Overfit deep neural network for predicting drug-target interactions.

Drug-target interactions (DTIs) prediction is an important step in drug discovery. As traditional biological experiments or high-throughput screening are high cost and time-consuming, many deep learning models have been developed. Overfitting must be avoided when training deep learning models. We propose a simple framework, called OverfitDTI, for DTI prediction. In OverfitDTI, a deep neural network (DNN) model is overfit to sufficiently learn the features of the chemical space of drugs and the biological space of targets. The weights of trained DNN model form an implicit representation of the nonlinear relationship between drugs and targets. Performance of OverfitDTI on three public datasets showed that the overfit DNN models fit the nonlinear relationship with high accuracy. We identified fifteen compounds that interacted with TEK, a receptor tyrosine kinase contributing to vascular homeostasis, and the predicted AT9283 and dorsomorphin were experimentally demonstrated as inhibitors of TEK in human umbilical vein endothelial cells (HUVECs).

Effectiveness of acupoint application of Xiaozhong Zhitong Tie on diarrhea in patients: a retrospective cohort study in China.

OBJECTIVE: To provide the evidence for the efficacy of acupoint application (AA) for patients with diarrhea in a real-world setting. METHODS: This study is a national multicenter retrospective cohort study. Our study consecutively collected outpatient medical records of patients with diarrhea from hundreds of primary hospitals nationwide registered in Chun Bo Wan Xiang cloud platform from 22nd August, 2020 to 5th November, 2020. The patients were divided into the treatment group and the control group according to patient's condition and willingness. The control group was treated with Western Medicine, oral Chinese Medicine decoction, or both. The treatment group was added with AA based on the control group. Multiple logistic regression was used to evaluate the independent efficacy of AA in diarrheal recovery on the 3rd, 7th, 14th and 28th day. As a next step, we also performed stratified analysis and likelihood ratio test (LRT). Sensitivity analyses included propensity score matching (PSM), four PSM-related analyses and E-value. RESULTS: The treatment group showed better efficacy than the control group on the 14th and 28th day [the 14th day: = 1.58, 95% (1.15, 2.19), 0.005; the 28th day: = 2.03, 95% (1.43, 2.88), < 0.001]. No difference was observed in efficacy of AA for the treatment of diarrhea among the subgroups ( > 0.05). PSM-related analyses confirmed the efficacy of AA in diarrheal recovery. The findings are unlikely to be nullified by an unmeasured confounding variable according to the results of E-values. CONCLUSIONS: The efficacy in the treatment group was significantly more improved than that in the control group on the 14th and 28th day.

The influence of stigma and disability acceptance on psychosocial adaptation in patients with stoma: A multicenter cross-sectional study.

Background: The stoma can cause serious physical and psychological distress to the patient, leading to an inability to live a normal life; although it effectively improves the 5-year survival rate of patients. Objective: The purpose of this study is to explore the status of stigma and disability acceptance of patients with stoma and their influences on psychosocial adaptation. Design: A multicenter cross-sectional study. Methods: A total of 259 patients with stoma in 6 hospitals from southeast China were enrolled. And this research adhered to the STROBE guideline and approved by the Ethics Committee of Fu Jian Provincial Hospital. The ostomy adjustment inventory-20、acceptance of disability scale and social impact scale were used to collect data. The hypothetical path model was tested using the SPSS version 22.0 software and AMOS version 26.0 software. Results: Stigma, disability acceptance and psychosocial adaptation was associated. The sense of stigma was severe (72.76 ± 12.73), the acceptance of disability was medium (179.24 ± 32.29) and the psychosocial adaptation was poor (38.06 ± 8.76). Also, the hypothesis model of this study fitted the data well (AGFI = 0.967>0.08; χ 2/df = 1.723, p = 0.08 > 0.05), and the results showed that disability acceptance positively affected psychosocial adaptation; while stigma negatively affected psychosocial adaptation, and disability acceptance mediated between stigma and psychosocial adaptation (p < 0.01). Conclusion: The stigma and disability acceptance of patients with stoma are serious problems that are closely related to their psychosocial adaptation. Medical staff should take some interventions based on different paths to reduce stoma patients' stigma and guide them to improve disability acceptance, thus to improve the level of psychosocial adaptation of patients with stoma.

Compassionate Use of Yuanjiang Decoction, a Traditional Chinese Medicinal Prescription, for Symptomatic Bradyarrhythmia.

Background: No effective medication is available for symptomatic bradyarrhythmia, particularly in low socioeconomic status (SES) population. Objective: To explore the safety and efficacy of Yuanjiang decoction, a traditional Chinese medicinal prescription, for symptomatic bradyarrhythmia on a compassionate-use basis. Methods: This compassionate-use study was conducted in Beijing, China between January 2019 and January 2020. Eligible participants were recruited and treated with Yuanjiang decoction (composed of 6 Chinese herbal medicines), 200 ml twice daily for 16 weeks. Analyses were done with the intention-to-treat (ITT) approach. The primary outcome measure was the proportion of participants who achieved a favorable treatment outcome at 16 weeks. Results: As of January 2020, 184 patients were included. After 16-weeks treatment, 12 participants were lost to contact while 21 participants were terminated from this study, with a drop-out rate of 17.93%. The most common treatment-related adverse events were xerostomia (6.52%), constipation (6.45%) and sleepiness (3.26%). The proportion of participants with favorable treatment outcome was 65.22% at 4 weeks, 59.78% at 8 weeks (OR: 1.11, 95% CI: 0.71-1.73), 61.41% at 12 weeks (OR: 1.16, 95% CI: 0.92-1.45) and 60.87% at 16 weeks (OR: 1.15, 95% CI: 0.98-1.35). In the multifactor regression analysis, the favorable treatment outcome at 16 weeks was significantly associated with completing at least 8 weeks treatment (OR: 2.053, 95% CI: 1.064-3.560), while unfavorable treatment outcome was significantly associated with an atrioventricular block (OR: 0.255, 95% CI: 0.083-0.784), current smoking (OR: 0.343, 95% CI: 0.027-0.487), and syncope in the month before treatment (OR: 0.321, 95%CI: 0.114-0.904). Conclusion: This compassionate-use study showed encouraging outcomes of treatment with Yuanjiang decoction, without serious adverse events. This study identified several key factors that may affect outcomes. These findings helped inform the design and assess the feasibility of a large-scale randomized clinical trial.

Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations.

OBJECTIVES: To determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed between carriers and noncarriers. METHODS: Using target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment. RESULTS: Of 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5-4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017). CONCLUSION: Among Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype.

High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus.

CONTEXT: Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with first recognition during pregnancy, is a heterogeneous form of diabetes characterized by various degrees of ß-cell dysfunction. OBJECTIVES: We aimed to estimate the prevalence of possibly pathogenic variants in the maturity-onset diabetes of the young genes GCK, HNF1A, HNF4A, HNF1B, and INS among women with GDM. Furthermore, we examined the glucose tolerance status in variant carriers vs noncarriers at follow-up. DESIGN SETTING AND PATIENTS: We sequenced the coding regions and intron/exon boundaries of GCK, HNF1A, HNF4A, HNF1B, and INS using targeted region capture and next-generation sequencing in 354 Danish women with diet-treated GDM. Glucose tolerance was examined at follow-up 10 years after the index pregnancy. MAIN OUTCOME MEASURES: The prevalence of possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, and INS was estimated, and differences in anthropometric traits, high-sensitivity C-Reactive Protein (CRP), and glucose metabolism were measured. RESULTS: At baseline, 17 possibly disease-causing variants were found in 21 women, revealing a combined GCK, HNF1A, HNF4A, HNF1B, and INS variant prevalence of 5.9% (95% confidence interval: 3.5% to 8.4%). At follow-up, 15 out of 135 women with diabetes (11%) were carriers of variants in GCK, HNF1A, HNF4A, HNF1B, or INS. CONCLUSIONS: Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, or INS. These women are at high risk of developing diabetes after pregnancy. Thus screening for variants in GCK, HNF1A, HNF4A, HNF1B, and INS should be considered among women with GDM.

Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function.

GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional. By analyses of chimeric human/mouse and human/bonobo receptors, bonobo receptor mutants, and the single nucleotide polymorphism database at NCBI, we identify an insertion/deletion variation in the third intracellular loop responsible for the intracellular retention and lack of function of the human ortholog. Genetic analyses of the 1000 genome database and the Inter99 cohort of 6,000 Danes establish the distribution of genotypes among ethnic groups, showing that the cell surface-expressed and functional variant is much more prevalent in the African population than in European and Asian populations and that this variant is partly linked with a stop codon early in the receptor sequence (rs6907580, amino acid position 57). In conclusion, our data solve a more than decade-old question of why the cloned human GPRC6A receptor is not cell surface-expressed and functional and provide a genetic framework to study human phenotypic traits in large genome sequencing projects linked with physiological measurement and biomarkers.

[Effect of data management quality on clinical research evidence evaluation].

Current clinical evaluation of literature quality has various ways. Most of them lay special emphasis on the evaluation of the design quality, but the evaluation of the implementation process quality is not perfect. Especially data management is not fully emphasized during the enforcement of clinical trials. Data from clinical research were bases for evaluating clinical findings. Although strict specifications and requirements for data management might be strictly written clearly in research protocols, they were not embodied in current clinical research evidence evaluation system. Data management is an important part of implementing the whole clinical trial process, which is a comprehensive reflection of data collecting, logging, sorting, and managing. Its objective is to obtain high quality research data for statistical analysis, thereby coming to a true and reliable conclusion. In order to overall evaluating clinical design and implement, we suggest that present quality evaluation indicators of clinical trails should be completed, and add data management quality evaluation during the whole implement process. Data management plans, standards and requirements for data checking, and management regulations for disobeying data and exception data should be added in quality evaluation indicators for clinical research evidence. The effect of data management quality on clinical research evidence evaluation should be emphasized.

High frequency electro-acupuncture enhances striatum DAT and D1 receptor expression, but decreases D2 receptor level in 6-OHDA lesioned rats.

The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6-hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100 Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10 ± 11.41% of the level on the non-lesioned rats vs. 21.22 ± 5.52% in the non-EA group, P<0.05) and reduce motor deficits (207.80 ± 31.14 vs. 476.11 ± 68.80 turns/30 min, P<0.05), whereas it only slightly restored the 6-hydroxydopamine-induced loss of striatal DA (P>0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100 Hz EA group (P<0.05 vs. the non-EA group). Moreover, high frequency EA induced increases in striatal D1-like receptor mRNA and protein levels of 81.88% and 62.62%, respectively (P<0.001 and P<0.05 vs. the non-EA group). However, the D2-like DA receptor up-regulation observed in the non-EA group was suppressed in high frequency group (P>0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system.