Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release.

The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS-CoV-2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS-CoV-2 viral titres. We investigate the potential viral proteins involved in abrogating tetherin function and find that SARS-CoV-2 ORF3a reduces tetherin localisation within biosynthetic organelles where Coronaviruses bud, and increases tetherin localisation to late endocytic organelles via reduced retrograde recycling. We also find that expression of Spike protein causes a reduction in cellular tetherin levels. Our results confirm that tetherin acts as a host restriction factor for SARS-CoV-2 and highlight the multiple distinct mechanisms by which SARS-CoV-2 subverts tetherin function.

Lower Humoral and Cellular Immunity Following Asymptomatic SARS-CoV-2 Infection Compared to Symptomatic Infection in Education (The ACE Cohort).

PURPOSE: Asymptomatic SARS-CoV-2 infections were widely reported during the COVID-19 pandemic, acting as a hidden source of infection. Many existing studies investigating asymptomatic immunity failed to recruit true asymptomatic individuals. Thus, we conducted a longitudinal cohort study to evaluate humoral- and cell-mediated responses to infection and vaccination in well-defined asymptomatic young adults (the Asymptomatic COVID-19 in Education [ACE] cohort). METHODS: Asymptomatic testing services located at three UK universities identified asymptomatic young adults who were subsequently recruited with age- and sex-matched symptomatic and uninfected controls. Blood and saliva samples were collected after SARS-CoV-2 Wuhan infection, and again after vaccination. 51 participant's anti-spike antibody titres, neutralizing antibodies, and spike-specific T-cell responses were measured, against both Wuhan and Omicron B.1.1.529.1. RESULTS: Asymptomatic participants exhibited reduced Wuhan-specific neutralization antibodies pre- and post-vaccination, as well as fewer Omicron-specific neutralization antibodies post-vaccination, compared to symptomatic participants. Lower Wuhan and Omicron-specific IgG titres in asymptomatic individuals were also observed pre- and post-vaccination, compared to symptomatic participants. There were no differences in salivary IgA levels. Conventional flow cytometry analysis and multi-dimensional clustering analysis indicated unvaccinated asymptomatic participants had significantly fewer Wuhan-specific IL-2 secreting CD4+ CD45RA+ T cells and activated CD8+ T cells than symptomatic participants, though these differences dissipated after vaccination. CONCLUSIONS: Asymptomatic infection results in decreased antibody and T cell responses to further exposure to SARS-CoV-2 variants, compared to symptomatic infection. Post-vaccination, antibody responses are still inferior, but T cell immunity increases to match symptomatic subjects, emphasising the importance of vaccination to help protect asymptomatic individuals against future variants.

From urges to tics in children with Tourette syndrome: associations with supplementary motor area GABA and right motor cortex physiology.

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges.

Humoral and cellular immunity in patients with rare autoimmune rheumatic diseases following SARS-CoV-2 vaccination.

OBJECTIVES: Coronavirus 2019 vaccine responses in rare autoimmune rheumatic diseases (RAIRDs) remain poorly understood; in particular there is little known about whether people develop effective T cell responses. We conducted an observational study to evaluate the short-term humoral and cell-mediated T cell response after the second severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in RAIRD patients compared with healthy controls (HCs). METHODS: Blood samples were collected after the second dose and anti-spike, anti-nucleocapsid antibody levels and SARS-CoV-2-specific T cell responses were measured and compared with those of HCs. Activation-induced marker and deep phenotyping assays were used to identify differences in T cells between high and no/low antibody groups, followed by multidimensional clustering. RESULTS: A total of 50 patients with RAIRDs were included (31 with AAV, 4 with other systemic vasculitis, 9 with SLE and 6 with myositis). The median anti-spike levels were significantly lower in RAIRD patients compared with HCs (P < 0.0001). Fifteen (33%) patients had undetectable levels and 26 (57%) had levels lower than the lowest HC. Rituximab in the last 12 months (P = 0.003) was associated with reduced immunogenicity compared with a longer pre-vaccination period. There was a significant difference in B cell percentages (P = 0.03) and spike-specific CD4+ T cells (P = 0.02) between no/low antibody vs high antibody groups. Patients in the no/low antibody group had a higher percentage of terminally differentiated (exhausted) T cells. CONCLUSIONS: Following two doses, most RAIRD patients have lower antibody levels than the lowest HC and lower anti-spike T cells. RAIRD patients with no/low antibodies have diminished numbers and poor quality of memory T cells that lack proliferative and functional capacities.

Appointment Non-attendance for Telehealth Versus In-Person Primary Care Visits at a Large Public Healthcare System.

BACKGROUND: Appointment non-attendance has clinical, operational, and financial implications for patients and health systems. How telehealth services are associated with non-attendance in primary care is not well-described, nor are patient characteristics associated with telehealth non-attendance. OBJECTIVE: We sought to compare primary care non-attendance for telehealth versus in-person visits and describe patient characteristics associated with telehealth non-attendance. DESIGN: An observational study of electronic health record data. PARTICIPANTS: Patients with primary care encounters at 23 adult primary care clinics at a large, urban public healthcare system from November 1, 2019, to August 31, 2021. MAIN MEASURES: We analyzed non-attendance by modality (telephone, video, in-person) during three time periods representing different availability of telehealth using hierarchal multiple logistic regression to control for patient demographics and variation within patients and clinics. We stratified by modality and used hierarchal multiple logistic regression to assess for associations between patient characteristics and non-attendance in each modality. KEY RESULTS: There were 1,219,781 scheduled adult primary care visits by 329,461 unique patients: 754,149 (61.8%) in-person, 439,295 (36.0%) telephonic, and 26,337 (2.2%) video visits. Non-attendance for telephone visits was initially higher than that for in-person visits (adjusted odds ratio 1.04 [95% CI 1.02, 1.07]) during the early telehealth availability period, but decreased later (0.82 [0.81, 0.83]). Non-attendance for video visits was higher than for in-person visits during the early (4.37 [2.74, 6.97]) and later (2.02 [1.95, 2.08]) periods. Telephone visits had fewer differences in non-attendance by demographics; video visits were associated with increased non-attendance for patients who were older, male, had a primary language other than English or Spanish, and had public or no insurance. CONCLUSIONS: Telephonic visits may improve access to care and be more easily adoptable among diverse populations. Further attention to implementation may be needed to avoid impeding access to care for certain populations using video visits.

Pharmacoepidemiology and costs of medications dispensed during pregnancy: A retrospective population-based study.

OBJECTIVE: To describe the pharmacoepidemiology and costs associated with medications dispensed during pregnancy. DESIGN: Pharmacoepidemiological study and cost analysis. SETTING: Queensland, Australia. POPULATION: All women who gave birth in Queensland between January 2013 and June 2018. METHODS: We used a whole-of-population linked administrative dataset, Maternity1000, to describe medications approved for public subsidy that were dispensed to 255 408 pregnant women. We describe the volume of medications dispensed and their associated costs from a Government and patient perspective. MAIN OUTCOME MEASURES: Prevalence of medication use; proportion of total dispensings; total medication costs in AUD 2020/21 ($1AUD = $0.67USD/£0.55GBP in December 2022). RESULTS: During pregnancy, 61% (95% CI 60.96-61.29%) of women were dispensed at least one medication approved for public subsidy. The mean number of items dispensed per pregnancy increased from 2.14 (95% CI 2.11-2.17) in 2013 to 2.47 (95% CI 2.44-2.51) in 2017; an increase of 15%. Furthermore, mean Government cost per dispensing increased by 41% from $21.60 (95% CI $20.99-$22.20) in 2013 to $30.44 (95% CI $29.38-$31.49) in 2017. These factors influenced the 53% increase in total Government expenditure observed for medication use during pregnancy between 2013 and 2017 ($2,834,227 versus $4,324,377); a disproportionate rise compared with the 17% rise in women's total out-of-pocket expenses observed over the same timeframe ($1,880,961 versus $2,204,415). CONCLUSIONS: Prevalence of medication use in pregnancy is rising and is associated with disproportionate and rapidly escalating cost implications for the Government.

Patient Characteristics Associated with Telehealth Scheduling and Completion in Primary Care at a Large, Urban Public Healthcare System.

Understanding patient characteristics associated with scheduling and completing telehealth visits can identify potential biases or latent preferences related to telehealth usage. We describe patient characteristics associated with being scheduled for and completing audio and video visits. We used data from patients at 17 adult primary care departments in a large, urban public healthcare system from August 1, 2020 to July 31, 2021. We used hierarchical multivariable logistic regression to generate adjusted odds ratios (aOR) for patient characteristics associated with having been scheduled for and completed telehealth (vs in-person) visits and for video (vs audio) scheduling and completion during two time periods: a telehealth transition period (N = 190,949) and a telehealth elective period (N = 181,808). Patient characteristics were significantly associated with scheduling and completion of telehealth visits. Many associations were similar across time periods, but others changed over time. Patients who were older (≥ 65 years old vs 18-44 years old: aOR for scheduling 0.53/completion 0.48), Black (0.86/0.71), Hispanic (0.76/0.62), or had Medicaid (0.93/0.84) were among those less likely to be scheduled for or complete video (vs audio) visits. Patients with activated patient portals (1.97/3.34) or more visits (≥ 3 scheduled visits vs 1 visit: 2.40/1.52) were more likely to be scheduled for or complete video visits. Variation in scheduling/completion explained by patient characteristics was 7.2%/7.5%, clustering by provider 37.2%/34.9%, and clustering by facility 43.1%/37.4%. Stable and dynamic associations suggest persistent gaps in access and evolving preferences/biases. Variation explained by patient characteristics was relatively low compared with that explained by provider and facility clustering.

Relationship Between Anxiety, Depression, and Susceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Proof of Concept.

BACKGROUND: Psychological factors can influence susceptibility to viral infections. We examined whether such influences are evident in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Participants (n = 102) completed measures of anxiety, depression, positive mood, and loneliness and provided a blood sample for the measurement of antibodies to the SARS-CoV-2 spike and nucleocapsid proteins. RESULTS: SARS-CoV-2 was significantly negatively associated with anxiety and depression. The model remained significant after adjustment for age and gender, although anxiety and depression were no longer significant independent predictors. CONCLUSIONS: These findings offer early support for the hypothesis that psychological factors may influence susceptibility to SARS-CoV-2 infection.

Coronavirus Disease 2019 (COVID-19) Vaccination Coverage, Intentions, Attitudes, and Barriers by Race/Ethnicity, Language of Interview, and Nativity-National Immunization Survey Adult COVID Module, 22 April 2021-29 January 2022.

The National Immunization Survey Adult COVID Module used a random-digit-dialed phone survey during 22 April 2021-29 January 2022 to quantify coronavirus disease 2019 (COVID-19) vaccination, intent, attitudes, and barriers by detailed race/ethnicity, interview language, and nativity. Foreign-born respondents overall and within racial/ethnic categories had higher vaccination coverage (80.9%), higher intent to be vaccinated (4.2%), and lower hesitancy toward COVID-19 vaccination (6.0%) than US-born respondents (72.6%, 2.9%, and 15.8%, respectively). Vaccination coverage was significantly lower for certain subcategories of national origin or heritage (eg, Jamaican [68.6%], Haitian [60.7%], Somali [49.0%] in weighted estimates). Respondents interviewed in Spanish had lower vaccination coverage than interviewees in English but higher intent to be vaccinated and lower reluctance. Collection and analysis of nativity, detailed race/ethnicity and language information allow identification of disparities among racial/ethnic subgroups. Vaccination programs could use such information to implement culturally and linguistically appropriate focused interventions among communities with lower vaccination coverage.

Disparities in COVID-19 Vaccination Status, Intent, and Perceived Access for Noninstitutionalized Adults, by Disability Status - National Immunization Survey Adult COVID Module, United States, May 30-June 26, 2021.

Estimates from the 2019 American Community Survey (ACS) indicated that 15.2% of adults aged ≥18 years had at least one reported functional disability (1). Persons with disabilities are more likely than are those without disabilities to have chronic health conditions (2) and also face barriers to accessing health care (3). These and other health and social inequities have placed persons with disabilities at increased risk for COVID-19-related illness and death, yet they face unique barriers to receipt of vaccination (4,5). Although CDC encourages that considerations be made when expanding vaccine access to persons with disabilities,* few public health surveillance systems measure disability status. To describe COVID-19 vaccination status and intent, as well as perceived vaccine access among adults by disability status, data from the National Immunization Survey Adult COVID Module (NIS-ACM) were analyzed. Adults with a disability were less likely than were those without a disability to report having received ≥1 dose of COVID-19 vaccine (age-adjusted prevalence ratio [aPR] = 0.88; 95% confidence interval [CI] = 0.84-0.93) but more likely to report they would definitely get vaccinated (aPR = 1.86; 95% CI = 1.43-2.42). Among unvaccinated adults, those with a disability were more likely to report higher endorsement of vaccine as protection (aPR = 1.29; 95% CI = 1.16-1.44), yet more likely to report it would be or was difficult to get vaccinated than did adults without a disability (aPR = 2.69; 95% CI = 2.16-3.34). Reducing barriers to vaccine scheduling and making vaccination sites more accessible might improve vaccination rates among persons with disabilities.

Altered frontal-mediated inhibition and white matter connectivity in pediatric chronic tic disorders.

Tics are unique from most movement disorders, in that they are partially suppressible. As part of the inhibitory motor network, the pre-supplementary motor area is engaged in motor control and may be involved in tic physiology. We used dual-site transcranial magnetic stimulation to assess inhibitory connectivity between right pre-supplementary motor area and left primary motor cortex, which has previously been demonstrated in healthy adults. We also used diffusion tensor imaging to investigate white matter connectivity in children with chronic tics. Twelve children with chronic tic disorder and fourteen typically developing controls underwent MRI with diffusion tensor imaging indices analysis followed by single and paired-pulse transcranial magnetic stimulation with conditioning pulse over the right pre-supplementary motor area followed by left motor cortex test pulse. Neurophysiologic and imaging data relationships to measures of tic severity and suppressibility were also evaluated in tic patients. Pre-supplementary motor area-mediated inhibition of left motor cortex was present in healthy control children but not in chronic tic disorder participants. Less inhibition correlated with worse tic suppressibility (ρ = - 0.73, p = 0.047). Imaging analysis showed increased fractional anisotropy in the right superior longitudinal fasciculus, corpus callosum, corona radiata and posterior limb of the internal capsule (p < 0.05) in tic participants, which correlated with lower self-reported tic suppressibility (ρ = - 0.70, p = 0.05). Physiologic data revealed impaired frontal-mediated motor cortex inhibition in chronic tic participants, and imaging analysis showed abnormalities in motor pathways. Collectively, the neurophysiologic and neuroanatomic data correlate with tic suppressibility, supporting the relevancy to tic pathophysiology.

Adapting to the Reimbursement Landscape: The Future of Value-Based Care.

This article explores one of the undeniable driving forces in health care: payment, and the shift toward value-based reimbursement as a lever to better align provider incentives toward appropriate utilization of health care services. The increasing burden of heart failure has made it an attractive target for many payment reform efforts and alternative payment models. As the ultimate goal of "value-based care" interventions is to reduce costs and improve quality outcomes and experience for patients while simultaneously improving the caregiver experience, financial models require a level of clinical translation to yield sustainable care redesign improvements.

Discrete or indiscrete? Redefining the colour polymorphism of the land snail Cepaea nemoralis.

Biologists have long tried to describe and name the different phenotypes that make up the shell polymorphism of the land snail Cepaea nemoralis. Traditionally, the view is that the ground colour of the shell is one of a few major colour classes, either yellow, pink or brown, but in practise it is frequently difficult to distinguish the colours, and define different shades of the same colour. To understand whether colour variation is in reality continuous, and to investigate how the variation may be perceived by an avian predator, we applied psychophysical models of colour vision to shell reflectance measures. We found that both achromatic and chromatic variation are indiscrete in Cepaea nemoralis, being continuously distributed over many perceptual units. Nonetheless, clustering analysis based on the density of the distribution did reveal three groups, roughly corresponding to human-perceived yellow, pink and brown shells. We also found large-scale geographic variation in the frequency of these groups across Europe, and some covariance between shell colour and banding patterns. Although further studies are necessary, the observation of continuous variation in colour is intriguing because the traditional theory is that the underlying supergene that determines colour has evolved to prevent phenotypes from "dissolving" into continuous trait distributions. The findings thus have significance for understanding the Cepaea polymorphism, and the nature of the selection that acts upon it, as well as more generally highlighting the need to measure colour objectively in other systems.

Automated Risk Assessment for School Violence: a Pilot Study.

School violence has increased over the past ten years. This study evaluated students using a more standard and sensitive method to help identify students who are at high risk for school violence. 103 participants were recruited through Cincinnati Children's Hospital Medical Center (CCHMC) from psychiatry outpatient clinics, the inpatient units, and the emergency department. Participants (ages 12-18) were active students in 74 traditional schools (i.e. non-online education). Collateral information was gathered from guardians before participants were evaluated. School risk evaluations were performed with each participant, and audio recordings from the evaluations were later transcribed and manually annotated. The BRACHA (School Version) and the School Safety Scale (SSS), both 14-item scales, were used. A template of open-ended questions was also used. This analysis included 103 participants who were recruited from 74 different schools. Of the 103 students evaluated, 55 were found to be moderate to high risk and 48 were found to be low risk based on the paper risk assessments including the BRACHA and SSS. Both the BRACHA and the SSS were highly correlated with risk of violence to others (Pearson correlations>0.82). There were significant differences in BRACHA and SSS total scores between low risk and high risk to others groups (p-values <0.001 under unpaired t-test). In particular, there were significant differences in individual SSS items between the two groups (p-value <0.001). Of these items, Previous Violent Behavior (Pearson Correlation = 0.80), Impulsivity (0.69), School Problems (0.64), and Negative Attitudes (0.61) were positively correlated with risk to others. The novel machine learning algorithm achieved an AUC of 91.02% when using the interview content to predict risk of school violence, and the AUC increased to 91.45% when demographic and socioeconomic data were added. Our study indicates that the BRACHA and SSS are clinically useful for assessing risk for school violence. The machine learning algorithm was highly accurate in assessing school violence risk.

A Sex-Specific Analysis of Nutrition Label Use and Health, Douglas County, Nebraska, 2013.

INTRODUCTION: In 2014 the US Food and Drug Administration proposed a series of changes to its 1992 guidelines on nutrition facts labeling to help consumers make informed food choices. To date, few studies have examined the association between consumers' use of the nutrition label and health. The objective of this study was to assess the association between nutrition label use and health and to determine whether the association differs by sex. METHODS: Using data from a population-based, random sample survey of 1,503 participants conducted in Nebraska in 2013, we performed χ(2) tests to examine bivariate associations between selected health variables and nutrition label use, followed by logistic regression analysis to estimate these associations in a multivariate framework. RESULTS: A U-shaped relationship between self-rated health (SRH) and nutrition label use was observed. Both excellent and poor SRH were associated with a higher likelihood of nutrition label use than the 3 SRH categories in between. Being obese or having 1 of 4 chronic conditions (hypertension, diabetes, heart disease, high cholesterol) were both associated with higher odds of nutrition label use (odds ratio [OR] = 2.63, P < .001; OR = 1.71, P < .05, respectively) among men. These associations, however, were not significant among women. CONCLUSION: A close association existed between health and nutritional label use. This association was more pronounced among men than among women. Nutrition education may benefit from factoring in the association between health and use of nutrition labels and the differences in these associations by sex.

How the structural determinants of health inequities impact access to prescription medication for pregnant women in Australia: a narrative review.

Structural factors that contribute to health disparities (e.g., population-level policies, cultural norms) impact the distribution of resources in society and can affect medication accessibility; even in high-income countries like Australia. Industry practices and regulatory approaches (e.g., a conservative approach to testing medicines in pregnant women) influence the availability of safety and efficacy data necessary for the licencing and funding of prescription medications used during pregnancy. Consequently, pregnant women may be prescribed medications outside of regulatory or funder-approved indications, posing risks for both prescribers and pregnant women and potentially compromising equitable access to medications. This review examines the regulatory and legislative structural factors that contribute to health disparities and perpetuate the deeply ingrained social norm that we should be protecting pregnant women from clinical research rather than safeguarding them through such research. Addressing these challenges requires a renewed commitment to integrated, woman-centred maternal healthcare and strengthened collaboration across all sectors. Funding: Australian Government Research Training Program Stipend from the University of Technology Sydney, National Health and Medical Research Council (NHMRC) Fellowship, Channel 7 Children's Research Foundation Fellowship (CRF-210323).

Understanding Patients' Negative Experiences with Telehealth: A Content Analysis of Survey Data.

Understanding differences in how demographic groups experience telehealth may be relevant in addressing potential disparities in telehealth usage. We seek to identify and examine themes most pertinent to patients' negative telehealth experiences by age and race in order to inform interventions to improve patients' future telehealth experiences. We performed a content analysis of Press Ganey patient experience surveys from adult patients at 17 primary care sites of a large, public healthcare system with visits from April 30, 2020 to August 27, 2021. We used sentiment analysis to identify negative comments. We coded for content themes and analyzed their frequency, stratifying by age and race. We analyzed 745 negative comments. Most frequent themes differed by demographic categories, but overall, the most commonly applied codes were "Contacting the Clinic" (n = 97), "Connectivity" (n = 84), and "Webside Manner" (n = 79). The top three codes accounted for >40% of the negative codes in each race category and >35% of the negative codes in each age category. While there were common negative experiences among groups, patients of different demographics highlighted different aspects of their telehealth experiences for potential improvement.

Patient Experiences With Telehealth During Versus After a System-Wide Telehealth Mandate During the COVID-19 Pandemic.

This study examines whether patients' telehealth experiences differed during a health system mandate for telehealth encounters due to the COVID-19 pandemic versus after the mandate was relaxed. Patient experience surveys from telehealth visits across 17 adult (age 18+) primary care sites at a large, urban public health system were analyzed during two periods: when a mandate was active (March 1, 2020-June 30, 2020) and when the mandate was relaxed and any appointment modality was available (July 1, 2020-November 30, 2021). Primary outcomes were odds ratios (ORs) comparing top-box percentages of survey responses at multiple levels: individual questions, four domains, and all questions together as a composite. Key findings: Patients had higher odds of selecting top-box answers in the elective telehealth period for the Care Provider (1.09 [95% confidence interval 1.03, 1.16]) and General Assessment (1.13 [1.02, 1.24]) domains and the survey composite (1.08 [1.04, 1.13]), but there was no difference for individual questions.Women reported more positive experiences during the elective telehealth period in the Access (1.22 [1.01, 1.47]), Care Provider (1.32 [1.17, 1.50]), and Telemedicine Technology (1.24 [1.04, 1.50]) domains.Our findings suggest that patients had better telehealth experiences when mandates were relaxed.

Effect of a Telehealth Navigator Program on Video Visit Scheduling and Completion in Primary Care.

INTRODUCTION: Patients and clinicians face challenges in participating in video telehealth visits. Patient navigation has been effective in other settings in enhancing patients' engagement with clinical programs. Our objective was to assess whether implementing a telehealth navigator program to support patients and clinicians affected video visit scheduling, video usage, and non-attendance. METHODS: This was a quasi-experimental quality improvement project using difference-in-differences. We included data from 17 adult primary care sites at a large, urban public healthcare system from October 1, 2021 to October 31, 2022. Six sites received telehealth navigators and 11 sites were used as comparators. Navigators contacted patients (by phone) with upcoming video visits to assess and address potential barriers to successful video visit completion. They also provided on-site support to patients and clinicians regarding telehealth visits and usage of an electronic patient portal. The primary outcomes were difference-in-differences for the proportion of telehealth visits scheduled and, separately, completed as video visits and non-attendance for visits scheduled as video visits. RESULTS: There were 65 488 and 71 504 scheduled telehealth appointments at intervention and non-intervention sites, respectively. The adjusted difference-in-differences for the proportion of telehealth visits scheduled as video was -9.1% [95% confidence interval -26.1%, 8.0%], the proportion of telehealth visits completed as video visits 1.3% [-4.9%, 7.4%], and non-attendance for visits scheduled as video visits -3.7% [-6.0%, -1.4%]. CONCLUSIONS: Sites with telehealth navigators had comparatively lower video visit non-attendance but did not have comparatively different video visit scheduling or completion rates. Despite this, navigators' on-the-ground presence can help identify opportunities for improvements in care design.

Bioengineered small extracellular vesicles deliver multiple SARS-CoV-2 antigenic fragments and drive a broad immunological response.

The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence of SARS-CoV-2 breakthrough infections highlights the need for additional vaccine modalities to provide stronger, long-lived protective immunity. Here we report the design and preclinical testing of small extracellular vesicles (sEVs) as a multi-subunit vaccine. Cell lines were engineered to produce sEVs containing either the SARS-CoV-2 Spike receptor-binding domain, or an antigenic region from SARS-CoV-2 Nucleocapsid, or both in combination, and we tested their ability to evoke immune responses in vitro and in vivo. B cells incubated with bioengineered sEVs were potent activators of antigen-specific T cell clones. Mice immunised with sEVs containing both sRBD and Nucleocapsid antigens generated sRBD-specific IgGs, nucleocapsid-specific IgGs, which neutralised SARS-CoV-2 infection. sEV-based vaccines allow multiple antigens to be delivered simultaneously resulting in potent, broad immunity, and provide a quick, cheap, and reliable method to test vaccine candidates.