Costs and health care resource utilization among Medicare beneficiaries diagnosed with chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. However, published studies of CLL have either only focused on costs among individuals diagnosed with CLL without a non-CLL comparator group or focused on costs associated with specific CLL treatments. An examination of utilization and costs across different care settings provides a holistic view of utilization associated with CLL. OBJECTIVE: To quantify the health care costs and resource utilization types attributable to CLL among Medicare beneficiaries and identify predictors associated with each of the economic outcomes among beneficiaries diagnosed with CLL. METHODS: This retrospective study used a random 20% sample of the Medicare Chronic Conditions Data Warehouse (CCW) database covering the 2017-2019 period. The study population consisted of individuals with and without CLL. The CLL cohort and non-CLL cohort were matched using a 1:5 hard match based on baseline categorical variables. We characterized economic outcomes over 360 days across cost categories and places of services. We estimated average marginal effects using multivariable generalized linear regression models of total costs and across type of services. Total cost was compared between CLL and non-CLL cohorts using the matched sample. We used generalized linear models appropriate for the count or binary outcome to identify factors associated with various categories of health care resource utilization, such as inpatient admissions, emergency department (ED) visits, and oncologist/hematologist visits. RESULTS: A total of 2,736 beneficiaries in the CLL cohort and 13,571 beneficiaries in the non-CLL matched cohort were identified. Compared with the non-CLL cohort, the annual cost for the CLL cohort was higher (CLL vs non-CLL, mean [SD]: $22,781 [$37,592] vs $13,901 [$24,725]), mainly driven by health care provider costs ($6,535 vs $3,915) and Part D prescription drug costs ($5,916 vs $2,556). The main categories of health care resource utilization were physician evaluation/management visits, oncologist/hematologist visits, and laboratory services. Compared with beneficiaries aged 65-74 years, beneficiaries aged 85 years or older had lower use and cost in maintenance services (ie, oncologist visits, hospital outpatient costs, and prescription drug cost) but higher use and cost in acute services (ie, ED). Compared with residency in a metropolitan area, living in a nonmetropolitan area was associated with fewer physician visits but higher ED visits and hospitalizations. CONCLUSIONS: The cooccurrence of lower utilization of routine care services, along with higher utilization of acute care services among some individuals, has implications for patient burden and warrants further study.

Real-World Effectiveness of the Gla-300 + Cap + App Program in Adult Users Living with Type 2 Diabetes in Taiwan.

INTRODUCTION: Health2Sync (H2S) is a digital health technology platform that provides coaching and titration support to patients with diabetes. The Mallya cap converts a conventional insulin pen into a smart connected device that can automatically synchronize dose values and associated timestamps (upon injection) to the H2S platform. This single-arm real-world study evaluated the effectiveness of insulin glargine 300 U/mL (Gla-300) combined with H2S and Mallya cap (Gla-300 + Cap + App program) on clinical outcomes among users with type 2 diabetes (T2D) in Taiwan. METHODS: Adults (aged ≥ 20 years) with T2D who were registered H2S users and initiated Mallya cap for a new/existing Gla-300 regimen (identification period May 1, 2021-May 31, 2022) were included in this retrospective cohort study. Follow-up data from H2S were collected for 90 days. Glycated hemoglobin (HbA1c) change (baseline to follow-up) and HbA1c goal attainment were primary outcomes. Hypoglycemia incidence and usage metrics of Mallya cap were secondary outcomes. RESULTS: Of 83 participants, 38.6% were new Gla-300 users. HbA1c was reduced in both new (- 2.4 [2.7] %, - 26.2 [29.5] mmol/mol) and previous Gla-300 users (- 0.5 [1.6] %, - 5.5 [17.5] mmol/mol). Reduction in HbA1c was significant (p < 0.05) in both groups. At follow-up, 43.4% of users had a reduction of > 0.5%. Mean HbA1c reductions increased numerically with higher baseline HbA1c and with longer duration of Mallya cap usage. CONCLUSIONS: Use of digital technology within a connected ecosystem such as Gla-300 + Cap + App program could help people with type 2 diabetes to improve their glycemic condition.

Curcumin regulates pulmonary extracellular matrix remodeling and mitochondrial function to attenuate pulmonary fibrosis by regulating the miR-29a-3p/DNMT3A axis.

Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5 mg/kg) and treated with CCM (25 mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff-Van Gieson, Picro sirius red, and Masson's trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.

Disparity in treatment patterns among Medicare beneficiaries diagnosed with chronic lymphocytic leukemia: an analysis of patient and contextual factors.

This study characterizes the patterns and timing of CLL treatment and, to our knowledge, is the first to identify social vulnerability factors associated with CLL treatment receipt in the Medicare population. A total of 3508 Medicare beneficiaries diagnosed with CLL from 2017 to 2019 were identified. We reported the proportion of individuals who received CLL treatment and the time until the first CLL treatment receipt after the first observed claim with a CLL diagnosis. Logistic regression and time-to-event models provided adjusted odds ratios and hazard ratios associated with baseline individual-level and county-level factors. Sixteen percent of individuals received CLL treatment, and the median follow-up time was 540 d. The median time to receipt of CLL treatment was 61 d. Older age and residence in a county ranked high in social vulnerability (as defined by minority status and language) were negatively associated with treatment receipt and time to treatment receipt.

Ex Vivo Evaluation of Combination Immunotherapy Using Tumor-Microenvironment-on-Chip.

Combination immunotherapy has emerged as a promising strategy to address the challenges associated with immune checkpoint inhibitor (ICI) therapy in breast cancer. The efficacy of combination immunotherapy hinges upon the intricate and dynamic nature of the tumor microenvironment (TME), characterized by cellular heterogeneity and molecular gradients. However, current methodologies for drug screening often fail to accurately replicate these complex conditions, resulting in limited predictive capacity for treatment outcomes. Here, a tumor-microenvironment-on-chip (TMoC), integrating a circulation system and ex vivo tissue culture with physiological oxygen and nutrient gradients, is described. This platform enables spatial infiltration of cytotoxic CD8+ T cells and their targeted attack on the tumor, while preserving the high complexity and heterogeneity of the TME. The TMoC is employed to assess the synergistic effect of five targeted therapy drugs and five chemotherapy drugs in combination with immunotherapy, demonstrating strong concordance between chip and animal model responses. The TMoC holds significant potential for advancing drug development and guiding clinical decision-making, as it offers valuable insights into the complex dynamics of the TME.

Long-term administration of Western diet induced metabolic syndrome in mice and causes cardiac microvascular dysfunction, cardiomyocyte mitochondrial damage, and cardiac remodeling involving caveolae and caveolin-1 expression.

BACKGROUND: Long-term consumption of an excessive fat and sucrose diet (Western diet, WD) has been considered a risk factor for metabolic syndrome (MS) and cardiovascular disease. Caveolae and caveolin-1 (CAV-1) proteins are involved in lipid transport and metabolism. However, studies investigating CAV-1 expression, cardiac remodeling, and dysfunction caused by MS, are limited. This study aimed to investigate the correlation between the expression of CAV-1 and abnormal lipid accumulation in the endothelium and myocardium in WD-induced MS, and the occurrence of myocardial microvascular endothelial cell dysfunction, myocardial mitochondrial remodeling, and damage effects on cardiac remodeling and cardiac function. METHODS: We employed a long-term (7 months) WD feeding mouse model to measure the effect of MS on caveolae/vesiculo-vacuolar organelle (VVO) formation, lipid deposition, and endothelial cell dysfunction in cardiac microvascular using a transmission electron microscopy (TEM) assay. CAV-1 and endothelial nitric oxide synthase (eNOS) expression and interaction were evaluated using real-time polymerase chain reaction, Western blot, and immunostaining. Cardiac mitochondrial shape transition and damage, mitochondria-associated endoplasmic reticulum membrane (MAM) disruption, cardiac function change, caspase-mediated apoptosis pathway activation, and cardiac remodeling were examined using TEM, echocardiography, immunohistochemistry, and Western blot assay. RESULTS: Our study demonstrated that long-term WD feeding caused obesity and MS in mice. In mice, MS increased caveolae and VVO formation in the microvascular system and enhanced CAV-1 and lipid droplet binding affinity. In addition, MS caused a significant decrease in eNOS expression, vascular endothelial cadherin, and ß-catenin interactions in cardiac microvascular endothelial cells, accompanied by impaired vascular integrity. MS-induced endothelial dysfunction caused massive lipid accumulation in the cardiomyocytes, leading to MAM disruption, mitochondrial shape transition, and damage. MS promoted brain natriuretic peptide expression and activated the caspase-dependent apoptosis pathway, leading to cardiac dysfunction in mice. CONCLUSION: MS resulted in cardiac dysfunction, remodeling by regulating caveolae and CAV-1 expression, and endothelial dysfunction. Lipid accumulation and lipotoxicity caused MAM disruption and mitochondrial remodeling in cardiomyocytes, leading to cardiomyocyte apoptosis and cardiac dysfunction and remodeling.

Magnolol regulates miR-200c-3p to inhibit epithelial-mesenchymal transition and retinoblastoma progression by modulating the ZEB1/E-cadherin axis in vitro and in vivo.

BACKGROUND: Retinoblastoma, the most common pediatric intraocular malignancy, can develop during embryogenesis, with most children being diagnosed at 3-4 years of age. Multimodal therapies are typically associated with high levels of cytotoxicity and side effects. Therefore, the development of novel treatments with minimal side effects is crucial. Magnolol has a significant anti-tumor effect on various cancers. However, its antitumor effect on retinoblastoma remains unclear. PURPOSE: The study aimed to determine the effects of magnolol on the regulation of EMT, migration, invasion, and cancer progression in retinoblastoma and the modulation of miR-200c-3p expression and the Wnt/ zinc finger E-box binding homeobox 1 (ZEB1)/E-cadherin axis in vivo and in vitro. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay was used to evaluate magnolol-induced cell toxicity in the Y79 retinoblastoma cell line. Flow cytometry and immunostaining assays were performed to investigate the magnolol-regulated mitochondrial membrane potential and the intracellular and mitochondrial reactive oxygen species levels in Y79 retinoblastoma cells. Orthotopic and subcutaneous xenograft experiments were performed in eight-week-old male null mice to study retinoblastoma progression and metastasis. In situ hybridization and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays were performed to evaluate the level of the anti-cancer miRNA miR-200c-3p. The mRNA and protein levels of E-cadherin, ß-catenin, α-smooth muscle actin (α-SMA), fibronectin-1, and ZEB1 were analyzed using RT-qPCR, immunoblot, immunocytochemistry, and immunohistochemistry assays in vitro and in vivo. RESULTS: Magnolol increased E-cadherin levels and reduced the activation of the EMT signaling pathway, EMT, tumor growth, metastasis, and cancer progression in the Y79 retinoblastoma cell line as well as in the orthotopic and subcutaneous xenograft animal models. Furthermore, magnolol increased the expression of miR-200c-3p. Our results demonstrate that miRNA-200c-3p inhibits EMT progression through the Wnt16/ß-catenin/ZEB1/E-cadherin axis, and the ZEB1 silencing response shows that miR-200c-3p regulates ZEB1-mediated EMT in retinoblastoma. CONCLUSION: Magnolol has an antitumor effect by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma. The anti-tumor effect of magnolol by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma has been elucidated for the first time.

Delivery of nitric oxide with a pH-responsive nanocarrier for the treatment of renal fibrosis.

Fibrosis is an excessive accumulation of extracellular matrix (ECM) that may cause severe organ dysfunction. Nitric oxide (NO), a multifunctional gaseous signaling molecule, may inhibit fibrosis, and delivery of NO may serve as a potential antifibrotic strategy. However, major limitations in the application of NO to treat fibrotic diseases include its nonspecificity, short half-life and low availability in fibrotic tissue. Herein, we aimed to develop a stimuli-responsive drug carrier to deliver NO to halt kidney fibrosis. We manufactured a nanoparticle (NP) composed of pH-sensitive poly[2-(diisopropylamino)ethyl methacrylate (PDPA) polymers to encapsulate a NO donor, a dinitrosyl iron complex (DNIC; [Fe2(µ-SEt)2(NO)4]). The NPs were stable at physiological pH 7.4 but disintegrated at pH 4.0-6.0. The NPs showed significant cytotoxicity to cultured human myofibroblasts and were able to inhibit the activation of myofibroblasts, as indicated by a lower expression level of α-smooth muscle actin and the synthesis of a major ECM component, collagen I, in cultured human myofibroblasts. When given to mice treated with unilateral ureteral ligation/obstruction (UUO) to induce kidney fibrosis, these NPs remained in blood at a stable concentration for as long as 24 h and might enter the fibrotic kidneys to suppress myofibroblast activation and collagen I production, leading to a 70% reduction in the fibrotic area. In summary, our strategy to assemble a NO donor, the iron nitrosyl complex DNIC, into pH-responsive NPs proves effective in treating renal fibrosis and warrants further investigation for its therapeutic potential.

Economic burden of interstitial lung disease in a commercially insured population with Sjögren syndrome in the United States.

BACKGROUND: Patients with Sjögren syndrome (SjS) have substantial cost burden on the health care system; among these patients, those who develop interstitial lung disease (ILD) experience poorer quality of life and have a higher mortality risk. However, the economic burden of ILD has not been documented. OBJECTIVE: To estimate the direct health care costs associated with ILD among patients with SjS in a representative sample of the commercially insured population in the United States. METHODS: Individuals with a diagnosis of SjS between January 1, 2006, and September 30, 2015, with and without a diagnosis of ILD, were identified from the PharMetrics Plus for Academics database. The index date was defined as the later date of the first claim with a diagnosis of SjS or the first claim with a diagnosis of ILD for individuals with SjS and ILD (SjS-ILD), and the first claim with a diagnosis of SjS for SjS-only controls. All baseline variables were measured in the 180 days preindex period. A 5:1 propensity score matching was applied to controls for baseline demographic and geographic variables. The cost ratio and average marginal effect for total direct medical costs comparing SjS patients with and without ILD were estimated using a generalized linear model. Costs per health care resource utilization category were also reported. All costs were represented from a health plan payer perspective and inflated to 2020 US dollars. RESULTS: After applying the inclusion criteria, 815 SjS-ILD cases were identified and matched to 4,075 SjS-only controls based on the 5:1 propensity score matching procedure. The 180-day total cost of SjS-ILD cases was about 2 times higher compared with that of SjS-only controls (adjusted cost ratio = 1.95; 95% CI = 1.76-2.15). The average difference in total cost between patients with and without ILD was $8,814 (95% CI = $7,149-$10,479). Costs were mainly contributed from outpatient services other than physician office visit (such as radiological and pathological tests), inpatient services, and outpatient pharmacy cost components for both groups (39.4%, 38.8%, and 16.3% for SjS-ILD cases; 43.7%, 22.6%, and 22.9% for SjS-only controls, respectively). CONCLUSIONS: Total direct health care cost was substantially higher in patients with SjS and ILD compared with patients with SjS without ILD. Our findings provide the foundation for further economic evaluation for preventive strategies to reduce the clinical and economic burden imposed by ILD among patients with SjS.

External validation of lung function predictions in real-world cohorts of COPD.

BACKGROUND: An individualized FEV1 prediction model has recently been developed based on the Lung Health Study (LHS). An ongoing evaluation of the utility of prediction models in representative settings outside the setup of clinical trials is needed. OBJECTIVE: To evaluate the external validity of the LHS FEV1 prediction model in a representative sample of Canadian ever-smoker COPD patients. METHODS: We used the sample of ever-smokers with spirometrically-confirmed COPD from the Canadian Cohort of Obstructive Lung Disease (CanCOLD), an ongoing prospective, longitudinal, multicenter population-based cohort study. We compared the mean predicted against the mean observed FEV1 at follow-up visits. We calculated the root mean square error (RMSE) and the actual coverage probability of the 95% individualized prediction intervals. RESULTS: The final CanCOLD sample consisted of 360 ever-smoker COPD patients, contributing to 970 FEV1 observations over an average of 3 years of follow-up (standard deviation (SD): 0.6 years). The mean observed vs. predicted FEV1 for the first follow-up visit (1.67 years from baseline) was 2.28L vs. 2.28L, and for the second visit (3.13 years from baseline) was 2.19L vs. 2.18L. The RMSE of the predictions was 0.205L, and the actual coverage probability of the 95% prediction intervals was 93%. The model had a similar performance across multiple subgroups. CONCLUSIONS: The model showed robust performance in predicting FEV1 in the entire sample and in several subgroups of CanCOLD. Our results demonstrate that LHS predictions are valid for at least three years in the general COPD population.

Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis.

Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. SIGNIFICANCE STATEMENT: Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.

Endocardial Endothelial Dysfunction and Unknown Polymorphic Composite Accumulation in Heart Failure.

The accumulation of unknown polymorphic composites in the endocardium damages the endocardial endothelium (EE). However, the composition and role of unknown polymorphic composites in heart failure (HF) progression remain unclear. Here, we aimed to explore composite deposition during endocardium damage and HF progression. Adult male Sprague-Dawley rats were divided into two HF groups-angiotensin II-induced HF and left anterior descending artery ligation-induced HF. Heart tissues from patients who had undergone coronary artery bypass graft surgery (non-HF) and those with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) were collected. EE damage, polymorphic unknown composite accumulation, and elements in deposits were examined. HF progression reduced the expression of CD31 in the endocardium, impaired endocardial integrity, and exposed the myofibrils and mitochondria. The damaged endocardial surface showed the accumulation of unknown polymorphic composites. In the animal HF model, especially HF caused by myocardial infarction, the weight and atomic percentages of O, Na, and N in the deposited composites were significantly higher than those of the other groups. The deposited composites in the human HF heart section (DCM) had a significantly higher percentage of Na and S than the other groups, whereas the percentage of C and Na in the DCM and ICM groups was significantly higher than those of the control group. HF causes widespread EE dysfunction, and EndMT was accompanied by polymorphic composites of different shapes and elemental compositions, which further damage and deteriorate heart function.

miR-29a-3p/THBS2 Axis Regulates PAH-Induced Cardiac Fibrosis.

Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects.

Cost-utility analysis of inotuzumab ozogamicin for relapsed or refractory B cell acute lymphoblastic leukemia from the perspective of Taiwan's health care system.

OBJECTIVES: We conduct a cost-utility analysis of inotuzumab ozogamicin (INO) versus chemotherapy as the standard of care (SOC) for adults with relapsed or refractory B cell acute lymphoblastic leukemia. METHODS: A Markov model incorporating transition probabilities between health states was applied to simulate disease progression. The model inputs, including overall survival, progression-free survival, and utility parameters, were obtained from the INO-VATE ALL trial and literatures. The Taiwan Cancer Registry Database and the Health and Welfare Database were utilized to identify the patient cohort and medical costs from the perspective of National Health Insurance Administration. The lifetime medical costs (in 2017 US dollars), quality-adjusted life years (QALYs) gained, and associated incremental cost-effectiveness ratio (ICER) were the main study outcomes. RESULTS: The lifetime medical costs for INO and SOC were $176,795 and $69,496, and the QALYs gained were 2.25 and 0.84, respectively. The ICER for INO versus SOC was $76,044 per QALY gained, which is slightly more than three times Taiwan's gross domestic product per capita (i.e., $73,224). Favorable economic results for INO versus SOC were found with an increased time horizon for model simulation, less discounting for the future benefit, and higher stem cell transplantation (SCT) rate after INO treatment; and among patients aged less than 55 years, with no SCT history, or in the first salvage treatment. CONCLUSIONS: INO versus SOC has higher costs but is more effective. The use of INO is favorable for patients in the early treatment course and when more future benefit associated with INO is considered.

Cost-effectiveness of long-acting insulin analogues vs intermediate/long-acting human insulin for type 1 diabetes: A population-based cohort followed over 10 years.

AIMS: This study assessed the cost-effectiveness of long-acting insulin analogues (LAIAs) vs intermediate/long-acting human insulin (ILAHI) for patients with type 1 diabetes (T1D) in real-world clinical practice. METHODS: Individual-level analyses were conducted within a longitudinal population-based cohort of 540 propensity score-matched T1D patients (LAIAs, n = 270; ILAHI, n = 270) with over 10 years of follow-up using Taiwan's National Health Insurance Research Database, 2004-2013, from third-party payer and healthcare sector perspectives. The study outcomes included the number needed to treat (NNT) to prevent one case of clinical events (eg, hypoglycaemia, diabetes-related complications), medical costs, and cost per case of events prevented. Cost estimates are presented in 2013 British pounds (GBP, £). RESULTS: The NNTs using LAIAs vs ILAHI to avoid one case of hypoglycaemia requiring medical assistance, outpatient hypoglycaemia and any diabetes-related complications were 12, 9 and 10 for mean follow-up periods of 5.84, 6.02 and 3.62 years, respectively. From third-party payer and healthcare sector perspectives, using LAIAs instead of ILAHI saved GBP6924-GBP7116 per case of hypoglycaemia requiring medical assistance prevented, GBP5346-GBP5508 per case of outpatient hypoglycaemia prevented, and GBP3570-GBP3680 per case of any diabetes-related complications prevented. Sensitivity analyses considering sampling uncertainty showed that using LAIAs over ILAHI yields at least a 76% probability of cost-saving for avoiding one case of hypoglycaemia requiring medical assistance, outpatient hypoglycaemia or any diabetes-related complications. CONCLUSIONS: This real-world evidence reveals that compared with ILAHI, the greater pharmaceutical costs associated with LAIAs for patients with T1D could be substantially offset by savings from averted hypoglycaemia or diabetes-related complications.

Comparative risks of diabetes-related complications of basal insulins: a longitudinal population-based cohort of type 1 diabetes 1999-2013 in Taiwan.

AIM: We compared the effects of two types of basal insulin: long-acting insulin analogues vs. intermediate/long-acting human insulin, on diabetes-related complications in type 1 diabetes. METHODS: A total of 1188 patients with type 1 diabetes who had recently started on long-acting insulin analogues or intermediate/long-acting human insulin were identified in 2004-2008 and followed until death or the end of 2013. Clinical outcomes included acute (i.e. hyperglycaemia, hypoglycaemia) and chronic (i.e. nephropathy, retinopathy, neuropathy, cardiovascular diseases) complications. Diabetes-related complications were measured as a composite outcome which included acute and chronic complications. Cox proportional hazards models were used to assess the time to event hazard ratio. Three propensity score (PS) methods were applied to adjust for baseline imbalances between basal insulin groups, including the PS-matching approach (as the main analysis), standardized mortality ratio weighting (SMRW) and inverse probability of treatment weighting (IPTW). RESULTS: Long-acting insulin analogues vs. intermediate/long-acting human insulin had a lower risk for a composite of diabetes-related complications {adjusted hazards ratios [aHRs] [95% confidence interval (CI)] 0.782 [0.639, 0.956], 0.743 [0.598, 0.924] and 0.699 [0.577, 0.846] according to the PS-matching approach, SMRW and IPTW, respectively}. Compared with intermediate/long-acting human insulin, using long-acting insulin analogues had a lower hypoglycaemia risk: aHRs (95% CI) 0.681 (0.498, 0.930), 0.662 (0.466, 0.943) and 0.639 (0.471, 0.867) from the PS-matching approach, SMRW and IPTW, respectively. No statistical differences were found between two types of insulin on individual chronic complications. CONCLUSION: A trend of lower diabetes-related complications associated with long-acting insulin analogues vs. intermediate/long-acting human insulin was observed. A reduced hypoglycaemia risk with long-acting insulin analogues was confirmed in this 'real-world' study.

Development of diabetes-specific quality of life module to be in conjunction with the World Health Organization quality of life scale brief version (WHOQOL-BREF).

BACKGROUND: Although numerous health-related quality of life (HRQoL) instruments are available for patients with diabetes, the length of these measures may limit their feasibility to routine practice. Also, these measures do not distinguish items for generic and diabetes-specific HRQoL. This study was aimed to develop a diabetes-specific quality of life questionnaire module (DMQoL) to be in conjunction with the World Health Organization Quality of Life scale brief version (WHOQOL-BREF). METHODS: One hundred seventeen patients with diabetes were enrolled from a medical center in Taiwan. The item content of DMQoL was constructed based on an extensive review of existing HRQoL instruments for diabetes, expert discussions and patient interviews. A series of psychometric tests were conducted to ensure the reliability and validity of DMQoL. The WHOQOL-BREF served as an existing HRQoL measure for construct validity testing. The response scale of DMQoL was adopted from the 5-point Likert scale of WHOQOL-BREF. RESULTS: A total of 10 items without ceiling or floor effects were selected from 20 items. Exploratory factor analysis (EFA) with parallel analysis and Rasch analysis concluded that the 10 items were embedded in the same underlying concept. The corrected item-total correlations and factor loadings from EFA were all above 0.4. The internal consistency of the 10 items was satisfactory (Cronbach's α = 0.84). The DMQoL total score was moderately correlated with that of WHOQOL-BREF (r = 0.48, p < 0.001). The known-group validity showed that patients with HbA1c ≤ 7% had significantly higher mean scores of DMQoL than did those with HbA1c > 8% (3.66 ± 0.47 vs. 3.41 ± 0.53; p = 0.037). CONCLUSIONS: The DMQoL with only 10 items is developed and it is sensitive to the change of diabetes progression in early phases (e.g., glycemic changes). The combination of WHOQOL-BREF and DMQoL provides a comprehensive picture of overall HRQoL in patients with diabetes and enhance the instrument's ability to detect clinically meaningful changes in diabetes.

Pharmacoeconomic analysis of antifungal therapy for primary treatment of invasive candidiasis caused by Candida albicans and non-albicans Candida species.

BACKGROUND: Cost-effectiveness studies of echinocandins for the treatment of invasive candidiasis, including candidemia, are rare in Asia. No study has determined whether echinocandins are cost-effective for both Candida albicans and non-albicans Candida species. There have been no economic evaluations that compare non-echinocandins with the three available echinocandins. This study was aimed to assess the cost-effectiveness of individual echinocandins, namely caspofungin, micafungin, and anidulafungin, versus non-echinocandins for C. albicans and non-albicans Candida species, respectively. METHODS: A decision tree model was constructed to assess the cost-effectiveness of echinocandins and non-echinocandins for invasive candidiasis. The probability of treatment success, mortality rate, and adverse drug events were extracted from published clinical trials. The cost variables (i.e., drug acquisition) were based on Taiwan's healthcare system from the perspective of a medical payer. One-way sensitivity analyses and probability sensitivity analyses were conducted. RESULTS: For treating invasive candidiasis (all species), as compared to fluconazole, micafungin and caspofungin are dominated (less effective, more expensive), whereas anidulafungin is cost-effective (more effective, more expensive), costing US$3666.09 for each life-year gained, which was below the implicit threshold of the incremental cost-effectiveness ratio in Taiwan. For C. albicans, echinocandins are cost-saving as compared to non-echinocandins. For non-albicans Candida species, echinocandins are cost-effective as compared to non-echinocandins, costing US$652 for each life-year gained. The results were robust over a wide range of sensitivity analyses and were most sensitive to the clinical efficacy of antifungal treatment. CONCLUSIONS: Echinocandins, especially anidulafungin, appear to be cost-effective for invasive candidiasis caused by C. albicans and non-albicans Candida species in Taiwan.

Incidence of diabetes-related complications in Chinese patients with type 1 diabetes: a population-based longitudinal cohort study in Taiwan.

OBJECTIVE: To estimate the incidence densities and cumulative incidence of diabetes-related complications in patients with type 1 diabetes for a maximum of 15-year follow-up. The estimations were further stratified by gender and age at diagnosis (ie, early onset: 0-12 years, late onset:≥13 years). DESIGN: A population-based retrospective longitudinal cohort study. SETTING: Taiwan's National Health Insurance medical claims. PARTICIPANTS: 4007 patients newly diagnosed with type 1 diabetes were identified during 1999-2012. OUTCOME MEASURES: Acute complications included diabetic ketoacidosis (DKA) and hypoglycaemia. Chronic complications were cardiovascular diseases (CVD), retinopathy, neuropathy and nephropathy. RESULTS: The incidence density of retinopathy was greatest (97.74 per 1000 person-years), followed by those of nephropathy (31.36), neuropathy (23.93) and CVD (4.39). Among acute complications, the incidence density of DKA was greatest (121.11 per 1000 person-years). The cumulative incidences of acute complications after 12 years following diagnosis were estimated to be 52.1%, 36.1% and 4.1% for DKA, outpatient hypoglycaemia and hospitalised hypoglycaemia, respectively. For chronic complications, the cumulative incidence of retinopathy after 12 years following diagnosis was greatest (65.2%), followed by those of nephropathy (30.2%), neuropathy (23.7%) and CVD (4.1%). Females with late-onset diabetes were greatly affected by advanced retinopathy (ie, sight-threatening diabetic retinopathy) and hospitalised hypoglycaemia, whereas those with early-onset diabetes were more vulnerable to DKA. Chronic complications were more commonly seen in late-onset diabetes, whereas early-onset diabetes were most affected by acute complications. CONCLUSIONS: Ethnic Chinese patients with type 1 diabetes were greatly affected by DKA and retinopathy. The incidence of diabetes-related complications differed by age at diagnosis and sex.

Multifunctional Polymer Nanoparticles for Dual Drug Release and Cancer Cell Targeting.

Multifunctional polymer nanoparticles have been developed for cancer treatment because they could be easily designed to target cancer cells and to enhance therapeutic efficacy according to cancer hallmarks. In this study, we synthesized a pH-sensitive polymer, poly(methacrylic acid-co-histidine/doxorubicin/biotin) (HBD) in which doxorubicin (DOX) was conjugated by a hydrazone bond to encapsulate an immunotherapy drug, imiquimod (IMQ), to form dual cancer-targeting and dual drug-loaded nanoparticles. At low pH, polymeric nanoparticles could disrupt and simultaneously release DOX and IMQ. Our experimental results show that the nanoparticles exhibited pH-dependent drug release behavior and had an ability to target cancer cells via biotin and protonated histidine.