Relational and individual stress pathways linking discrimination and ageing cardiometabolic health.

Perceived discrimination is a significant risk factor for worse ageing health outcomes. Yet, the specific individual and relational stress pathways linking discrimination to disease are less understood, especially in the context of cardiometabolic health. We tested family stress and psychophysiological distress (negative affect and high-risk lipid/fat metabolism) as mediators linking perceived discrimination to cardiometabolic morbidity and health appraisal over 20 years for midlife adults. Using data from participants who completed the Biomarker Project (2004-2009) of the Midlife in the U.S. project, and examining data over the study's three waves (1995-1996, 2004-2006, and 2013-2014), we used structural equation modelling to test pathways for participants who reported zero cardiometabolic conditions at baseline (n = 799). Greater Time 1 discrimination was associated with greater Time 2 family strain, which was in turn associated with worse negative affect; worse Time 2 negative affect was associated with worse Time 3 health appraisal; metabolic lipids risk did not serve as an indirect pathway to Time 3 cardiometabolic morbidity (χ2  = 147.74, p < 0.001; RMSEA = 0.056; CFI = 0.902; SRMR = 0.047). The inclusion of family in interventions to mitigate the impact of discrimination may be indicated for promoting cardiometabolic wellness.

First and second doses of Covishield vaccine provided high level of protection against SARS-CoV-2 infection in highly transmissible settings: results from a prospective cohort of participants residing in congregate facilities in India.

OBJECTIVES: This study aimed to determine the effectiveness of Covishield vaccine among residents of congregate residential facilities. DESIGN: A prospective cohort study in congregate residential facilities. SETTING: Dharamshala, Himachal Pradesh, India, from December 2020 to July 2021. PARTICIPANTS: Residents of all ages in seven facilities-three monasteries, two old age homes and two learning centres-were enrolled. EXPOSURES: First and second doses of Covishield vaccine against SARS-CoV-2 infection. MAIN OUTCOMES MEASURES: Primary outcome was development of COVID-19. Secondary outcome was unfavourable outcomes, defined as a composite of shortness of breath, hospitalisation or death. Vaccine effectiveness (%) was calculated as (1-HR)×100. RESULTS: There were 1114 residents (median age 31 years) participating in the study, 82% males. Twenty-eight per cent (n=308/1114) were unvaccinated, 50% (n=554/1114) had received one dose and 23% (n=252/1114) had received two doses of Covishield. The point prevalence of COVID-19 for the facilities ranged from 11% to 57%. Incidence rates (95% CI) of COVID-19 were 76 (63 to 90)/1000 person-months in the unvaccinated, 25 (18 to 35)/1000 person-months in recipients of one dose and 9 (4 to 19)/1000 person-months in recipients of two doses. The effectiveness of first and second doses of Covishield were 71% (adjusted HR (aHR) 0.29; 95% CI 0.18 to 0.46; p<0.001) and 80% (aHR 0.20; 95% CI 0.09 to 0.44; p<0.001), respectively, against SARS-CoV-2 infection and 86% (aHR 0.24; 95% CI 0.07 to 0.82; p=0.023) and 99% (aHR 0.01; 95% CI 0.002 to 0.10; p<0.001), respectively, against unfavourable outcome. The effectiveness was higher after 14 days of receiving the first and second doses, 93% and 98%, respectively. Risk of infection was higher in persons with chronic hepatitis B (aHR 1.78; p=0.034) and previous history of tuberculosis (aHR 1.62; p=0.047). CONCLUSION: Covishield was effective in preventing SARS-CoV-2 infection and reducing disease severity in highly transmissible settings during the second wave of the pandemic driven by the Delta variant.

72-year-old man • fever • new-onset urinary frequency • altered mental state • Dx?

► Fever ► New-onset urinary frequency ► Altered mental state.

Risk of developing active tuberculosis following tuberculosis screening and preventive therapy for Tibetan refugee children and adolescents in India: An impact assessment.

BACKGROUND: Tuberculosis (TB) rates among Tibetan refugee children and adolescents attending boarding schools in India are extremely high. We undertook a comprehensive case finding and TB preventive treatment (TPT) program in 7 schools in the Zero TB Kids project. We aimed to measure the TB infection and disease burden and investigate the risk of TB disease in children and adults who did and did not receive TPT in the schools. METHODS AND FINDINGS: A mobile team annually screened children and staff for TB at the 7 boarding schools in Himachal Pradesh, India, using symptom criteria, radiography, molecular diagnostics, and tuberculin skin tests. TB infection (TBI) was treated with short-course regimens of isoniazid and rifampin or rifampin. TB disease was treated according to Tibetan and Indian guidelines. Between April 2017 and December 2019, 6,582 schoolchildren (median age 14 [IQR 11-16] years) and 807 staff (median age 40 [IQR 33-48] years) were enrolled. Fifty-one percent of the students and 58% of the staff were females. Over 13,161 person-years of follow-up in schoolchildren (median follow-up 2.3 years) and 1,800 person-years of follow-up in staff (median follow-up 2.5 years), 69 TB episodes occurred in schoolchildren and 4 TB episodes occurred in staff, yielding annual incidence rates of 524/100,000 (95% CI 414-663/100,000) person-years and 256/100,000 (95% CI 96-683/100,000) person-years, respectively. Of 1,412 schoolchildren diagnosed with TBI, 1,192 received TPT. Schoolchildren who received TPT had 79% lower risk of TB disease (adjusted hazard ratio [aHR] 0.21; 95% CI 0.07-0.69; p = 0.010) compared to non-recipients, the primary study outcome. Protection was greater in recent contacts (aHR 0.07; 95% CI 0.01-0.42; p = 0.004), the secondary study outcome. The prevalence of recent contacts was 28% (1,843/6,582). Two different TPT regimens were used (3HR and 4R), and both were apparently effective. No staff receiving TPT developed TB. Overall, between 2017 and 2019, TB disease incidence decreased by 87%, from 837/100,000 (95% CI 604-1,129/100,000) person-years to 110/100,000 (95% CI 36-255/100,000) person-years (p < 0.001), and TBI prevalence decreased by 42% from 19% (95% CI 18%-20%) to 11% (95% CI 10%-12%) (p < 0.001). A limitation of our study is that TB incidence could be influenced by secular trends during the study period. CONCLUSIONS: In this study, following implementation of a school-wide TB screening and preventive treatment program, we observed a significant reduction in the burden of TB disease and TBI in children and adolescents. The benefit of TPT was particularly marked for recent TB contacts. This initiative may serve as a model for TB detection and prevention in children and adolescents in other communities affected by TB.

High Prevalence of Active and Latent Tuberculosis in Children and Adolescents in Tibetan Schools in India: The Zero TB Kids Initiative in Tibetan Refugee Children.

BACKGROUND: Tuberculosis (TB) prevalence is high among Tibetan refugees in India, with almost half of cases occurring in congregate facilities, including schools. A comprehensive program of TB case finding and treatment of TB infection (TBI) was undertaken in schools for Tibetan refugee children. METHODS: Schoolchildren and staff in Tibetan schools in Himachal Pradesh, India, were screened for TB with an algorithm using symptoms, chest radiography, molecular diagnostics, and tuberculin skin testing. Individuals with active TB were treated and those with TBI were offered isoniazid-rifampicin preventive therapy for 3 months. RESULTS: From April 2017 to March 2018, we screened 5391 schoolchildren (median age, 13 years) and 786 staff in 11 Tibetan schools. Forty-six TB cases, including 1 with multidrug resistance, were found in schoolchildren, for a prevalence of 853 per 100 000. Extensively drug-resistant TB was diagnosed in 1 staff member. The majority of cases (66%) were subclinical. TBI was detected in 930 of 5234 (18%) schoolchildren and 334 of 634 (53%) staff who completed testing. Children in boarding schools had a higher prevalence of TBI than children in day schools (915/5020 [18%] vs 15/371 [4%]; P < .01). Preventive therapy was provided to 799 of 888 (90%) schoolchildren and 101 of 332 (30%) staff with TBI; 857 (95%) people successfully completed therapy. CONCLUSIONS: TB prevalence is extremely high among Tibetan schoolchildren. Effective active case finding and a high uptake and completion of preventive therapy for children were achieved. With leadership and community mobilization, TB control is implementable on a population level.

Novel CARM1-Interacting Protein, DZIP3, Is a Transcriptional Coactivator of Estrogen Receptor-α.

Coactivator-associated arginine methyltransferase 1 (CARM1) is known to promote estrogen receptor (ER)α-mediated transcription in breast cancer cells. To further characterize the regulation of ERα-mediated transcription by CARM1, we screened CARM1-interacting proteins by yeast two-hybrid. Here, we have identified an E3 ubiquitin ligase, DAZ (deleted in azoospermia)-interacting protein 3 (DZIP3), as a novel CARM1-binding protein. DZIP3-dependent ubiquitination of histone H2A has been associated with repression of transcription. However, ERα reporter gene assays demonstrated that DZIP3 enhanced ERα-mediated transcription and cooperated synergistically with CARM1. Interaction with CARM1 was observed with the E3 ligase RING domain of DZIP3. The methyltransferase activity of CARM1 partially contributed to the synergy with DZIP3 for transcription activation, but the E3 ubiquitin ligase activity of DZIP3 was dispensable. DZIP3 also interacted with the C-terminal activation domain 2 of glucocorticoid receptor-interacting protein 1 (GRIP1) and enhanced the interaction between GRIP1 and CARM1. Depletion of DZIP3 by small interfering RNA in MCF7 cells reduced estradiol-induced gene expression of ERα target genes, GREB1 and pS2, and DZIP3 was recruited to the estrogen response elements of the same ERα target genes. These results indicate that DZIP3 is a novel coactivator of ERα target gene expression.