Human life expectancy and season of birth in Taiwan: A retrospective cohort study.

Prior research has indicated a correlation between the birth season and life expectancy; however, many of these studies did not sufficiently account for comorbidities. In this comprehensive investigation, we aimed to meticulously explore the association between the birth month and life expectancy, giving due consideration to comorbidities. We used a robust dataset derived from Taiwan's National Health Insurance Research Database (2000-2013), which allowed us to conduct a thorough examination. We divided our participants into four groups based on their season of birth: spring, summer, autumn, and winter. Propensity score matching was used to ensure an equitable distribution of demographic and clinical characteristics across the groups. Propensity scores were computed using logistic regression. Our model incorporated a broad range of demographic factors and comorbidities, providing rigorous adjustment for potential confounders. Our findings revealed a significantly increased risk of all-cause mortality among individuals born in spring, even after stringent adjustment for demographic factors and comorbidities. People born in spring demonstrated a 1.05-fold increase in the risk of all-cause mortality, with a hazard ratio of 1.05 and a 95% confidence interval of 1.01-1.09. Our study provides compelling evidence that helps understand the potential long-term impacts of a person's birth season, which acts as a proxy for pregnancy / early-life environmental exposure, on life expectancy. These findings underscore the crucial need for additional research to illuminate the underlying biological and environmental mechanisms linking the birth season and lifespan of a person. The elucidation of these links could guide the development of innovative health promotion and disease prevention strategies that are tailored to an individual's birth season.

Hypoxia inducible factor (HIF) 3α prevents COPD by inhibiting alveolar epithelial cell ferroptosis via the HIF-3α-GPx4 axis.

Rationale: COPD patients are largely asymptomatic until the late stages when prognosis is generally poor. In this study, we shifted the focus to pre-COPD and smoking stages, and found enrichment of hypoxia inducible factor (HIF)-3α is in pre-COPD samples. Smoking induced regional tissue hypoxia and emphysema have been found in COPD patients. However, the mechanisms underlying hypoxia especially HIF-3α and COPD have not been investigated. Methods: We performed bulk-RNA sequencing on 36 peripheral lung tissue specimens from non-smokers, smokers, pre-COPD and COPD patients, and using "Mfuzz" algorithm to analysis the dataset dynamically. GSE171541 and EpCAM co-localization analyses were used to explore HIF-3α localization. Further, SftpcCreert2/+R26LSL-Hif3a knock-in mice and small molecular inhibitors in vitro were used to explore the involvement of HIF-3α in the pathophysiology of COPD. Results: Reactive oxygen species (ROS) and hypoxia were enriched in pre-COPD samples, and HIF-3α was downregulated in alveolar epithelial cells in COPD. In vitro experiments using lentivirus transfection, bulk-RNA seq, and RSL3 showed that the activation of the HIF-3α-GPx4 axis inhibited alveolar epithelial cell ferroptosis when treated with cigarettes smoking extracts (CSE). Further results from SftpcCreert2/+R26LSL-Hif3a knock-in mice demonstrated overexpression of HIF-3α inhibited alveolar epithelial cells ferroptosis and prevented the decline of lung function. Conclusion: Hypoxia and oxidation-related damage begins years before the onset of COPD symptoms, suggesting the imbalance and impairment of intracellular homeostatic system. The activation of the HIF-3α-GPx4 axis is a promising treatment target. By leveraging this comprehensive analysis method, more potential targets could be found and enhancing our understanding of the pathogenesis.

Single cell sequencing reveals cellular landscape alterations in the airway mucosa of patients with pulmonary long COVID.

To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who reported persistent pulmonary symptoms.Adults with and without long COVID were recruited from the general community in Greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID (PLC), which was defined as persons with new or worsening respiratory symptoms following at least one year from their initial acute SARS-CoV-2 infection (N=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had no history of acute COVID-19 (N=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced.A total of 56 906 cells were recovered for the downstream analysis, with 34 840 cells belonging to the PLC group, which strikingly showed a unique cluster of neutrophils in the PLC group (p<0.05). Ingenuity Pathway Analysis revealed that the neutrophil degranulation pathway was enriched across epithelial cell clusters. Differential gene expression analysis between the PLC and control groups demonstrated upregulation of inflammatory chemokines and epithelial barrier dysfunction across epithelial cell clusters, as well as over-expression of mucin genes across secretory cell clusters.In conclusion, a single-cell transcriptomic landscape of the small airways suggest that neutrophils may play a significant role in mediating the chronic small airway inflammation driving pulmonary symptoms of long COVID.

Origin of Pinning Disorder in Magnetic-Field-Induced Wigner Solids.

At low Landau level filling factors (ν), Wigner solid phases of two-dimensional electron systems in GaAs are pinned by disorder and exhibit a pinning mode, whose frequency is a measure of the disorder that pins the Wigner solid. Despite numerous studies spanning the past three decades, the origin of the disorder that causes the pinning and determines the pinning mode frequency remains unknown. Here, we present a study of the pinning mode resonance in the low-ν Wigner solid phases of a series of ultralow-disorder GaAs quantum wells which are similar except for their varying well widths d. The pinning mode frequencies f_{p} decrease strongly as d increases, with the widest well exhibiting f_{p} as low as ≃35 MHz. The amount of reduction of f_{p} with increasing d can be explained remarkably well by tails of the wave function impinging into the alloy-disordered Al_{x}Ga_{1-x}As barriers that contain the electrons. However, it is imperative that the model for the confinement and wave function includes the Coulomb repulsion in the growth direction between the electrons as they occupy the quantum well.

Evaluation of non-additive genetic effects on carcass and meat quality traits in Korean Hanwoo cattle using genomic models.

The traditional genetic evaluation methods generally consider additive genetic effects only and often ignore non-additive (dominance and epistasis) effects that may have contributed to genetic variation of complex traits of livestock species. The available dense single nucleotide polymorphisms (SNPs) panels offer to investigate the potential benefits of including non-additive genetic effects in the genomic evaluation models. Data from 16 971 genotyped (Illumina Bovine 50 K SNP chip) Korean Hanwoo cattle were used to estimate genetic variance components and prediction accuracy of genomic breeding values (GEBVs) for four carcass and meat quality traits: carcass weight (CWT), eye muscle area (EMA), back fat thickness (BFT) and marbling score (MS). Five different genetic models were evaluated through including additive, dominance and epistatic interactions (additive by additive, A × A; additive by dominance, A × D and dominance by dominance, D × D) successively in the models. The estimates of additive genetic variances and narrow sense heritabilities (ha2) were found similar across the evaluated models and traits except when additive interaction (A × A) was included. The dominance variance estimates relative to phenotypic variance ranged from 1.7-3.4% for CWT and MS traits, whereas, they were close to zero for EMA and BFT traits. The magnitude of A × A epistatic heritability (haa2) ranged between 14.8 and 27.7% in all traits. However, heritability estimates for A × D and D × D epistatic interactions (had2 and hdd2) were quite low compared to haa2 and were contributed only 0.0-9.7% of the total phenotypic variation. In general, broad sense heritability (hG2) estimates were almost twice (ranging between 0.54 and 0.68) the ha2 for all of the investigated traits. The inclusion of dominance effects did not improve the prediction accuracy of GEBV but improved 2.0-3.0% when epistatic effects were included in the model. More importantly, rank correlation revealed that partitioning of variance components considering dominance and epistatic effects in the model would enable to re-rank of top animals with better prediction of GEBV. The present result suggests that dominance and epistatic effects could be included in the genomic evaluation model for better estimates of variance components and more accurate prediction of GEBV for carcass and meat quality traits in Korean Hanwoo cattle.

Clinical characteristics and management of orbital apex syndrome: a 10-year multicentre experience.

BACKGROUND: Orbital apex syndrome (OAS) is a condition characterised by lesions within the orbital apex, leading to various ophthalmologic symptoms. This study aimed to analyse the clinical characteristics and treatment strategies of OAS with respect to aetiology. METHODS: This retrospective analysis utilised data from 5 medical institutions between 2013 and 2022. Patients who were diagnosed with OAS were initially enrolled, but patients who failed to follow up at least 1 month were excluded. The prevalence of initial ophthalmologic symptoms and visual improvement after treatment was compared according to aetiology. Factors related to visual improvement were analysed. RESULTS: Among 73 enrolled patients, the leading aetiology was tumours, followed by fungal infections and inflammation. Visual impairment and proptosis were prevalent in tumour-related OAS cases. Inflammation-related OAS exhibited a higher likelihood of painful eye movements and ophthalmoplegia. Ptosis was most frequently observed in fungal infection-related OAS. Notably, fungal infections emerged as the sole significant factor negatively impacting vision progression. In inflammation-related OAS, the time interval between symptom onset and the administration of steroids was longer in patients without visual improvement, even though there was no statistically significant difference. CONCLUSIONS: Tumours were the predominant cause of OAS. Visual impairment was a common manifestation in tumour-related OAS, while fungal infections were strongly associated with a poor visual prognosis. The timely administration of steroids might be helpful for improving vision in patients with inflammation-related OAS. However, further studies are needed to enhance understanding and management of OAS.

Signatures of Correlated Defects in an Ultraclean Wigner Crystal in the Extreme Quantum Limit.

Low-disorder two-dimensional electron systems in the presence of a strong, perpendicular magnetic field terminate at very small Landau level filling factors in a Wigner crystal (WC), where the electrons form an ordered array to minimize the Coulomb repulsion. The nature of this exotic, many-body, quantum phase is yet to be fully understood and experimentally revealed. Here we probe one of WC's most fundamental parameters, namely, the energy gap that determines its low-temperature conductivity, in record mobility, ultrahigh-purity, two-dimensional electrons confined to GaAs quantum wells. The WC domains in these samples contain ≃1000 electrons. The measured gaps are a factor of three larger than previously reported for lower quality samples, and agree remarkably well with values predicted for the lowest-energy, intrinsic, hypercorrelated bubble defects in a WC made of flux-electron composite fermions, rather than bare electrons. The agreement is particularly noteworthy, given that the calculations are done for disorder-free composite fermion WCs, and there are no adjustable parameters. The results reflect the exceptionally high quality of the samples, and suggest that composite fermion WCs are indeed more stable compared to their electron counterparts.

High-fidelity initialization and control of electron and nuclear spins in a four-qubit register.

Single electron spins bound to multi-phosphorus nuclear spin registers in silicon have demonstrated fast (0.8 ns) two-qubit SWAP gates and long spin relaxation times (~30 s). In these spin registers, when the donors are ionized, the nuclear spins remain weakly coupled to their environment, allowing exceptionally long coherence times. When the electron is present, the hyperfine interaction allows coupling of the spin and charge degrees of freedom for fast qubit operation and control. Here we demonstrate the use of the hyperfine interaction to enact electric dipole spin resonance to realize high-fidelity ( F = 10 0 - 6 + 0 %) initialization of all the nuclear spins within a four-qubit nuclear spin register. By controllably initializing the nuclear spins to ⇓ ⇓ ⇓ , we achieve single-electron qubit gate fidelities of F = 99.78 ± 0.07% (Clifford gate fidelities of 99.58 ± 0.14%), above the fault-tolerant threshold for the surface code with a coherence time of T 2 * = 12 µ s .

Outcome of Contemporary Nonsurgical Endodontic Retreatment: A Systematic Review of Randomized Controlled Trials and Cohort Studies.

INTRODUCTION: The success rates of NS-ReTx have varied across decades of prior research. Nonetheless, recent endodontic advances have substantially enhanced case management. This systematic review aimed to identify rigorous studies on contemporary NS-ReTx, investigating both periapical healing-evaluated strictly for complete resolution or loosely for size reduction of periapical radiolucency-and success, denoting clinical normalcy combined with periapical healing. METHODS: We systematically searched MEDLINE, Embase, Web of Science, the Cochrane Library, and gray literature from January 1988 to December 2022. Article selection and data extraction were independently conducted by 3 reviewers. Selected studies underwent risk of bias assessment, and evidence quality using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Meta-analysis and meta-regression established pooled outcome rates, 95% confidence intervals (CIs), and significant clinical prognostic factors (P < .05). RESULTS: Twenty-nine articles were included. Pooled periapical healing rates using strict and loose criteria were 78.8% (95% CI: 75.2-82.4) and 87.5% (95% CI: 83.8-91.2), respectively. Pooled success rates using strict and loose criteria were 78.0% (95% CI: 74.9-81.2) and 86.4% (95% CI: 82.6-90.1), respectively. Meta-regression analyses revealed significant influences on NS-ReTx outcomes (P < .05), including periapical status, lesion size, apical root filling extent, and follow-up duration. CONCLUSIONS: Contemporary NS-ReTx shows encouraging outcomes, achieving periapical healing and success rates ranging from approximately 78% (strict criteria) to 87% (loose criteria). The absence of or smaller preoperative lesions, adequate root filling length, and extended follow-ups significantly improve NS-ReTx outcomes. Integrating these factors into treatment planning is pivotal for optimizing the outcome of NS-ReTx.

Prescription characteristics of Xue-Fu-Zhu-Yu-Tang in pain management: a population-based study using the National Health Insurance Research Database in Taiwan.

Objective: To explore the prevalence and distinctive features of Xue-Fu-Zhu-Yu-Tang (XFZYT) prescriptions by analyzing the National Health Insurance Research Database (NHIRD) to identify the specific medical problems for which XFZYT is prescribed. Methods: This nationwide, population-based, cross-sectional study included 109,073 XFZYT users and 532,848 XFZYT non-users among Chinese herbal product (CHP) users in NHIRD. Chi-squared tests were used to analyze disparities between the XFZYT user and XFZYT non-user cohorts, and the mean age was evaluated using the Wilcoxon rank-sum test. Logistic regression was used to compute the odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: XFZYT was frequently used to treat pain. The top five conditions for which the Taiwanese traditional Chinese medicine (TCM) practitioners would prescribe XFZYT were chest pain; headache; myalgia and myositis; lumbago; and neuralgia, neuritis, and radiculitis. Conclusion: This study represents an inaugural comprehensive survey conducted on the utilization of XFZYT prescriptions among patients with diverse diseases. XFZYT is mostly used to treat pain conditions in Taiwan. Combined with the combination use of other CHPs, XFZYT is used to treat symptoms of the chest and respiratory system, soft tissue conditions, menstruation disorders, and joint and back discomfort. These results suggest that further clinical trials are warranted to verify the effects of XFZYT in pain management.

Development of Allison scanner to measure transverse emittance at low energy beam transport of rare-isotope accelerator complex for ON-line experiments.

The Rare-isotope Accelerator complex for ON-line experiments is a heavy-ion accelerator facility that accelerates a stable or rare isotope beam up to 400 kW with an energy of 200 MeV/u. Various heavy-ion beams are generated from the Electron Cyclotron Resonance Ion Source, with an energy of 10 keV/u and separated according to A/Q at the first dipole magnet (DM). To measure beam transverse emittance at the Low Energy Beam Transport section, two Allison scanners are installed behind the DM for the X and Y directions. It consist of a servo motor for driving, a Faraday cup for current measurement, deflection plates, and electronic device. The measurable range of beam angle in of the Allison scanner is determined by the structure of the deflection plate and designed based on mathematical calculations. Experimental Physics and Industrial Control System (EPICS) is adopted to integrate and control a variety of devices. To control the complex measurement sequence of the Allison scanner, an EPICS sequencer module was used. Normalized emittance is calculated by python code with Pyepics module using phase space distribution data. In this paper, we present the detailed design of the Allison scanner, the configuration of the control system, and the experimental results using an Ar9+ 30 µA beam.

Moving Crystal Phases of a Quantum Wigner Solid in an Ultra-High-Quality 2D Electron System.

In low-disorder, two-dimensional electron systems (2DESs), the fractional quantum Hall states at very small Landau level fillings (ν) terminate in a Wigner solid (WS) phase, where electrons arrange themselves in a periodic array. The WS is typically pinned by the residual disorder sites and manifests an insulating behavior, with nonlinear current-voltage (I-V) and noise characteristics. We report here measurements on an ultralow-disorder, dilute 2DES, confined to a GaAs quantum well. In the ν<1/5 range, superimposed on a highly insulating longitudinal resistance, the 2DES exhibits a developing fractional quantum Hall state at ν=1/7, attesting to its exceptional high quality and dominance of electron-electron interaction in the low filling regime. In the nearby insulating phases, we observe remarkable nonlinear I-V and noise characteristics as a function of increasing current, with current thresholds delineating three distinct phases of the WS: a pinned phase (P1) with very small noise, a second phase (P2) in which dV/dI fluctuates between positive and negative values and is accompanied by very high noise, and a third phase (P3) where dV/dI is nearly constant and small, and noise is about an order of magnitude lower than in P2. In the depinned (P2 and P3) phases, the noise spectrum also reveals well-defined peaks at frequencies that vary linearly with the applied current, suggestive of washboard frequencies. We discuss the data in light of a recent theory that proposes different dynamic phases for a driven WS.

Development of a unilateral porcine emphysema model induced by porcine pancreatic elastase.

Emphysema is one of the pathological hallmarks of chronic obstructive pulmonary disease. We have recently reported that radiofrequency therapy improves lung function in rodent models of emphysema. However, preclinical data using large animals is necessary for clinical translation. Here, we describe the work performed to establish a unilateral porcine emphysema model. Different doses of porcine pancreatic elastase (PPE) were instilled into the left lung of 10 Yucatan pigs. Three additional pigs were used as controls. Six weeks after instillation, lungs were harvested. Lung compliance was measured by a water displacement method and plethysmography. Systematic uniform random sampling of the left and right lungs was performed independently to measure alveolar surface area using micro-computed tomography (micro-CT) and histology. In pigs instilled with 725-750 U/kg of PPE (PPE group, n = 6), the compliance of the left lung was significantly higher by 37.6% than that of the right lung (P = 0.03) using the water displacement method. With plethysmography, the volume of the left lung was significantly larger than that of the right lung at 3, 5, and 10 cmH2O. Measurements from either micro-CT or histology images showed a significant decrease in alveolar surface area by 14.2% or 14.5% (P = 0.031) in the left lung compared with the right lung of the PPE group. A unilateral model for mild emphysema in Yucatan pigs has been established, which can now be used for evaluating novel therapeutics and interventional strategies.NEW & NOTEWORTHY For clinical translation, preclinical data using large animal models is necessary. However, papers describing an emphysema model in pigs, which are anatomically and physiologically similar to humans, are lacking. Here, we report success in creating a unilateral mild-emphysema model in pigs with only one single dose of porcine pancreatic elastase. This model will be useful in bringing novel technologies and therapies from small animals to humans with emphysema.

Highly Anisotropic Even-Denominator Fractional Quantum Hall State in an Orbitally Coupled Half-Filled Landau Level.

The even-denominator fractional quantum Hall states (FQHSs) in half-filled Landau levels are generally believed to host non-Abelian quasiparticles and be of potential use in topological quantum computing. Of particular interest is the competition and interplay between the even-denominator FQHSs and other ground states, such as anisotropic phases and composite fermion Fermi seas. Here, we report the observation of an even-denominator fractional quantum Hall state with highly anisotropic in-plane transport coefficients at Landau level filling factor ν=3/2. We observe this state in an ultra-high-quality GaAs two-dimensional hole system when a large in-plane magnetic field is applied. By increasing the in-plane field, we observe a sharp transition from an isotropic composite fermion Fermi sea to an anisotropic even-denominator FQHS. Our data and calculations suggest that a unique feature of two-dimensional holes, namely the coupling between heavy-hole and light-hole states, combines different orbital components in the wave function of one Landau level, and leads to the emergence of a highly anisotropic even-denominator fractional quantum Hall state. Our results demonstrate that the GaAs two-dimensional hole system is a unique platform for the exploration of exotic, many-body ground states.

Influence of antipsychotic medications on hyperlipidemia risk in patients with schizophrenia: evidence from a population-based cohort study and in vitro hepatic lipid homeostasis gene expression.

Introduction: Schizophrenia increases the risk of mortality and cardiovascular disease (CVD) risk. However, the correlation between antipsychotics (APs) and CVD remains controversial. Hyperlipidemia is a significant risk factor for CVD. Methods: We conducted a nationwide population-based retrospective cohort study to investigate the effects of APs on the risk of hyperlipidemia and lipid homeostasis gene expression. We used data from the Longitudinal Health Insurance Database of Taiwan on new-onset schizophrenia patients and a comparison cohort without schizophrenia. We used a Cox proportional hazards regression model to analyze the differences in hyperlipidemia development between the two cohorts. Furthermore, we examined the effects of APs on the hepatic expression of lipid homeostasis-related genes. Results: After adjusting for potential interrelated confounding factors, the case group (N = 4,533) was found to have a higher hyperlipidemia risk than the control cohort (N = 4,533) [adjusted hazard ratio (aHR), 1.30, p < 0.001]. Patients with schizophrenia without APs had a significantly higher risk of hyperlipidemia (aHR, 2.16; p < 0.001). However, patients receiving APs had a significantly lower risk of hyperlipidemia than patients not receiving APs (all aHR ≤ 0.42, p < 0.001). First-generation antipsychotics (FGAs) induce the expression of hepatic lipid catabolism genes in an in vitro model. Discussion: Patients with schizophrenia had a higher risk of hyperlipidemia than controls; however, compared with non-treated patients, AP users had a lower risk of hyperlipidemia. Early diagnosis and management of hyperlipidemia may help prevent CVD.

Delocalization and Universality of the Fractional Quantum Hall Plateau-to-Plateau Transitions.

Disorder and electron-electron interaction play essential roles in the physics of electron systems in condensed matter. In two-dimensional, quantum Hall systems, extensive studies of disorder-induced localization have led to the emergence of a scaling picture with a single extended state, characterized by a power-law divergence of the localization length in the zero-temperature limit. Experimentally, scaling has been investigated via measuring the temperature dependence of plateau-to-plateau transitions between the integer quantum Hall states (IQHSs), yielding a critical exponent κ≃0.42. Here we report scaling measurements in the fractional quantum Hall state (FQHS) regime where interaction plays a dominant role. Our Letter is partly motivated by recent calculations, based on the composite fermion theory, that suggest identical critical exponents in both IQHS and FQHS cases to the extent that the interaction between composite fermions is negligible. The samples used in our experiments are two-dimensional electron systems confined to GaAs quantum wells of exceptionally high quality. We find that κ varies for transitions between different FQHSs observed on the flanks of Landau level filling factor ν=1/2 and has a value close to that reported for the IQHS transitions only for a limited number of transitions between high-order FQHSs with intermediate strength. We discuss possible origins of the nonuniversal κ observed in our experiments.

Glucagon-like Peptide-1 Receptor Agonist Use in Patients With Liver Cirrhosis and Type 2 Diabetes.

BACKGROUND AND AIMS: Liver cirrhosis is often associated with type 2 diabetes (T2D), but research on treatment of T2D in cirrhotic patients is scarce. We investigated the long-term outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with T2D and cirrhosis. METHODS: Using propensity score matching, we selected 467 matched pairs of GLP-1 RA users and nonusers from the National Health Insurance Research Database of Taiwan from January 1, 2008, to December 31, 2019. Multivariable-adjusted Cox proportional hazards models were used to compare the outcomes between GLP-1 RA users and nonusers. RESULTS: The mean follow-up time was 3.28 and 3.06 years for GLP-1 RA users and nonusers, respectively. The rates of death were 27.46 and 55.90 per 1000 person-years for GLP-1 RA users and nonusers, respectively. The multivariable-adjusted models showed that GLP-1 RA users had lower risks of mortality (adjusted hazard ratio [aHR], 0.47; 95% confidence interval [CI], 0.32-0.69), cardiovascular events (aHR, 0.6; 95% CI, 0.41-0.87), decompensated cirrhosis (aHR, 0.7; 95% CI, 0.49-0.99), hepatic encephalopathy (aHR, 0.59; 95% CI, 0.36-0.97), and liver failure (aHR, 0.54; 95% CI, 0.34-0.85) than nonusers. A longer cumulative duration of GLP-1 RA use had a lower risk of these outcomes than GLP-1 RA nonuse. CONCLUSIONS: This population-based cohort study showed that GLP-1 RA users exhibited a significantly lower risk of death, cardiovascular events, decompensated cirrhosis, hepatic encephalopathy, and liver failure in patients with T2D and compensated liver cirrhosis. Additional studies are needed to confirm our results.

Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation.

Introduction: A potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship. Methods: We extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated. Results: After adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ. Discussion: Our study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM.