A predictive study of the efficacy of transcutaneous auricular vagus nerve stimulation in the treatment of major depressive disorder: An fMRI-based machine learning analysis.

BACKGROUND: In order to improve taVNS efficacy, the usage of fMRI to explore the predictive neuroimaging markers would be beneficial for screening the appropriate MDD population before treatment. METHODS: A total of 86 MDD patients were recruited in this study, and all subjects were conducted with the clinical scales and resting-state functional magnetic resonance imaging (fMRI) scan before and after 8 weeks' taVNS treatment. A two-stage feature selection strategy combining Machine Learning and Statistical was used to screen out the critical brain functional connections (FC) that were significantly associated with efficacy prediction, then the efficacy prediction model was constructed for taVNS treating MDD. Finally, the model was validated by separated the responding and non-responding patients. RESULTS: This study showed that taVNS produced promising clinical efficacy in the treatment of mild and moderate MDD. Eleven FCs were selected out and were found to be associated with the cortico-striatal-pallidum-thalamic loop, the hippocampus and cerebellum and the HAMD-17 scores. The prediction model was created based on these FCs for the efficacy prediction of taVNS treatment. The R-square of the conducted regression model for predicting HAMD-17 reduction rate is 0.44, and the AUC for classifying the responding and non-responding patients is 0.856. CONCLUSION: The study demonstrates the validity and feasibility of combining neuroimaging and machine learning techniques to predict the efficacy of taVNS on MDD, and provides an effective solution for personalized and precise treatment for MDD.

An ultra-compact promoter drives widespread neuronal expression in mouse and monkey brains.

Promoters are essential tools for basic and translational neuroscience research. An ideal promoter should possess the shortest possible DNA sequence with cell-type selectivity. However, whether ultra-compact promoters can offer neuron-specific expression is unclear. Here, we report the development of an extremely short promoter that enables selective gene expression in neurons, but not glial cells, in the brain. The promoter sequence originates from the human CALM1 gene and is only 120 bp in size. The CALM1 promoter (pCALM1) embedded in an adeno-associated virus (AAV) genome directed broad reporter expression in excitatory and inhibitory neurons in mouse and monkey brains. Moreover, pCALM1, when inserted into an all-in-one AAV vector expressing SpCas9 and sgRNA, drives constitutive and conditional in vivo gene editing in neurons and elicits functional alterations. These data demonstrate the ability of pCALM1 to conduct restricted neuronal gene expression, illustrating the feasibility of ultra-miniature promoters for targeting brain-cell subtypes.

Potential risk of drug-drug interactions of ponatinib via inhibition against human UDP-glucuronosyltransferases.

Ponatinib is an efficient oral tyrosine kinase inhibitor (TKI) for T315I-positive Ph + ALL and T315I-positive chronic myeloid leukemia (CML) or BCR-ABL when no other TKIs can be prescribed. In this research, we evaluated the inhibitory effects of ponatinib on human recombinant UDP-glucuronosyltransferases (UGTs) and predicted the magnitude of potential drug-drug interaction (DDI) risk of co-treatment with ponatinib and UGTs substrates by using in vitro-in vivo extrapolation (IVIVE) method. Our study presented that ponatinib showed a broad-spectrum inhibition against UGTs. Particularly, ponatinib exhibited potent inhibitory effects towards UGT1A7, UGT1A1, and UGT1A9 with IC50 values of 0.37, 0.41, and 0.89 µM, respectively, which might lead to clinically significant DDI.

Applicability of photovoltaic panel rainwater harvesting system in improving water-energy-food nexus performance in semi-arid areas.

Growing food demand challenges the expansion of agriculture, while water and energy shortages have seriously jeopardized agricultural sustainability. Therefore, the water-energy-food (WEF) nexus must be integrated into sustainable agriculture management. However, despite the increasing sophistication of models for WEF optimization, more studies have considered only how to reduce resource consumption and less on how to increase resource supply. This paper outlines an agricultural WEF optimization model based on photovoltaic panel rainwater harvesting (PVRH). The model innovatively incorporates the PVRH system into the agricultural WEF nexus, providing a decision-making framework that exploits and conserves resources in parallel, while contributing to economic benefits. The model was applied in a rural case study in a semi-arid region of China. The results highlight the significant potential of the PVRH system to exploit water and energy, and the increased resources are allocated to irrigated alfalfa and vegetables, which would significantly increase revenue. However, the model does not recommend large-scale vegetable cultivation, which would increase water and energy consumption and reduce the WEF indicator values indicating agricultural sustainability. The final scheme will build a 98.92MWp PV power station, develop 1.31 × 108 kW·h of electricity and 1.97 × 107 m3 of rainwater into agricultural production. And through cropping restructuring, it will increase 23.61 % of economic revenue and save 57.74 % of water and 3.24 % of energy. In general, the model framework is transferable and applicable to similar agricultural areas under semi-arid climatic conditions.

Left atrial size and risk of recurrent ischemic stroke in cardiogenic cerebral embolism.

BACKGROUND: Left atrial enlargement (LAE) was reported to be associated with ischemic stroke and its recurrence. Limited data are available on the relationship of LAE and cardiogenic cerebral embolism (CCE). Our aim is to access the association of left atrial size and the recurrence of ischemic stroke in CCE. METHODS: We prospectively included 303 CCE patients who underwent transthoracic echocardiography (TTE). Left atrial size was estimated with left atrial diameter (LAD), diameter/height (LAD/H), and left atrial diameter/body surface area (LAD/BSA). The endpoint was one-year recurrent ischemic stroke. Cox proportional hazard models were performed to access the association between left atrial size and recurrent ischemic stroke. RESULTS: During follow-up, 27 patients suffered recurrent ischemic stroke. In multivariate COX regression models adjusted for confounders including age, gender, hypertension, diabetes, and history of stroke or transient ischemic attack (TIA), platelet count, fasting blood glucose (FBG), antithrombotic drugs at discharge, stroke volume, and cardiac output, LAD, LAD/H, and LAD/BSA all were independent risk factors of recurrent ischemic stroke [LAD: HR 1.065, 95% CI (1.006-1.128), p = .029; LAD/H: HR 1.157, 95% CI (1.066-1.255), p < .001; LAD/BSA: HR 1.128, 95% CI (1.059-1.202), p < .001]. Receiver-operator characteristic curves showed that LAD/BSA had better predicting effect. The area under the curve (AUC) was 0.543 [95%CI (0.444-0.642), p = .461) for LAD, 0.626 [95%CI (0.530-0.723), p = .03] for LAD/H, and 0.655 [95%CI (0.558-0.752), p = .008] for LAD/BSA. CONCLUSION: LAE is an independent risk factor for one-year recurrence of ischemic stroke in patients with CCE.

Prognostic Nutritional Index for Predicting 3-Month Outcomes in Ischemic Stroke Patients Undergoing Thrombolysis.

Objective: Malnutrition has been reported to be related to adverse prognosis in acute ischemic stroke (AIS) patients. Unfortunately, traditional nutritional assessment tools usually increase the workload of neurologists, which makes them unfeasible in the daily clinic work. We aimed to elucidate the association between the prognostic nutritional index (PNI), an easily obtainable baseline nutritional marker, and 3-month outcomes in AIS patients receiving intravenous thrombolysis (IVT). Research methods and procedures: The present study retrospectively included 405 patients. PNI was calculated as 5*lymphocyte count (109 /L) + serum albumin concentration (g/L), and the good prognosis was defined as modified Rankin Scale score of 0-3. The relationship between PNI and clinical parameters was evaluated. The multiple logistic regression model was performed to find out independent predictors of the 3-month outcomes. Results: We found that the patients in the low PNI group had a higher frequency of anemia (12.9 vs. 2.3%, P < 0.001) and a higher level of the Controlling nutritional status (CONUT) score (P < 0.001). The relationship between PNI and nutrition-related factors, such as body mass index (r = 0.208, P = 0.001), age (r = -0.329, P < 0.001), total cholesterol (r = 0.268, P < 0.001) and hemoglobin concentration (r = 0.328, P < 0.001), was significant. Low PNI value (adjusted odds ratio: 2.250, confidence interval: 1.192-4.249, p = 0.012) stayed as an independent predictor for the poor outcome at three months, after adjustment for potential confounders. Conclusions: The PNI was independently associated with 3-month outcomes in AIS patients undergoing IVT. As an easily obtainable nutritional marker, PNI may be a useful nutritional assessment tool in the clinic work.

Predicting the One-Year Prognosis and Mortality of Patients with Acute Ischemic Stroke Using Red Blood Cell Distribution Width Before Intravenous Thrombolysis.

PURPOSE: Red blood cell (RBC) distribution width (RDW) is known to reflect the heterogeneity of RBC volume, which may be associated with cardiovascular events or mortality after myocardial infarction. However, the association between RDW and stroke, especially regarding endpoints such as death, remains ambiguous. This study aimed to explore the prognostic value of RDW and its effect on mortality among patients with acute ischemic stroke (AIS) undergoing intravenous thrombolysis (IVT) after one year. PATIENTS AND METHODS: We retrospectively reviewed patients with AIS treated with IVT between January 2016 and March 2018. We grouped the patients according to modified ranking scale (MRS) scores as follows:0-2, favorable functional outcome group; and 3-6, unfavorable functional outcome. Predictors were determined using multivariate logistic regression (MVLR). The area under receiver-operating characteristic curve (AUC) was used to evaluate the predictive capability of variables. Furthermore, the Cox proportional hazard model was used to assess the contribution of risk factors to the outcome of death at one year later. RESULTS: MVLR analysis showed that RDW (odds ratio [OR], 1.179; 95% confidence interval [CI], 0.900-1.545; p = 0.232) was not an independent predictor of unfavorable functional outcome, but it (OR 1.371; 95% CI 1.109-1.696; p = 0.004) was an independent biomarker for all-cause mortality. The optimal RDW cut-off value to predict mortality was 14.65% (sensitivity: 42%, specificity: 88.3%, AUC: 0.649, p < 0.001). Furthermore, higher RDW (hazard ratio, 2.860; 95% CI, 1.724-4.745; p < 0.001) indicated a greater risk of death. CONCLUSION: The baseline RDW is a potential predictor of mortality in patients with AIS undergoing IVT, but RDW might not be associated with worse survival function among stroke survivors, which will help us to improve treatments and the management of patients with AIS.

Drug-induced lymphocyte stimulation test in the prediction of drug-induced hypersensitivity to antituberculosis drugs.

Antituberculosis (TB) chemotherapeutic drugs may cause a variety of adverse drug reactions (ADRs). To assess the potential of drug-induced lymphocyte stimulation test (DLST) in screening ADRs in patients treated with anti-TB drugs, we performed DLST in 272 TB patients (176 cases with ADRs and 96 controls without ADRs) treated with anti-TB drugs isoniazid (INH), rifampicin (RFP), ethambutol (EMB), and pyrazinamide (PZA). The ADRs were diagnosed by drug provocation test based on clinical and laboratory examinations. The sensitivities of DLST in the diagnosis of INH-, RFP-, EMB-, or PZA-induced ADRs were 57.8%, 37.1%, 42.4%, and 23.1%, respectively, with the corresponding specificities being 93.4%, 94.0%, 97.5%, and 98.8%. DLST has high specificity and limited sensitivity in the diagnosis of anti-TB drug-induced ADRs. In combination with clinical observation and drug use history, DLST could have a predictive validity of ADRs, especially when a positive result is obtained.

Long-term exposure to decabrominated diphenyl ether impairs CD8 T-cell function in adult mice.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) at doses of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine (IFN-γ, IL-2 and TNF-α) production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenes expressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.