Risk of Dementia and Alzheimer's Disease Associated With Antidiabetics: A Bayesian Network Meta-Analysis.

INTRODUCTION: Dementia risk is substantially elevated in patients with diabetes. However, evidence on dementia risk associated with various antidiabetic regimens is still limited. This study aims to comprehensively investigate the risk of dementia and Alzheimer's disease (AD) associated with various antidiabetic classes. METHODS: Cochrane Central Register of Controlled Trials, Embase, MEDLINE (PubMed), and Scopus were searched from inception to March 2024 (PROSPERO CRD 42022365927). Observational studies investigating dementia and AD incidences after antidiabetic initiation were identified. Bayesian network meta-analysis was performed to determine dementia and AD risks associated with antidiabetics. Preferred Reporting Items for Systematic Reviews-Network Meta-Analyses (PRISMA-NMA) guidelines were followed. Statistical analysis was performed and updated in November 2023 and March 2024, respectively. RESULTS: A total of 1,565,245 patients from 16 studies were included. Dementia and AD risks were significantly lower with metformin and sodium glucose co-transporter-2 inhibitors (SGLT2i). Metformin displayed the lowest risk of dementia across diverse antidiabetics, whereas α-glucosidase inhibitors demonstrated the highest risk. SGLT2i exhibited the lowest dementia risk across second-line antidiabetics. Dementia risk was significantly higher with dipeptidyl peptidase-4 inhibitor (DPP4i), metformin, sulfonylureas, and thiazolidinediones (TZD) compared to SGLT2i in the elderly (≥75 years). Dementia risk associated with metformin was substantially lower, regardless of diabetic complication status or baseline A1C. DISCUSSION: Metformin and SGLT2i demonstrated lower dementia risk than other antidiabetic classes. Patient-specific factors may affect this relationship and cautious interpretation is warranted as metformin is typically initiated at an earlier stage with fewer complications. Hence, further large-scaled clinical trials are required.

A nationwide pharmacovigilance investigation on trends and seriousness of adverse events induced by anti-obesity medication.

Introduction: Despite rising concerns regarding the safety of anti-obesity medications, there is a lack of comprehensive pharmacovigilance investigations utilising real-world data. We aimed to characterise the prevalence and seriousness of adverse drug events (ADEs) related to anti-obesity medications and to identify predictors associated with increased risk of serious adverse events (SAE), thereby conveying evidence on drug safety. Methods: We conducted a cross-sectional analysis on ADE cases spontaneously reported to the Korea Adverse Event Reporting System Database (KIDS-KD). ADE reports pertaining to anti-obesity medications prescribed for overweight, obesity (International Classification of Disease, 10th revision (ICD-10) code E66) and abnormal weight gain (ICD-10 code E63.5) were included in the analysis. We performed a disproportionality to detect the association of the system organ class-based ADEs with their seriousness an individual's sex by estimating reporting odds ratios (RORs) and their 95% confidence intervals (CIs). We performed logistic regression to investigate factors that are substantially associated with increased SAE risks by estimating odds ratio (OR) and their 95% CIs. Results: The most common causative anti-obesity medication was phentermine, followed by liraglutide. ADEs associated with psychiatric disorders (ROR = 1.734; 95% CI = 1.111-2.707), liver and biliary system disorders (ROR = 22.948; 95% CI = 6.613-70.635), cardiovascular disorders (ROR = 5.707; 95% CI = 1.965-16.574), and respiratory disorders (ROR = 4.567; 95% CI = 1.774-11.762) were more likely to be serious events. Additionally, men are more likely to experience ADEs related gastrointestinal disorders (ROR = 1.411) and less likely to have heart and rhythm disorders (ROR = 0.507). The risk of SAE incidences was positively correlated with being male (OR = 2.196; 95% CI = 1.296-3.721), dual or triple combination of anti-obesity medications (OR = 3.258; 95% CI = 1.633-6.501 and OR = 8.226; 95% CI = 3.046-22.218, respectively), and concomitant administration of fluoxetine (OR = 5.236; 95% CI = 2.218-12.365). Conclusions: Seriousness of anti-obesity medication-related ADEs differs among system-organ class, while sex-related differences in ADE profiles are also present. The predictors substantially increasing risk of SAE incidences include being male, having a higher number of concomitant medications (including multiple combination of anti-obesity medications), and concurrent use of fluoxetine. Nonetheless, further pharmacovigilance investigation and monitoring are needed to enhance awareness on ADEs induced by anti-obesity medications.

The Effect of Boron (B) and Copper (Cu) on the Microstructure and Graphite Morphology of Spheroidal Graphite Cast Iron.

This study examines the impacts of copper and boron in parts per million (ppm) on the microstructure and mechanical properties of spheroidal graphite cast iron (SCI). Boron's inclusion increases the ferrite content whereas copper augments the stability of pearlite. The interaction between the two significantly influences the ferrite content. Differential scanning calorimetry (DSC) analysis indicates that boron alters the enthalpy change of the α + Fe3C → γ conversion and the α → γ conversion. Scanning electron microscope (SEM) analysis confirms the locations of copper and boron. Mechanical property assessments using a universal testing machine show that the inclusion of boron and copper decreases the tensile strength and yield strength of SCI, but simultaneously enhances elongation. Additionally, in SCI production, the utilization of copper-bearing scrap and trace amounts of boron-containing scrap metal, especially in the casting of ferritic nodular cast iron, offers potential for resource recycling. This highlights the importance of resource conservation and recycling in advancing sustainable manufacturing practices. These findings provide critical insights into the effects of boron and copper on SCI's behavior, contributing to the design and development of high-performance SCI materials.

Clinical outcomes of renin angiotensin system inhibitor-based dual antihypertensive regimens in chronic kidney disease: a network meta-analysis.

This study comprehensively investigated clinical outcomes associated with renin angiotensin system inhibitor-based dual antihypertensive regimens in non-dialysis chronic kidney disease (CKD) patients. Keyword searches of databases were performed per PRISMA-NMA guidelines. Frequentist network meta-analysis were conducted with 16 head-to-head randomized controlled trials. The effect sizes of dichotomous and continuous variables were estimated with odds ratio (OR) and standard mean differences (SMD), respectively. The protocol is registered in PROSPERO (CRD42022365927). Dual antihypertensive regimens with combination of angiotensin receptor blockers (ARB) and calcium channel blockers (CCB) demonstrated substantially reduced odd of major cardiovascular disease (CVD) events over other regimens including angiotensin converting enzyme inhibitor (ACEI) monotherapy (OR 3.19) and ARB monotherapy (OR 2.64). Most significant reductions in systolic (SBP) and diastolic blood pressure (DBP) were observed with ARB-based CCB dual regimen over ACEI monotherapy (SMD 17.60 SBP and 9.40 for DBP), ACEI-based CCB regimen (SMD 12.90 for SBP and 9.90 for DBP), and ARB monotherapy (SMD 13.20 for SBP and 5.00 for DBP). However, insignificant differences were noticed for the odds of hyperkalemia, end stage renal disease progression, and all-cause mortality. ARB-based CCB regimen has the greatest benefits on BP reduction as well as major CVD risks in non-dialysis CKD patients.

A Real-World Data Derived Pharmacovigilance Assessment on Drug-Induced Nephropathy: Implication on Gaps in Patient Care.

This retrospective cross-sectional study aims to investigate the prevalence and seriousness of drug-induced nephrotoxicity and to identify clinical predictors intensifying the seriousness of nephrotoxicity. Adverse drug events (ADEs) reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were investigated. The association between the seriousness and the etiologic drug was estimated in reporting odds ratio (ROR) based on disproportionality analysis. Logistic regression was utilized to recognize predictors associated with serious nephrotoxicity. The majority of ADEs were reported in ages 30 to 59, and immunosuppressants were the most etiologic medications. ADEs involving antibiotics, including vancomycin (ROR 0.268; 95% CI 0.129-0.557), were less likely to be serious. More than 93% of cyclosporine-related ADEs were serious nephrotoxicity, whereas tacrolimus was less likely to report serious nephrotoxicity (ROR 0.356; 95% CI 0.187-0.680). The risk of serious nephrotoxicity was decreased with aging (ROR 0.955; 95% CI 0.940-0.972) while increased in women (OR 2.700; 95% CI 1.450-5.008). Polypharmacy was associated with increased risk of interstitial nephritis (OR 1.019; 95% CI 1.001-1.038). However, further studies investigating the impact of clinical practice on ADE incidences as well as clinical prognosis related to nephrotoxicity are obligated.

Safety Assessment on Serious Adverse Events of Targeted Therapeutic Agents Prescribed for RAS Wild-Type Metastatic Colorectal Cancer: Systematic Review and Network Meta-Analysis.

Despite substantially elevated risk of serious adverse events (SAEs) from targeted therapy in combination with chemotherapy, comprehensive pharmacovigilance research is limited. This study aims to systematically assess SAE risks of commonly prescribed targeted agents (bevacizumab, cetuximab, and panitumumab) in patients with rat sarcoma viral oncogene homolog (RAS) wild-type metastatic colon cancer. Keyword searches of Cochrane Library, Clinical Key and MEDLINE were conducted per PRISMA-NMA guidelines. Frequentist network meta-analysis was performed with eight randomized controlled trials to compare relative risk (RR) of 21 SAE profiles. The risks of hematological, gastrointestinal, neurological SAE were insignificant among targeted agents (p > 0.05). The risk of serious hypertension was substantially elevated in bevacizumab-based chemotherapy (p < 0.05), whereas panitumumab-based chemotherapy had markedly elevated risk of serious thromboembolism (RR 3.65; 95% CI 1.30−10.26). Although both cetuximab and panitumumab demonstrated increased risk of serious dermatological and renal toxicities, panitumumab-based chemotherapy has relatively higher risk of skin toxicity (RR 15.22; 95% CI 7.17−32.35), mucositis (RR 3.18; 95% CI 1.52−6.65), hypomagnesemia (RR 20.10; 95% CI 5.92−68.21), and dehydration (RR 2.81; 95% CI 1.03−7.67) than cetuximab-based chemotherapy. Thus, further studies on risk stratification and SAE management are warranted for safe administration of targeted agents.

Age-dependent shifts and spatial variation in the diet of endangered Black-faced Spoonbill (Platalea minor) chicks.

The endangered Black-faced Spoonbill (Platalea minor) strictly breeds in marine environments and is threatened by the rapid loss of coastal wetlands within its breeding range. Adults with chicks are thought to gradually switch feeding sites from freshwater wetlands to coastal mudflats as the chicks' osmoregulatory system develops. We investigated age-dependent shifts in the diet of Black-faced Spoonbill chicks at four breeding colonies with varying freshwater habitat availability by examining stable isotopes (δ13C, δ15N) between the tip (grown at the age of 10 days) and middle (grown at the age of 22 days) portions of their primary feathers. The δ13C value of the middle portions was significantly higher than that of the tips, which suggested that the ratio of marine resources increased with the growth and development of chicks. A Bayesian isotope mixing model revealed that the diet proportion of marine prey in the early-chick rearing season was slightly higher than in the late-chick rearing season at three colonies in inshore areas, although this proportion was approximately 60% even in the early chick-rearing period. In contrast, isotopic values and reconstructed diet composition suggested that chicks in an offshore colony with limited freshwater wetlands relied more heavily on freshwater diets for both chick-rearing periods (>80%). Our results suggest that the shifts in feeding sites seen in previous studies might be related to the age-dependent dietary shift of chicks, highlighting the importance of freshwater wetlands for spoonbills on offshore islands without an inflow of freshwater in nearby intertidal mudflats. These findings emphasize the importance of freshwater prey and wetlands even for the endangered marine-breeding spoonbills, even though the negative impact of salt stress remains inconclusive.

Predicting climate-driven shifts in the breeding phenology of Varied Tits (Sittiparus various) in South Korean forests.

Phenological shifts of plants and animals due to climate change can vary among regions and species, requiring study of local ecosystems to understand specific impacts. The reproductive timing of insectivorous songbirds in temperate forests is tightly synchronized with peak prey abundance, and thus they can be susceptible to such shift in timing. We aimed to investigate the effect of future climate change on the egg-laying phenology of the Varied Tit (Sittiparus various), which is common and widely distributed in South Korean forests. We developed the predictive model by investigating their egg-laying dates in response to spring temperatures along geographical gradients, and our model indicated that the tits lay eggs earlier when the average of daily mean and daily maximum temperatures rise. We predicted future shifts in egg-laying dates based on the most recent climate change model published by the Intergovernmental Panel on Climate Change (IPCC), under a scenario with no climate change mitigation and under a scenario with moderate mitigation. Under this outcome, this species might be unable to adapt to rapid climate change due to asynchrony with prey species during the reproductive period. If no mitigation is undertaken, our model predicts that egg-laying dates will be advanced by more than 10 days compared to the present in 83.58% of South Korea. However, even moderate mitigation will arrest this phenomenon and maintain present egg-laying dates. These results demonstrate the first quantitative assessment for the effect of warming temperatures on the phenological response of insectivorous songbirds in South Korea.

High-Temperature Stable Operation of Nanoribbon Field-Effect Transistors.

We experimentally demonstrated that nanoribbon field-effect transistors can be used for stable high-temperature applications. The on-current level of the nanoribbon FETs decreases at elevated temperatures due to the degradation of the electron mobility. We propose two methods of compensating for the variation of the current level with the temperature in the range of 25-150°C, involving the application of a suitable (1) positive or (2) negative substrate bias. These two methods were compared by two-dimensional numerical simulations. Although both approaches show constant on-state current saturation characteristics over the proposed temperature range, the latter shows an improvement in the off-state control of up to five orders of magnitude (-5.2 × 10(-6)).

Synthesis and properties of acyclic ammonium-based ionic liquids with allyl substituents as electrolytes.

Several new acyclic ammonium-TFSI ionic liquids with an allyl substituent(s) were synthesized and their physicochemical and electrochemical properties were characterized. [AAMM]Am-TFSI (3) with two allyl groups showed the widest electrochemical stability window (5.9 V) among the ammonium-based ILs reported to date because of the increment of both the anodic and cathodic limits. The charge-discharge performance of a LiCoO(2)-based half-cell containing [AAMM]Am-TFSI as an electrolyte was better in cycleability (the capacity retention ratio: 99% after 20 cycles) than that of the cell with the corresponding partially saturated analogue, [AMMP]Am-TFSI (2) (the capacity retention ratio: 92% after 20 cycles).

Nitric oxide mediates membrane depolarization-promoted survival of rat neuronal PC12 cells.

Membrane depolarization promotes neuronal survival through increases in intracellular calcium. Nitric oxide (NO) is a signaling molecule involved in many neuronal activity-dependent events. Since neuronal NO is generated by NO synthase (NOS) in a calcium-dependent manner and was shown to promote cell survival, we tested whether NO is involved in depolarization-promoted survival in neuronally differentiated PC12 cells. NOS inhibitor attenuated depolarization-promoted survival and NO donors promoted survival. This effect was partially cGMP-dependent as a guanylyl cyclase inhibitor decreased NO-promoted survival. Ras inhibitor, Erk blocker or phosphatidylinositol 3-kinase inhibitor decreased depolarization- or NO donor-promoted survival. Depolarization-induced Ras activation was blocked by NOS inhibitor. Inducible expression of dominant negative Ras or S-nitrosylation-defective Ras attenuated depolarization- or NO donor-promoted survival. Thus, NO might be a mediator via Ras and cGMP pathways in depolarization-promoted survival in neuronal PC12 cells.