epidemiological samples.
To examine the prevalence of trypophobia in a population-representative youth sample, its association with mental health and functioning, and its interaction with external stress.
A total of 2065 young people were consecutively recruited from a household-based epidemiological youth mental health study in Hong Kong. Trypophobia, symptoms of anxiety, depression and stress, and exposure to personal stressors were assessed. Logistic regression was used to assess the relationships between trypophobia and mental health. Potential additive and interaction effects of trypophobia and high stress exposure on mental health were also tested.
The prevalence of trypophobia was 17.6%. Trypophobia was significantly associated with severe symptoms of anxiety (odds ratio (OR) = 1.83, 95% CI = 1.32–2.53), depression (OR = 1.78, 95% CI = 1.24–2.56) and stress (OR = 1.68, 95% CI = 1.11–2.53), even when accounting for sociodemographic factors, personal and family psychiatric history, resilience and stress exposure. Dose–response relationships were observed, and trypophobia significantly potentiated the effects of stress exposure on symptom outcomes, particularly for depressive symptoms. Those with trypophobia also showed significantly poorer functioning across domains and poorer health-related quality of life.
Screening for trypophobia in young people may facilitate early risk detection and intervention, particularly among those with recent stress exposure. Nevertheless, the generally small effect sizes suggest that other factors have more prominent roles in determining recent mental health outcomes in population-based samples; these should be explored in future work.
Clinical trials provide the “gold standard” evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources – data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor.
Three examples of real-world trials that leverage different types of data sources – wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived.
Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity.
Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials.
Despite replicated cross-sectional evidence of aberrant levels of peripheral inflammatory markers in individuals with major depressive disorder (MDD), there is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies.
To assess associations between plasma levels of pro-inflammatory markers and treatment response to escitalopram and adjunctive aripiprazole in adults with MDD.
In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10– 20 mg daily for 8 weeks. Responders continued on escitalopram while non-responders received adjunctive aripiprazole 2–10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers – C-reactive protein, Interleukin (IL)-1β, IL-6, IL-17, Interferon gamma (IFN)-Γ, Tumour Necrosis Factor (TNF)-α, and Chemokine C–C motif ligand-2 (CCL-2) - measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyses to assess associations between inflammatory markers and treatment response.
Pre-treatment levels of IFN-Γ and CCL-2 were significantly higher in escitalopram non-responders compared to responders. Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.
Pre-treatment levels of IFN-Γ and CCL-2 were predictive of response to escitalopram. Increasing levels of these pro-inflammatory markers may predict non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
Undergraduate students encounter developmental challenges during their transition into adulthood. Previous studies have claimed that adults with later chronotypes usually manifest negative psychological effects: poor sleep quality, greater stress, depression, and cognitive dysfunction. However, knowledge about the relationship between chronotype, stress, and sleep quality among young adults is lacking.
The present study investigated the relationship between undergraduates’ chronotypes and perceived stress on sleep quality.
An online survey with a descriptive, cross-sectional design was conducted with a convenience sample of undergraduate students at a university in southern Taiwan. Those who were 20-25 years old and enrolled as a student were included; but who had been suspended or had deferred graduation were excluded. Students’ chronotype, stress, and sleep quality were assessed with three self-reported instruments: Munich Chronotype Questionnaire (MCTQ), Perceived Stress Scale (PSS), and Pittsburgh Sleep Quality Index (PSQI).
Of 161 undergraduates who completed the questionnaires, 51 reported using an alarm clock to wake and were removed from data analysis. One hundred and ten students’ mean age is 20.3 and perceived moderate stress. Sixty-one percent were poor-quality sleepers. The mean chronotype score was 5.7, and 85.5% had an intermediate chronotype, while 13.6% had an evening chronotype. Chronotype and perceived stress were positively correlated with sleep quality (p < .001). Social jetlag was positively correlated with chronotype (p =.036). Undergraduate’s later chronotype and higher stress perception predicted 30% of poorer sleep quality (p < .001).
Undergraduate students’ chronotype and perceived stress were positively correlated and acted as predictors of the sleep quality. The findings could help to develop health-promotion interventions for these emerging adults to adjust their daily routines; and reduce their social jetlag, stress levels, and sleep disturbance.
Mental Health Literacy (MHL) includes four distinct but interrelated components: maintenance of positive mental health (MH), recognition of mental disorders (R), mental illness stigma attitudes (S), and help-seeking efficacy (E). A fifth component, help-seeking attitude (A) was included in a MHL model because it is a strong predictor of help-seeking behaviors. The five-factor model of MHL has been validated previously. In the study of multiple mediation model of MHL, it demonstrated the mediation role of help-seeking efficacy between recognition of mental disorders and help-seeking attitude (R-E-A path), but the roles of mental illness stigma attitudes or maintenance of positive mental health remain unknown.
The present study aimed to examine the theory-based multifaceted MHL model by utilizing a meta-analytic structural equation modeling analyses (MASEM) method.
Systematic search of articles from electronic databases, including APA PsycArticles, ERIC, MEDLINE, Psychology and Behavioral Sciences Collection, Pubmed, and Airiti Library (Chinese), from inception up to July 31, 2022, was conducted by raters independently assessed study eligibility, and extracted 127 empirical, quantitative, non-interventional studies with properly reported effect sizes (k=192). MASEM analyses were conducted via a two-stage approach. First, a pooled correlation matrix was obtained for each mediation model by applying a multivariate random-effects model using Comprehensive Meta-Analysis Version 3.3. Second, a structural equation model was fitted on the pooled correlation matrices to test for mediation effects (i.e., indirect effects) using IBM SPSS Amos.
In the single-mediator model analysis, there was a significant partial mediation effect of help-seeking efficacy and Mental illness stigma attitudes on the relationship between recognition of mental disorders and help-seeking attitude (R-E-A path & R-S-A path, p <.05). The multiple-mediator model has showed adequate fit (RMSEA = 0.09, SRMR = 0.04, CFI = 0.93, GFI = .99). It confirmed the help-seeking efficacy served as a mediator. A sequential mediation of maintenance of positive mental health and mental illness stigma attitudes was found (p <.05) between recognition of mental disorders and help-seeking attitude (R-MH-S-A path).
There is a robust mediation effect of Help-seeking efficacy on the relationship between recognition of mental disorders and help-seeking attitude either in the single mediation model or the multiple mediation model. Furthermore, increased recognition of mental disorder was related to increased maintenance of positive mental health, therefore decreased mental illness stigma attitude, and eventually increased help-seeking attitude. Future research directions regarding pathways in the MHL models were discussed.
We present the third data release from the Parkes Pulsar Timing Array (PPTA) project. The release contains observations of 32 pulsars obtained using the 64-m Parkes “Murriyang” radio telescope. The data span is up to 18 years with a typical cadence of 3 weeks. This data release is formed by combining an updated version of our second data release with ∼ 3 years of more recent data primarily obtained using an ultra-wide-bandwidth receiver system that operates between 704 and 4032 MHz. We provide calibrated pulse profiles, flux-density dynamic spectra, pulse times of arrival, and initial pulsar timing models. We describe methods for processing such wide-bandwidth observations, and compare this data release with our previous release.
The industrialisation of Western food systems has reduced the regular consumption of lacto-fermented vegetables (LFV). Consuming LFV may exert health benefits through the alteration of the gut microbiome, but the mechanisms involved remain unclear. To start understanding the possible benefits of LFV, we compared faecal microbial diversity and composition, as well as dietary habits between individuals who regularly consume LFV (n = 23) and those who do not (n = 24). We utilised microbial DNA amplicon sequencing (16S rRNA and ITS2) and untargeted metabolomics (LC–MS) to analyse stool samples. Study participants also provided three consecutive days of dietary data. Results show minor effects on microbiome composition; with the enrichment of a few microorganisms potentially associated with vegetable ferments, such as Leuconostoc mesenteroides and Rhodotorula mucilaginosa (P < 0.05), in LFV consumers. However, LFV consumption had greater effects on the faecal metabolome, with higher abundances of butyrate, acetate, and valerate (P < 0.05) and significantly greater metabolome diversity (P < 0.001). Overall, the observations of minor changes in the faecal microbiome and greater effects on the faecal metabolome from LFV consumption warrant further investigations on the health significance of LFV as regular components of the daily diet in humans.
We examined the effect of an antimicrobial stewardship program (ASP), procalcitonin testing and rapid blood-culture identification on hospital mortality in a prospective quality improvement project in critically ill septic adults. Secondarily, we have reported antimicrobial guideline concordance, acceptance of ASP interventions, and antimicrobial and health-resource utilization.
Individuals who self-harm have increased suicide rates. Brief interventions are associated with reduced repeated suicide attempts. However, very few previous studies investigated the acceptability of brief interventions before implementing new trials.
We aimed to explore the perceptions of individuals who self-harm toward a brief intervention, the Chinese version of the volitional help sheet (VHS-C), which encourages people to link a critical situation with an appropriate response.
Fourteen participants who presented to hospitals with self-harm were interviewed about their perspectives regarding the acceptability of the paper- and web-based VHS-C. Data were analysed with the framework method.
The participants could understand the intended goal of the VHS-C by reading the written instructions, but indicated that having verbal instructions would also help. They shared the reasons why they felt the VHS-C was helpful (e.g. relatable contents, useful coping strategies and appropriate instructions that made them feel understood) or unhelpful (e.g., being not specific enough, not useful during the crisis and triggering negative emotional responses). Some indicated that the VHS-C might not be applicable to people experiencing ongoing distress in emergency departments. Most participants preferred the web-based to the paper-based VHS-C, and suggested that the format and frequency of follow-up reminders could leave the patient to decide.
The contents of the VHS-C were acceptable for people who presented to hospitals with self-harm. The VHS-C may be more helpful before individuals encounter suicidal thoughts than when they have an ongoing crisis.
Background: Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation technique, which in theta burst mode (tbTUS) can increase cortical excitability. Parkinson’s disease (PD) has altered cortical excitability of motor cortex (M1). We evaluated the neurophysiological and clinical effects of M1 tbTUS in PD patients. Methods: Sixteen PD patients (4F, 59.5±9.7 years) in ON and OFF dopaminergic medication states, and 15 controls (5F, 61.9±8.7 years) were evaluated. tbTUS was applied for 80 seconds at M1 with 20W/cm2. Motor evoked potential (MEP) was recorded at baseline, at 5-minutes (T5), T30, and T60 after tbTUS. Motor (m)UPDRS was evaluated in PD at baseline and T60. Results: A linear mixed model on MEP amplitudes comparing PD-ON, PD-OFF and controls showed significant effect of time (F=4.83, p=0.003). Post-hoc analysis showed significant difference between baseline and T30 timepoints (p=0.0003). The MEP increase at T30 was higher in controls (66%), followed by PD-ON (41%) and PD-OFF (21%). PD-ON showed reduced mUPDRS at T60 when compared to PD-OFF, with significant effect of time (F=6.14, p=0.017) and group (F=5.39, p=0.025). Conclusions: tbTUS induced motor cortical plasticity is reduced in PD-OFF, that is partially restored by dopaminergic medications.Repeated sessions of tbTUS can be further investigated as a novel non-invasive treatment for PD.
Background: Lower socioeconomic status is associated with worse outcomes after stroke. We evaluated the differences in acute revascularization treatments in patients with acute ischemic stroke (AIS) who were materially deprived compared to those who were not. Methods: In a population-based cohort study, we used linked administrative data to identify community-dwelling adults hospitalized for AIS between 2017-2022 in Ontario, Canada. The main exposure was neighborhood-level material deprivation quintiles. Multivariable logistic regression was used to obtain the adjusted odds ratio (aOR) of receiving revascularization treatments (thrombolysis or thrombectomy) for patients in each deprivation quintile compared to the least deprived quintile. Results: We identified 57,709 patients (median age 74 years; 45.9% female). Compared to patients in the least deprived quintile, those with higher deprivation were younger and more likely to have hypertension and diabetes, but less likely to have atrial fibrillation. Compared to patients in the least deprived quintile, fewer patients in the very deprived quintile (17.9% vs 19.6%, aOR 0.88, 95%CI [0.82,0.95]) and in the most deprived quintile (16.6% vs 19.6%, 0.77 [0.71,0.83]) received revascularization treatments. Conclusions: Our results suggest disparities in the use of acute ischemic stroke revascularization treatments by socioeconomic status despite access to universal health care.
Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
It is unknown how much variation in adult mental health problems is associated with differences between societal/cultural groups, over and above differences between individuals.
To test these relative contributions, a consortium of indigenous researchers collected Adult Self-Report (ASR) ratings from 16 906 18- to 59-year-olds in 28 societies that represented seven culture clusters identified in the Global Leadership and Organizational Behavioral Effectiveness study (e.g. Confucian, Anglo). The ASR is scored on 17 problem scales, plus a personal strengths scale. Hierarchical linear modeling estimated variance accounted for by individual differences (including measurement error), society, and culture cluster. Multi-level analyses of covariance tested age and gender effects.
Across the 17 problem scales, the variance accounted for by individual differences ranged from 80.3% for DSM-oriented anxiety problems to 95.2% for DSM-oriented avoidant personality (mean = 90.7%); by society: 3.2% for DSM-oriented somatic problems to 8.0% for DSM-oriented anxiety problems (mean = 6.3%); and by culture cluster: 0.0% for DSM-oriented avoidant personality to 11.6% for DSM-oriented anxiety problems (mean = 3.0%). For strengths, individual differences accounted for 80.8% of variance, societal differences 10.5%, and cultural differences 8.7%. Age and gender had very small effects.
Overall, adults' self-ratings of mental health problems and strengths were associated much more with individual differences than societal/cultural differences, although this varied across scales. These findings support cross-cultural use of standardized measures to assess mental health problems, but urge caution in assessment of personal strengths.
Despite over a decade of both quantitative and qualitative studies, food insecurity among US college/university students remains a pervasive problem within higher education. The purpose of this perspective piece was to highlight research gaps in the area of college food insecurity and provide rationale for the research community to focus on these gaps going forward. A group of food insecurity researchers from a variety of higher education institutions across the United States identified five thematic areas of research gaps: screening and estimates of food insecurity; longitudinal changes in food insecurity; impact of food insecurity on broader health and academic outcomes; evaluation of impact, sustainability and cost effectiveness of existing programmes and initiatives; and state and federal policies and programmes. Within these thematic areas, nineteen specific research gaps were identified that have limited or no peer-reviewed, published research. These research gaps result in a limited understanding of the magnitude, severity and persistence of college food insecurity, the negative short- and long-term impacts of food insecurity on health, academic performance and overall college experience, and effective solutions and policies to prevent or meaningfully address food insecurity among college students. Research in these identified priority areas may help accelerate action and interdisciplinary collaboration to alleviate food insecurity among college students and play a critical role in informing the development or refinement of programmes and services that better support college student food security needs.
OBJECTIVES/GOALS: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by slow gait and subjective cognitive complaints. In the Atherosclerosis Risk in Communities (ARIC) study, we aim to (1) identify plasma proteins and protein modules associated with MCR and (2) compare the proteomic signature of MCR to that of mild cognitive impairment (MCI). METHODS/STUDY POPULATION: Nondemented ARIC participants were classified by MCR status (yes/no) according to a memory questionnaire and 4-meter walk. MCI status (yes/no) was classified by expert diagnosis using standardized criteria. We measured 4,877 proteins in plasma collected at ARIC Visit 5 (late-life) and Visit 2 (midlife) utilizing the SomaScan4 proteomic assay. Multivariable logistic regression”adjusted for demographic variables, kidney function, cardiovascular risk factors, and APOE4 status”related each protein to MCR at late-life. An FDR corrected P RESULTS/ANTICIPATED RESULTS: Proteome-wide association study among 4076 ARIC participants (mean age=75; 58% women, 17% Black, 4% MCR+, 21% MCI+; MCR+ and MCI+ groups overlapped) at late-life identified 26 MCR-associated proteins involved in metabolism, vascular/visceral smooth muscle, and extracellular matrix organization. At an uncorrected P DISCUSSION/SIGNIFICANCE: This proteomic characterization of MCR identifies novel plasma proteins and networks, both distinct from and overlapping with those of MCI, thus highlighting the partially divergent mechanisms underlying these pre-dementia syndromes. These findings may be leveraged toward dementia prognostication and targeted therapeutic approaches.
As clinical trials adopt remote methodologies, there is need to optimize efficiency of remote enrollment. Within a remote clinical trial, we aim to (1) assess if sociodemographic factors differ among those consenting via mail vs. technology-based procedures (e-consent), (2) determine if, among those consenting via mail, a small unconditional monetary reward ($5) increases likelihood of subsequent enrollment, (3) economically evaluate additional cost per additional participant enrolled with $5 reward.
In the parent nationwide randomized clinical trial of adult smokers (N = 638), participants could enroll via mail or e-consent. Logistic regression models assessed relationships between sociodemographics and enrollment via mail (vs e-consent). Mailed consent packets were randomized (1:4) to include $5 unconditional reward or not, and logistic regression modeling examined impact of reward on subsequent enrollment, allowing for a randomized study within a study. Incremental cost-effectiveness ratio analysis estimated additional cost per additional participant enrolled with $5 incentive.
Older age, less education, lower income, and female sex predicted enrolling via mail vs e-consent (p < .05’s). In adjusted model, older age (AOR = 1.02, p = .016) and less education (AOR = 2.23, p < .001) remained predictive of mail enrollment. The $5 incentive (vs none) increased enrollment rate by 9% (AOR = 1.64, p = .007), with estimated cost of additional $59 per additional participant enrolled.
As e-consent methods become more common, they have potential to reach many individuals but with perhaps diminished inclusion across all sociodemographic groups. Provision of an unconditional monetary incentive is possibly a cost-effective mechanism to increase recruitment efficiency for studies employing mail-based consenting procedures.
This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive.
A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors.
Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001).
Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer’s disease while considering the burden on the healthcare system.
Computerized-adaptive testing (CAT) may increase reliability or reduce respondent burden for assessing patient-reported outcomes compared with static short forms (SFs). We compared CAT versus SF administration of the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Pediatric measures in pediatric inflammatory bowel disease (IBD).
Participants completed 4-item CAT, 5- or 6-item CAT, and 4-item SF versions of the PROMIS Pediatric measures. We compared average T-scores, intra-class correlations (ICCs), floor and ceiling effects, and standard error of measurement (SEM) across forms, along with mean effect sizes between active versus quiescent IBD disease activity groups.
Average PROMIS T-scores across forms were <3 points (minimally important difference) of each other. All forms correlated highly with each other (ICCs ≥0.90) and had similar ceiling effects, but the CAT-5/6 had lower floor effects. The CAT-5/6 had lower SEM than the CAT-4 and SF-4, and the CAT-4 had a lower SEM than the SF-4. Mean effect sizes were similar across forms when contrasting disease activity groups.
The CAT and SF forms produced similar score results, but the CAT had better precision and lower floor effects. Researchers should consider PROMIS pediatric CAT if they anticipate that their sample will skew toward symptom extremes.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) rapidly replaced Delta (B.1.617.2) to become dominant in England. Our study assessed differences in transmission between Omicron and Delta using two independent data sources and methods. Omicron and Delta cases were identified through genomic sequencing, genotyping and S-gene target failure in England from 5–11 December 2021. Secondary attack rates for named contacts were calculated in household and non-household settings using contact tracing data, while household clustering was identified using national surveillance data. Logistic regression models were applied to control for factors associated with transmission for both methods. For contact tracing data, higher secondary attack rates for Omicron vs. Delta were identified in households (15.0% vs. 10.8%) and non-households (8.2% vs. 3.7%). For both variants, in household settings, onward transmission was reduced from cases and named contacts who had three doses of vaccine compared to two, but this effect was less pronounced for Omicron (adjusted risk ratio, aRR 0.78 and 0.88) than Delta (aRR 0.62 and 0.68). In non-household settings, a similar reduction was observed only in contacts who had three doses vs. two doses for both Delta (aRR 0.51) and Omicron (aRR 0.76). For national surveillance data, the risk of household clustering, was increased 3.5-fold for Omicron compared to Delta (aRR 3.54 (3.29–3.81)). Our study identified increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta. We identified a reduced effectiveness of vaccination in lowering risk of transmission, a likely contributor for the rapid propagation of Omicron.