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Protocol for the economic evaluation alongside the PARTICIPATE (PArticipatory Research model for medicaTIon adherenCe In People with diAbetes and hyperTEnsion) multicenter cluster randomized trial

Por: John · D. · Reddy · P. · Jha · A. · Gupta · H. · Verma · V. · Kumar · D. · Bansal · A. K. · Mahapatra · S. · Rehman · T. · Parida · S. K. · Jena · M. · Pon Ruban · A. C. · Kalyanaraman · S. · Sunitha · K. · Cherian · J. J. · Anand · T.
Introduction

Using the community-based participatory research (CBPR) methodology, sustained peer group treatment has effectively improved medication adherence. Although many studies investigate the effectiveness of peer group therapy, there is a lack of evidence addressing the cost-effectiveness of CBPR models in low- and middle-income countries. This protocol outlines the methods for the economic evaluation of the PArticipatory Research model for medicaTIon adherenCe In People with diAbetes and hyperTEnsion (PARTICIPATE) trial to determine whether the CBPR approach to enhance medication adherence among patients with diabetes and/or hypertension is cost-effective in India.

Methods and analysis

A within-trial cost-effectiveness analysis (CEA) from a societal perspective will be conducted alongside a multicentre cluster randomised controlled trial to identify, measure and evaluate the key resource and outcome impacts of a CBPR model compared with usual care aimed at improving medication adherence in adult rural Indian patients with diabetes and/or hypertension. The CEA will provide results in terms of the cost per improvement in medication adherence score, and a cost-utility analysis (CUA) will express the findings as the cost per disability-adjusted life year (DALY) or quality-adjusted life year (QALY) gained. Intervention costs and effects will be projected for the population of Indian adults with diabetes and/or hypertension who are on medication, analysed over the cohort’s lifetime. Results from the modelled CUA will detail incremental costs, costs per death averted and costs per DALY averted/QALY gained for the interventions relative to the comparator. Incremental cost-effectiveness ratios will be computed by dividing the cost difference between the intervention and comparator by the difference in benefits. Health economic evaluation methods, including a lifetime horizon, a 3% discount rate for costs and benefits and a societal perspective, will be followed. The effects of sampling uncertainty on estimated incremental costs and effectiveness parameters, as well as the influence of methodological assumptions (such as the discount rate and study perspective), will be examined through both deterministic and probabilistic sensitivity analyses. Relevant differences in costs, outcomes or cost-effectiveness disparities among subgroups of patients with varying baseline characteristics will also be reported. Results will be illustrated using cost-effectiveness acceptability curves across a range of willingness-to-pay thresholds. Modelled CUA will broaden the target population and time frame to offer decision-makers insights into the cost-effectiveness of the CBPR approach for enhancing medication adherence. Furthermore, a return on investment analysis will be performed to express benefits in monetary terms relative to investments made, allowing for a comprehensive expression of both costs and the full spectrum of intervention benefits in monetary units.

Ethics and dissemination

The Institutional Ethics Committee of Sri Aurobindo Medical College and PGI, Indore, provided ethics approval. The results of the main trial and economic evaluation will be submitted for publication in a peer-reviewed journal and disseminated through reports to Indian Council of Medical Research and conference presentations.

Trial registration number

Clinical Trial Registry of India (CTRI) CTRI/2024/01/061939.

The histone deacetylase inhibitor CT-101 flips the switch to fetal hemoglobin expression in sickle cell disease mice

by Mayuko Takezaki, Biaoru Li, Hongyan Xu, Nikhil Patel, Rudolf Lucas, Ryan E. Cerbone, Sivanagireddy Koti, Clifford L. Hendrick, Louis H. Junker, Betty S. Pace

The most common hemoglobin disorder worldwide is sickle cell disease (SCD) caused by a point mutation in the adult β-globin gene. As a result, hemoglobin S production occurs leading to clinical symptoms including vaso-occlusive pain, organ damage, and a shortened lifespan. Hydroxyurea is the only FDA-approved fetal hemoglobin (HbF) inducer in the United States that ameliorates the clinical severity of SCD. Due to challenges with hydroxyurea, our study aimed to address the unmet need for the development of non-chemotherapeutic HbF inducers. We investigated the ability of CT-101, a Class 1 histone deacetylase inhibitor, to flip the γ-globin to β-globin switch in a humanized SCD mouse model. Pharmacokinetic parameters were assessed in CD-1 and Townes SCD mice after a single intraperitoneal drug dose. Similar drug uptake and half-life were observed in both animals. Subsequent studies in β-YAC mice expressing human γ-globin and β-globin genes established the optimal dose of CT-101 that induces HbF without peripheral blood toxicity. Subsequent confirmatory studies were conducted in the SCD mouse treated with intraperitoneal CT-101, demonstrating increases in F-cells, HbF, and γ-globin gene mRNA levels. Hydroxyurea combined with CT-101 significantly decreased spleen size and hemorrhagic infarcts and improved splenic extramedullary hematopoiesis. Our novel agent, CT-101, flipped the switch by activating γ-globin gene transcription and HbF protein synthesis in the preclinical SCD mouse model without significant toxicity in the peripheral blood. These findings support the development of an oral CT-101 formulation for clinical testing in SCD.

Deciphering the dose-dependent effects of thymoquinone on cellular proliferation and transcriptomic changes in A172 glioblastoma cells

by Rachana Pandey, Purushothaman Natarajan, Umesh K. Reddy, Wei Du, Cristian Sirbu, Moussa Sissoko, Gerald R. Hankins

Glioblastoma multiforme (GBM), the most prevalent primary malignant brain tumor in adults, exhibits a dismal 6.9% five-year survival rate post-diagnosis. Thymoquinone (TQ), the most abundant bioactive compound in Nigella sativa, has been extensively researched for its anticancer properties across various human cancers. However, its specific anti-cancer mechanisms and pathways in glioblastoma remain to be completely elucidated. In this study, we assessed the impact of different TQ concentrations on the viability of A172 cells using WST-8 and Toluidine blue assays, followed by RNA sequencing (RNA-Seq) to identify differentially expressed genes (DEGs). We confirmed their expression levels through quantitative RT-PCR and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. RNA-seq revealed no significant gene expression changes at 2.5 μM and 5 μM TQ concentrations. However, at 25 μM and 50 μM, TQ significantly reduced cell viability dose-dependently. We identified 1548 DEGs at 25 μM TQ (684 up-regulated, 864 down-regulated) and 2797 DEGs at 50 μM TQ (1528 up-regulated, 1269 downregulated), with 1202 DEGs common to both concentrations. TQ inhibited key pathways such as PI3K-Akt signaling, calcium signaling, focal adhesion, and ECM-receptor interaction in A172 cells. It downregulated several potential oncogenes (e.g., AEBP1, MIAT) and genes linked to GBM proliferation and migration (e.g., SOCS2, HCP5) while modulating Wnt signaling and up-regulating tumor suppressor genes (e.g., SPRY4, BEX2). TQ also affected p53 downstream targets, maintaining p53 levels. This study elucidates the anti-cancer mechanisms of TQ in A172 GBM cells, underscoring its effects on multiple signaling pathways and positioning TQ as a promising candidate for innovative glioblastoma treatment strategies.

Association of Gut Microbiota With Fatigue in Black Women With Polycystic Ovary Syndrome

imageBackground Fatigue is a highly prevalent symptom for individuals with polycystic ovary syndrome (PCOS); however, characterization of fatigue and investigation into the gut microbiome—a pathway that may contribute to fatigue—remains inadequately explored in Black women with PCOS. Objectives The purpose of this cross-sectional study was to examine fatigue and its relationship to the gut microbiome in adult Black women with PCOS. Methods Adult Black women with a diagnosis of PCOS were recruited for this cross-sectional study. The Multidimensional Fatigue Inventory-20 (MFI-20) and the PROMIS Fatigue Short Form were used to measure fatigue. The V3/V4 region of the bacterial 16S rRNA gene was sequenced to investigate gut microbial composition. Relative abundance and diversity values were calculated. Results We found that Black women with PCOS experience mild to moderate levels of fatigue. An inverse relationship between fatigue scores and alpha diversity values was found for the gut microbiome. We also found distinct beta diversity profiles based on fatigue. Lastly, when controlling for hypertension and body mass index, Ruminococcus bromii, Blautia obeum, Roseburia, and HT002 were associated with three subscales of the MFI-20. Discussion Black women with PCOS experience mild to moderate fatigue. Clinicians should be cognizant of this population’s increased risk for fatigue to adequately address their healthcare needs. We also found that gut microbial composition was associated with fatigue in Black women with PCOS. Specifically, a higher relative abundance of certain gut bacteria involved in short-chain fatty acid production and anti-inflammatory pathways was correlated with lower fatigue levels. Future studies should further investigate the link between the gut microbiome and fatigue to determine whether this relationship is causal as better insight could inform tailored diet and exercise interventions to alter the gut microbiome and reduce fatigue.
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