Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription.

The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.

Wealth and education-related inequalities in the utilisation of reproductive, maternal, newborn, and child health interventions within scheduled tribes in India: an analysis of Odisha and Jharkhand.

BACKGROUND: The utilisation of Reproductive, Maternal, Newborn and Child Health (RMNCH) services remains lower among the Scheduled Tribes (ST) in India than among the rest of the country's population. The tribal population's poorest and least-educated households are further denied access to RMNCH care due to the intersection of their social status, wealth, and education levels. The study analyses the wealth- and education-related inequalities in the utilisation of RMNCH services within the ST population in Odisha and Jharkhand. METHODOLOGY: We have constructed two summary measures, namely, the Co-coverage indicator and a modified Composite Coverage Index (CC), to determine wealth- and education-related inequalities in the utilisation of RMNCH indicators within the ST population in Odisha and Jharkhand. The absolute and relative inequalities with respect to wealth and education within the ST population are estimated by employing the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII). RESULTS: The results of the study highlight that access to RMNCH services is easier for women who are better educated and belong to wealthier households. The SII and RII values in the co-coverage indicator and modified CCI exhibit an increase in wealth-related inequalities in Odisha between NFHS-4 (2015-16) and NFHS-5 (2019-21) whereas in Jharkhand, the wealth- and education-related absolute and relative inequalities present a reduction between 2016 and 2021. Among the indicators, utilisation of vaccination was high, while the uptake of Antenatal Care Centre Visits and Vitamin A supplementation should be improved. INTERPRETATION: The study results underscore the urgent need of targeted policies and interventions to address the inequalities in accessing RMNCH services among ST communities. A multi-dimensional approach that considers the socioeconomic, cultural and geographical factors affecting healthcare should be adopted while formulating health policies to reduce inequalities in access to healthcare.

Variations in the prevalence of caesarean section deliveries in India between 2016 and 2021 - an analysis of Tamil Nadu and Chhattisgarh.

BACKGROUND: The prevalence of C-sections in India increased from 17.2% to 2006 to 21.5% in 2021. This study examines the variations in C-section prevalence and the factors correlating to these variations in Tamil Nadu (TN) and Chhattisgarh (CG). METHODS: Delivery by C-section as the outcome variable and several demographic, socio-economic, and clinical variables were considered as explanatory variables to draw inferences from unit-level data from the National Family Health Survey (NFHS-4; 2015-16 and NFHS-5; 2019-21). Descriptive statistics, bivariate percentage distribution, Pearson's Chi-square test, and multivariate binary logistic regression models were employed. The Slope Index of Inequality (SII) and the Concentration Index (CIX) were used to analyse absolute and relative inequality in C-section rates across wealth quintiles in public- and private-sector institutions. RESULTS: The prevalence of C-sections increased across India, TN and CG despite a decrease in pregnancy complications among the study participants. The odds of caesarean deliveries among overweight women were twice (OR = 2.11; 95% CI 1.95-2.29; NFHS-5) those for underweight women. Women aged 35-49 were also twice (OR = 2.10; 95% CI 1.92-2.29; NFHS-5) as likely as those aged 15-24 to have C-sections. In India, women delivering in private health facilities had nearly four times higher odds (OR = 3.90; 95% CI 3.74-4.06; NFHS-5) of having a C-section; in CG, the odds were nearly ten-fold (OR = 9.57; 95% CI:7.51,12.20; NFHS-5); and in TN, nearly three-fold (OR = 2.65; 95% CI-2.27-3.10; NFHS-5) compared to those delivering in public facilities. In public facilities, absolute inequality by wealth quintile in C-section prevalence across India and in CG increased in the five years until 2021, indicating that the rich increasingly delivered via C-sections. In private facilities, the gap in C-section prevalence between the poor (the bottom two quintiles) and the non-poor narrowed across India. In TN, the pattern was inverted in 2021, with an alarming 73% of the poor delivering via C-sections compared to 64% of those classified as non-poor. CONCLUSION: The type of health facility (public or private) had the most impact on whether delivery was by C-section. In India and CG, the rich are more likely to have C-sections, both in the private and in the public sector. In TN, a state with good health indicators overall, the poor are surprisingly more likely to have C-sections in the private sector. While the reasons for this inversion are not immediately evident, the implications are worrisome and pose public health policy challenges.

Development of a Choice-framework for Covid vaccines in India using a multi-criteria decision analysis approach.

BACKGROUND: Vaccines were crucial in controlling the Covid-19 pandemic. As more vaccines receive regulatory approval, stakeholders will be faced with several options and must make an appropriate choice for themselves. We proposed a multi-criteria decision analysis (MCDA) framework to guide decision-makers in comparing vaccines for the Indian context. METHODS: We adhered to the ISPOR guidance for the MCDA process. Seven vaccine options were compared under ten criteria. Through three virtual workshops, we obtained opinions and weights from citizens, private-sector hospitals, and public health organisations. Available evidence was rescaled and incorporated into the performance matrix. The final score for each vaccine was calculated for the different groups. We performed different sensitivity analyses to assess the consistency of the rank list. RESULTS: The cost, efficacy and operational score of the vaccines had the highest weights among the stakeholders. From the six scenario groups, Janssen had the highest score in four. This was driven by the advantage of having a single dose of vaccination. In the probabilistic sensitivity analysis for the overall group, Covaxin, Janssen, and Sputnik were the first three options. The participants expressed that availability, WHO approvals and safety, among others, would be crucial when considering vaccines. CONCLUSIONS: The MCDA process has not been capitalised on in healthcare decision-making in India and LMICs. Considering the available data and stakeholder preference at the time of the study, Covaxin, Janssen, and Sputnik were preferred options. The choice framework with the dynamic performance matrix is a valuable tool that could be adapted to different population groups and extended based on increasing vaccine options and emerging evidence. *ISPOR - The Professional Society for Health Economics and Outcomes Research.

Economic and Societal Impact of a Systems-of-Care Approach for STEMI Management in Low and Middle-Income Countries: Insights from the TN STEMI Program.

The TN STEMI Program was a multicenter, prospective, observational study conducted in Tamil Nadu, India, that assessed the effects of implementing the STEMI India Model for the management of STEMI. We discuss the economic and societal impact in this article. Given that the intervention resulted in an absolute mortality reduction of 3.4%, we calculated a number needed to treat of 30 patients. At an annualized project cost of INR 15.11 million, this approximately calculates to INR 193,749 (USD 3,311) per life saved. The utility of the TN-STEMI Program can be estimated to be 1,108 life-years. This calculates to approximately INR 13,643 (USD 233) per life-year saved. Our estimates will likely be of particular interest to policy makers in low and middle-income countries, where financial and resource constraints pose a perennial public health challenge.