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Background Mapping disease rates is an important aspect of epidemiological research because it helps inform public health policy. Disease maps are often drawn according to local administrative areas (LAAs), such as counties, cities, or towns. In LAAs with small populations, disease rates are unstable and are prone to appear extremely high or low. The empirical Bayes methods consider variance differences among different LAAs, thereby stabilizing the disease rates. The methods of kriging break the constraints of geopolitical boundaries and produce a smooth curved surface in the form of contour lines, but the methods lack the stabilizing effect of the empirical Bayes methods. Methods An easy-to-implement stabilized kriging method is proposed to map disease rates, which allows different errors in different LAAs. Results Monte Carlo simulations revealed that the stabilized kriging method had smaller symmetric mean absolute percentage error than three other types of methods (original LAA-based method, empirical Bayes methods, and traditional kriging methods) in nearly all scenarios considered. Real-world data analysis of oral cancer incidence rates in men from Taiwan demonstrated that the age-standardized rates in the central mountainous sparsely-populated region of Taiwan were stabilized using our proposed method, with no more large differences in numerical values, whereas the rates in other populous regions were not over smoothed. Additionally, the stabilized kriging map had improved resolution and helped locate several hot and cold spots in the incidence rates of oral cancer. Conclusions We recommend the use of the stabilized kriging method for mapping disease rates.

Background Effects of the major ginsenoside Rg1 on mammalian longevity and physical vitality are rarely reported. Purpose To examine longevity, tumor, and spontaneous locomotor activity in rats consuming Rg1. Methods A total of 138 Wistar rats were randomized into 2 groups: control (N = 69) and Rg1 (N = 69). Rg1 (0.1 mg/kg per day) were orally supplemented from 6 months of age until natural death. Spontaneous mobility was measured by video-tracking together with body composition (dual energy x-ray absorptiometry) and inflammation markers at 5, 14, 21, and 28 months of age. Results No significant differences in longevity (control: 706 days; Rg1: 651 days, p = 0.77) and tumor incidence (control: 19%; Rg1: 12%, p = 0.24) were observed between the two groups. Movement distance in the control group declined significantly by ∼60% at 21 months of age, together with decreased TNF-α (p = 0.01) and increased IL-10 (p = 0.02). However, the movement distance in the Rg1 group was maintained ∼50% above the control groups (p = 0.01) at 21 months of age with greater magnitudes of TNF-α decreases and IL-10 increases. Glucose, insulin, and body composition (bone, muscle and fat percentages) were similar for both groups during the entire observation period. Conclusion The results of the study suggest a delay age-dependent decline in physical vitality during late life by lifelong Rg1 consumption. This improvement is associated with inflammatory modulation. Significant effects of Rg1 on longevity and tumorigenesis were not observed.

Background Before 2010, guidelines recommended adenosine 6, 12, and a repeat dose of 12 mg for paroxysmal supraventricular tachycardia (PSVT). After 2010, these doses were reduced to two. This study aims to outline adenosine using trend from 2000 to 2012 in Taiwan emergency departments (EDs). Methods This was an ecological study. PSVT were drawn from one million individuals of the National Health Insurance Database. The χ2 test was used to determine an association between different adenosine doses and other antiarrhythmic drugs (OADs), including verapamil, diltiazem, amiodarone, digoxin, and labetalol. Results There were 3361 PSVT visits from 2000 to 2012; 834 (24.8%) did not receive an antiarrhythmic drug, and 2527 (75.2%) did, either adenosine with/without OADs or OADs alone. The use of an OAD was significantly different between the adenosine 6–18 mg and 19 + mg groups. Conclusions Most PSVT episodes converted with adenosine within 18 mg, and the success conversion rate was 62.2%. It could be up to 65.2% if they received more. Of the patients who did not have their PSVT reverted with

An 81-year-old woman with no history of immunocompromise presented with 2 days of upper abdominal pain associated with nausea. On arrival, her physical examination was unremarkable apart from mild epigastric and right hypochondriac tenderness, and laboratory investigations were unremarkable apart from mild thrombocytopenia and transaminitis. A CT scan performed on the day of admission revealed a tiny 0.3 cm stone in the common bile duct, with no upstream dilatation. On day 2 of admission, she developed a vesicular rash and with acutely worsening transaminitis. She deteriorated rapidly and demised from complications of acute liver failure within the next 24 hours. The diagnosis of varicella was confirmed with antibody testing. Fulminant varicella hepatitis is an extremely rare and lethal condition with only a handful of reported cases in the current literature. We aim to share our clinical experience and summarise the salient points from existing case reports.

BACKGROUND Geographic isolation and travel distance to specialist care is a known social determinant of health and contributes to poorer oncology survival outcomes. AIMS Our objective was to compare survival and toxicity outcomes for patients travelling long distances (>50 km) for treatment on clinical trials with local patients (

Muscle strength after detraining is still higher than the level before training, which is an important issue for middle-aged and older adults. The purpose of the present study was to examine the effects of detraining duration (DD), resistance training duration (RTD), and intensity on the maintenance of resistance training (RT) benefits after detraining in middle-aged and older adults. A systematic search yielded 15 randomized control trails (n = 383) eligible for inclusion. The results showed that RTD ≥ 24 weeks and DD ≥ RTD, the RT benefits were still significantly maintained even with medium and low intensity (standardized mean difference = 1.16, 95% confidence interval, CI [0.38, 1.94], p = .004). When RTD p = .0002; DD 8–16 weeks: standardized mean difference = 1.35, 95% CI [0.66, 2.04], p = .0001). However, when DD > RTD, the RT benefits were not maintained even with high intensity. In summary, when RTD was less than 24 weeks, RTD > DD was an important factor in maintaining muscle strength.

BACKGROUND Atherosclerosis and vascular inflammatory response have been considered as risk factors for non-typhoidal Salmonella (NTS) vascular infection. The study aims to assess the risk of vascular infection by measuring atherosclerosis severity, NTS vascular infection (NTSVI) score, and serum levels of inflammatory markers in people with NTS bacteremia. METHODS A prospective observational study was conducted in two medical centers and two regional hospitals. Adults aged ≥50 years with NTS bacteremia who underwent computed tomography (CT) scan for revealing vascular infections were enrolled. The degree of atherosclerosis was scaled by a calcium score determined by a CT scan. Serum concentrations of inflammatory biomarkers were determined in the patients enrolled in a medical center. RESULTS Fourteen (20.3%) of 69 patients with NTS bacteremia had vascular infections. Calcium scores over the thoracic (12,540 vs. 3,261, P = 0.0005) and abdominal (9755 vs. 3,461, P = 0.0006) aorta of those with vascular infections were higher than those without vascular infection. All vascular infections were present in the high-risk group (NTSVI score ≥1), yielding a sensitivity of 100% and specificity of 30.9%. Among 17 low-risk patients (NTSVI score

Glucagon-like peptide-1(GLP-1) is a multifunctional polypeptide throughout the lifespan via activating Glucagon-like peptide-1 receptor (GLP-1R).GLP-1 can affect food ingestion, enhance the secretion of insulin from pancreatic islets induced by glucose and be utilized to treat type 2 diabetes mellitus(T2DM).But, accumulating evidences from the decades suggest that activation GLP-1R can not only regulate the blood glucose, but also sustain the homeostasis of intracellular environment and protect neuron from various damaged responses such as oxidative stress, inflammation, excitotoxicity, ischemia and so on. And more and more pre-clinical and clinical studies identified that GLP-1 and its analogues may play a significant role in improving multiple central nervous system (CNS) diseases including neurodegenerative diseases, epilepsy, mental disorders, ischemic stroke, hemorrhagic stroke, traumatic brain injury, spinal cord injury, chronic pain, addictive disorders, other diseases neurological complications and so on. In order to better reveal the relationship between GLP-1/GLP-1R axis and the growth, development and survival of neurons, herein, this review is aimed to summarize the multi-function of GLP-1/GLP-1R axis in CNS diseases.

Background Interstitial lung disease (ILD) is associated with substantial morbidity and mortality, which is one of the key systematic manifestations of connective tissue disease (CTD). Tripterygium wilfordii, known as Leigongteng in Chinese, has been applied to treat connective tissue disease-related interstitial lung disease (CTD-ILD) for many years. Triptolide is a key effective component from Tripterygium wilfordii. But the molecular mechanism of Triptolide for treating CTD-ILD is not yet clear. Methods Gaining insight into the molecular mechanism of Triptolide intervention CTD-ILD, we used the method of network pharmacology. And then we conducted drug-target networks to analyse the potential protein targets between Triptolide and CTD-ILD. Finally, AutoDock Vina was selected for molecular docking. Results By analysing the interaction genes between Triptolide and CTD-ILD, 242 genes were obtained. The top 10 targets of the highest enrichment scores were STAT3, AKT1, MAPK1, IL6, TP53, MAPK3, RELA, TNF, JUN, JAK2. GO and KEGG enrichment analysis exhibited that multiple signalling pathways were involved. PI3K-Akt, multiple virus infections, cancer signalling, chemokine, and apoptosis signalling pathway are the main pathways for Triptolide intervention CTD-ILD. And it is related to various biological processes such as inflammation, infection, cell apoptosis, and cancer. Molecular docking shows Triptolide can bind with its target protein in a good bond by intermolecular force. Conclusions This study preliminarily reveals the internal molecular mechanism of Triptolide interfere with CTD-ILD through multiple targets, multiple access, validated through molecular docking.KEY MESSAGES Triptolide intervention CTD-ILD, which are related to various biological processes such as inflammation, infection, cell apoptosis, and cancer. PI3K-Akt, multiple virus infections, and apoptosis signalling pathway are the main pathways for Triptolide intervention CTD-ILD. Triptolide can bind with related target protein in a good bond by Intermolecular force, exhibiting a good docking activity.

Background: Rhabdomyolysis (RM) associated acute kidney injury (AKI) is the most common systemic complication of RM. The present study aimed to assess the clinical characteristics and risk factors for intensive care unit (ICU) transfer for patients with RM-associated AKI.Methods: We included all patients who were age ≥ 18 years old with a diagnosis of RM from September 2012 to October 2018 and divided them into RM-associated AKI group and RM without AKI group. The primary outcome was transferring to ICU treatment. Regression analysis was performed to identify factors associated with ICU treatment and recovery of renal function.Results: Among the 149 patients with RM, 68 (45.6%) developed AKI. The percentage of patients with AKI who transferred to ICU was higher than patients without AKI (33.8% versus 12.3%, P < 0.002). Additionally, patients with AKI had higher percentage of undergoing dialysis (19.1% versus 2.5%, P < 0.01), all-cause mortality (13.2% versus 1.2%, P < 0.01), cost of hospitalization [10.8 1,000 yuan, IQR (5.5, 3.5) versus 5.9 1,000 yuan, IQR 5.9 (3.6, 9.9), P = 0.03], as well as longer length of hospital stay [8.0 (5.0, 14.0)] versus [6.0 (4.0, 11.0)], P = 0.02). Moreover, most patients with AKI achieved complete recovery (77.9%) at discharge. After adjusting for potential risk factors, RM-associated AKI remained an independent risk factor for ICU transfer (OR = 3.0, 95% CI, 1.11–8.3, P = 0.03). However, ICU transfer was not associated with recovery of renal function (OR = 0.88, 95% CI, 0.22–3.57, P = 0.856).Conclusion: RM leaded to AKI in most patients. RM-associated AKI could cause worse clinical outcome and predict ICU transfer for patients with RM.

To report three-decade changes of clinical characteristics, progress of treatments, and risk factors associated with mortality and enucleation in patients with retinoblastoma in China.Retrospective cohort study.This multicenter study included 2552 patients diagnosed with retinoblastoma in 38 medical centers in 31 provinces in China from 1989 to 2017, with follow-up data. Kendall's tau-b value was used to describe correlation coefficients between the three eras (between 1989 and 2008, between 2009 and 2013, and between 2014 and 2017) and clinical or demographic features. Hazard ratios and odds ratios were applied to measure risk factors.A total of 324 (13%) patients died and 1414 (42%) eyes were removed. The 1-year, 3-year, and 5-year overall survival rates were 95%, 86%, and 83%, respectively. Patients were diagnosed at a better stage by International Classification for Retinoblastoma over time (Kendall's tau-b value = -0.084, P.001). Pathological risk factors were also observed less in recent eras. New conservative therapies were adopted and used in more patients. The eye removal rate gradually decreased (Kendall's tau-b value = -0.167, P.001). The overall survival rates were 81%, 83%, and 91% in the three eras. By multivariate Cox regression, bilateral tumors and extraocular extension were identified as risk factors for death. Among intraocular disease, Group E indicated higher risk of mortality. By multivariate logistics regression, unilateral tumors, earlier era of diagnosis, and extraocular extension were risk factors for eye salvage failure. Among intraocular retinoblastoma, Groups D and E had higher risk of eye salvage failure.Patients were diagnosed at an earlier stage in recent eras. Conservative therapies, including intra-arterial chemotherapy, were increasingly being used. The above changes may contribute to the decreasing enucleation rate. Although no significant impact was identified on the mortality by the three eras, a decreasing trend was shown.

Background/purpose Streptococcus pneumoniae causes pneumonia and other invasive diseases, and is a leading cause of mortality in the elderly population. The present study aimed to provide current antimicrobial resistance and epidemiological profiles of S. pneumoniae infections in Taiwan. Methods A total of 252 nonduplicate S. pneumoniae isolates were collected from patients admitted to 16 hospitals in Taiwan between January 2017 and December 2019, and were analyzed. The minimum inhibitory concentration of antibiotics was determined using the Vitek 2 automated system for antimicrobial susceptibility testing. Furthermore, epidemiological profiles of S. pneumoniae infections were analyzed. Results Among the strains analyzed, 88% were recognized as invasive pneumococcal strains. According to the Clinical and Laboratory Standards Institute criteria for non-meningitis, the prevalence of penicillin-non-susceptible S. pneumoniae demonstrated a declining trend from 43.6% in 2017 to 17.2% in 2019. However, the rate of penicillin-non-susceptible S. pneumoniae was 85.7% based on the criteria for meningitis. Furthermore, the prevalence of ceftriaxone-non-susceptible S. pneumoniae was 62.7% based on the criteria for meningitis. Isolates demonstrated higher susceptibility toward doripenem and ertapenem than toward meropenem and imipenem. An increased rate of non-susceptibility toward levofloxacin was observed in southern Taiwan (15.1%) and elderly patients (≥65 years; 11.4%). Most isolates were susceptible to vancomycin and linezolid. Conclusion Empirical treatment with ceftriaxone monotherapy for pneumococcal meningitis should be carefully monitored owing to its high non-susceptibility rate. The susceptibility rates of most isolates to penicillin (used for treating non-meningitis pneumococcal diseases), carbapenems (ertapenem and doripenem), respiratory quinolones (moxifloxacin and levofloxacin), vancomycin, and linezolid suggested the potential of these antibiotics in treating pneumococcal diseases in Taiwan.

Kidney injury caused by transplant-associated thrombotic microangiopathy (TA-TMA) in patients who underwent allogeneic hematopoietic stem cell transplantation (allo HSCT) is relatively frequent. However, it is rarely reported in patients undergoing autologous HSCT (aHSCT). There are a few studies reported that TA-TMA could occur in pediatric patients undergoing aHSCT, but the condition in adult patients is rarely described. Furthermore, almost all the patients who suffered from TA-TMA developed typical and severe manifestations which should be treated with aggressive target therapy. Nevertheless, we presented two cases of kidney injury caused by TA-TMA after aHSCT with specific clinical features. Case 1, a 33-year-old Chinese male diagnosed with Hodgkin's lymphoma developed TA-TMA -associated kidney injury 4 months after transplantation. Case 2, a 49-year-old Chinese female with central nervous lymphoma developed TA-TMA-related kidney injury 3 months after transplantation. Both patients presented "mild" and atypical features of TA-TMA and their kidney function was managed effectively with low-dose prednisone therapy. TA-TMA related kidney injury can occur in patients who underwent aHSCT. Patients with TA-TMA could develop atypically "mild" features. Low-dose prednisone may be effective in place of routine eculizumab treatment regimen. We recommend that clinicians prompt an investigation for TA-TMA in patients presenting kidney injury in the background of aHSCT to facilitate early diagnosis.

BACKGROUND Galectin-1 is a glycan-binding protein with broad anti-inflammatory properties. Left ventricular diastolic dysfunction (DD) is associated with heart failure and mortality. The pathophysiology of DD is complex and our study aimed to investigate the associations between serum galectin-1 level, DD, and heart failure with preserved ejection fraction (HFpEF). METHODS Patients with symptoms of angina pectoris were enrolled. Serum galectin-1 levels and echocardiography were assessed. The study endpoint was a composite of all-cause mortality or new-onset HFpEF. RESULTS In total, 258 patients were enrolled (63% male; mean age 68±12 years) and grouped into tertiles based on galectin-1 levels. Patients in the highest galectin-1 group had increased left ventricular mass indexes, left atrial diameters, and prevalence of DD compared to those in the lower tertiles (all p

Aim Abnormal ankle-brachial index (ABI) is regarded as peripheral artery disease and can be used to predict cardiovascular (CV) outcomes. However, the usefulness of ABI for the prediction of CV outcome in patients with normal ABI is limited. Upstroke time per cardiac cycle (UTCC) is recently reported to be associated with mortality in patients with acute myocardial infarction and the elderly. Therefore, we aimed to evaluate UTCC, left ventricular ejection fraction (LVEF), brachial-ankle pulse wave velocity (baPWV), and ABI for the prediction of mortality in patients with normal ABI. Methods Patients arranged for echocardiographic examinations were enrolled, and 1076 patients with normal ABI were included. ABI, baPWV, and UTCC were measured by an ABI-form device. Results The median follow-up to mortality was 95 months. There were 88 CV and 244 all-cause deaths. After multivariate analysis, UTCC was associated with increased CV and all-cause mortality (P ≤ 0.004). Age, diabetes, heart failure, left ventricular hypertrophy, baPWV, and LVEF were also independent predictors of CV and all-cause mortality, but ABI was not. Furthermore, UTCC had a better additive predictive value than ABI, baPWV, and LVEF for CV mortality (P ≤ 0.012). It also had a better additive predictive value than ABI and LVEF for all-cause mortality (P ≤ 0.013). Conclusions UTCC is an independent predictor for CV and all-cause mortality in patients with normal ABI. It also has a better additive predictive value of CV and all-cause mortality than ABI and LVEF. Therefore, UTCC is a simple, novel, and useful parameter for identifying high-risk patients with normal ABI.

To systematically evaluate the clinicopathological and prognostic value of extra-hepatic bile duct resection (EHBDR) in the surgical management of patients with gallbladder carcinoma (GBC), especially in non-jaundiced patients.PubMed, EMBASE and the Cochrane Library were searched up to March 1EHBDR did not correlate with a better overall survival (OS) (P = 0.17) or disease-free survival (P = 0.27). No survival benefit was also observed in patients with T2N1 (P = 0.4), T3N0 (P = 0.14) disease and node-positive patients (P = 0.75), rather, EHBDR was even harmful for patients with T2N0 (P = 0.01) and node-negative disease (P = 0.02). Significantly higher incidences of recurrent disease (P = 0.0007), postoperative complications (P 0.00001) and positive margins (P = 0.02) were detected in the bile duct-resected group. The duration of postoperative hospital stay between the two groups was comparable (P = 0.58). Selection bias was also detected in our analysis that a significantly higher proportion of advanced lesions with T3-4 or III-IV disease was observed in the bile duct-resected group (P 0.00001). EHBDR only contributed to a greater lymph yield (P = 0.01).EHBDR has no survival advantage for patients with GBC, especially for those with non-jaundiced disease. Considering the unfairness of comparing OS between jaundiced patients receiving EHBDR with non-jaundiced patients without EHBDR, we could only conclude that routine EHBDR in non-jaundiced patients is not recommended and future well-designed studies with more specific subgroup analyses are required for further validation.

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.

The intentional use of viruses for cancer therapy dates back over a century. As viruses are inherently immunogenic and naturally optimized delivery vehicles, repurposing viruses for drug delivery, tumor antigen presentation, or selective replication in cancer cells represents a simple and elegant approach to cancer treatment. While early virotherapy was fraught with harsh side effects and low response rates, virus-based therapies have recently seen a resurgence due to newfound abilities to engineer and tune oncolytic viruses, virus-like particles, and virus-mimicking nanoparticles for improved safety and efficacy. However, despite their great potential, very few virus-based therapies have made it through clinical trials. In this review, we present an overview of virus-inspired approaches for cancer therapy, discuss engineering strategies to enhance their mechanisms of action, and highlight their application for overcoming the challenges of traditional cancer therapies.

Background The aim of this study was to use tractography and diffusion kurtosis imaging (DKI) to evaluate cerebral white matter (WM) changes in patients with cerebrotendinous xanthomatosis (CTX) after stopping chenodeoxycholic acid (CDCA) treatment. Material and methods Two siblings with CTX aged 40 and 38 years, respectively, who had been diagnosed with CTX for 16 years were enrolled. They had received CDCA treatment from 2005 until 2015, after which CDCA was no longer available in Taiwan. Serial brain magnetic resonance imaging (MRI) studies were used to record brain changes, and a seres of neuropsychiatric tests were used to evaluate cognitive changes 3 years after stopping CDCA treatment. Results The conventional MRI studies revealed progressive changes in dentate nuclei and surrounding cerebellar hemispheres, but no obvious changes in cerebral white matter (WM). Tractography captured in 2018 showed a general reduction in fiber density, especially involving frontal lobe fibers, compared to 2015. In addition, the DKI studies performed in 2018 showed a decreased axonal water fraction in diffuse WM structures and increased RadEAD in frontal WM. Comparisons of the neuropsychiatric test results between 2015 and 2018 showed a marked decline in executive function including design fluency, digit backward span and digit forward span, and this cognitive impairment highly suggested frontal lobe dysfunction. Conclusions This study may suggest that cerebral tractography and DKI study results can identify changes in cerebral WM in CTX patients shortly after stopping CDCA treatment, and that they may have a better correlation with the results of neuropsychiatric tests.

Background: Long non-coding RNA actin filament-associated protein1-antisense RNA 1 (AFAP1-AS1) was confirmed to be associated with tumorigenesis. However, the role of AFAP1-AS1 in breast cancer was...

The reliance on thermal power plants as well as increased vehicle emissions have constituted the primary factors of serious air pollution. Inhaling too much particulate air pollution may lead to respiratory diseases and even death, especially PM2.5. By predicting the air pollutant concentration, people can take precautions to avoid overexposure to air pollutants. Consequently, accurate PM2.5 prediction becomes more important. In this thesis, we propose a PM2.5 prediction system, which utilizes the dataset from EdiGreen Airbox and Taiwan EPA. Autoencoder and Linear interpolation are adopted for solving the missing value problem. Spearman's correlation coefficient is used to identify the most relevant features for PM2.5. Two prediction models (i.e., LSTM and LSTM based on K-means) are implemented which predict PM2.5 value for each Airbox device. To assess the performance of the model prediction, the daily average error and the hourly average accuracy for the duration of a week are calculated. The experimental results show that LSTM based on K-means has the best performance among all methods.

On-target–off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates1,2. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock, enabling the brain-restricted inhibition of their respective kinase targets.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1–3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

BACKGROUND To investigate associations between exposure to various trajectories of severe hypoglycemic events and risk of dementia in patients with type 2 diabetes. METHODS In 2002-2003, 677618 patients in Taiwan were newly diagnosed as having type 2 diabetes. Among them, 35720 (5.3%) experienced severe hypoglycemic events during the 3-year baseline period following diagnosis. All patients were followed from the first day after baseline period to the date of dementia diagnosis, death, or the end of 2011. A group-based trajectory model was used to classify individuals with severe hypoglycemic events during the baseline period. Cox proportional hazard models with the competing risk method were used to relate dementia risk to various severe hypoglycemia trajectories. RESULTS After a median follow-up 6.70 and 6.10 years for patients with and without severe hypoglycemia at baseline, respectively, 1952 (5.5%) individuals with severe hypoglycemia and 23492 (3.7%) without developed dementia during follow-up, for incidence rates of 109.80 and 61.88 per 10000 person-years, respectively. Four groups of severe hypoglycemia trajectory were identified with a proportion of 18.06%, 33.19%, 43.25%, and 5.50%, respectively for Groups 1 to 4. Groups 3 (early manifestation but with later decrease) and 4 (early and sustained manifestation) were associated with a significantly increased risk of dementia diagnosis, with a covariate-adjusted subdistribution hazard ratio of 1.22 (95% confidence interval, 1.14-1.31) and 1.25 (95% confidence interval, 1.02-1.54), respectively. CONCLUSIONS Our analysis highlighted that early manifestation of severe hypoglycemic events may contribute more than does late manifestation to the risk of dementia among individuals newly diagnosed as having type 2 diabetes.