Comparison of Netarsudil/Latanoprost Therapy with Latanoprost Monotherapy for Lowering Intraocular Pressure: A Systematic Review and Meta-analysis.

PURPOSE: Netarsudil is a Rho kinase inhibitor and the first new class of clinically useful ocular hypotensive agents. In this study, we conducted a systematic literature review and meta-analysis to summarize and synthesize the available evidence on the efficacy and safety of fixed-dose combination (FDC) therapy with netarsudil/latanoprost in patients with glaucoma. METHODS: We identified relevant studies in PubMed, Ovid Medline, Embase, and Cochrane Central until April 2021. The quality of the studies and the level of evidence were assessed using the Risk of Bias tool. Efficacy was measured as the mean difference in reducing intraocular pressure (IOP), and safety was assessed by the risk of conjunctival hyperemia (CH) due to FDC therapy, netarsudil monotherapy, or latanoprost monotherapy. RESULTS: Four studies met the predefined eligibility criteria and were included in the meta-analysis. The mean difference in the reduction in IOP after 2 weeks and 4 to 6 weeks of drug administration was -2.41 mmHg (95% confidence interval [CI], -2.95 to -1.87) and -1.77 mmHg (95% CI, -2.31 to -1.87), respectively, in patients receiving FDC therapy versus those receiving latanoprost monotherapy. On the other hand, latanoprost monotherapy had a greater effect in reducing IOP than netarsudil monotherapy after 4 to 6 weeks of administration (mean difference, 0.95 mmHg; 95% CI, 0.43 to 1.47). The risk of CH was significantly higher with both FDC therapy and netarsudil monotherapy compared to latanoprost monotherapy in week 12, where the relative ratio was 3.01 (95% CI, 1.95 to 4.66) and 2.33 (95% CI, 1.54 to 3.54), each. CONCLUSIONS: Netarsudil/latanoprost FDC therapy has a significantly greater effect on reducing IOP than latanoprost alone. The symptoms of CH were mostly mild, and only a few glaucoma patients discontinued the medication owing to CH in earlier clinical trials. Therefore, it would be beneficial to consider the administration of netarsudil/latanoprost FDC therapy in patients with glaucoma.

Efficacy and Safety of Opicapone for Motor Fluctuations as an Adjuvant to Levodopa Therapy in Patients with Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Long-term levodopa administration for treating Parkinson's disease (PD) may shorten the duration of effect and cause dyskinesias, inducing the need for catechol-O-methyltransferase (COMT) inhibitors as adjuvant therapy. OBJECTIVE: We provide pooled scientific evidence highlighting the efficacy and safety of opicapone, a newly approved COMT inhibitor, as an adjuvant to levodopa. METHODS: We searched Ovid Medline, Embase, and Cochrane databases for relevant reports. Efficacy and safety were evaluated as off-time reduction and risk ratio (RR) of dyskinesia, respectively. Data were independently extracted using predefined criteria. Selected placebo-controlled trials were divided into double-blind and open-label periods. Using a random-effects model, the mean difference (MD) of the off-time reduction (efficacy), RR for the occurrence of dyskinesia, and on-time without/with troublesome dyskinesia (TD; safety assessment) were compared between opicapone and placebo groups. RESULTS: Five studies from three randomized controlled trials were included, and a meta-analysis was performed with 407 patients receiving opicapone 50 mg and 402 patients receiving placebo. Compared with the placebo, opicapone (50 mg) reduced off-time by 49.91 min during the double-blind period (95% confidence intervals [CIs] = -71.39, -28.43; I2 = 0%). The RR of dyskinesia was 3.43 times greater in the opicapone 50 mg group than in the placebo group (95% CI = 2.14, 5.51; I = 0%). Compared with the placebo, opicapone increased the on-time without TD by 44.62 min (95% CI = 22.60, 66.64; I2 = 0%); the on-time increase with TD did not differ between treatments. CONCLUSION: Opicapone can play a positive role as an adjuvant to levodopa in patients with PD by reducing off-time and prolonging on-time without PD.

Estimating cost-effectiveness of screening for colorectal cancer in Vietnam.

Background:Presently, there are no national screening programs for cancer in Vietnam. This study aimed to analyze the cost-effectiveness of an annual colorectal cancer (CRC) screening program from the healthcare service provider's perspective for the Vietnamese population.Methods:The economic model consisted of adecision tree and aMarkov model. Adecision tree was constructed for comparing two strategies, including ascreening group with aguaiac-based fecal occult blood test (gFOBT) and ano-screening group in general populations, aged 50 years and above. The Markov model projected outcomes over a25-year horizon. The cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER) represented by costs per quality-adjusted life-years (QALYs).Results:When compared with no screening, ICER was $1,388per QALY with an increased cost of $ 43.98 and again of 0.032 QALY (Willingness to pay $2,590). The uptake rate of gFOBT, cost of colonoscopy, and the total cost of screening contributed to the largest impact on the ICER. PSA showed that results were robust to variation in parameter estimates, with annual screening remaining cost-effective compared with no screening.Conclusion:Our screening strategy could be considered cost-effective compared to ano screening strategy. Our findings could be potentially used to develop aCRC national screening program.

Effect of angiotensin converting enzyme inhibitor and angiotensin II receptor blocker on the patients with sepsis.

BACKGROUND/AIMS: Inhibitors of the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), reportedly have anti-inflammatory effects. This study assessed the association of prior use of ACE inhibitors and ARBs with sepsis-related clinical outcomes. METHODS: A population-based observational study was conducted using the Health Insurance Review and Assessment Service claims data. Among the adult patients hospitalized with new onset of sepsis in 2012, patients who took ARBs or ACE inhibitors at least 30 days prior to hospitalization were analyzed. Generalized linear models and logistic regression were used to examine the relation between the prior use of medication and clinical outcomes, such as in-hospital mortality, mechanical ventilation, and length of stay. RESULTS: Of a total of 27,628 patients who were hospitalized for sepsis, the ACE inhibitor, ARB, and non-user groups included 1,214 (4.4%), 3,951 (14.4%), and 22,463 (82.1%) patients, respectively. As the patients in the ACE inhibitor and ARB groups had several comorbid conditions, higher rates of intensive care unit admission, hemodialysis, and mechanical ventilation were observed. However, after covariate adjustment, the use of ACE inhibitor (odds ratio [OR], 0.752; 95% confidence interval [CI], 0.661 to 0.855) or ARB (OR, 0.575; 95% CI, 0.532 to 0.621) was significantly associated with a lower rate of in-hospital mortality. CONCLUSION: Pre-hospitalization use of ACE inhibitors or ARBs for sepsis was an independent factor for a lower rate of in-hospital mortality.

Measurement of Health-Related Quality of Life Among Colorectal Cancer Patients Using the Vietnamese Value Set of the EQ-5D-5L.

PURPOSE: Health-related quality of life (HRQoL) is an important construct in clinical settings, and it is crucial that it should be properly measured. As the EuroQol-5-dimensions-5 levels (EQ-5D-5L) is more effective for such measurement than the 3-level model, data on economic models, clinical studies, and public health evaluations previously collected through the EQ-5D-3L need to be revaluated using the EQ-5D-5L. This study evaluated colorectal cancer (CRC) patients' HRQoL scores using the Vietnamese EQ-5D-5L value set. PATIENTS AND METHODS: The cross-sectional study included CRC patients treated at a tertiary public hospital. HRQoL was assessed using the EQ-5D-5L, and HRQoL utility scores were calculated using the Vietnamese value set. Tobit regression examined factors associated with HRQoL. RESULTS: The analysis included 197 CRC patients. Ages ranged from 20 to 87 years (M = 57.64, SD = 13.5); 42.2% and 57.8% were diagnosed with cancer of the colon or rectum/anus, respectively. Mean EQ-5D-5L was 0.561 (range, -0.5115 to 1). Most participants experienced anxiety/depression (88%), followed by pain/discomfort (87%), mobility (71%), usual activity (69%), and self-care (67%). Advanced CRC stage (stage II: ß -0.303, se 0.08; stage III: ß -0.305, se 0.07; stage IV: ß -0.456, se 0.07) and surgery (ß -0.113, se 0.05) were negatively associated with EQ-5D-5L scores. Advanced education (high school: ß 0.273, se 0.07); college/vocational: ß 0.134se 0.05; university/higher: Coef 0.213, se 0.08;) and older age (age group 35-44: ß 0.253, se 0.10; 45-54: ß 0.327, se 0.09; 55-64: ß 0.355 se 0.09; 65+ ß 0.204, se 0.09) were positively associated with EQ-5D-5L scores. CONCLUSION: Patients in advanced CRC stages or undergoing surgery experienced lower HRQoL and higher prevalence of anxiety/depression and pain/discomfort. Older age and high educational attainment predicted high HRQoL. This study provides information on CRC patients' health utility based on various patient characteristics, which can be used in future economic evaluations.

The Direct and Indirect Costs of Colorectal Cancer in Vietnam: An Economic Analysis from a Social Perspective.

The incidence and mortality of colorectal cancer (CRC) has increased rapidly in Vietnam, but the economic burden of this disease has never been estimated. We estimate the direct and indirect cost of CRC patients in Vietnam in 2018 using a prevalence-based approach and human capital method. The total economic cost of CRC was VND 3041.88 billion (~$132.9 million), representing 0.055% of the 2018 gross domestic product. Notably, indirect costs comprised 83.58 % of the total cost, 82.61% of which is future income loss, because CRC occurs during productive years. The economic burden of CRC in Vietnam is substantial. The medical cost for CRC diagnosis and treatment is higher for younger patients and for those in advanced stages. Strategies to decrease the economic burden of CRC at the patient and national level, such as screening programs, should be developed and implemented in Vietnam.

The Impact of National Surveillance for Liver Cancer: Results from Real-World Setting in Korea.

Background/Aims: The National Liver Cancer Surveillance Program (NLCSP) was established in 2003 to reduce the socioeconomic burden imposed by liver cancer (LC). We aimed to investigate the effectiveness of the NLCSP in South Korea with respect to survival benefits and cost, after adjusting for various confounding factors. Methods: We used the National Health Insurance Service claims data linked with the NLCSP from 2004 to 2015. The Cox proportional hazard model and generalized linear model were used to determine the effects of the NLCSP on the early detection of LC, survival, and medical costs. Results: From 2006 to 2010, 66,632 patients (surveillance group: 10,527 and no surveillance group: 56,105) newly diagnosed with LC were included in the study. The odds of the early detection of LC was 1.82 (95% confidence interval [CI], 1.73 to 1.93) times higher among patients who participated in the NLCSP once within the 2-year period prior to the diagnosis of LC than among those who did not participate in the surveillance program. The mortality rate of patients who participated in the NLCSP was 22.0% lower (hazard ratio, 0.78; 95% CI, 0.76 to 0.80) than that of those who did not participate. When compared with the group who did not participate in surveillance, the group who participated in the NLCSP had higher total medical costs; however, their cost per day was lower after adjustment during the follow-up period. Conclusions: This study highlights the survival benefit in patients who participated in the NLCSP and the need for continuous improvements of the NLCSP in South Korea.

Procalcitonin-Guided Treatment on Duration of Antibiotic Therapy and Cost in Septic Patients (PRODA): a Multi-Center Randomized Controlled Trial.

BACKGROUND: The objective of this study was to establish the efficacy and safety of procalcitonin (PCT)-guided antibiotic discontinuation in critically ill patients with sepsis in a country with a high prevalence of antimicrobial resistance and a national health insurance system. METHODS: In a multi-center randomized controlled trial, patients were randomly assigned to a PCT group (stopping antibiotics based on a predefined cut-off range of PCT) or a control group. The primary end-point was antibiotic duration. We also performed a cost-minimization analysis of PCT-guided antibiotic discontinuation. RESULTS: The two groups (23 in the PCT group and 29 in the control group) had similar demographic and clinical characteristics except for need for renal replacement therapy on ICU admission (46% vs. 14%; P = 0.010). In the per-protocol analysis, the median duration of antibiotic treatment for sepsis was 4 days shorter in the PCT group than the control group (8 days; interquartile range [IQR], 6-10 days vs. 14 days; IQR, 12-21 days; P = 0.001). However, main secondary outcomes, such as clinical cure, 28-day mortality, hospital mortality, and ICU and hospital stays were not different between the two groups. In cost evaluation, PCT-guided therapy decreased antibiotic costs by USD 30 (USD 241 in the PCT group vs. USD 270 in the control group). The results of the intention-to-treat analysis were similar to those obtained for the per-protocol analysis. CONCLUSION: PCT-guided antibiotic discontinuation in critically ill patients with sepsis could reduce the duration of antibiotic use and its costs with no apparent adverse outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02202941.

Comparative Efficacy and Safety of Long-acting Injectable and Oral Second-generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Review and Meta-analysis.

We aimed to compare the efficacy and safety of long-acting injectable (LAI) and oral second-generation antipsychotics (SGAs) in treating schizophrenia by performing a systematic review and meta-analysis. MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library, as well as five Korean databases, were systemically searched to identify studies published from 2000 to 16 April 2015, which compared the efficacy and safety of LAI and oral SGAs. Using data from randomized controlled trials (RCTs), meta-analyses were conducted. In addition, the GRADE (the Grading of Recommendations, Assessment, Development and Evaluation) approach was applied to explicitly assess the quality of the evidence. A total of 30 studies including 17 RCTs and 13 observational studies were selected. The group treated with LAI SGAs was characterized by significantly lower relapse rates, longer times to relapse and fewer hospital days, but also by a higher occurrence of extrapyramidal syndrome and prolactin-related symptoms than that in the group treated with oral SGAs. Our findings demonstrate that there is moderate to high level of evidence suggesting that in the treatment of schizophrenia, LAI SGAs have higher efficacy and are associated with higher rates of extrapyramidal syndrome and prolactin-related symptoms. Additionally, the use of LAI SGAs should be combined with appropriate measures to reduce dopamine D2 antagonism-related symptoms.

Risk factors for developing liver cancer in people with and without liver disease.

BACKGROUND: The National Liver Cancer Surveillance Program (NLCSP) targets patients with liver diseases that lead to liver cancer in South Korea. This study aimed to investigate the risk of liver disease leading to liver cancer using nationally representative data to establish an efficient NLCSP. METHODS: This study used data from the National Health Insurance Service National Sample Cohort (NHIS-NSC) from 2002 to 2013. A retrospective matched cohort design was applied to compare the development of liver cancer in patients with and without liver disease. Cox- proportional hazard regression for liver cancer with competing risk of death was performed for all subjects or each group stratified according to age or income level. RESULTS: A total of 66,192 patients with liver disease and matched subjects without liver disease were included in the study. The incidences of liver cancer among patients with and without liver disease within a median 8-year follow-up period were 2.68% (n = 1,772) and 0.34% (n = 210), respectively. Cox- regression analysis for liver cancer incidence indicated that cirrhosis had the highest risk (hazard ratio [HR]: 18.13, 95% confidence interval [CI]: 15.24-21.58), followed by hepatitis B (HR: 9.32, 95% CI: 8.00-10.85). Subgroup analysis showed that the presence of liver disease was an important risk factor in younger as well as elderly people, and a higher risk of liver disease was also observed in the patients with Medicaid. CONCLUSIONS: Attention should be paid to the development of liver cancer in young people under 50 years old and preventive efforts to decrease the incidence of liver cancer among Medicaid recipients is needed.

Comparison of mid- to long-term clinical outcomes between anatomical testing and usual care in patients with suspected coronary artery disease: A meta-analysis of randomized trials.

BACKGROUND: Controversies remain regarding clinical outcomes following initial strategies of coronary computed tomography angiography (CCTA) vs usual care with functional testing in patients with suspected coronary artery disease (CAD). HYPOTHESIS: CCTA as initial diagnostic strategy results in better mid- to long-term outcomes than usual care in patients with suspected CAD. METHODS: We searched PubMed, Embase, and Cochrane Library for randomized controlled trials comparing clinical outcomes during ≥6 months' follow-up between initial anatomical testing by CCTA vs usual care with functional testing in patients with suspected CAD. Occurrence of all-cause mortality, nonfatal myocardial infarction (MI), and major adverse cardiovascular events (MACE), and use of invasive coronary angiography and coronary revascularization, were compared between the 2 diagnostic strategies. RESULTS: Twelve trials were included (20 014 patients; mean follow-up, 20.5 months). Patients undergoing CCTA as initial noninvasive testing had lower risk of nonfatal MI compared with those treated with usual care (risk ratio [RR]: 0.70, 95% confidence interval [CI]: 0.52-0.94, P = 0.02). There was a tendency for reduced MACE following initial CCTA strategy, but not for risk of all-cause mortality. Compared with functional testing, the CCTA strategy increased use of invasive coronary angiography (RR: 1.53, 95% CI: 1.12-2.09, P = 0.007) and coronary revascularization (RR: 1.49, 95% CI: 1.11-2.00, P = 0.007). CONCLUSIONS: Anatomical testing with CCTA as the initial noninvasive diagnostic modality in patients with suspected CAD resulted in lower risk of nonfatal MI than usual care with functional testing, at the expense of more frequent use of invasive procedures.

Identification of differentially expressed proteins in the heart of translationally controlled tumor protein over-expressing transgenic mice.

We previously reported that transgenic (TG) mice over-expressing translationally controlled tumor protein (TCTP) developed systemic arterial hypertension at about 6 weeks after birth. In the present study, we identified, using proteomics technologies, 24 other proteins that were differentially expressed in the heart of TCTP over-expressing TG mice. These 24 proteins are involved in a variety of biological processes such as reactive oxygen species metabolism, cytoskeleton organization, fatty acid metabolism, amino acid metabolism and energy metabolism. We determined protein expression levels of the peroxiredoxin (Prx)2, Prx3, myosin light chain 1, stress protein (heat shock protein) 25K, and T-complex protein 1 alpha subunit by western blot analysis. Over-expression of TCTP probably regulates the expression of other proteins which play a pivotal role in a variety of cellular functions in TCTP over-expressing TG mice.

Transgenic overexpression of translationally controlled tumor protein induces systemic hypertension via repression of Na+,K+-ATPase.

Inhibition of Na(+),K(+)-ATPase has been implicated in the pathogenesis of hypertension via its effect on smooth muscle reactivity and myocardial contractility. We recently demonstrated that translationally controlled tumor protein (TCTP) interacts with the 3rd cytoplasmic domain of Na(+),K(+)-ATPase alpha(1)-subunit and acts as its cytoplasmic repressor. Therefore, we hypothesized that repression of Na(+),K(+)-ATPase by overexpressed TCTP might underlie the development of hypertension. In the present study, we confirmed that transgenic mice overexpressing TCTP developed systemic arterial hypertension at about 6 weeks after birth. Vascular smooth muscle of TCTP-overexpressing transgenic mice also displayed augmented contractile response to vasoconstrictors and attenuated relaxation response to vasodilators. These responses seem to be caused by reduced Na(+),K(+)-ATPase activity and increased intracellular calcium, suggesting that inhibition of Na(+),K(+)-ATPase by overexpression of TCTP is involved in the pathogenesis of hypertension. This study provides a new link between alteration of sodium pump activity and hypertension in vivo, and suggests that TCTP might be a therapeutic target for the treatment of hypertension.

Molecular mechanism of cofilin dephosphorylation by ouabain.

We previously reported that phosphorylated cofilin-triosephosphate isomerase (TPI) complex interacts with Na,K-ATPase and enhances the pump activity through the phosphorylation of cofilin via Rho-mediated signaling pathway. In this study, we tested the hypothesis that the dephosphorylation of cofilin may be induced through Na,K-ATPase inhibition by ouabain. The phosphorylation level of cofilin by ouabain which decreases in a time- and dose-dependent manner in various human cell lines, remains unchanged by pretreatment with Src inhibitor, PP2; epidermal growth factor receptor (EGFR) inhibitor, AG1478; Raf-1 kinase (Raf) inhibitor, GW5074; and ERK kinase (MEK) inhibitor, PD98059, and by transfection of Ras dominant negative mutant (RasN17). This suggests that ouabain dephosphorylates cofilin through the Src/EGFR/Ras/Raf/MEK pathway. Ouabain activates Ras/Raf/MEK pathway, but down-regulates Rho kinase (ROCK)/LIM kinase (LIMK)/cofilin pathway, implying that there may be a cross-talk by ouabain between the Ras/Raf/MEK and the ROCK/LIMK/cofilin pathways. Immunofluorescence and flow cytometry suggest that ouabain-induced active form of cofilin may be involved in cytoskeletal reorganization and cell volume regulation. Thus, these findings demonstrate a new molecular mechanism for the dephosphorylation of cofilin through the inhibition of Na,K-ATPase by ouabain.