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Aims/hypothesis: Although the benefits of sodium-glucose cotransporter 2 inhibitor (SGLT2i) use in chronic kidney disease (CKD) are well established, the effects of these therapeutic agents in patients with advanced CKD are less certain. We hypothesised that the continued use of these drugs, even when renal function deteriorates to stage 4 CKD or worse, is safe and associated with improved cardiorenal survival., Methods: This is a retrospective cohort study utilising data from medical records from two institutions. All patients with type 2 diabetes mellitus who were prescribed an SGLT2i between 1 January 2016 and 31 December 2021, who subsequently had eGFR <30 ml/min per 1.73 m 2 recorded on two occasions at least 90 days apart, were identified. The date on which the eGFR first reached any level less than 30 ml/min per 1.73 m 2 was defined as the index date. Individuals were then categorised into the SGLT2i continuation group or the discontinuation group according to the use of SGLT2i after the index date. Inverse probability of treatment weighting (IPTW) was performed to minimise confounding. Outcomes of interest included heart failure outcomes, cardiovascular outcomes, renal outcomes and safety outcomes., Results: According to the eligibility criteria, 337 patients in the continuation group and 358 in the discontinuation group were identified. After IPTW, continuation of SGLT2i use was associated with significantly lower risks of the composite of major adverse cardiovascular events compared with discontinuation of SGLT2i use (HR 0.65 [95% CI 0.43, 0.99]), largely driven by reduced risk of myocardial infarction during follow-up (subdistribution HR [SHR] 0.43 [95% CI 0.21, 0.89]). The incidences of an eGFR decline of 50% or more (SHR 0.58 [95% CI 0.42, 0.81]) and all-cause hospital admission (SHR 0.77 [95% CI 0.64, 0.94]) were also significantly lower in the continuation group. None of the studied safety outcomes were significantly different when comparing the two groups. Blood haemoglobin levels were significantly higher in the continuation group at the end of follow-up (114.6 g/l vs 110.4 g/l, with a difference of 4.12 g/l; p=0.047)., Conclusions/interpretation: In patients with CKD who were treated with an SGLT2i, continuation of SGLT2i use after eGFR declined to 30 ml/min per 1.73 m 2 or less was associated with lower risks of cardiovascular and renal events compared with discontinuation of SGLT2i use. Continued use of SGLT2i throughout the course of CKD should be considered to optimise patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are both recommended for patients with diabetes, yet their effects on the development or progression of diabetic retinopathy (DR) are largely unknown., Methods: In this retrospective cohort study, data were collected from a nationwide database. Patients with diabetes who initiated treatment with a GLP1RA or SGLT2i between 1 May 2016 and 31 December 2017, were identified. Patients were divided into those with or without a previous diagnosis of DR and then categorized into the GLP1RA and the SGLT2i groups according to drug use. The primary outcome of interest in the DR group was the composite of new-onset proliferative DR, vitreous haemorrhage and tractional retinal detachment (RD). In the non-DR group, the primary outcome was the composite of newly diagnosed DR of any severity, vitreous haemorrhage and RD., Results: In total, 97 413 patients were identified. After matching, 1517 patients were treated with a GLP1RA and 3034 with an SGLT2i in the DR cohort. In the non-DR cohort, 9549 initiated a GLP1RA and 19 098 initiated an SGLT2i. In patients with pre-existing DR, the incidence of any DR progression event was significantly higher in the GLP1RA group than the SGLT2i group (subdistribution hazard ratio 1.50, 95% confidence interval 1.01-2.23), primarily because of the increased risk of tractional RD. In patients without DR at baseline, the risks of all ocular outcomes were similar between the GLP1RA and SGLT2i groups., Conclusions: In patients with diabetes mellitus and established DR, GLP1RA treatment was associated with increased risks of DR progression compared with SGLT2i use., (© 2024 John Wiley & Sons Ltd.)

The left ventricular global longitudinal strain (LVGLS) is a crucial prognostic indicator. However, inconsistencies in measurements due to the speckle tracking algorithm and manual adjustments have hindered its standardization and democratization. To solve this issue, we proposed a fully automated strain measurement by artificial intelligence-assisted LV segmentation contours. The LV segmentation model was trained from echocardiograms of 368 adults (11,125 frames). We compared the registration-like effects of dynamic time warping (DTW) with speckle tracking on a synthetic echocardiographic dataset in experiment-1. In experiment-2, we enrolled 80 patients to compare the DTW method with commercially available software. In experiment-3, we combined the segmentation model and DTW method to create the artificial intelligence (AI)-DTW method, which was then tested on 40 patients with general LV morphology, 20 with dilated cardiomyopathy (DCMP), and 20 with transthyretin-associated cardiac amyloidosis (ATTR-CA), 20 with severe aortic stenosis (AS), and 20 with severe mitral regurgitation (MR). Experiments-1 and -2 revealed that the DTW method is consistent with dedicated software. In experiment-3, the AI-DTW strain method showed comparable results for general LV morphology (bias - 0.137 ± 0.398%), DCMP (- 0.397 ± 0.607%), ATTR-CA (0.095 ± 0.581%), AS (0.334 ± 0.358%), and MR (0.237 ± 0.490%). Moreover, the strain curves showed a high correlation in their characteristics, with R-squared values of 0.8879-0.9452 for those LV morphology in experiment-3. Measuring LVGLS through dynamic warping of segmentation contour is a feasible method compared to traditional tracking techniques. This approach has the potential to decrease the need for manual demarcation and make LVGLS measurements more efficient and user-friendly for daily practice., (© 2024. The Author(s).)

The purpose of the present study was to investigate the development of verapamil-induced cardiorenal failure and the response of epidermal ionocytes in zebrafish embryos to this syndrome. Zebrafish embryos were exposed to verapamil for 24 h at different developmental stages (48, 72, and 96 h post-fertilization). The exposure resulted in the generation of edema in the pericardial and yolk sac regions, with more-pronounced effects observed in later-stage embryos. Cardiac parameters showed a suppressed heart rate at all stages, with a more-significant effect appearing in later stages. Verapamil also affected cardiac parameters including the end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), and cardiac output (CO), indicating negative overall effects on cardiac performance. mRNA levels of heart failure markers (nppa and nppb genes) were upregulated in verapamil-exposed embryos at all stages. Renal function was impaired as FITC-dextran excretion was suppressed. A whole-embryo ion content analysis revealed significant increases in sodium and calcium contents in verapamil-exposed embryos. The density of epidermal ionocytes increased, and the apical membrane of ionocytes was enlarged, indicating upregulation of ion uptake. In addition, mRNA levels of several ion transporter genes (rhcg1, slc9a3, atp6v1a, atp2b1a, trpv6, and slc12a10.2) were significantly upregulated in verapamil-exposed embryos. In summary, prolonged exposure to verapamil can induce cardiorenal failure which triggers compensatory upregulation of ionocytes in zebrafish embryos., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Abscisic acid signaling has been implicated in plant responses to water deficit-induced osmotic stress. However, the underlying molecular mechanism remains unelucidated. This study identified the RING-type E3 ubiquitin ligase RING ZINC FINGER PROTEIN1 (PtrRZFP1) in poplar (Populus trichocarpa), a woody model plant. PtrRZFP1 encodes a ubiquitin E3 ligase that participates in protein ubiquitination. PtrRZFP1 mainly functions in the nucleus and endoplasmic reticulum and is activated by drought and abscisic acid. PtrRZFP1-overexpressing transgenic poplars (35S:PtrRZFP1) showed greater tolerance to drought, whereas PtrRZFP1-knockdown lines (KD-PtrRZFP1) showed greater sensitivity to drought. Under treatment with polyethylene glycol and abscisic acid, PtrRZFP1 promoted the production of NO and H2O2 in stomatal guard cells, ultimately enhancing stomatal closure and improving drought tolerance. Additionally, PtrRZFP1 physically interacted with the clade A Protein Phosphatase 2C protein PtrPP2C-9, a core regulator of abscisic acid signaling, and mediated its ubiquitination and eventual degradation through the ubiquitination-26S proteasome system, indicating that PtrRZFP1 positively regulates the abscisic acid signaling pathway. Furthermore, the PtrPP2C-9-overexpression line was insensitive to abscisic acid and more sensitive to drought than the wild-type plants, whereas the opposite phenotype was observed in 35S:PtrRZFP1 plants. In general, PtrRZFP1 negatively regulates the stability of PtrPP2C-9 to mediate poplar drought tolerance. The results of this study provide a theoretical framework for the targeted breeding of drought-tolerant traits in perennial woody plants., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To assess the effects of colchicine, which has been shown to reduce the risks of coronary artery disease but scarcely studied in peripheral artery disease (PAD), on major adverse limb events (MALE) in patients with PAD., Methods: This is a retrospective study based on a nationwide database. Patients who were diagnosed with PAD between 2010 and 2020 and prescribed with colchicine after the diagnosis of PAD were identified. Patients were then categorized into the colchicine or the control group according to drug use. Propensity score matching was performed to mitigate selection bias. Risks of MALE (including lower limb revascularization and nontraumatic amputation) and major adverse cardiovascular events were compared between the two groups., Results: After patient selection and propensity score matching, there were 60,219 patients in both colchicine and control groups. After a mean follow-up of 4.5 years, the risk of MALE was significantly lower in the colchicine group compared with control (subdistribution HR, 0.75; 95% CI, 0.71 to 0.80), as were the incidence of both components of MALE, lower limb revascularization and major amputations. Colchicine treatment was also associated with lower risk of cardiovascular death. The lower risk of MALE observed with colchicine therapy was accentuated in the subgroup of patients receiving concomitant urate-lowering medications., Conclusion: In patients diagnosed with PAD, the use of colchicine is associated with lower risks of MALE and cardiovascular death. Anti-inflammatory therapy with colchicine may provide benefits in vascular beds beyond the coronary arteries., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objectives: To delineate the effects of exposure to air pollution on the risk of venous thromboembolism (VTE)., Background: The association between air pollution and arterial occlusive diseases has been well reported in the literature. VTE is the third most common acute cardiovascular syndrome; however, its relationship with exposure to air pollution has been controversial., Methods: This study linked data from the Taiwan National Health Insurance Research Database with that from the Taiwan Environmental Protection Administration. Patients who were first admitted for VTE between January 1, 2001, and December 31, 2013, were analyzed. A time-stratified, case-crossover design was employed. Three different exposure periods were defined: exposure for 1 month, one quarter, and 1 year. Four control periods were designated for each exposure period. The association between exposure to air pollutants and the risk of VTE was tested using logistic regression analysis. Subgroup analyses were also performed, stratified by age, sex, type of VTE, the use of hormone therapy, and level of urbanization at the site of residence., Results: Exposures to particulate matter (PM) smaller than 2.5 µm (PM 2.5 ) and those smaller than 10 µm (PM 10 ) were associated with higher risks of VTE, with longer exposures associated with higher risk. The concentration of PM 2.5 exposure for 1 month was linearly associated with a greater risk of VTE up to 28.0 µg/m 3 , beyond which there was no association. PM 2.5 exposure for one quarter or 1 year remained significantly associated with higher risks of VTE at higher concentrations. The increased risk in VTE associated with exposure to PM 2.5 was more prominent in older patients and in patients not under hormone therapy. Similar results were observed for PM 10 exposures., Conclusions: Exposure to PM, particularly PM 2.5 , leads to an increased risk of VTE, with possible accumulative effects. With increased PM production in industrializing countries, the effects of PM on VTE occurrence warrant further attention., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Although the benefits of sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) are well established, patients with hemodynamically significant mitral regurgitation (MR) were excluded from pivotal trials. We aimed to assess the effects of sacubitril/valsartan on survival in patients with HFrEF and concomitant significant MR. All patients from a single center who underwent echocardiography between June 2008 and December 2020, with a left ventricular ejection fraction (LVEF) of less than 40% and hemodynamically significant MR were recruited. Patients were categorized according to drug use and year of the index echocardiogram into the angiotensin receptor/neprilysin inhibitor (ARNI), non-ARNI before 2017, and non-ARNI after 2017 groups. Patients in the ARNI and non-ARNI after 2017 groups were compared directly, whereas patients in the non-ARNI before 2017 group were matched to the ARNI group in a 3:1 ratio. The outcome of interest was all-cause mortality. Death was compared between the groups using univariate and multivariate Cox proportional hazard models. After exclusion by criteria and matching, there remained 610 patients in the ARNI group, 434 in the non-ARNI after 2017 group, and 1,722 in the non-ARNI before 2017 group. During follow-up, all-cause mortality was significantly lower in the ARNI group compared with both non-ARNI after 2017 and non-ARNI before 2017 groups. Multivariate analysis of both pairs of comparison between groups found the use of ARNI to be significantly associated with increased survival. In patients with HFrEF and concomitant significant MR, treatment with sacubitril/valsartan was associated with lower risks of all-cause death., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: While current guidelines recommend amiodarone and dronedarone for rhythm control in patients with atrial fibrillation (AF) and coronary artery disease (CAD), there was no comparative study of antiarrhythmic drugs (AADs) on the cardiovascular outcomes in general practice., Methods: This study included patients with AF and CAD who received their first prescription of amiodarone, class Ic AADs (flecainide, propafenone), dronedarone or sotalol between January 2016 and December 2020. The primary outcome was a composite of hospitalization for heart failure (HHF), stroke, acute myocardial infarction (AMI), and cardiovascular death. We used Cox proportional regression models, including with inverse probability of treatment weighting (IPTW), to estimate the relationship between AADs and cardiovascular outcomes., Results: Among the AF cohort consisting of 8752 patients, 1996 individuals had CAD, including 477 who took dronedarone and 1519 who took other AADs. After a median follow-up of 38 months, 46.3% of patients who took dronedarone and 54.4% of patients who took other AADs experienced cardiovascular events. Compared to dronedarone, the use of other AADs was associated with increased cardiovascular events after adjusting for covariates (hazard ratio [HR] 1.531, 95% confidence interval [CI] 1.112-2.141, p = 0.023) and IPTW (HR 1.491, 95% CI 1.174-1.992, p = 0.012). The secondary analysis showed that amiodarone and class Ic drugs were associated with an increased risk of HHF. The low number of subjects in the sotalol group limits data interpretation., Conclusion: For patients with AF and CAD, dronedarone was associated with better cardiovascular outcomes than other AADs. Amiodarone and class Ic AADs were associated with a higher risk of cardiovascular events, particularly HHF., Competing Interests: Declaration of competing interest The corresponding author has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of interests is none., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The ever-growing requirement for electrochemical energy storage has exacerbated the production of spent batteries, and the recycling of valuable battery components has recently received a remarkable attention. Among all battery components, copper foil is widely utilized as a current collector for stable zinc platting and stripping in zinc metal batteries (ZMBs) due to the perfect lattice matching of between metal copper and zinc, which is accompanied by the formation of multiple copper-zinc alloy components during the cycling process. Herein, a novel "two birds with one-stone" strategy through a one simple heat treatment step to revive the discarded copper foil in zinc metal battery is reported to further obtain a lithiophilic current collector (Cu x Zn y -Cu) with multiple copper-zinc alloy components on the surface of the discarded copper foil. Such revived Cu x Zn y -Cu current collector greatly reduces the lithium nucleation overpotential and realizes uniform lithium deposition and further inhibits lithium dendrites growth. The formed multiple Cu x Zn y alloy phases on the surface of discarded copper foil exhibit a low Li nucleation overpotential of only 15 mV at 0.5 mA cm -2 for the first cycle. Moreover, such a Cu x Zn y -Cu current collector could achieve stable cycle for 220 cycles at 0.5 mA cm -2 and 110 cycles at 1 mA cm -2 with a Li plating capacity of 1 mAh cm -2 . Theoretical calculations indicate that, compared with pure Cu foil, the formed multiple alloy components of CuZn 5 , CuZn 8 , Cu 0.61 Zn 0.39 and CuZn have low adsorption energy of -2.17, -2.55, -2.16 and -2.35 eV with lithium atoms, respectively, which result in reduced lithium nucleation overpotential. The full cell composed of Cu x Zn y alloy current collector with deposition of 5 mAh cm -2 metal Li anode coupled with LiFePO 4 (LFP) cathode exhibits a reversible capacity of 125.6 mAh/g after 110 cycles at a current of 0.5 C with capacity retention of 85.1 %. This work proposed a promising strategy to regenerate the discarded copper foil in rechargeable batteries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for ∼60% of CPVT patients which is inherited in an autosomal dominant pattern., Objective: This study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide., Methods: Clinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included., Results: This is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002)., Conclusion: The discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Several studies suggest an "obesity paradox," associating obesity with better cardiovascular outcomes in patients with type 2 diabetes mellitus (DM) or aortic stenosis (AS) compared to normal or underweight individuals. This study explores the impact of body mass index (BMI) on diabetic patients with AS., Methods: Between 2014 and 2019, patients with DM who underwent echocardiography were analyzed. Outcomes included all-cause mortality, cardiovascular, and non-cardiovascular death. Patients were categorized as underweight, normal weight, or obese based on BMI (<18.5, 18.5 to 27, and >27 kg/m2, respectively)., Results: Among 74,835 DM patients, 734 had AS. Normal weight comprised 65.5% (n=481), underweight 4.1% (N=30), and 30.4% were obese. Over a 6-year follow-up, underweight patients had significantly higher all-cause mortality (HR 1.96, 95% CI 1.22 - 3.14, p = 0.005), while obese patients had significantly lower mortality (HR 0.79, 95% CI 0.68 - 0.91, p=0.001) compared to the normal group. Regarding etiologies, underweight patients had a higher risk of non-cardiovascular death (HR 2.47, 95% CI 1.44-4.25, p = 0.001), while obese patients had a lower risk of cardiovascular death (HR 0.66, 95% CI 0.50-0.86, p=0.003). Subgroup analysis showed a consistent trend without significant interaction., Conclusions: BMI significantly impacts mortality in DM patients with AS. Being underweight is associated with worse non-cardiovascular death, while obesity is linked to improved cardiovascular death outcomes.

Background: Diastolic dysfunction and alterations in cardiac geometry are early indicators of diabetic cardiomyopathy. However, the association between cardiac changes across the glucose continuum and the contribution of epicardial adipose tissue (EAT) to these changes has not yet been investigated., Purpose: In this study, we aim to investigated the EAT on cardiac diastolic function and structural alterations along the diabetic continuum using cardiac magnetic resonance imaging (CMRI)., Methods: We enrolled individuals who were categorized into groups based on glucose tolerance status. Left ventricular structure and diastolic function were assessed using echocardiography and CMRI to determine the EAT, intramyocardial fat, and associated parameters. Multivariable logistic regression models were also used., Results: In a study of 370 patients (209 normal glucose tolerance, 82 prediabetes, 79 diabetes), those with prediabetes and diabetes showed increased heart dimensions and diastolic dysfunction, including E/E' (the ratio of early mitral inflow velocity to mitral annular early diastolic velocity) (7.9±0.51 vs. 8.5±0.64 vs. 10.0±0.93, p=0.010), left atrial volume index (28.21±14.7 vs. 33.2±12.8 vs. 37.4±8.2 mL/m2, p<0.001), and left ventricular peak filling rate (4.46±1.75 vs. 3.61±1.55 vs. 3.20±1.30 mL/s, p<0.001). EAT significantly increased in prediabetes and diabetes (26.3±1.16 vs. 31.3±1.83 vs. 33.9±1.9 gm, p=0.001), while intramyocardial fat did not differ significantly. Prediabetes altered heart geometry, but not diastolic function (OR 1.22 [1.02-1.83], p=0.012; and 1.70 [0.79-3.68], p=0.135). Diabetes significantly affected both heart structure and diastolic function (OR 1.42 [1.11-1.97], p=0.032; and 2.56 [1.03-5.40], p=0.034) after adjusting for covariates., Conclusions: Elevated EAT was observed in patients with prediabetes and is associated with adverse alterations in cardiac structure and diastolic function, potentially serving as an underlying mechanism for the early onset of diabetic cardiomyopathy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: The enhanced precision and selectivity of liquid chromatography-tandem mass spectrometry (LC-MS/MS) makes it an attractive alternative to certain clinical immunoassays. Easily transferrable work flows could help facilitate harmonization and ensure high-quality patient care. We aimed to evaluate the interlaboratory comparability of antibody-free multiplexed insulin and C-peptide LC-MS/MS measurements., Methods: The laboratories that comprise the Targeted Mass Spectrometry Assays for Diabetes and Obesity Research (TaMADOR) consortium verified the performance of a validated peptide-based assay (reproducibility, linearity, and lower limit of the measuring interval [LLMI]). An interlaboratory comparison study was then performed using shared calibrators, de-identified leftover laboratory samples, and reference materials., Results: During verification, the measurements were precise (2.7% to 3.7%CV), linear (4 to 15 ng/mL for C-peptide and 2 to 14 ng/mL for insulin), and sensitive (LLMI of 0.04 to 0.10 ng/mL for C-peptide and 0.03 ng/mL for insulin). Median imprecision across the 3 laboratories was 13.4% (inter-quartile range [IQR] 11.6%) for C-peptide and 22.2% (IQR 20.9%) for insulin using individual measurements, and 10.8% (IQR 8.7%) and 15.3% (IQR 14.9%) for C-peptide and insulin, respectively, when replicate measurements were averaged. Method comparison with the University of Missouri reference method for C-peptide demonstrated a robust linear correlation with a slope of 1.044 and r2 = 0.99., Conclusions: Our results suggest that combined LC-MS/MS measurements of C-peptide and insulin are robust and adaptable and that standardization with a reference measurement procedure could allow accurate and precise measurements across sites, which could be important to diabetes research and help patient care in the future., (Published by Oxford University Press on behalf of Association for Diagnostics & Laboratory Medicine 2024.)

Objective: Individuals with hyperthyroidism are at an increased risk of atrial fibrillation (AF), but the association between autoantibodies and AF or cardiovascular mortality in individuals who have returned to normal thyroid function remains unclear., Methods: The study utilized electronic medical records from National Taiwan University Hospital between 2000 and 2022. Each hyperthyroidism patient had at least 1 thyrotropin-binding inhibiting immunoglobulin (TBII) measurement. The relationship between TBII levels and the risk of AF and cardiovascular mortality was assessed using multivariable Cox regression models and Kaplan-Meier survival analysis., Results: Among the 14 618 enrolled patients over a 20-year timeframe, 173 individuals developed AF, while 46 experienced cardiovascular mortality. TBII values exceeding 35% were significantly associated with an elevated risk of AF for both the first TBII (hazard ratio {HR} 1.48 [1.05-2.08], P = .027) and mean TBII (HR 1.91 [1.37-2.65], P < .001). Furthermore, after free T4 levels had normalized, a borderline association between first TBII and AF (HR 1.59 [0.99-2.56], P = .056) was observed, while higher mean TBII increased AF (HR 1.78 [1.11-2.85], P = .017). Higher first and mean TBII burden continued to significantly impact the incidence of cardiovascular mortality (HR 6.73 [1.42-31.82], P = .016; 7.87 [1.66-37.20], P = .009). Kaplan-Meier analysis demonstrated that elevated TBII levels increased the risk of AF and cardiac mortality (log-rank P = .035 and .027, respectively)., Conclusion: In euthyroid individuals following antithyroid treatment, elevated circulating TBII levels and burden are associated with an elevated risk of long-term incident AF and cardiovascular mortality. Further reduction of TBII level below 35% will benefit to clinical outcomes., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Uncertainties have grown around the world during the last few decades. Pandemic uncertainty has a substantial impact on economic activities, which may have a big influence on energy consumption. The goal of this investigation is to appraise the asymmetric influence of pandemic uncertainty on nonrenewable and renewable energy consumption in the top 10 energy consumer economies of the European Union (Germany, Poland, Spain, Netherlands, France, Italy, Belgium, Sweden, Czech Republic, and Finland). Previously, panel data approaches were utilized to obtain reliable outcomes on the pandemic-energy consumption nexus, regardless of the fact that various nations did not autonomously exhibit similar relationship. This investigation, on the other hand, implements a special technique "Quantile-on-Quantile" that supports us to appraise time-series interdependence in each economy by providing international yet nation-specific perceptions of the connection among the variables. Estimates show that pandemic uncertainty reduces both nonrenewable and renewable energy consumption in most selected nations at stated quantiles of the data distribution. Nonrenewable energy consumption is much more influenced by pandemic uncertainty than renewable energy consumption. Furthermore, the rank of asymmetries across our variables differentiates by the economy, emphasizing the need for decisionmakers to pay much attention to pandemics-related uncertainty and the energy sector., (© 2023 Society for Risk Analysis.)

Background: Lacosamide is frequently used as a mono- or adjunctive therapy for the treatment of adults with epilepsy. Although lacosamide is known to act on both neuronal and cardiac sodium channels, potentially leading to cardiac arrhythmias, including Brugada syndrome (BrS), its adverse effects in individuals with genetic susceptibility are less understood., Case: We report a 33-year-old female with underlying epilepsy who presented to the emergency department with a four-day history of seizure clusters, and was initially treated with lacosamide therapy. During the intravenous lacosamide infusion, the patient developed sudden cardiac arrest caused by ventricular arrhythmias necessitating resuscitation. Of note, the patient had a family history of sudden cardiac death. Workup including routine laboratory results, 12-lead electrocardiogram (ECG), echocardiogram, and coronary angiogram was non-specific. However, a characteristic type 1 Brugada ECG pattern was identified by ajmaline provocation testing; thus, confirming the diagnosis of BrS. Subsequently, the genotypic diagnosis was confirmed by Sanger sequencing, which revealed a heterozygous mutation (c.2893C>T, p.Arg965Cys) in the SCN5A gene. Eventually, the patient underwent implantable cardioverter-defibrillator implantation and was discharged with full neurological recovery., Conclusion: This case highlights a rare but lethal adverse event associated with lacosamide treatment in patients with genetic susceptibility. Further research is warranted to investigate the interactions between lacosamide and SCN5A variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Shen, Wu, Lin, Chang, Su and Juang.)

Objective: To explore the related factors influencing the detection rate of mosaic embryo and the pregnancy outcomes of mosaic embryo transfer in preimplantation genetic testing for aneuploidy (PGT-A) based on next generation sequencing (NGS) technology. Methods: A retrospective study was performed to analyze the clinical data of patients in 745 PGT-A cycles from January 2019 to May 2023 at Chongqing Health Center for Women and Children, including 2 850 blastocysts. The biopsy cells were tested using NGS technology, and the embryos were divided into three groups based on the test results, namely euploid embryos, aneuploid embryos and mosaic embryos. The influence of population characteristics and laboratory-related parameters on the detection rate of mosaic embryo were analyzed, and the pregnancy outcomes of 98 mosaic embryo transfer cycles and 486 euploid embryo transfer cycles were compared during the same period, including clinical pregnancy rate and live birth rate. Results: Among the embryos tested ( n =2 850), the number and proportion of euploid embryos, aneuploid embryos and mosaic embryos were 1 489 (52.2%, 1 489/2 850), 917 (32.2%, 917/2 850) and 444 (15.6%, 444/2 850), respectively. Among mosaic embryos, 245 (55.2%, 245/444) were segmental mosaic embryos, 118 (26.6%, 118/444) were whole-chromosome mosaic embryos, and 81 (18.2%, 81/444) were complex mosaic embryos. NGS technology was performed in 4 genetic testing institutions and the detection rate of mosaic embryo fluctuated from 13.5% to 27.0%. The distributions of female age, level of anti-Müllerian hormone, PGT-A indications, ovulation-inducing treatments, gonadotropin (Gn) dosage, Gn days, inner cell mass grade, trophectoderm cell grade, genetic testing institutions and developmental stage of blastocyst were significantly different among the three groups (all P < 0.05). Multi-factor analysis showed that the trophectoderm cell grade and genetic testing institutions were significantly related to the detection rate of mosaic embryo; compared with the trophectoderm cell graded as A, the detection rate of mosaic embryo was significantly increased in the trophectoderm cell graded as B-( OR =1.59, 95% CI : 1.04-2.44, P =0.033); compared with genetic testing institution a, the detection rate of mosaic embryo was significantly higher ( OR =2.89, 95% CI : 2.10-3.98, P < 0.001) in the testing institution c. The clinical pregnancy rate and live birth rate with mosaic embryos transfer were significantly lower than those of euploid embryos transfer (clinical pregnancy rate: 51.0% vs 65.2%, P =0.008; live birth rate: 39.4% vs 53.2%, P =0.017). After adjustment for age, PGT-A indications, trophectoderm cell grade and days of embryo culture in vitro, the clinical pregnancy rate and live birth rate with mosaic embryos transfer were significantly lower than those of euploid embryos transfer (clinical pregnancy rate: OR =0.52, 95% CI : 0.32-0.83, P =0.007; live birth rate: OR =0.50, 95% CI : 0.31-0.83, P =0.007). Conclusions: The trophectoderm cell grade and genetic testing institutions are related to the detection rate of mosaic embryo. Compared with euploid embryos transfer, the clinical pregnancy rate and live birth rate with mosaic embryos transfer are significantly reduced. For infertile couple without euploid embryos, transplantable mosaic embryos could be recommended according to the mosaic ratio and mosaic type in genetic counseling to obtain the optimal pregnancy outcome.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Atrial fibrillation (AF) recurrence rates in 1 year after cryoballoon ablation catheter (CBCA) are still high. We purposed to identify strong predictors for AF recurrence after the successful CBCA procedure and develop a new scoring system based only on pre-procedural parameters., Methods: In the derivation phase, a systematic review and meta-analysis identified the strong predictors of AF recurrence after the CBCA. The pooled hazard ratio (HR) was used to create the new scoring system. The second phase validated the new scoring system in the cohort population., Results: A meta-analysis including 29 cohort studies with 16196 participants confirmed that persistent AF, stroke, heart failure, and left atrial diameter (LAD) >40 mm were powerful predictors for AF recurrence after the CBCA procedure. The HeLPS-Cryo (heart failure [1], left atrial dilatation [1], persistent AF [2], and stroke [2]) was developed based on those pre-procedural predictors. It was validated in 140 patients receiving CBCA procedures and revealed excellent predictive performance for 1-year AF recurrence (AUC = 0.8877; 95% CI = 0.8208 to 0.9546). The HeLPS-Cryo score of ≥3 could predict 1-year AF recurrence with sensitivity and specificity of 78.9% and 87.9%, respectively. The positive predictive value was 66.7%, and the negative predictive value was 93.1%., Conclusion: The HeLPS-Cryo score can help the physician estimate the probability of 1-year AF recurrence after the successful CBCA procedure. Patients with HeLPS-Cryo score <3 are good candidates for the CBCA procedure., (© 2024 Wiley Periodicals LLC.)

Objective: Deep vein thrombosis (DVT) formation of lower extremities can lead to serious complications including pulmonary embolism (PE) and chronic post-thrombotic syndrome (PTS). We aimed to explore the relationship between the ratio of thrombotic density and the occurrence of PE and PTS in patients with DVT of the lower extremities., Methods: A retrospective analysis was conducted in patients who performed computed tomography venography, dividing into DVT with PE group (54 patients) and DVT-alone group (34 patients), The clinical data were recorded. Univariate and multivariate logistic regression analysis were used to analysis variables associated with PE. The ability of thrombosis density ratio and Wells score to diagnose PE was evaluated by using the receiver operating characteristic curve (ROC) area under the curve (AUC). According to the treatment and follow-up results, subgroup analysis was performed, and the Villata score was used to determine the presence or absence of PTS and its severity., Results: Compare with the DVT-alone group, more patients had dyspnea and chest pain in the DVT with PE group. DVT with PE group had lower the percentage of neutrophils, white blood cell count and platelet count, while had higher blood cell count, D-dimer, wells score, thrombus and thrombus density ratio. Multivariate logistic analysis showed that percentage of neutrophils (OR(95% CIs)=1.15 (1.01,1.31), P = 0.040), platelets (OR(95% CIs)=0.96 (0.93,0.99), P = 0.011), and thrombus density ratio (OR(95% CIs)=5.99 (1.96,18.35), P = 0.002) are independent predictors of PE. The Wells score and thrombosis density ratio were consistent in the diagnostic efficacy of PE. In the subgroup analysis, there was a relevance between the ratio of thrombosis density and the Villalta score., Conclusion: Percentage of neutrophils, platelets, and thrombus density ratio are independent predictors of PE. The thrombosis density of DVT patients may be an index to predict the risk of PE and PTS in DVT patients.

Low-intensity transcranial ultrasound stimulation (LITUS) is a novel non-invasive neuromodulation technique. We conducted a systematic review to evaluate current evidence on the efficacy and safety of LITUS neuromodulation. Five databases were searched from inception to May 31, 2023. Randomized controlled human trials and controlled animal studies were included. The neuromodulation effects of LITUS on clinical or pre-clinical, neurophysiological, neuroimaging, histological and biochemical outcomes, and adverse events were summarized. In total, 11 human studies and 44 animal studies were identified. LITUS demonstrated therapeutic efficacy in neurological disorders, psychiatric disorders, pain, sleep disorders and hypertension. LITUS-related changes in neuronal structure and cortical activity were found. From histological and biochemical perspectives, prominent findings included suppressing the inflammatory response and facilitating neurogenesis. No adverse effects were reported in controlled animal studies included in our review, while reversible headache, nausea, and vomiting were reported in a few human subjects. Overall, LITUS alleviates various symptoms and modulates associated brain circuits without major side effects. Future research needs to establish a solid therapeutic framework for LITUS., Competing Interests: Declaration of Competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: In patients with atrial fibrillation (AF) and end-stage renal disease (ESRD), oral anticoagulants are contraindicated, and left atrial appendage occlusion (LAAO) is an alternative treatment. However, the efficacy of thromboembolic prevention using LAAO in these patients has rarely been reported in Asian populations. To our knowledge, this is the first long-term LAAO study in patients with AF undergoing dialysis in Asia., Methods: In this study, 310 patients (179 men) with a mean age of 71.3 ± 9.6 years and mean CHA2DS2-VASc 4.2 ± 1.8 were consecutively enrolled at multiple centers in Taiwan. The outcomes of 29 patients with AF and ESRD undergoing dialysis who underwent LAAO were compared to those without ESRD. The primary composite outcomes were stroke, systemic embolization, or death., Results: No difference in mean CHADS-VASc score was noted between patients with versus without ESRD (4.1 ± 1.8 vs. 4.6 ± 1.9, p = 0.453). After a mean follow-up of 38 ± 16 months, the composite endpoint was significantly higher in patients with ESRD (hazard ratio, 5.12 [1.4-18.6]; p = 0.013) than in those without ESRD after LAAO therapy. Mortality was also higher in patients with ESRD (hazard ratio, 6.6 [1.1-39.7]; p = 0.038). The stroke rate was numerically higher in patients with versus without ESRD, but the difference was not statistically significant (hazard ratio, 3.2 [0.6-17.7]; p = 0.183). Additionally, ESRD was associated with device-related thrombosis (odds ratio, 6.15; p = 0.047)., Conclusion: Long-term outcomes of LAAO therapy may be less favorable in patients with AF undergoing dialysis, possibly because of the poor condition of patients with ESRD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Prostate cancer (PCa) is the most common non-skin cancer among men in the United States. However, the widely used protein biomarker in PCa, prostate-specific antigen (PSA), while useful for initial detection, its use alone cannot detect aggressive PCa and can lead to overtreatment. This chapter provides an overview of PCa protein biomarker development. It reviews the state-of-the-art liquid chromatography-mass spectrometry-based proteomics technologies for PCa biomarker development, such as enhancing the detection sensitivity of low-abundance proteins through antibody-based or antibody-independent protein/peptide enrichment, enriching post-translational modifications such as glycosylation as well as information-rich extracellular vesicles, and increasing accuracy and throughput using advanced data acquisition methodologies. This chapter also summarizes recent PCa biomarker validation studies that applied those techniques in diverse specimen types, including cell lines, tissues, proximal fluids, urine, and blood, developing novel protein biomarkers for various clinical applications, including early detection and diagnosis, prognosis, and therapeutic intervention of PCa., (Copyright © 2024. Published by Elsevier Inc.)