Severe Acute Respiratory Syndrome Coronavirus 2 Incidence and Risk Factors in a National, Community-Based Prospective Cohort of US Adults.

BACKGROUND: Prospective cohort studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incidence complement case-based surveillance and cross-sectional seroprevalence surveys. METHODS: We estimated the incidence of SARS-CoV-2 infection in a national cohort of 6738 US adults, enrolled in March-August 2020. Using Poisson models, we examined the association of social distancing and a composite epidemiologic risk score with seroconversion. The risk score was created using least absolute shrinkage selection operator (LASSO) regression to identify factors predictive of seroconversion. The selected factors were household crowding, confirmed case in household, indoor dining, gathering with groups of ≥10, and no masking in gyms or salons. RESULTS: Among 4510 individuals with ≥1 serologic test, 323 (7.3% [95% confidence interval (CI), 6.5%-8.1%]) seroconverted by January 2021. Among 3422 participants seronegative in May-September 2020 and retested from November 2020 to January 2021, 161 seroconverted over 1646 person-years of follow-up (9.8 per 100 person-years [95% CI, 8.3-11.5]). The seroincidence rate was lower among women compared with men (incidence rate ratio [IRR], 0.69 [95% CI, .50-.94]) and higher among Hispanic (2.09 [1.41-3.05]) than white non-Hispanic participants. In adjusted models, participants who reported social distancing with people they did not know (IRR for always vs never social distancing, 0.42 [95% CI, .20-1.0]) and with people they knew (IRR for always vs never, 0.64 [.39-1.06]; IRR for sometimes vs never, 0.60 [.38-.96]) had lower seroconversion risk. Seroconversion risk increased with epidemiologic risk score (IRR for medium vs low score, 1.68 [95% CI, 1.03-2.81]; IRR for high vs low score, 3.49 [2.26-5.58]). Only 29% of those who seroconverted reported isolating, and only 19% were asked about contacts. CONCLUSIONS: Modifiable risk factors and poor reach of public health strategies drove SARS-CoV-2 transmission across the United States.

Determinants and Trends of COVID-19 Vaccine Hesitancy and Vaccine Uptake in a National Cohort of US Adults: A Longitudinal Study.

We estimated the trends and correlates of vaccine hesitancy and its association with subsequent vaccine uptake among 5,458 adults in the United States. Participants belonged to the Communities, Households, and SARS-CoV-2 Epidemiology COVID (CHASING COVID) Cohort, a national longitudinal study. Trends and correlates of vaccine hesitancy were examined longitudinally in 8 interview rounds from October 2020 to July 2021. We also estimated the association between willingness to vaccinate and subsequent vaccine uptake through July 2021. Vaccine delay and refusal decreased from 51% and 8% in October 2020 to 8% and 6% in July 2021, respectively. Compared with non-Hispanic (NH) White participants, NH Black and Hispanic participants had higher adjusted odds ratios (aOR) for both vaccine delay (for NH Black, aOR = 2.0 (95% confidence interval (CI): 1.5, 2.7), and for Hispanic, 1.3 (95% CI: 1.0, 1.7)) and vaccine refusal (for NH Black, aOR = 2.5 (95% CI: 1.8, 3.6), and for Hispanic, 1.4 (95% CI: 1.0, 2.0)) in June 2021. COVID-19 vaccine hesitancy, compared with vaccine-willingness, was associated with lower odds of subsequent vaccine uptake (for vaccine delayers, aOR = 0.15, 95% CI: 0.13, 0.18; for vaccine refusers, aOR = 0.02; 95% CI: 0.01, 0.03 ), adjusted for sociodemographic factors and COVID-19 history. Vaccination awareness and distribution efforts should focus on vaccine delayers.

Exploring the complex associations over time among albendazole treatment, cyst evolution, and seizure outcomes in neurocysticercosis.

OBJECTIVE: To develop a causal model for the occurrence of neurocysticercosis (NC)-related seizures and test hypotheses generated from the model. METHODS: We used data from a randomized controlled trial comparing albendazole with placebo among patients newly diagnosed with NC. Based on our causal model, we explored the associations among albendazole treatment, NC cyst evolution, and seizure outcomes over 24 months of follow-up using generalized linear mixed effect models. RESULTS: We included 153 participants, of whom 51% received albendazole. The association between seizure outcomes and treatment over time demonstrated lack of linearity and heterogeneity, requiring the inclusion of time-treatment interaction terms for valid modeling. Participants in the albendazole group had fewer seizures overall and of partial onset at all time points compared with the placebo group, but the difference increased over the first few months following treatment, then decreased over time. Generalized seizures exhibited a more complex association; those in the albendazole group had fewer seizures compared with those in the placebo group for the first few months after treatment, and then the association reversed and those in the placebo arm had fewer seizures. Adjusting for the number of NC cysts in each phase resulted in an attenuation of the strength of association between albendazole and seizure outcomes, consistent with mediation. Among participants in whom all cysts had disappeared (n = 21), none continued to have seizures. SIGNIFICANCE: Albendazole treatment is associated with a possible reduction in focal seizures in the short term (3-6 months), perhaps by hastening the resolution of the cysts. However, the effect is not discernible over the long term, because most cysts either calcify or resolve completely, regardless of whether treated with albendazole. The stage of evolution of the cysticercus is an important consideration in the evaluation of albendazole effect on seizure outcome.

Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.

Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridize to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated Gys1 knockdown in the Gaa -/- mouse model of PD led to a robust reduction in glycogen accumulation in skeletal and cardiac muscle. In addition, combining Gys1 ASO with ERT further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in Gaa -/- mice. Our results provide a strong foundation for further validation of the use of Gys1 ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of Gys1 ASO in combination with ERT may be the key to preventative treatment options in PD.

Dissociation of response variability from firing rate effects in frontal eye field neurons during visual stimulation, working memory, and attention.

Recent studies suggest that trial-to-trial variability of neuronal spiking responses may provide important information about behavioral state. Observed changes in variability during sensory stimulation, attention, motor preparation, and visual discrimination suggest that variability may reflect the engagement of neurons in a behavioral task. We examined changes in spiking variability of frontal eye field (FEF) neurons in a change detection task requiring monkeys to remember a visually cued location and direct attention to that location while ignoring distracters elsewhere. In this task, the firing rates (FRs) of FEF neurons not only continuously reflect the location of the remembered cue and select targets, but also predict detection performance on a trial-by-trial basis. Changes in FEF response variability, as measured by the Fano factor (FF), showed clear dissociations from changes in FR. The FF declined in response to visual stimulation at all tested locations, even in the opposite hemifield, indicating much broader spatial tuning of the FF compared with the FR. Furthermore, despite robust spatial modulation of the FR throughout all epochs of the task, spatial tuning of the FF did not persist throughout the delay period, nor did it show attentional modulation. These results indicate that changes in variability, at least in the FEF, are most effectively driven by visual stimulation, while behavioral engagement is not sufficient. Instead, changes in variability may reflect shifts in the balance between feedforward and recurrent sources of excitatory drive.

Food Insecurity During the First Year of COVID-19: Employment and Sociodemographic Factors Among Participants in the CHASING COVID Cohort Study.

OBJECTIVE: While much has been reported about the impact of the COVID-19 pandemic on food insecurity, longitudinal data and the variability experienced by people working in various industries are limited. This study aims to further characterize people experiencing food insecurity during the pandemic in terms of employment, sociodemographic characteristics, and degree of food insecurity. METHODS: The study sample consisted of people enrolled in the Communities, Households and SARS-CoV-2 Epidemiology (CHASING) COVID Cohort Study from visit 1 (April-July 2020) through visit 7 (May-June 2021). We created weights to account for participants with incomplete or missing data. We used descriptive statistics and logistic regression models to determine employment and sociodemographic correlates of food insecurity. We also examined patterns of food insecurity and use of food support programs. RESULTS: Of 6740 participants, 39.6% (n = 2670) were food insecure. Non-Hispanic Black and Hispanic (vs non-Hispanic White) participants, participants in households with children (vs no children), and participants with lower (vs higher) income and education levels had higher odds of food insecurity. By industry, people employed in construction, leisure and hospitality, and trade, transportation, and utilities industries had the highest prevalence of both food insecurity and income loss. Among participants reporting food insecurity, 42.0% (1122 of 2670) were persistently food insecure (≥4 consecutive visits) and 43.9% (1172 of 2670) did not use any food support programs. CONCLUSIONS: The pandemic resulted in widespread food insecurity in our cohort, much of which was persistent. In addition to addressing sociodemographic disparities, future policies should focus on the needs of those working in industries vulnerable to economic disruption and ensure those experiencing food insecurity can access food support programs for which they are eligible.

The Importance of Incorporating At-Home Testing Into SARS-CoV-2 Point Prevalence Estimates: Findings From a US National Cohort, February 2022.

BACKGROUND: Passive, case-based surveillance underestimates the true extent of active infections in the population due to undiagnosed and untested cases, the exclusion of probable cases diagnosed point-of-care rapid antigen tests, and the exclusive use of at-home rapid tests which are not reported as part of case-based surveillance. The extent in which COVID-19 surveillance may be underestimating the burden of infection is likely due to time-varying factors such as decreased test-seeking behaviors and increased access to and availability of at-home testing. OBJECTIVE: The objective of this study is to estimate the prevalence of SARS-CoV-2 based on different definitions of a case to ascertain the extent to which cases of SARS-CoV-2 may be underestimated by case-based surveillance. METHODS: A survey on COVID-19 exposure, infection, and testing was administered to calculate point prevalence of SARS-CoV-2 among a diverse sample of cohort adults from February 8, 2022, to February 22, 2022. Three-point prevalence estimates were calculated among the cohort, as follows: (1) proportion positives based on polymerase chain reaction (PCR) and rapid antigen tests; (2) proportion positives based on testing exclusively with rapid at-home tests; and (3) proportion of probable undiagnosed cases. Test positivity and prevalence differences across booster status were also examined. RESULTS: Among a cohort of 4328, there were a total of 644 (14.9%) cases. The point prevalence estimate based on PCR or rapid antigen tests was 5.5% (95% CI 4.8%-6.2%), 3.7% (95% CI 3.1%-4.2%) based on at-home rapid tests, and 5.7% (95% CI 5.0%-6.4%) based on the case definition of a probable case. The total point prevalence across all definitions was 14.9% (95% CI 13.8%-16.0%). The percent positivity among PCR or rapid tests was 50.2%. No statistically significant differences were observed in prevalence between participants with a COVID-19 booster compared to fully vaccinated and nonboosted participants except among exclusive at-home rapid testers. CONCLUSIONS: Our findings suggest a substantial number of cases were missed by case-based surveillance systems during the Omicron B.1.1.529 surge, when at-home testing was common. Point prevalence surveys may be a rapid tool to be used to understand SARS-CoV-2 prevalence and would be especially important during case surges to measure the scope and spread of active infections in the population.

Cohort profile: a national, community-based prospective cohort study of SARS-CoV-2 pandemic outcomes in the USA-the CHASING COVID Cohort study.

PURPOSE: The Communities, Households and SARS-CoV-2 Epidemiology (CHASING) COVID Cohort Study is a community-based prospective cohort study launched during the upswing of the USA COVID-19 epidemic. The objectives of the cohort study are to: (1) estimate and evaluate determinants of the incidence of SARS-CoV-2 infection, disease and deaths; (2) assess the impact of the pandemic on psychosocial and economic outcomes and (3) assess the uptake of pandemic mitigation strategies. PARTICIPANTS: We began enrolling participants from 28 March 2020 using internet-based strategies. Adults≥18 years residing anywhere in the USA or US territories were eligible. 6740 people are enrolled in the cohort, including participants from all 50 US states, the District of Columbia, Puerto Rico and Guam. Participants are contacted regularly to complete study assessments, including interviews and dried blood spot specimen collection for serologic testing. FINDINGS TO DATE: Participants are geographically and sociodemographically diverse and include essential workers (19%). 84.2% remain engaged in cohort follow-up activities after enrolment. Data have been used to assess SARS-CoV-2 cumulative incidence, seroincidence and related risk factors at different phases of the US pandemic; the role of household crowding and the presence of children in the household as potential risk factors for severe COVID-19 early in the US pandemic; to describe the prevalence of anxiety symptoms and its relationship to COVID-19 outcomes and other potential stressors; to identify preferences for SARS-CoV-2 diagnostic testing when community transmission is on the rise via a discrete choice experiment and to assess vaccine hesitancy over time and its relationship to vaccine uptake. FUTURE PLANS: The CHASING COVID Cohort Study has outlined a research agenda that involves ongoing monitoring of the incidence and determinants of SARS-CoV-2 outcomes, mental health outcomes and economic outcomes. Additional priorities include assessing the incidence, prevalence and correlates of long-haul COVID-19.

SARS-CoV-2 incidence and risk factors in a national, community-based prospective cohort of U.S. adults.

BACKGROUND: Epidemiologic risk factors for incident SARS-CoV-2 infection as determined via prospective cohort studies greatly augment and complement information from case-based surveillance and cross-sectional seroprevalence surveys. METHODS: We estimated the incidence of SARS-CoV-2 infection and risk factors in a well-characterized, national prospective cohort of 6,738 U.S. adults, enrolled March-August 2020, a subset of whom (n=4,510) underwent repeat serologic testing between May 2020 and January 2021. We examined the crude associations of sociodemographic factors, epidemiologic risk factors, and county-level community transmission with the incidence of seroconversion. In multivariable Poisson models we examined the association of social distancing and a composite score of several epidemiologic risk factors with the rate of seroconversion. FINDINGS: Among the 4,510 individuals with at least one serologic test, 323 (7.3%, 95% confidence interval [CI] 6.5%-8.1%) seroconverted by January 2021. Among 3,422 participants seronegative in May-September 2020 and tested during November 2020-January 2021, we observed 161 seroconversions over 1,646 person-years of follow-up (incidence rate of 9.8 per 100 person-years [95%CI 8.3-11.5]). In adjusted models, participants who reported always or sometimes social distancing with people they knew (IRRalways vs. never 0.43, 95%CI 0.21-1.0; IRRsometimes vs. never 0.47, 95%CI 0.22-1.2) and people they did not know (IRRalways vs. never 0.64, 95%CI 0.39-1.1; IRRsometimes vs. never 0.60, 95%CI 0.38-0.97) had lower rates of seroconversion. The rate of seroconversion increased across tertiles of the composite score of epidemiologic risk (IRRmedium vs. low 1.5, 95%CI 0.92-2.4; IRRhigh vs. low 3.0, 95%CI 2.0-4.6). Among the 161 observed seroconversions, 28% reported no symptoms of COVID-like illness (i.e., were asymptomatic), and 27% reported a positive SARS-CoV-2 diagnostic test. Ultimately, only 29% reported isolating and 19% were asked about contacts. INTERPRETATION: Modifiable epidemiologic risk factors and poor reach of public health strategies drove SARS-CoV-2 transmission across the U.S during May 2020-January 2021. FUNDING: U.S. National Institutes of Allergy and Infectious Diseases (NIAID).

Selection and maintenance of spatial information by frontal eye field neurons.

Voluntary attention is often allocated according to internally maintained goals. Recent evidence indicates that the frontal eye field (FEF) participates in the deployment of spatial attention, even in the absence of saccadic eye movements. In addition, many FEF neurons maintain persistent representations of impending saccades. However, the role of persistent activity in the general maintenance of spatial information, and its relationship to spatial attention, has not been explored. We recorded the responses of single FEF neurons in monkeys trained to remember cued locations in order to detect changes in targets embedded among distracters in a task that did not involve saccades. We found that FEF neurons persistently encoded the cued location throughout the trial during the delay period, when no visual stimuli were present, and during visual discrimination. Furthermore, FEF activity reliably predicted whether monkeys would detect the target change. Population analyses revealed that FEF neurons with persistent activity were more effective at selecting the target from among distracters than neurons lacking persistent activity. These results demonstrate that FEF neurons maintain spatial information in the absence of saccade preparation and suggest that this maintenance contributes to the selection of relevant visual stimuli.

Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism.

PURPOSE: Selective cyclooxygenase-2 (COX-2) inhibitors may suppress carcinogenesis by both COX-2-dependent and COX-2-independent mechanisms. The primary purpose of this study was to evaluate whether celecoxib or rofecoxib, two widely used selective COX-2 inhibitors, possess COX-2-independent antitumor activity. EXPERIMENTAL DESIGN: PC3 and LNCaP human prostate cancer cell lines were used to investigate the growth inhibitory effects of selective COX-2 inhibitors in vitro. To complement these studies, we evaluated the effect of celecoxib on the growth of PC3 xenografts. RESULTS: COX-1 but not COX-2 was detected in PC3 and LNCaP cells. Clinically achievable concentrations (2.5-5.0 micromol/L) of celecoxib inhibited the growth of both cell lines in vitro, whereas rofecoxib had no effect over the same concentration range. Celecoxib inhibited cell growth by inducing a G(1) cell cycle block and reducing DNA synthesis. Treatment with celecoxib also led to dose-dependent inhibition of PC3 xenograft growth without causing a reduction in intratumor prostaglandin E(2). Inhibition of tumor growth occurred at concentrations (2.37-5.70 micromol/L) of celecoxib in plasma that were comparable with the concentrations required to inhibit cell growth in vitro. The highest dose of celecoxib led to a 52% reduction in tumor volume and an approximately 50% decrease in both cell proliferation and microvessel density. Treatment with celecoxib caused a marked decrease in amounts of cyclin D1 both in vitro and in vivo. CONCLUSIONS: Two clinically available selective COX-2 inhibitors possess different COX-2-independent anticancer properties. The anticancer activity of celecoxib may reflect COX-2-independent in addition to COX-2-dependent effects.

Latency of chromatic information in area V4.

In the primate visual system, information about color is known to be carried in separate divisions of the retino-geniculo-cortical pathway. From the retina, responses of photoreceptors to short (S), medium (M), and long (L) wavelengths of light are processed in two different opponent pathways. Signals in the S-opponent pathway, or blue/yellow channel, have been found to lag behind signals in the L/M-opponent pathway, or red/green channel in primary visual area V1, and psychophysical studies have suggested similar perceptual delays. However, more recent psychophysical studies have found that perceptual differences are negligible with the proper controls, suggesting that information between the two channels is integrated at some stage of processing beyond V1. To study the timing of color signals further downstream in visual cortex, we examined the responses of neurons in area V4 to colored stimuli varying along the two cardinal axes of the equiluminant opponent color space. We used information theory to measure the mutual information between the stimuli presented and the neural responses in short time windows in order to estimate the latency of color information in area V4. We found that on average, despite the latency difference in V1, information about S-opponent signals arrives in V4 at the same time as information about L/M-opponent signals. This work indicates a convergence of signal timing among chromatic channels within extrastriate cortex.

Top-down control of visual attention.

Top-down visual attention improves perception of selected stimuli and that improvement is reflected in the neural activity at many stages throughout the visual system. Recent studies of top-down attention have elaborated on the signatures of its effects within visual cortex and have begun identifying its causal basis. Evidence from these studies suggests that the correlates of spatial attention exhibited by neurons within the visual system originate from a distributed network of structures involved in the programming of saccadic eye movements. We summarize this evidence and discuss its relationship to the neural mechanisms of spatial working memory.

Presaccadic discrimination of receptive field stimuli by area V4 neurons.

Previous studies have shown that the visual responses of neurons in extrastriate area V4 are enhanced prior to saccadic eye movements that target receptive field (RF) stimuli. We used receiver-operator characteristic (ROC) analysis to quantify how well V4 neurons could discriminate stable RF stimuli targeted by visually-guided saccades or ignored during saccades elsewhere. We found that discrimination was transiently enhanced prior to saccades to RF stimuli whereas it was reduced prior to saccades elsewhere. Similar to what is observed during covert attention and after frontal eye field microstimulation, the changes in stimulus discrimination were due in part to changes in response magnitude. In addition, we found evidence of an increased reliability of responses when saccades were made to the RF stimulus. These results highlight the similarity of mechanisms driving covert spatial attention and the preparation of visually-guided saccades.

Tobacco smoke induces CYP1B1 in the aerodigestive tract.

Several members of the P450 family, including cytochrome P450 1B1 (CYP1B1), can convert tobacco smoke (TS) procarcinogens, including benzo[a]pyrene (B[a]P), to carcinogenic intermediates. In this study we investigated the effects of TS condensate and B[a]P on the expression of CYP1B1 in vitro and in vivo. CYP1B1 mRNA and protein were induced by both TS condensate and B[a]P in cell lines derived from the human aerodigestive tract. Treatment with TS condensate stimulated binding of the aryl hydrocarbon receptor (AhR) to an oligonucleotide containing a canonical xenobiotic response element (XRE) site and induced XRE-luciferase activity. These findings are consistent with prior evidence that polycyclic aromatic hydrocarbons, known ligands of the AhR, stimulate CYP1B1 transcription by an XRE-dependent mechanism. To determine whether these in vitro findings applied in vivo, both murine and human studies were carried out. Short-term exposure to TS induced CYP1B1 in the tongue, esophagus, lung and colon of experimental mice. In contrast, CYP1B1 was not induced by TS in the aorta of these mice. Levels of CYP1B1 mRNA were also elevated in the bronchial mucosa of human tobacco smokers versus never smokers (P < 0.05). Taken together, these results support a role for CYP1B1 in TS-induced carcinogenesis in the aerodigestive tract.