The Determination of Diabetes Utilities, Costs, and Effects Model: A Cost-Utility Tool Using Patient-Level Microsimulation to Evaluate Sensor-Based Glucose Monitoring Systems in Type 1 and Type 2 Diabetes: Comparative Validation.

OBJECTIVES: To assess the accuracy and validity of the Determination of Diabetes Utilities, Costs, and Effects (DEDUCE) model, a Microsoft-Excel-based tool for evaluating diabetes interventions for type 1 and type 2 diabetes. METHODS: The DEDUCE model is a patient-level microsimulation, with complications predicted based on the Sheffield and Risk Equations for Complications Of type 2 diabetes models for type 1 and type 2 diabetes, respectively. For this tool to be useful, it must be validated to ensure that its complication predictions are accurate. Internal, external, and cross-validation was assessed by populating the DEDUCE model with the baseline characteristics and treatment effects reported in clinical trials used in the Fourth, Fifth, and Ninth Mount Hood Diabetes Challenges. Results from the DEDUCE model were evaluated against clinical results and previously validated models via mean absolute percentage error or percentage error. RESULTS: The DEDUCE model performed favorably, predicting key outcomes, including cardiovascular disease in type 1 diabetes and all-cause mortality in type 2 diabetes. The model performed well against other models. In the Mount Hood 9 Challenge comparison, error was below the mean reported from comparator models for several outcomes, particularly for hazard ratios. CONCLUSIONS: The DEDUCE model predicts diabetes-related complications from trials and studies well when compared with previously validated models. The model may serve as a useful tool for evaluating the cost-effectiveness of diabetes technologies.

Indirect treatment comparisons of the gene therapy etranacogene dezaparvovec versus extended half-life factor IX therapies for severe or moderately severe haemophilia B.

INTRODUCTION: Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6-month lead-in period of prophylaxis with FIX products in the phase 3 trial, HOPE-B. In the absence of head-to-head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used. AIM: To compare the efficacy of etranacogene dezaparvovec versus rIX-FP, rFIXFc and N9-GP using ITC, and support HOPE-B results. METHODS: Data were leveraged from Phase 3 pivotal trials: HOPE-B, PROLONG-9FP, B-LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons. RESULTS: Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX-FP were 0.19 (p < .0001), 0.08 (p < .0001) and 0.09 (p < .0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p < .0001), 0.13 (p = .0083) and 0.15 (p = .0111), respectively. Rate ratios for ABR and AsBR, versus N9-GP were 0.24 (p = .0231) and 0.13 (p = .0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX-FP and rFIXFc; odds ratios: 17.60 (p < .0001) and 5.65 (p = .0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators. CONCLUSIONS: ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies.

Benefits of fracture liaison services (FLS) in four Latin American countries: Brazil, Mexico, Colombia, and Argentina.

AIMS: Fracture liaison services (FLS) use a multidisciplinary approach to treat patients who have experienced an osteoporotic fracture to reduce the risk of subsequent fractures. To date, there has been minimal FLS implementation in Latin America where fractures continue to be undertreated. This study aims to estimate the number of fractures averted, bed days avoided, and costs saved resulting from universal FLS implementation in Brazil, Mexico, Colombia, and Argentina. MATERIALS AND METHODS: A calculator was developed to estimate the annual benefits of FLS programs in Brazil, Mexico, Colombia, and Argentina from a public hospital perspective. It was assumed all patients with a hip, vertebral, or wrist fracture were referred to an FLS program. Country-specific data were obtained from a previous systematic review and interviews with osteoporosis experts. Hospitalization and post-hospitalization costs were expressed in 2019 USD without discounting. Costs of FLS implementation were not considered. RESULTS: In 2019, the number of FLS patients prevented from having a subsequent hip, vertebral, or wrist fracture was estimated as 15,607 in Brazil, 8,168 in Mexico, 5,190 in Argentina, and 2,435 in Colombia with total bed days saved of 142,378 in Brazil, 75,877 in Mexico, 52,301 in Argentina, and 21,725 in Colombia. The annual cost savings in 2019 were highest in Argentina (28.1 million USD), followed by Mexico (19.6 million USD), Brazil (7.64 million USD) and Colombia (3.04 million USD). Over five years (2019-2023) the cumulative cost savings were 145 million USD in Argentina, 106 million USD in Mexico, 40.5 million USD in Brazil, and 16.1 million USD in Colombia. CONCLUSION: Universal FLS implementation in Brazil, Mexico, Colombia, and Argentina was predicted to prevent 31,400 fractures, avoid 292,281 bed days, and save 58.4 million USD in 2019, though caution is warranted in the interpretation of these results due to high uncertainty. Increased implementation of FLS programs in Latin American countries may help to realize these benefits.

The burden of osteoporosis in four Latin American countries: Brazil, Mexico, Colombia, and Argentina.

Objective: Osteoporosis is under-diagnosed and under-treated worldwide. Information on the burden of osteoporosis in Latin American countries is limited. This study aimed to estimate the economic burden of osteoporosis in adults aged 50-89 years in Brazil, Mexico, Colombia, and Argentina. Methods: Analyses were conducted using a burden of illness model. Where possible, country-specific model inputs were informed by a systematic review and expert opinion. Osteoporosis-related fracture costs were calculated for hospitalizations, testing, surgeries, prescription drugs, and patient productivity losses. Costs were expressed in 2018 USD for the annual burden, annual burden per 1,000 at risk, and projected 5-year burden. No discounting was applied. Results: Over 840,000 osteoporosis-related fractures were predicted to occur in 2018, amounting to a total annual cost of ∼1.17 billion USD. The total projected 5-year cost was ∼6.25 billion USD. Annual costs were highest in Mexico (411 million USD), followed by Argentina (360 million USD), Brazil (310 million USD), and Colombia (94 million USD). The average burden per 1,000 at risk was greatest in Argentina (32,583 USD), followed by Mexico (16,671 USD), Colombia (8,240 USD), and Brazil (6,130 USD). Conclusions: Over the next 5 years, ∼4,485,352 fractures are anticipated to occur in Brazil, Mexico, Colombia, and Argentina. To control and prevent these fractures, stakeholders must work together to close the care gap. Efforts to identify individuals at high fracture risk, initiate treatment, and improve long-term treatment persistence will be essential in minimizing the financial and patient burden of osteoporosis in Latin America.

Conserved Pbp1/Ataxin-2 regulates retrotransposon activity and connects polyglutamine expansion-driven protein aggregation to lifespan-controlling rDNA repeats.

Ribosomal DNA (rDNA) repeat instability and protein aggregation are thought to be two major and independent drivers of cellular aging. Pbp1, the yeast ortholog of human ATXN2, maintains rDNA repeat stability and lifespan via suppression of RNA-DNA hybrids. ATXN2 polyglutamine expansion drives neurodegeneration causing spinocerebellar ataxia type 2 and promoting amyotrophic lateral sclerosis. Here, molecular characterization of Pbp1 revealed that its knockout or subjection to disease-modeling polyQ expansion represses Ty1 (Transposons of Yeast) retrotransposons by respectively promoting Trf4-depedendent RNA turnover and Ty1 Gag protein aggregation. This aggregation, but not its impact on retrotransposition, compromises rDNA repeat stability and shortens lifespan by hyper-activating Trf4-dependent turnover of intergenic ncRNA within the repeats. We uncover a function for the conserved Pbp1/ATXN2 proteins in the promotion of retrotransposition, create and describe powerful yeast genetic models of ATXN2-linked neurodegenerative diseases, and connect the major aging mechanisms of rDNA instability and protein aggregation.

Non-coding RNA in neural function, disease, and aging.

Declining brain and neurobiological function is arguably one of the most common features of human aging. The study of conserved aging processes as well as the characterization of various neurodegenerative diseases using different genetic models such as yeast, fly, mouse, and human systems is uncovering links to non-coding RNAs. These links implicate a variety of RNA-regulatory processes, including microRNA function, paraspeckle formation, RNA-DNA hybrid regulation, nucleolar RNAs and toxic RNA clearance, amongst others. Here we highlight these connections and reveal over-arching themes or questions related to recently appreciated roles of non-coding RNA in neural function and dysfunction across lifespan.

Roles for Pbp1 and caloric restriction in genome and lifespan maintenance via suppression of RNA-DNA hybrids.

Intergenic transcription within repetitive loci such as the ribosomal DNA (rDNA) repeats of yeast commonly triggers aberrant recombination. Major mechanisms suppressing aberrant rDNA recombination rely on chromatin silencing or RNAPII repression at intergenic spacers within the repeats. We find ancient processes operating at rDNA intergenic spacers and other loci to maintain genome stability via repression of RNA-DNA hybrids. The yeast Ataxin-2 protein Pbp1 binds noncoding RNA, suppresses RNA-DNA hybrids, and prevents aberrant rDNA recombination. Repression of RNA-DNA hybrids in Pbp1-deficient cells through RNaseH overexpression, deletion of the G4DNA-stabilizing Stm1, or caloric restriction operating via RNaseH/Pif1 restores rDNA stability. Pbp1 also limits hybrids at non-rDNA G4DNA loci including telomeres. Moreover, cells lacking Pbp1 have a short replicative lifespan that is extended upon hybrid suppression. Thus, we find roles for Pbp1 in genome maintenance and reveal that caloric restriction counteracts Pbp1 deficiencies by engaging RNaseH and Pif1.

The fine line between lifespan extension and shortening in response to caloric restriction.

Caloric restriction (CR) is generally linked to lifespan extension in various organisms and may limit age-associated diseases. Processes through which caloric restriction promotes lifespan include obesity-countering weight loss, increased DNA repair, control of ribosomal and telomeric DNA repeats, mitochondrial regulation, activation of antioxidants, and protective autophagy. Several of these protective cellular processes are linked to the suppression of TOR (target of rapamycin) or the activation of sirtuins. In stark contrast, CR fails to extend or even shortens lifespan in certain settings. CR-dependent lifespan shortening is linked to weight loss in the non-obese, mitochondrial hyperactivity, genomic inflexibility, and several other processes. Deciphering the balance between positive and negative effects of CR is critical to understanding its ultimate impact on aging. This knowledge is especially needed in order to fulfil the promise of using CR or its mimetic drugs to counteract age-associated diseases and unhealthy aging.