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Treating neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) remains highly challenging. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) is of considerable interest in this context. To investigate the efficacy and safety of a novel technique involving simultaneous application of rTMS and tDCS (rTMS–tDCS) over bilateral angular gyrus (AG, P5/P6 electrode site) for AD-related NPS. Eighty-four AD patients were randomized to receive rTMS–tDCS, single-rTMS, single-tDCS, or sham stimulation for 4 weeks, with evaluation at week-4 (W4, immediately after treatment) and week-12 (W12, follow-up period) after initial examination. Primary outcome comprising Neuropsychiatric Inventory (NPI) score and secondary outcomes comprising mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and Pittsburgh sleep quality index (PSQI) scores were collected and analyzed by a two-factor (time and treatment), mixed-design ANOVA. rTMS–tDCS produced greater improvement in NPI scores than single-tDCS and sham at W4 and W12 (both P < 0.017) and trended better than single-rTMS (W4: P = 0.058, W12: P = 0.034). rTMS–tDCS improved MMSE scores compared with single-tDCS at W4 (P = 0.011) and sham at W4 and W12 (both P < 0.017). rTMS–tDCS also significantly improved PSQI compared with single-rTMS and sham (both P < 0.017). Interestingly, rTMS–tDCS-induced NPI/PSQI improvement was significantly associated with MMSE/ADAS-cog improvement. tDCS- and/or rTMS-related adverse events appeared slightly and briefly. rTMS–tDCS application to bilateral AG can effectively improve AD-related NPS, cognitive function, and sleep quality with considerable safety. • Simultaneous application of rTMS–tDCS in Alzheimer's Disease is safe and promising. • rTMS–tDCS produces greater improvement in neuropsychiatric symptoms than unimodal (tDCS or rTMS) and sham stimulation. • rTMS–tDCS achieves better effect on cognitive function, sleep quality than unimodal (tDCS or rTMS) and sham stimulation. • The improvements in NPS or sleep quality induced by rTMS–tDCS were significantly associated with cognitive improvement. [ABSTRACT FROM AUTHOR]

Background: Surgical treatment remains the best option for patients with hepatocellular carcinoma (HCC) caused by chronic hepatitis B virus (HBV) infection. However, there is no optimal tool based on readily accessible clinical parameters to predict postoperative complications. Herein, our study aimed to develop models that permitted risk of severe complications to be assessed before and after liver resection based on conventional variables. Methods: A total of 1,047 patients treated by hepatectomy for HCC with HBV infection at three different centers were recruited retrospectively between July 1, 2014, and July 1, 2018. All surgical complications were recorded and scored by the Comprehensive Complication Index (CCI). A CCI ≥26.2 was used as a threshold to define patients with severe complications. We built two models for the CCI, one using preoperative and one using preoperative and postoperative data. Besides, CCI and other potentially relevant factors were evaluated for their ability to predict early recurrence and metastasis. All the findings were internally validated in the Hangzhou cohort and then externally validated in the Lanzhou and Urumqi cohorts. Results: Multivariable analysis identified National Nosocomial Infections Surveillance (NNIS) index, tumor number, gamma-glutamyltransferase (GGT), total cholesterol (TC), potassium, and thrombin time as the key preoperative parameters related to perioperative complications. The nomogram based on the preoperative model [preoperative CCI After Surgery for Liver tumor (CCIASL-pre)] showed good discriminatory performance internally and externally. A more accurate model [postoperative CCI After Surgery for Liver tumor (CCIASL-post)] was established, combined with the other four postoperative predictors including leukocyte count, basophil count, erythrocyte count, and total bilirubin level. No significant association was observed between CCI and long-term complications. Conclusion: Based on the widely available clinical data, statistical models were established to predict the complications after hepatectomy in patients with HBV infection. All the findings were extensively validated and shown to be applicable nationwide. Such models could be used as guidelines for surveillance follow-up and the design of post-resection adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Recent studies report that hospital staff at the forefront of caring for COVID-19 patients experience increased psychological distress. To effectively manage the outbreak of COVID-19, China established COVID-19 designated and non-designated hospitals. To date, few studies have examined the impacts of COVID-19 on psychological health of staff working at non-designated hospitals. This study is to explore factors affecting psychological health of non-designated hospital staff in China during the COVID-19 pandemic. Methods: Data were collected through an online questionnaire between February and March 2020. The questionnaire consists of General Health Questionnaire (GHQ-20), Social Support Rating Scale (SSRS), Simplified Coping Style Questionnaire (SCSQ), sociodemographic characteristics, employment history, health status, and contact history of COVID-19. The questionnaire was distributed through hospital WeChat groups and work colleague referrals. A total of 470 non-designated hospital staff members completed the questionnaire. Multiple Linear Regression analysis was used to interpret the associations among social support, coping styles, sociodemographic factors, job roles, and psychological status. Data were analyzed using SPSS version 21.0. Results: The non-designated hospital staff differed significantly in anxiety and depression subscores of the GHQ-20 by their job roles, levels of social support, and history of mental disorders. Staff with medical job roles, good self-reported health status, no previous mental disorders, adequate social support, and positive coping styles scored lower in GHQ-20 total score, which indicated healthier psychological status. Conclusions: The results indicate that history of mental health disorders, non-medical job roles, and inadequate social support are associated with greater psychological distress. Personalized support should be provided to those who are vulnerable and in need of social and psychological support. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OV) is one of the leading causes of cancer deaths in women worldwide. Late diagnosis and heterogeneous treatment result to poor survival outcomes for patients with OV. Therefore, we aimed to develop novel biomarkers for prognosis prediction from the potential molecular mechanism of tumorigenesis. Eight eligible data sets related to OV in GEO database were integrated to identify differential expression genes (DEGs) between tumour tissues and normal. Enrichment analyses discovered DEGs were most significantly enriched in G2/M checkpoint signalling pathway. Subsequently, we constructed a multi‐gene signature based on the LASSO Cox regression model in the TCGA database and time‐dependent ROC curves showed good predictive accuracy for 1‐, 3‐ and 5‐year overall survival. Utility in various types of OV was validated through subgroup survival analysis. Risk scores formulated by the multi‐gene signature stratified patients into high‐risk and low‐risk, and the former inclined worse overall survival than the latter. By incorporating this signature with age and pathological tumour stage, a visual predictive nomogram was established, which was useful for clinicians to predict survival outcome of patients. Furthermore, SNRPD1 and EFNA5 were selected from the multi‐gene signature as simplified prognostic indicators. Higher EFNA5 expression or lower SNRPD1 indicated poorer outcome. The correlation between signature gene expression and clinical characteristics was observed through WGCNA. Drug‐gene interaction was used to identify 16 potentially targeted drugs for OV treatment. In conclusion, we established novel gene signatures as independent prognostic factors to stratify the risk of OV patients and facilitate the implementation of personalized therapies. [ABSTRACT FROM AUTHOR]

Background: Tai Chi exercise is a non-pharmacological therapy that has received increased attention in recent years. A Tai Chi program has been specifically modified for older people with cognitive impairments by the research team.Objective: We aim to assess the effects of this Tai Chi program on mild dementia.Methods: Eighty older people with mild dementia were recruited and randomly assigned to a Tai Chi group or a control group. The Tai Chi group practiced the Tai Chi program three times a week for 10 months, while the control group continued receiving routine treatments. All participants were assessed for cognitive function, behavior/mood, and activities of daily living at baseline, 5 months, and 10 months.Results: The Tai Chi group performed better than the control group. Repeated measures ANOVA revealed a significant group×time interaction in the Montreal Cognitive Assessment (MoCA). Further analysis of sub-items of the MoCA showed a significant time effect in naming and abstraction. It was statistically significant in both main effect of time and group×time interaction in the Neuropsychiatric Inventory (NPI) and Geriatric Depression Scale (GDS). Paired sample t test showed the Tai Chi group scored lower at 5 and 10 months in the NPI and at 10 months in the GDS compared with baseline. The Tai Chi group scored lower than the control group at 10 months in the NPI and GDS.Conclusion: The results suggest this Tai Chi program may help improve cognitive function and mental well-being for older adults with mild dementia. [ABSTRACT FROM AUTHOR]

Background The existence of an association between migraine and essential tremor has long been controversial. The prevalence of migraine in essential tremor patients was surveyed to explore the association between the two diseases. Methods A case–control clinical study was conducted to investigate the prevalence of migraine in 150 consecutive essential tremor patients and in 150 matched controls without tremor. Detailed information about essential tremor and migraine was obtained using a structured questionnaire at a face-to-face interview. Moreover, a functional variant of the dopamine receptor D3 gene (Ser9Gly, rs6280) was studied in 46 essential tremor patients with and without migraine using direct sequencing analysis. Results The prevalence of lifetime migraine in essential tremor patients was significantly higher than that in controls (22.0% vs. 12.7%; p = 0.035; odds ratio = 1.95; 95% confidence interval = 1.05–3.60). No significant difference was found in the migraine features between the essential tremor and control groups and most tremor characteristics were no different in essential tremor patients with and without migraine. A higher male prevalence of essential tremor patients without migraine was observed. Moreover, 44 of 46 (95.7%) essential tremor patients had the dopamine receptor D3 Ser9Gly variant, but no significant difference was found in the frequencies of the variant between essential tremor patients with and without migraine (87.5% vs. 100.0%; p = 0.22). Conclusion Our data suggest that essential tremor patients have a higher risk of lifetime migraine than do controls and the dopamine receptor D3 Ser9Gly variant may be lower in essential tremor with migraine than the general essential tremor patients. [ABSTRACT FROM AUTHOR]

Brassinosteroids (BRs) are steroidal phytohormones that regulate various physiological processes, such as root development and stress tolerance. In the present study, we showed that brassinolide (BL) affects potato root in vitro growth in a dose-dependent manner. Low BL concentrations (0.1 and 0.01 μg/L) promoted root elongation and lateral root development, whereas high BL concentrations (1–100 μg/L) inhibited root elongation. There was a significant (P<0.05) positive correlation between root activity and BL concentrations within a range from 0.01 to 100 μg/L, with the peak activity of 8.238 mg TTC·g−1 FW·h−1 at a BL concentration of 100 μg/L. Furthermore, plants treated with 50 μg/L BL showed enhanced salt stress tolerance through in vitro growth. Under this scenario, BL treatment enhanced the proline content and antioxidant enzymes’ (superoxide dismutase, peroxidase, and catalase) activity and reduced malondialdehyde content in potato shoots. Application of BL maintain K+ and Na+ homeostasis by improving tissue K+/Na+ ratio. Therefore, we suggested that the effects of BL on root development from stem fragments explants as well as on primary root development are dose-dependent and that BL application alleviates salt stress on potato by improving root activity, root/shoot ratio, and antioxidative capacity in shoots and maintaining K+/Na+ homeostasis in potato shoots and roots. [ABSTRACT FROM AUTHOR]

A novel method for the synthesis of the 17-deoxyroflamycoin roflamycoin analog was developed based on a series of alkylation reactions. The synthetic process was characterized by the alkylation of a nitrile anion with bromide to produce an intermediate product. The C6 iodide for the secondary alkylation reaction was synthesized via the deprotection and iodination of the intermediate product. The dinitrile from the second alkylation reaction is also a protected polyol that undergoes phosphonopropionate ester synthesis to produce the desired 17-deoxyroflamycoin.

Objective. To investigate the efficacy and safety of traditional Chinese medicine Duliang soft capsule (DSC) in prophylactic treatment for patients with chronic daily headache (CDH). Methods. A multicenter, double-blind, randomized, placebo-controlled clinical study was conducted at 18 Chinese clinical centers. The participants received either DSC or placebo for 4 weeks. The primary efficacy measure was headache-free rate (HFR) in a 4-week period between the pretreatment and posttreatment stages. The secondary efficacy measures were the decrease of headache days, the duration of headache attacks, the frequency of analgesic usage, quality of life, disability, and the headache severity (VAS scores). The accompanying symptoms and adverse events were also assessed. Results. Of 584 CDH patients assessed, 468 eligible patients were randomized. 338 patients received DSC, while 111 patients were assigned in the placebo group. Following treatment, there was a 16.56% difference in HFR favoring DSC over placebo (P<0.01). Significant differences were also observed between DSC and placebo groups in the secondary measures. However, no statistical difference was found between the two groups in the associated symptoms. No severe adverse effects were observed in the study. Conclusions. DSC might be an effective and well-tolerated option for the prophylactic treatment of patients with CDH. [ABSTRACT FROM AUTHOR]

Background: The existence of an association between migraine and essential tremor has long been controversial. The prevalence of migraine in essential tremor patients was surveyed to explore the association between the two diseases. Methods: A case-control clinical study was conducted to investigate the prevalence of migraine in 150 consecutive essential tremor patients and in 150 matched controls without tremor. Detailed information about essential tremor and migraine was obtained using a structured questionnaire at a face-to-face interview. Moreover, a functional variant of the dopamine receptor D3 gene (Ser9Gly, rs6280) was studied in 46 essential tremor patients with and without migraine using direct sequencing analysis. Results: The prevalence of lifetime migraine in essential tremor patients was significantly higher than that in controls (22.0% vs. 12.7%; p=0.035; odds ratio=1.95; 95% confidence interval=1.05-3.60). No significant difference was found in the migraine features between the essential tremor and control groups and most tremor characteristics were no different in essential tremor patients with and without migraine. A higher male prevalence of essential tremor patients without migraine was observed. Moreover, 44 of 46 (95.7%) essential tremor patients had the dopamine receptor D3 Ser9Gly variant, but no significant difference was found in the frequencies of the variant between essential tremor patients with and without migraine (87.5% vs. 100.0%; p=0.22). Conclusion: Our data suggest that essential tremor patients have a higher risk of lifetime migraine than do controls and the dopamine receptor D3 Ser9Gly variant may be lower in essential tremor with migraine than the general essential tremor patients. [ABSTRACT FROM AUTHOR]

A series of substituted isoquinolinones were synthesized and their binding affinities and functional activities towards human melatonin MT1 and MT2 receptors were evaluated. Structure-activity relationship analysis revealed that substituted isoquinolinones bearing a 3-methoxybenzyloxyl group at C5, C6 or C7 position respectively (C5>C6>C7 in terms of their potency) conferred effective binding and selectivity toward the MT2 receptor, with 15b as the most potent compound. Most of the tested compounds were MT2-selective agonists as revealed in receptor-mediated cAMP inhibition, intracellular Ca2+ mobilization and phosphorylation of extracellular signal-regulated protein kinases. Intriguingly, compounds 7e and 7f bearing a 4-methoxybenzyloxyl group or 4-methylbenzyloxyl at C6 behaved as weak MT2-selective antagonists. These results suggest that substituted isoquinolinones represent a novel family of MT2-selective melatonin ligands. The position of the substituted benzyloxyl group, and the substituents on the benzyl ring appeared to dictate the functional characteristics of these compounds. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is associated with diabetes mellitus (DM) in population studies, but no case has been reported in a large HD family. We report a case of a five-generation Chinese family who is afflicted by both HD and DM. The prevalence of DM in HD of this family was high (72.7%). The diagnosis of HD in 11 family members was confirmed by the genetic test of the proband who had 42 CAG repeats. Furthermore, the proband's daughter had abnormal locus at G3460T in MT-ND1 among mtDNA genome. Our case report suggests a genetic link between HD and DM. [ABSTRACT FROM AUTHOR]

Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a natural pentacyclic triterpenoic acid found in many fruits, herbs and medicinal plants. In the past decade, increasing evidence has suggested that oleanolic acid exhibits inhibitory activities against different types of cancer including skin cancer and colon cancer, but not leukemia. We report here that a derivative of oleanolic acid, olean-12-eno[2,3-c] [1], [2], [5]oxadiazol-28-oic acid (designated OEOA) effectively blocks the proliferation of human leukemia cells. OEOA significantly reduces cell proliferation without inducing cell death in three types of leukemia cell lines, including K562, HEL and Jurket. Moreover, exposure of K562 cells to OEOA results in G1 cell cycle arrest, with a concomitant induction of cyclin-dependent kinase inhibitor p27 and downregulation of cyclins and Cdks that are essential for cell cycle progression. Interestingly, OEOA also enhances erythroid differentiation in K562 cells through suppressing the expression of Bcr-Abl and phosphorylation of Erk1/2. These findings identify a novel chemical entity for further development as therapeutics against leukemia. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel and selective N-[3-(6-benzyloxy-3-methoxyphenyl)propyl] amides has recently been shown to possess sub-nanomolar range binding affinity to the type 2 melatonin receptor (MT2). Pharmacokinetics studies suggested that these compounds were subject to vigorous CYP450-mediated metabolism, resulting in a series of metabolites with significantly decreased or diminished binding affinities toward MT2 receptor. The ether bonds were found to be the major positions susceptible to metabolism. In this study, the benzyl ether bond was either removed or replaced with a carbon–carbon bond in an attempt to improve metabolic stability and enhance their resistance towards phase I oxidation. The synthesis, receptor binding affinity, intrinsic potency and metabolic stability of modified structures are reported in this article. By removal or replacement of metabolic labile ether linkerage with carbon linkers, a novel compound was identified with good potency and MT2 selectivity, and with increased metabolic stability. [Copyright &y& Elsevier]

Abstract 1. 7-Methoxy-6-(3-methoxy-benzyloxy)-2-methylisoquinolin-1(2H)-one (named as IS0042) is a newly identified melatoninergic agonist which exhibits selectivity to the type 2 melatonin receptor. Here, we examined the in vitro and in vivo pharmacokinetics properties of IS0042 in rats. 2. IS0042 was considerably lipophilic with a modest aqueous solubility of 27.3 μg/mL. It was stable in simulated gastrointestinal fluid, and readily penetrated across differentiated Caco-2 cell model of intestinal barrier, suggesting good oral absorption. 3. IS0042 underwent metabolism in rat intestinal and liver microsomes with an in vitro half-life of 367.5 ± 36.6 and 17.5 ± 2.7 min, respectively. Metabolite identification suggested that the major biotransformation pathways included the cleavage of ether bond, hydroxylation and demethylation. The same metabolites were also present in blood circulation following oral administration, indicating a good correlation between in vitro and in vivo metabolism. 4. The pharmacokinetics parameters of IS0042 were evaluated after intravenous administration (10 or 25 mg/kg) and oral administration (100 mg/kg) of the drug to rats. IS0042 showed moderate clearance (0.73–1.02 L/h/kg), large volume of distribution (1.76–3.16 L/kg) and long elimination half-life (3.11–6.04 h) after intravenous administration. The absolute oral bioavailability of IS0042 was relatively low (9.8–18.6%). Overall, these results provide important parameters for the further development of this novel class of melatoninergic ligands. [ABSTRACT FROM AUTHOR]

Developing subtype-selective melatoninergic ligands has been a subject of considerable interest in drug discovery. A series of 3-methoxyphenylpropyl amide derivatives showing selective binding capacity to type 2 melatonin receptor with subnanomolar range of affinities has been identified recently by our laboratory. In the present study, their physicochemical properties, Caco-2 cell and mdr1-MDCK cell permeability, plasma protein binding, and metabolic stability were investigated. The selected compounds are lipophilic in nature, exhibiting aqueous solubility ranging from 40 to 200 µg/mL. Cell permeability studies on Caco-2 and mdr1-MDCK model revealed that they were readily transported through intestinal epithelium and possessed high penetration potential through blood–brain barrier, implying good oral absorption and central nervous system (CNS) distribution potential. They also showed substantial binding to human plasma protein ranging from 78.5% to 92.3%. These compounds were, however, subjected to rapid cytochrome P450-mediated degradation in rat and human liver microsomes with in vitro half-life of 9.5–31.9 min in rat and 5.5–66.7 min in human, which were much shorter than that of melatonin (∼73 min). Metabolite profiling unveiled that C6-ether linkage and methoxy substituents were likely the major metabolic soft spots in their structures, which provided important information for further improvement of their structural stability. [ABSTRACT FROM AUTHOR]

Abstract: A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their binding affinities towards human melatonin MT1 and MT2 receptors were evaluated. It was discovered that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT2 binding affinity and at the same time decreased MT1 binding affinity. [Copyright &y& Elsevier]

In clinical study, calculation for sample size is often done using the frequentist framework. However, several methods of calculation using the Bayesian framework have been proposed. In this paper, we propose a method for the determination of sample sizes using the index where X1 and X2 denote the binomial random variables for trials n1 and n2 and parameters π1 and π2, respectively. In this paper, we propose a new method of calculation, by which we determine in advance the estimated difference between the posterior proportions and the value to be derived at the end of the test to obtain the necessary sample size. We provide the lists of necessary sample sizes with various assumptions and the calculation program using Mathematica. [ABSTRACT FROM AUTHOR]

Nonparametric tests are commonly used tests for two sample comparison in clinical studies. However, the estimation of treatment effects associated with the tests may not be obvious, especially under the covariate adjustment. In this article, we evaluated the effect of covariate adjustment on estimating treatment effects based on the Wilcoxon Rank Sum test, the van Elteren test, aligned rank test, and Jaeckel, Hettmansperger-McKean test through Monte Carlo simulations via mean square error and coverage probability. Based on the simulation, commonly used ANCOVA-based approach do not have good estimation of treatment effect when the covariate imbalance is severe. Aligned rank test seems perform well across most scenarios. [ABSTRACT FROM AUTHOR]

Meta-analysis is a statistical methodology that combines the outcomes of several independent studies. Either a fixed-effects or a random-effectsmodel is used to combine the results of the independent studies. The choice depends on whether the outcomes can be considered homogeneous or not. Several methods have been developed to test the homogeneity of effect sizes. Although many of them have been compared already, they have not been studied in more realistic practical settings where individuals all have their own risk of an event and a complete overview is lacking. In this article, we investigate the performance of 10 statistical methods to test homogeneity of a binary exposure on a binary clinical outcome, using an extensive simulation study and a real life meta-analysis. We evaluated the Type I error and the statistical power. The fixed-effects regression model for treatment and study interactionwas found to be a slightly liberal test, while the Q-statistic and the Bliss statistic can be considered conservative tests. The random-effects regression model, the Peto statistic and the I2 perform rather poorly compared to the other methods. All chisquare tests that are based on the calculation of a specific odds ratio and the fixed-effects logistic regression analysis perform best. Among these chi-square tests, we recommend the Breslow-Day test, but only for convenience purposes, since it is available in most statistical software packages and the other tests are not. [ABSTRACT FROM AUTHOR]

Development of structure–activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52–59 (IC50=1.3–11.0 nM, PDE6/5=116–600). [Copyright &y& Elsevier]

This paper considers the estimation of parameters based on a progressively type-I interval-censored data from a mixed generalized exponential distribution. The maximum likelihood estimation is used but an analytic form cannot be obtained. The EM algorithm is applied to obtain the maximum likelihood estimates. The performance of the estimates is judged by a simulating study and a real data is presented to illustrate the method of estimation developed here. [ABSTRACT FROM AUTHOR]