Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function.

The expression levels of TCRs on the surface of human T cells define the avidity of TCR-HLA/peptide interactions. In this study, we have explored which components of the TCR-CD3 complex are involved in determining the surface expression levels of TCRs in primary human T cells. The results show that there is a surplus of endogenous TCR α/ß chains that can be mobilised by providing T cells with additional CD3γ,δ,ε,ζ chains, which leads to a 5-fold increase in TCR α/ß surface expression. The analysis of individual CD3 chains revealed that provision of additional ζ chain alone was sufficient to achieve a 3-fold increase in endogenous TCR expression. Similarly, CD3ζ also limits the expression levels of exogenous TCRs transduced into primary human T cells. Interestingly, transduction with TCR plus CD3ζ not only increased surface expression of the introduced TCR, but it also reduced mispairing with endogenous TCR chains, resulting in improved antigen-specific function. TCR reconstitution experiments in HEK293T cells that do not express endogenous TCR or CD3 showed that TCRα/ß and all four CD3 chains were required for optimal surface expression, while in the absence of CD3ζ the TCR expression was reduced by 50%. Together, the data show that CD3ζ is a key regulator of TCR expression levels in human T cells, and that gene transfer of exogenous TCR plus CD3ζ improved TCR surface expression, reduced TCR mispairing and increased antigen-specific function.

High prevalence of hepatitis C virus infection among incarcerated persons: Results from the Louisiana Hepatitis C Elimination Plan's opt-out testing program in prisons.

In the United States, modelling studies suggest a high prevalence of hepatitis C virus (HCV) infection in incarcerated populations. However, limited HCV testing has been conducted in prisons. Through the Louisiana Hepatitis C Elimination Plan, persons incarcerated in the eight state prisons were offered HCV testing from 20 September 2019 to 14 July 2022, and facility entry/exit HCV testing was introduced. Multivariable logistic regression was used to evaluate associations with HCV antibody (anti-HCV) positivity and viremia. Of 17,231 persons in the eight state prisons screened for anti-HCV, 95.1% were male, 66.7% were 30-57 years old, 3% were living with HIV, 68.2% were Black and 2904 (16.9%) were anti-HCV positive. HCV RNA was detected in 69.3% of anti-HCV positive individuals tested. In the multivariable model, anti-HCV positivity was associated with older age including those 30-57 (odds ratio [OR] 3.53, 95% confidence interval [CI] 2.96-4.20) and those ≥58 (OR 10.43, 95% CI 8.66-12.55) as compared to those ≤29 years of age, living with HIV (OR 1.68, 95% CI 1.36-2.07), hepatitis B (OR 1.83, 95% CI 1.25-2.69) and syphilis (OR 1.51, 95% CI 1.23-1.86). HCV viremia was associated with male sex (OR 1.89, 95% CI 1.36-2.63) and Black race (OR 1.42, 95% CI 1.20-1.68). HCV prevalence was high in the state prisons in Louisiana compared to community estimates. To the extent that Louisiana is representative, to eliminate HCV in the United States, it will be important for incarcerated persons to have access to HCV testing and treatment.

Corrigendum: Personalized digital intervention for depression based on social rhythm principles adds significantly to outpatient treatment.

[This corrects the article DOI: 10.3389/fdgth.2022.870522.].

HIV Pre-exposure Prophylaxis Services for Black and Hispanic or Latino Gay, Bisexual, and Other Men Who Have Sex With Men and Transgender Women in THRIVE, 2015-2020.

BACKGROUND AND SETTING: From 2015 to 2020, the THRIVE project supported 7 US health departments to improve HIV prevention services for Black or African American (Black) and Hispanic or Latino gay, bisexual, and other men who have sex with men (GBM) and transgender women (TGW). METHODS: We described services provided in the THRIVE PrEP continuum. Using Poisson regression models, we estimated associations between race or ethnicity and age and PrEP screening, linkage, and prescription. We examined associations between colocation of services and PrEP linkage and prescription for 2 sites. RESULTS: THRIVE served 12,972 GBM without HIV; 37% of PrEP-eligible GBM were prescribed PrEP. THRIVE served 1185 TGW without HIV; 45% of PrEP-eligible TGW were prescribed PrEP. Black and Hispanic or Latino GBM were 29% (RR = 0.71, 95% CI: 0.66-0.77) and 19% (RR = 0.81, 95% CI: 0.75-0.87) less likely, respectively, to be prescribed PrEP than White GBM. GBM aged 18-24 years and 55 years or older were 19% (RR = 0.81, 95% CI: 0.75-0.87) and 22% (RR = 0.78, 95% CI: 0.67-0.9) less likely, respectively, to be prescribed PrEP compared with those aged 35-44 years. Colocated services were associated with a 54% (RR = 1.54, 95% CI: 1.44-1.64) and a 31% (RR = 1.31, 95% CI: 1.19-1.43) greater likelihood of PrEP linkage and prescription, respectively, compared with services at different locations. CONCLUSIONS: THRIVE provided PrEP to higher proportions of PrEP-eligible persons than current national estimates; however, PrEP use disparities persist. Colocation of services may be a useful component of jurisdictional strategies to increase PrEP coverage.

Personalized digital intervention for depression based on social rhythm principles adds significantly to outpatient treatment.

We conducted a 16-week randomized controlled trial in psychiatric outpatients with a lifetime diagnosis of a mood and/or anxiety disorder to measure the impact of a first-of-its-kind precision digital intervention software solution based on social rhythm regulation principles. The full intent-to-treat (ITT) sample consisted of 133 individuals, aged 18-65. An exploratory sub-sample of interest was those individuals who presented with moderately severe to severe depression at study entry (baseline PHQ-8 score ≥15; N = 28). Cue is a novel digital intervention platform that capitalizes on the smartphone's ability to continuously monitor depression-relevant behavior patterns and use each patient's behavioral data to provide timely, personalized "micro-interventions," making this the first example of a precision digital intervention of which we are aware. Participants were randomly allocated to receive Cue plus care-as-usual or digital monitoring only plus care as usual. Within the full study and depressed-at-entry samples, we fit a mixed effects model to test for group differences in the slope of depressive symptoms over 16 weeks. To account for the non-linear trajectory with more flexibility, we also fit a mixed effects model considering week as a categorical variable and used the resulting estimates to test the group difference in PHQ change from baseline to 16 weeks. In the full sample, the group difference in the slope of PHQ-8 was negligible (Cohen's d = -0.10); however, the Cue group demonstrated significantly greater improvement from baseline to 16 weeks (p = 0.040). In the depressed-at-entry sample, we found evidence for benefit of Cue. The group difference in the slope of PHQ-8 (Cohen's d = -0.72) indicated a meaningfully more rapid rate of improvement in the intervention group than in the control group. The Cue group also demonstrated significantly greater improvement in PHQ-8 from baseline to 16 weeks (p = 0.009). We are encouraged by the size of the intervention effect in those who were acutely ill at baseline, and by the finding that across all participants, 80% of whom were receiving pharmacotherapy, we observed significant benefit of Cue at 16 weeks of treatment. These findings suggest that a social rhythm-focused digital intervention platform may represent a useful and accessible adjunct to antidepressant treatment (https://clinicaltrials.gov/ct2/show/NCT03152864?term=ellen+frank&draw=2&rank=3).

The Role of Csmd1 during Mammary Gland Development.

The Cub Sushi Multiple Domains-1 (CSMD1) protein is a tumour suppressor which has been shown to play a role in regulating human mammary duct development in vitro. CSMD1 knockdown in vitro demonstrated increased cell proliferation, invasion and motility. However, the role of Csmd1 in vivo is poorly characterised when it comes to ductal development and is therefore an area which warrants further exploration. In this study a Csmd1 knockout (KO) mouse model was used to identify the role of Csmd1 in regulating mammary gland development during puberty. Changes in duct development and protein expression patterns were analysed by immunohistochemistry. This study identified increased ductal development during the early stages of puberty in the KO mice, characterised by increased ductal area and terminal end bud number at 6 weeks. Furthermore, increased expression of various proteins (Stat1, Fak, Akt, Slug/Snail and Progesterone receptor) was shown at 4 weeks in the KO mice, followed by lower expression levels from 6 weeks in the KO mice compared to the wild type mice. This study identifies a novel role for Csmd1 in mammary gland development, with Csmd1 KO causing significantly more rapid mammary gland development, suggesting an earlier adult mammary gland formation.

Improving Engagement in HIV Care Using a Data-to-Care and Patient Navigation System in Louisiana, United States.

An estimated 57% of persons living with HIV (PLWH) in the United States are not connected to regular medical care or have lapsed from regular care (Centers for Disease Control and Prevention, 2018), increasing risk of HIV progression and transmission and delaying viral suppression. The state of Louisiana has consistently ranked in the top five US states for HIV case rates. We evaluated the impact of a combined data-to-care and patient navigation system that was implemented in 3 cities in Louisiana from 2013 to 2015. The program, LA Links, used a surveillance system to identify PLWH who were not in regular health care and connected them to a patient navigator. During the intervention period, persons who lapsed from care were 17% more likely to reengage in care than persons in the comparison group, and persons newly diagnosed during the intervention period were 56% more likely to link to care.

The Louisiana Wellness Centers Program for HIV/STD Prevention Among Gay and Bisexual Men and Transgender Persons.

CONTEXT: During the conduct of the described demonstration project (2012-2015), the Centers for Disease Control and Prevention funding standard for HIV testing was 1.0% newly diagnosed positivity in non-health care settings. For linkage to HIV medical care, the National HIV/AIDS Strategy goal was 85%, and the funding standard was 80% (the Centers for Disease Control and Prevention and National HIV/AIDS Strategy had no other quantified goals/standards relevant to the project). OBJECTIVE: To determine aggregate quantitative results of HIV/STD testing and engagement in HIV care. DESIGN: Information sources used for this case study analysis included the Louisiana Department of Health funding application, progress and final reports submitted to the Centers for Disease Control and Prevention, and records of communications between these agencies. SETTING: Six community-based Wellness Centers throughout Louisiana. PARTICIPANTS: Gay and bisexual men and transgender persons. MAIN OUTCOME MEASURES: New HIV/STD diagnoses from testing, linkage to HIV care, and reengagement in HIV medical care. RESULTS: The percentage of persons who were newly diagnosed with HIV was 1.4% (44/3214). Of the newly diagnosed persons, 91% (40/44) were linked to HIV medical care. Of persons who were identified as out of care, 83% (5/6) were reengaged in HIV medical care. STD testing results showed that 9.0% (294/3251) of the syphilis tests were positive, and 8.3% (803/9719) of the chlamydia/gonorrhea tests were positive. The pharyngeal chlamydia/gonorrhea positivity was 7.6% (256/3375); the rectal chlamydia/gonorrhea positivity was 13% (374/2948); and the urine chlamydia/gonorrhea positivity was 5.1% (173/3396). CONCLUSIONS: The demonstration project was successful. The results were used to discontinue funding for a less effective HIV screening program, continue demonstration project activities with other funds, and make policy changes so that extragenital screening for chlamydia/gonorrhea is now the standard at Louisiana clinics that serve gay and bisexual men and transgender persons.

Using Financial Incentives to Improve Rates of Viral Suppression and Engagement in Care of Patients Receiving HIV Care at 3 Health Clinics in Louisiana: The Health Models Program, 2013-2016.

OBJECTIVES: The Care and Prevention in the United States Demonstration Project aimed to reduce HIV/AIDS-related morbidity and mortality among racial/ethnic minority groups in 8 states. We evaluated Health Models, a pay-for-performance program piloted by the Louisiana Department of Health that used financial incentives to improve rates of engagement in HIV medical care and viral suppression among people with HIV. METHODS: We enrolled 2076 patients of 3 urban HIV specialty clinics in Louisiana in the Health Models pay-for-performance program on a rolling basis from September 2013 through September 2016 and gave patients cash incentives to attend HIV medical appointments, achieve or maintain viral suppression, and link to supportive services. We used laboratory data collected from Louisiana's HIV surveillance database to calculate rates of engagement in care and viral suppression during the first 24 months of enrollment. RESULTS: Of the 2076 patients who enrolled, 1400 (67.4%) were non-Hispanic black, 1480 (71.3%) were male, 1175 (56.6%) were men who have sex with men, and 1371 (66.0%) reported an annual income of <$15 000. At enrollment, 1456 (70.1%) patients were engaged in HIV care, and 1197 (57.7%) patients were virally suppressed. After 12 months of enrollment, 1474 of 1783 (82.7%) patients were virally suppressed. Of enrolled patients with at least 12 or 24 months of follow-up data, 1299 of 1317 (98.6%) patients were engaged in care during their first 12 months of enrollment, and 995 of 1033 (96.3%) patients were engaged in care between 12 and 24 months of enrollment. CONCLUSIONS: During the implementation of Health Models, enrolled patients had increases in rates of viral suppression and achieved rates of engagement in care and viral suppression that were higher than national levels; however, additional supportive services may be needed to further reduce socioeconomic disparities in the rates of viral suppression.

Implementing a Data to Care Strategy to Improve Health Outcomes for People With HIV: A Report From the Care and Prevention in the United States Demonstration Project.

OBJECTIVES: The Care and Prevention in the United States Demonstration Project included implementation of a Data to Care strategy using surveillance and other data to (1) identify people with HIV infection in need of HIV medical care or other services and (2) facilitate linkages to those services to improve health outcomes. We present the experiences of 4 state health departments: Illinois, Louisiana, Tennessee, and Virginia. METHODS: The 4 state health departments used multiple databases to generate listings of people with diagnosed HIV infection (PWH) who were presumed not to be in HIV medical care or who had difficulty maintaining viral suppression from October 1, 2013, through September 29, 2016. Each health department prioritized the listings (eg, by length of time not in care, by viral load), reviewed them for accuracy, and then disseminated the listings to staff members to link PWH to HIV care and services. RESULTS: Of 16 391 PWH presumed not to be in HIV medical care, 9852 (60.1%) were selected for follow-up; of those, 4164 (42.3%) were contacted, and of those, 1479 (35.5%) were confirmed to be not in care. Of 794 (53.7%) PWH who accepted services, 694 (87.4%) were linked to HIV medical care. The Louisiana Department of Health also identified 1559 PWH as not virally suppressed, 764 (49.0%) of whom were eligible for follow-up. Of the 764 PWH who were eligible for follow-up, 434 (56.8%) were contacted, of whom 269 (62.0%) had treatment adherence issues. Of 153 PWH who received treatment adherence services, 104 (68.0%) showed substantial improvement in viral suppression. CONCLUSIONS: The 4 health departments established procedures for using surveillance and other data to improve linkage to HIV medical care and health outcomes for PWH. To be effective, health departments had to enhance coordination among surveillance, care programs, and providers; develop mechanisms to share data; and address limitations in data systems and data quality.

Perspectives of HIV Clinic Staff on the Implementation of a Client Financial Incentives Program Targeting Viral Suppression.

We present perspectives of health care providers and clinic staff on the implementation of a financial incentive program for clients living with HIV in three Louisiana clinics. Interviews were conducted in May-June 2015 with 27 clinic staff to assess their perspectives on implementation of the Health Models financial incentive program, which was initiated in September 2013. Many providers and staff welcomed the program, but some were concerned about sustainability and the ethics of a program that paid patients to receive care. Most said they eventually found the program to be helpful for patients and clinic operations in general, by facilitating partnerships between providers and patients, improving appointment keeping, providing opportunities for patient education, engaging patients in care, and helping patients form new prevention habits. The findings can improve understanding of staff and leadership perceptions of incentive programs and can inform planning and implementation of these programs in the future.

Costs and effectiveness of partner counseling and referral services with rapid testing for HIV in Colorado and Louisiana, United States.

OBJECTIVE: Health departments offer partner counseling and referral services (PCRS) to HIV-infected index patients and their partners. Point-of-care rapid HIV testing makes it possible for partners of index patients to learn their HIV serostatus in nonclinical settings. STUDY DESIGN: We assessed costs and effectiveness of PCRS with rapid HIV testing in Colorado and Louisiana (April 2004-January 2006). Colorado provided PCRS to the index patients and partners statewide; Louisiana provided PCRS to those in Baton Rouge and New Orleans. The key effectiveness measures were number of partners tested and number of partners informed of a new HIV diagnosis after rapid testing. We obtained program costs for personnel, travel, utilities, supplies, equipment, and facility space. RESULTS: Colorado identified a yearly average of 328 index patients and 253 partners and tested 43 partners. Louisiana identified a yearly average of 81 index patients and 138 partners and tested 83 partners. The rates of previously undiagnosed HIV infection among partners tested were 6.6% in Colorado and 9.9% in Louisiana. The average costs per partner tested and per partner informed of a new HIV diagnosis were $1459 and $22,243 in Colorado and $714 and $7231 in Louisiana. CONCLUSIONS: Program costs varied substantially by location. Our analysis helps program managers and health care providers to understand the resources needed for implementing the PCRS in diverse settings.