Thymic epithelial organoids mediate T-cell development.

Although the advent of organoids has opened unprecedented perspectives for basic and translational research, immune system-related organoids remain largely underdeveloped. Here, we established organoids from the thymus, the lymphoid organ responsible for T-cell development. We identified conditions enabling mouse thymic epithelial progenitor cell proliferation and development into organoids with diverse cell populations and transcriptional profiles resembling in vivo thymic epithelial cells (TECs) more closely than traditional TEC cultures. In contrast to these two-dimensional cultures, thymic epithelial organoids maintained thymus functionality in vitro and mediated physiological T-cell development upon reaggregation with T-cell progenitors. The reaggregates showed in vivo-like epithelial diversity and the ability to attract T-cell progenitors. Thymic epithelial organoids are the first organoids originating from the stromal compartment of a lymphoid organ. They provide new opportunities to study TEC biology and T-cell development in vitro, paving the way for future thymic regeneration strategies in ageing or acute injuries.

Patient-derived mini-colons enable long-term modeling of tumor-microenvironment complexity.

Existing organoid models fall short of fully capturing the complexity of cancer because they lack sufficient multicellular diversity, tissue-level organization, biological durability and experimental flexibility. Thus, many multifactorial cancer processes, especially those involving the tumor microenvironment, are difficult to study ex vivo. To overcome these limitations, we herein implemented tissue-engineering and microfabrication technologies to develop topobiologically complex, patient-specific cancer avatars. Focusing on colorectal cancer, we generated miniature tissues consisting of long-lived gut-shaped human colon epithelia ('mini-colons') that stably integrate cancer cells and their native tumor microenvironment in a format optimized for real-time, high-resolution evaluation of cellular dynamics. We demonstrate the potential of this system through several applications: a comprehensive evaluation of drug effectivity, toxicity and resistance in anticancer therapies; the discovery of a mechanism triggered by cancer-associated fibroblasts that drives cancer invasion; and the identification of immunomodulatory interactions among different components of the tumor microenvironment. Similar approaches should be feasible for diverse tumor types.

Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo.

Three-dimensional organoid culture technologies have revolutionized cancer research by allowing for more realistic and scalable reproductions of both tumour and microenvironmental structures1-3. This has enabled better modelling of low-complexity cancer cell behaviours that occur over relatively short periods of time4. However, available organoid systems do not capture the intricate evolutionary process of cancer development in terms of tissue architecture, cell diversity, homeostasis and lifespan. As a consequence, oncogenesis and tumour formation studies are not possible in vitro and instead require the extensive use of animal models, which provide limited spatiotemporal resolution of cellular dynamics and come at a considerable cost in terms of resources and animal lives. Here we developed topobiologically complex mini-colons that are able to undergo tumorigenesis ex vivo by integrating microfabrication, optogenetic and tissue engineering approaches. With this system, tumorigenic transformation can be spatiotemporally controlled by directing oncogenic activation through blue-light exposure, and emergent colon tumours can be tracked in real-time at the single-cell resolution for several weeks without breaking the culture. These induced mini-colons display rich intratumoural and intertumoural diversity and recapitulate key pathophysiological hallmarks displayed by colorectal tumours in vivo. By fine-tuning cell-intrinsic and cell-extrinsic parameters, mini-colons can be used to identify tumorigenic determinants and pharmacological opportunities. As a whole, our study paves the way for cancer initiation research outside living organisms.

The Cost of Seasonal Influenza: A Systematic Literature Review on the Humanistic and Economic Burden of Influenza in Older (≥ 65 Years Old) Adults.

INTRODUCTION: Adults aged ≥ 65 years contribute a large proportion of influenza-related hospitalizations and deaths due to increased risk of complications, which result in high medical costs and reduced health-related quality of life (HRQoL). Although seasonal influenza vaccines are recommended for older adults, the effectiveness of current vaccines is dependent on several factors including strain matching and recipient demographic factors. This systemic literature review aimed to explore the economic and humanistic burden of influenza in adults aged ≥ 65 years. METHODS: An electronic database search was conducted to identify studies assessing the economic and humanistic burden of influenza, including influenza symptoms that impact the HRQoL and patient-related outcomes in adults aged ≥ 65 years. Studies were to be published in English and conducted in Germany, France, Spain, and Italy, the UK, USA, Canada, China, Japan, Brazil, Saudi Arabia, and South Africa. RESULTS: Thirty-eight studies reported on the economic and humanistic burden of influenza in adults aged ≥ 65 years. Higher direct costs were reported for people at increased risk of influenza-related complications compared to those at low risk. Lower influenza-related total costs were found in those vaccinated with adjuvanted inactivated trivalent influenza vaccine (aTIV) compared to high-dose trivalent influenza vaccine (TIV-HD). Older age was associated with an increased occurrence and longer duration of certain influenza symptoms. CONCLUSION: Despite the limited data identified, results show that influenza exerts a high humanistic and economic burden in older adults. Further research is required to confirm findings and to identify the unmet needs of current vaccines.

An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming.

Advanced strategies to interconvert cell types provide promising avenues to model cellular pathologies and to develop therapies for neurological disorders. Yet, methods to directly transdifferentiate somatic cells into multipotent induced neural stem cells (iNSCs) are slow and inefficient, and it is unclear whether cells pass through a pluripotent state with full epigenetic reset. We report iNSC reprogramming from embryonic and aged mouse fibroblasts as well as from human blood using an engineered Sox17 (eSox17FNV). eSox17FNV efficiently drives iNSC reprogramming while Sox2 or Sox17 fail. eSox17FNV acquires the capacity to bind different protein partners on regulatory DNA to scan the genome more efficiently and has a more potent transactivation domain than Sox2. Lineage tracing and time-resolved transcriptomics show that emerging iNSCs do not transit through a pluripotent state. Our work distinguishes lineage from pluripotency reprogramming with the potential to generate more authentic cell models for aging-associated neurodegenerative diseases.

Understanding the Global Burden of Influenza in Adults Aged 18-64 years: A Systematic Literature Review from 2012 to 2022.

INTRODUCTION: Adults aged 18-64 years comprise most of the working population, meaning that influenza infection can be disruptive, causing prolonged absence from the workplace, and reduced productivity and the ability to care for dependents. Influenza vaccine uptake is relatively low, even among the older adults in this population (i.e., aged 50-64 years), reflecting a lack of perceived need for vaccination. This systematic literature review (SLR) aimed to characterize the global burden of influenza in the 18-64 years population. METHODS: An electronic database search was conducted and supplemented with conference and gray literature searches. Eligible studies described at least one of clinical, humanistic, or economic outcomes in adults aged 18-64 years and conducted across several global regions. Included studies were published in English, between January 1, 2012, and September 20, 2022. RESULTS: A total of 40 publications were included, with clinical, humanistic, and economic outcomes reported in 39, 5, and 15, respectively. Risk of influenza-associated clinical outcomes were reported to increase with age among the 18-64 years population, including hospitalizations (Yamana et al. in Intern Med 60:3401-3408, 2021; Derqui et al. in Influenza Other Respir Viruses 16:862-872, 2022; Fuller et al. in Influenza Other Respir Viruses 16:265-275, 2022; Ortiz et al. in Crit Care Med 42:2325-2332, 2014; Yandrapalli et al. in Ann Transl Med 6:318, 2018; Zimmerman et al. in Influenza Other Respir Viruses 16:1133-1140, 2022). ICU admissions, mortality, ER/outpatient visits, and use of mechanical ventilation were recorded. Adults aged 18-64 years with underlying comorbidities were at higher risk of influenza-related hospitalizations, ICU admission, and mortality than otherwise healthy individuals. Length of hospital stay increased with age, although a lack of stratification across other economic outcomes prevented identification of further trends across age groups. CONCLUSIONS: High levels of hospitalization and outpatient visits demonstrated a clinical influenza-associated burden on patients and healthcare systems, which is exacerbated by comorbidities. Considering the size and breadth of the general population aged 18-64 years, the limited humanistic and economic findings of this SLR likely reflect an underreported burden. Greater investigation into indirect costs and prolonged absenteeism associated with influenza infection is required to fully understand the economic burden in this population.

High Clinical Burden of Influenza Disease in Adults Aged ≥ 65 Years: Can We Do Better? A Systematic Literature Review.

INTRODUCTION: Influenza is a respiratory infection associated with a significant clinical burden globally. Adults aged ≥ 65 years are at increased risk of severe influenza-related symptoms and complications due to chronic comorbidity and immunosenescence. Annual influenza vaccination is recommended; however, current influenza vaccines confer suboptimal protection, in part due to antigen mismatch and poor durability. This systematic literature review characterizes the global clinical burden of seasonal influenza among adults aged ≥ 65 years. METHODS: An electronic database search was conducted and supplemented with a conference abstract search. Included studies described clinical outcomes in the ≥ 65 years population across several global regions and were published in English between January 1, 2012 and February 9, 2022. RESULTS: Ninety-nine publications were included (accounting for > 156,198,287 total participants globally). Clinical burden was evident across regions, with most studies conducted in the USA and Europe. Risk of influenza-associated hospitalization increased with age, particularly in those aged ≥ 65 years living in long-term care facilities, with underlying comorbidities, and infected with A(H3N2) strains. Seasons dominated by circulating A(H3N2) strains saw increased risk of influenza-associated hospitalization, intensive care unit admission, and mortality within the ≥ 65 years population. Seasonal differences in clinical burden were linked to differences in circulating strains. CONCLUSIONS: Influenza exerts a considerable burden on adults aged ≥ 65 years and healthcare systems, with high incidence of hospitalization and mortality. Substantial influenza-associated clinical burden persists despite increasing vaccination coverage among adults aged ≥ 65 years across regions included in this review, which suggests limited effectiveness of currently available seasonal influenza vaccines. To reduce influenza-associated clinical burden, influenza vaccine effectiveness must be improved. Next generation vaccine production using mRNA technology has demonstrated high effectiveness against another respiratory virus-SARS-CoV-2-and may overcome the practical limitations associated with traditional influenza vaccine production.

Understanding the Barriers and Attitudes toward Influenza Vaccine Uptake in the Adult General Population: A Rapid Review.

Influenza is a common respiratory infection associated with a substantial clinical, humanistic, and economic burden globally. Vaccines are essential to prevent and control influenza and are recommended by public-health agencies, such as the WHO and US CDC; however, vaccination rates vary considerably across the globe. This review aimed to investigate the perceived barriers and attitudes to influenza vaccination in the global population, in order to identify strategies that may improve influenza vaccination coverage. A structured literature search was undertaken to identify studies that reported on patient-reported attitudes towards influenza vaccination, focused on the adult general population in 16 prespecified countries. Eighty studies were included in this review. Negative attitude towards healthcare were found to be the most agreed upon barrier to vaccine uptake (31.1% agreement). The most agreed promoter of influenza vaccination was trust in healthcare services (62.0% agreement). Approximately 50% of participants intended to receive the influenza vaccine in the following season. To improve influenza vaccination coverage, healthcare workers must strengthen the foundation of substantial trust in healthcare services and provide educational materials that improve influenza vaccination knowledge among the adult general population.

c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs.

Small intestinal villi are structural and functional units present in higher vertebrates and uniquely adapted to nutrient absorption. Villus enterocytes are organized in transcriptional "zones" dedicated to specialized tasks such as absorption of specific nutrients. We report that the transcription factor c-MAF is expressed in differentiated lower and mid-villus enterocytes and is a target of BMP signaling. Maf inactivation perturbed the villus zonation program by increasing carbohydrate-related transcripts while suppressing transcripts linked to amino-acid and lipid absorption. The formation of cytoplasmic lipid droplets, shuttling dietary fat to chylomicrons, was impaired upon Maf loss indicating its role in dietary lipid handling. Maf inactivation under homeostatic conditions expanded tuft cells and led to compensatory gut lengthening, preventing weight loss. However, delayed Maf-/- enterocyte maturation impaired weight recovery after acute intestinal injury, resulting in reduced survival. Our results identify c-MAF as a regulator of the intestinal villus zonation program, while highlighting the importance of coordination between stem/progenitor and differentiation programs for intestinal regeneration.

Developing a health economic model for Asians with type 2 diabetes based on the Japan Diabetes Complications Study and the Japanese Elderly Diabetes Intervention Trial.

INTRODUCTION: Cost-effectiveness analyses are becoming increasingly important in Japan following the introduction of a health technology assessment scheme. The study objective was to develop an economic model to evaluate the cost-effectiveness of two interventions for type 2 diabetes in a Japanese population. RESEARCH DESIGN AND METHODS: The Japan Diabetes Complications Study/Japanese Elderly Diabetes Intervention Trial risk engine (JJRE) Cost-Effectiveness Model (JJCEM) was developed, incorporating validated risk equations in Japanese patients with type 2 diabetes from the JJRE. Weibull regression models were developed for progression of the model outcomes, and a targeted literature review was performed to inform default values for utilities and costs. To illustrate outcomes, two simulated analyses were performed in younger (aged 40 years) and older (aged 80 years) Japanese populations, comparing a hypothetical treatment with placebo. RESULTS: The model considers a population based on user-defined values for 11 baseline characteristic parameters and simulates rates of diabetic complications over a defined time horizon. Costs, quality-adjusted life years, and an incremental cost-effectiveness ratio are estimated. The model provides disaggregated results for two competing interventions, allowing visualization of the key drivers of cost and utility. A scatterplot of simulations and cost-effectiveness acceptability curve are generated for each analysis. CONCLUSIONS: This is the first cost-effectiveness model for East Asian patients with type 2 diabetes, developed using Japan-specific risk equations. This population constitutes the largest share of the global population with diabetes, making this model highly relevant. The model can be used to evaluate the cost-effectiveness of anti-diabetic interventions in patients with type 2 diabetes in Japan and other East Asian populations.

A Japanese Study Assessing Glycemic Control with Use of IDegAsp Co-formulation in Patients with Type 2 Diabetes in Clinical Practice: The JAGUAR Study.

INTRODUCTION: The aim of this study was to evaluate the glycemic control and safety of insulin degludec/insulin aspart (IDegAsp) co-formulation in Japanese patients with type 2 diabetes (T2D) in a real-world clinical setting, including elderly patients (aged > 75 years). METHODS: Patients (≥ 18 years) diagnosed with T2D, previously treated with insulin were included from the Japanese Medical Data Vision database. Baseline data were taken at the index date, defined as the first IDegAsp prescription claim. Change in glycated hemoglobin (HbA1c) at 12 months was estimated using a mixed model repeated measures analysis. The proportion of patients achieving target HbA1c < 8.0% without experiencing hypoglycemia (identified by International Classification of Disease codes) was calculated at 12 months (365 ± 90 days) after baseline. RESULTS: Overall, 10,798 patients were included, 3940 were aged > 75 years, and 913 had baseline HbA1c values available. Switching to IDegAsp was associated with significantly improved HbA1c values at 12 months (- 1.23% [- 1.43, - 1.02]95%CI, p < 0.001) versus baseline. Moreover, relative to baseline, a significantly greater proportion of patients achieved HbA1c < 8.0% without hypoglycemia at 12 months, relative rate (RR) 1.30 [1.15, 1.45]95%CI, p < 0.001. Results were similar for patients aged ≤ 75 years and aged > 75 years; 66% and 64% of patients, respectively, achieved HbA1c < 8.0% without hypoglycemia at 12 months. CONCLUSION: Switching from insulin to IDegAsp co-formulation was associated with significantly improved glycemic control and a reduction in hypoglycemia rate during 12 months of follow-up in Japanese patients with T2D, including those aged > 75 years.

Effect of Orally Administered Semaglutide Versus Dulaglutide on Diabetes-Related Quality of Life in Japanese Patients with Type 2 Diabetes: The PIONEER 10 Randomized, Active-Controlled Trial.

INTRODUCTION: In the randomized Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 10 trial, once-daily orally administered semaglutide-the first oral glucagon-like peptide 1 receptor agonist (GLP-1RA)-was similarly tolerated with comparable (at 7 mg) or better (at 14 mg) efficacy versus the injectable GLP-1RA dulaglutide 0.75 mg. Health-related quality of life (HRQoL) in PIONEER 10 was assessed using the Japanese-specific Diabetes Therapy-Related Quality of Life (DTR-QoL) questionnaire. METHODS: The DTR-QoL comprises 29 questions, providing four domain and total scores. Answers were converted to a score between 0 and 100, with higher scores indicating greater HRQoL. Two estimands were prespecified: treatment policy (regardless of treatment discontinuation or rescue medication use) and trial product (assuming on treatment without rescue medication) in all randomized patients. Outcomes were assessed at weeks 26 and 52. RESULTS: Mean baseline DTR-QoL domain scores were similar between treatment arms and were generally lower (giving more scope for improvement) for "anxiety and dissatisfaction with treatment" (62.1-65.3) and "satisfaction with treatment" (53.9-57.9) than "burden on social activities and daily activities" (76.5-77.7) and "hypoglycemia" (83.5-88.2). Using the treatment policy estimand, orally administered semaglutide 7 and 14 mg improved HRQoL versus dulaglutide 0.75 mg for the total score (estimated mean change from baseline [CfB] 7.3 and 8.1 vs 3.3; estimated treatment difference [ETD] 3.9 and 4.8) and the "anxiety and dissatisfaction with treatment" domain (CfB 9.7 and 10.9 vs 3.7; ETD 6.0 and 7.2) at week 52. Orally administered semaglutide 14 mg improved the "satisfaction with treatment" domain versus dulaglutide 0.75 mg (CFB 13.8 vs 5.7; ETD 8.1). DTR-QoL scores for orally administered semaglutide tended to be more durable (sustained over time) than for dulaglutide. Outcomes for the trial product estimand were similar. CONCLUSION: Orally administered semaglutide 7 and 14 mg improved the patients' HRQoL measured by the Japanese-specific DTR-QoL instrument versus dulaglutide 0.75 mg at week 52. TRIAL REGISTRATION: ClinicalTrials.gov NCT03015220.

Clinical inertia in patients with type 2 diabetes treated with oral antidiabetic drugs: Results from a Japanese cohort study (JDDM53).

AIMS/INTRODUCTION: Treatment intensification is commonly delayed in people with type 2 diabetes, resulting in poor glycemic control for an unacceptable length of time and increased risk of complications. MATERIALS AND METHODS: This retrospective study investigated clinical inertia in 33,320 Japanese adults with type 2 diabetes treated with oral antidiabetic drugs (OADs) between 2009 and 2018, using data from the Computerized Diabetes Care (CoDiC® ) database. RESULTS: The median time from first reported glycated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) to treatment intensification was considerably longer and HbA1c levels were higher the more OADs the patient was exposed to. For patients receiving three OADs, the median times from HbA1c ≥7.0% (53 mmol/mol) to intensification with OAD, glucagon-like peptide-1 receptor agonist or insulin were 8.1, 9.1 and 6.7 months, with a mean HbA1c level at the time of intensification of 8.4%, 8.9% and 9.3%, respectively. The cumulative incidence for time since the first reported HbA1c ≥7.0% (≥53 mmol/mol) to intensification confirmed the existence of clinical inertia, identifying patients whose treatment was not intensified despite poor glycemic control. HbA1c levels ≥7.0% (≥53 mmol/mol) after ≥6 months on one, two or three OADs were observed in 42%, 51% and 58% of patients, respectively, showing that approximately 50% of patients are above HbA1c target regardless of how many OADs they take. CONCLUSIONS: Real-world data here show clinical inertia in Japanese adults with type 2 diabetes from early diabetes stages when they are receiving OADs, and illustrate a need for earlier, more effective OADs or injectable treatment intensification and better communication around the existence of clinical inertia.

Preference for Oral and Injectable GLP-1 RA Therapy Profiles in Japanese Patients with Type 2 Diabetes: A Discrete Choice Experiment.

INTRODUCTION: Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) approved to date are administered by injection; therefore, patient perceptions of an oral GLP-1 RA are unknown. This discrete choice experiment explored preferences for (unbranded) oral and injectable GLP-1 RA profiles among Japanese patients with type 2 diabetes (T2D). METHODS: An online survey was designed using literature review and qualitative interview findings, and administered to Japanese patients with T2D and HbA1c ≥ 7.0% receiving oral antiglycaemic medication (with no experience of injectable antiglycaemic medication). Therapy profiles were created using Japanese head-to-head trial data for orally administered semaglutide (7 mg and 14 mg), injectable dulaglutide (0.75 mg), and injectable liraglutide (0.9 mg). Profiles were not labelled. Choice tasks tested preference between hypothetical profiles, preference between profiles with actual trial data, and willingness to initiate treatment. Relative importance of attributes was determined using conditional logit regression. RESULTS: A total of 500 respondents were analysed: mean age 61.2 years; 93.8% male; mean HbA1c 7.6%; 78.2% with HbA1c ≥ 7.0 to < 8%; 89% with HbA1c above personal target. Mean BMI was 25.4 kg/m2; 49% had obesity (≥ 25 kg/m2). The treatment attribute with greatest importance was mode and frequency of administration (49.1%), followed by nausea risk (30.8%), weight change (11.3%), and HbA1c change (8.8%). Oral semaglutide 7 and 14 mg-like profiles were both preferred: the 7 mg-like profile was preferred over dulaglutide (by 91.0% of respondents) and liraglutide (by 89.4%); the 14 mg-like profile was preferred over dulaglutide (by 88.2%) and liraglutide (by 94.4%). Willingness to initiate treatment was also higher for orally administered semaglutide-like profiles: 62.4% with 7 mg and 64.0% with 14 mg, versus 13.6% and 11.0% with injectable GLP-1 RA-like profiles. Subgroup results were generally consistent with the overall sample. CONCLUSION: Japanese patients with T2D appear to prefer oral GLP-1 RA profiles over injectable GLP-1 RA profiles, and administration appears to be the most important factor in this decision. This highlights the unmet need for an effective and orally administered GLP-1 RA for the treatment of T2D in Japan.

Quality of Life and Utility Values for Cost-Effectiveness Modeling in Japanese Patients with Type 2 Diabetes.

INTRODUCTION: Reliable quality of life (QoL) measures and utility values are needed for patients with type 2 diabetes mellitus (T2DM) with a variety of comorbid conditions to help facilitate cost-effectiveness modeling. This study aimed to evaluate the Diabetes Treatment-Related Quality of Life (DTR-QOL) and EuroQol 5-dimension 5-level (EQ-5D-5L) questionnaires in patients with T2DM with and without diabetes complications and comorbidities in Japan. METHODS: This was an observational survey study involving 1000 patients with T2DM, at least 20 years old, receiving treatment at Nara University Hospital or Takamura Internal Medicine Clinic in Japan. Patients completed the DTR-QOL and EQ-5D-5L questionnaires and clinicians completed an accompanying case report form. The DTR-QOL and EQ-5D-5L are scored on a scale of 0-100 and 0-1, with 100 and 1 representing the best possible scores, respectively. RESULTS: Out of 1000 recruited patients, 978 were included in the final analysis. Patients reported an average EQ-5D-5L value of 0.92 ± 0.11. Utility values corresponded to the degree of severity of health conditions while few differences were observed when stratified by the HbA1c 7% threshold, age, or BMI level, nor did the values correspond to the degree of clinical risk factors. Patients reported an average total DTR-QOL score of 79.26 ± 13.26. The DTR-QOL was sensitive to detect differences in patients with T2DM with a variety of complications and comorbidities, risk factors, and treatments. CONCLUSION: This is the largest study to report QOL values for patients with diabetes in Japan and the first to include a variety of comorbid diabetic conditions. These findings may be useful for cost-effectiveness modeling of patients with T2DM in Japan.

Lower Drug Cost of Successfully Treating Patients with Type 2 Diabetes to Targets with Once-Weekly Semaglutide versus Once-weekly Dulaglutide in Japan: A Short-Term Cost-Effectiveness Analysis.

INTRODUCTION: In the head-to-head trial (SUSTAIN 7), the novel, injectable, once-weekly GLP-1 analogue semaglutide showed superiority in both glycemic outcomes and body weight reduction, compared with once-weekly dulaglutide in the treatment of type 2 diabetes (T2D). However, no economic evaluation using these data has yet been conducted in the Japanese setting. The objective of this analysis was to assess the short-term cost-effectiveness in Japan of once-weekly semaglutide 0.5 mg (the approved maintenance dose in Japan) compared with once-weekly dulaglutide 0.75 mg (the only licensed dose in Japan) over a 1-year period using Japanese cost data. METHODS: Responder endpoints were obtained from the SUSTAIN 7 trial to assess the cost of successfully treating patients to these targets ("cost of control"). Responder endpoint definitions consisted of single, dual, and triple composite endpoints related to glycemic control, body weight, and hypoglycemia outcomes. The cost of treatment was accounted from a healthcare payer perspective, capturing drug costs only. RESULTS: Treatment with once-weekly semaglutide 0.5 mg was associated with a lower cost and a lower cost per patient treated to target for all endpoints, compared with once-weekly dulaglutide 0.75 mg. For each JPY 1 spent on bringing patients to target with once-weekly semaglutide 0.5 mg, JPY 1.58, JPY 1.44, JPY 1.60, JPY 2.10, and JPY 2.33 would need to be spent on once-weekly dulaglutide 0.75 mg to achieve an equivalent outcome for endpoints of HbA1c ≤ 6.5%, HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia, and no weight gain, weight loss ≥ 5%, and ≥ 1.0% HbA1c reduction and ≥ 3.0% weight loss, respectively. CONCLUSIONS: These findings suggest that once-weekly semaglutide is a cost-effective treatment option compared with once-weekly dulaglutide for patients with T2D in Japan. In the future, this finding should be extrapolated to traditional long-term cost-effectiveness analysis, using common outcomes such as quality-adjusted life years.

Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation.

Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function.

Short-Term Cost-Effectiveness of Switching to Insulin Degludec in Japanese Patients with Type 2 Diabetes Receiving Basal-Bolus Therapy.

INTRODUCTION: With one of the fastest aging populations in the world, demographic changes in Japan are a major public health concern due to the substantial burden that aging-associated diseases, such as type 2 diabetes (T2D), place on public healthcare systems. The aim of this analysis was to evaluate the short-term cost-effectiveness of switching Japanese patients with T2D receiving basal-bolus insulin therapy from their previous basal insulin to insulin degludec (degludec) under conditions of routine clinical practice. METHODS: A previously published, open-source model developed in Microsoft Excel was used to evaluate the cost-effectiveness of switching basal-bolus insulin therapy from patients' previous basal insulin to degludec versus continuing the previous basal insulin therapeutic regimen in terms of costs (2018 Japanese Yen [JPY]) and quality-adjusted life years (QALYs), from a Japanese public healthcare payer perspective. The model captured hypoglycemia rates and insulin dosing over a 1-year time horizon, and was informed by Japanese real-world evidence from the T2D cohort (N = 135) of the Kumamoto Insulin Degludec Observational study. RESULTS: Treatment with degludec was associated with improved effectiveness (+ 0.0354 QALYs), driven by lower daytime non-severe hypoglycemia rates with degludec, at slightly higher annual treatment costs (JPY 9510) versus continuing the previous basal insulin. Switching basal insulin to degludec was found to be a cost-effective intervention with an incremental cost-effectiveness ratio (JPY 268,811 per QALY gained) substantially below the willingness-to-pay threshold of 5 million JPY per QALY used in the Japanese Health Technology Assessment framework. Sensitivity analyses confirmed the robustness of this finding and indicated that the daytime non-severe hypoglycemia benefit with degludec was a key driver of outcomes in the base case. CONCLUSION: Based on Japanese real-world evidence, our analysis suggests that switching Japanese patients with T2D receiving a basal-bolus regimen from their previous basal insulin to degludec would be highly cost-effective. These data may help decision-makers in Japan allocate healthcare resources efficiently. TRIAL REGISTRATION: The KIDUNA study is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR): UMIN000021569. FUNDING: Novo Nordisk Pharma Ltd. Japan.

Protein Spin Labeling with a Photocaged Nitroxide Using Diels-Alder Chemistry.

EPR spectroscopy of diamagnetic bio-macromolecules is based on site-directed spin labeling (SDSL). Herein, a novel labeling strategy for proteins is presented. A nitroxide-based spin label has been developed and synthesized that can be ligated to proteins by an inverse-electron-demand Diels-Alder (DAinv ) cycloaddition to genetically encoded noncanonical amino acids. The nitroxide moiety is shielded by a photoremovable protecting group with an attached tetra(ethylene glycol) unit to achieve water solubility. SDSL is demonstrated on two model proteins with the photoactivatable nitroxide for DAinv reaction (PaNDA) label. The strategy features high reaction rates, combined with high selectivity, and the possibility to deprotect the nitroxide in Escherichia coli lysate.