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Background This study was designed to examine the possible efficacy of the probiotic strain Lactobacillus acidophilus LB (Lacteol Fort) on attention-deficit/hyperactivity disorder (ADHD) symptomatology and evaluate its influence on cognition function. Methods In this randomized controlled trial, 80 children and adolescents with ADHD diagnosis, aged 6–16 years, were included. The participants were randomly assigned to two groups: one group received probiotics plus atomoxetine, whereas the other group received atomoxetine only. ADHD symptomatology was assessed using the Conners Parent Rating Scale–Revised Long Version (CPRS-R-L) and Child Behavioral Checklist (CBCL/6–18). The participants were evaluated for their vigilance and executive function using Conner’s Continuous Performance Test (CPT) and Wisconsin Card Sort Test (WCST). Both groups were assessed at the beginning of the study and the end of the twelve weeks. Results The probiotic group comprised 36 patients, whereas the control group comprised 40 patients in the final analysis after four patients dropped out of the trial. After 3 months of probiotic supplementation, a significant improvement in the CPRS-R-L and CBCL total T scores was observed compared with those in the control group ( p  = 0.032, 0.024, respectively). Additionally, the probiotic group demonstrated improved focus attention (target accuracy rate and omission errors; p  = 0.02, 0.043, respectively) compared with the control group. An analysis of the Wisconsin Card Sorting Test (WCST) performance demonstrated that the probiotic group had significantly lower perseverative ( p  = 0.017) and non-perseverative errors ( p  = 0.044) but no significant differences compared to the control group. Conclusion Lactobacillus acidophilus LB supplementation combined with atomoxetine for 3 months had a beneficial impact on ADHD symptomology and a favorable influence on cognitive performance. As a result, the efficacy of probiotics as an adjunctive treatment for managing ADHD may be promising. Trial registration ClinicalTrials.gov (identifier: NCT04167995). Registration date: 19–11-2019.

Inadequate adherence to insulin is a major concern, necessitating the use of reliable and valid metrics for assessing adherence. Up to date, there are no Arabic validated tools assessing adherence to insulin therapy among children with type 1 diabetes (T1DM). Thus, the aim of this study is to evaluate the psychometric properties of an Arabic version of the four-item Morisky Green Levine Medication Adherence Scale (MGLS-4) as a self-reported measure of adherence to insulin among a cohort of Egyptian children with T1DM. The MGLS-4 was translated using forward and backward translation. The Cronbach's alpha was used to assess reliability. Criterion validity of the scale was tested by examining the correlation coefficients between the compliance score (level of adherence) and the HbA1c levels. A total of 400 patients completed the Arabic version of MGLS-4. 26.25% of the studied cohort was found to be non-adherent to insulin therapy; non-adherent patients were significantly older (P=0.001). Decreased maternal education level, decreased frequency of blood glucose monitoring and prolonged disease duration best predicted the occurrence of non-adherence among the studied cohort. The internal consistency of the current version showed good reliability (Cronbach's alpha = 0.857). The adherence score and adherence level showed very strong correlation with HbA1c level (rho = 0.830, P < 0.001 and rho = 0.808, P < 0.001, respectively). The Arabic version of MGLS-4 showed good reliability and validity as a self-administered tool for assessing adherence to insulin in pediatric patients with T1DM.

Background With increasing survival rates following pediatric intensive care unit (PICU) hospitalization, assessing functional outcomes is imperative. We compared children’s psychosocial and adaptive functioning six weeks and six months after discharge from the PICU with children hospitalized in a general ward. Methods This prospective observational cohort study followed 100 children aged 2 to 11 years after PICU and ward discharge (control group) for six months. The two groups were compared for psychosocial and adaptive functioning using the Behavioral Assessment System for Children, Third Edition (BASC-3) parent report scale. Parents also completed the Parenting Stress Index-Short Form scale to assess parenting stress. Multivariate regression analysis adjusted for demographics, PICU-related factors, and parental stress was used to investigate the potential variables associated with children’s psychosocial and adaptive functioning six weeks and six months after PICU discharge. Results Our findings indicated that children experienced greater psychosocial problems and worse adaptive functioning up to six months after PICU discharge than children after ward discharge, P  < 0.05. The number of intervention procedures and parental stress were common factors associated with impaired psychosocial and adaptive functioning post-PICU discharge. Six months after PICU discharge, younger age and length of stay were associated with psychosocial problems, while internalizing and externalizing problems were associated with poorer adaptive functioning, P  < 0.05. Conclusion Given the impact of PICU experience on children’s psychosocial and adaptive outcomes, it is crucial to implement psychological assessments with a follow-up plan extended longitudinally after PICU discharge. This study underscores the need to integrate adaptive behavior assessment in children’s psychological evaluation to identify significant deficits, develop relevant behavioral management plans, and monitor their progress.

Nocturnal enuresis (NE) is a common voiding problem in pediatric populations. Relatively, few studies have investigated the 25-Hydroxyvitamin D and NE associations in children, which may open up a new research area on the effect of vitamin D as nutritional therapy in the treatment of NE. The aim of this study was to determine the level of 25-hydroxyl vitamin D among children and adolescents with nocturnal enuresis in comparison to non-enuretic Egyptian children. Fifty children (24 females, 26 males) who presented with primary mono-symptomatic nocturnal enuresis (PMNE) and 50 healthy children (23 females, 27 males) were recruited in this study. A structured questionnaire focusing on demographic, socioeconomic, and frequency of bed-wetting were collected, and vitamin D serum levels were assessed in all children. In the NE group, the mean value of serum vitamin D levels was lower than the control (19.0 ± 6.5 versus 23.89 ± 4.19; P < 0.0001). Serum 25-hydroxyvitamin D levels were abnormal (< 20 ng/mL) in 46% of children with NE and 16% of controls (P < 0.001). The higher bed-wetting frequencies were associated with lower levels of 25(OH) D (Every night: 7.0 ± 1.4, 3-5 time/week: 11.2 ± 1.7, 1-3 times/week: 17.6 ± 3.7, < 2times/week: 22.4 ± 2.9, Once/6 month: 24.1 ± 4.3 (ng/ml), P < 0.001). A difference in serum 25-hydroxyvitamin D levels was found between the two study groups. There is a need for more studies to explain vitamin D deficiency in larger series so that this test can be used in regular enuretic child investigations.

Early hepatocellular carcinoma (HCC) diagnosis is challenging. Moreover, for patients with alpha-fetoprotein (AFP)-negative HCC, this challenge is augmented. MicroRNAs (miRs) profiles may serve as potential HCC molecular markers. We aimed to assess plasma homo sapiens—(hsa)-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p—expression levels as a panel of biomarkers for HCC in chronic hepatitis C virus (CHCV) patients with liver cirrhosis (LC), especially AFP-negative HCC cases, as a step toward non-protein coding (nc) RNA precision medicine. Subjects and methods: 79 patients enrolled with CHCV infection with LC, subclassified into an LC group without HCC (n = 40) and LC with HCC (n = 39). Real-time quantitative PCR was used to measure plasma hsa-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p. Results: Plasma hsa-miR-21-5p and hsa-miR-155-5p demonstrated significant upregulation, while hsa-miR-199a-5p demonstrated significant downregulation in the HCC group (n = 39) when compared to the LC group (n = 40). hsa-miR-21-5p expression was positively correlated with serum AFP, insulin, and insulin resistance (r = 0.5, p < 0.001, r = 0.334, p = 0.01, and r = 0.303, p = 0.02, respectively). According to the ROC curves, for differentiating HCC from LC, combining AFP with each of hsa-miR-21-5p, hsa-miR-155-5p, and miR199a-5p improved the diagnostic sensitivity to 87%, 82%, and 84%, respectively, vs. 69% for AFP alone, with acceptable specificities of 77.5%, 77.5%, and 80%, respectively, and AUC = 0.89, 0.85, and 0.90, respectively vs. 0.85 for AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios discriminated HCC from LC at AUC = 0.76 and 0.71, respectively, with sensitivities = 94% and 92% and specificities = 48% and 53%, respectively. Upregulation of plasma hsa-miR-21-5p was considered as an independent risk factor for HCC development [OR = 1.198(1.063–1.329), p = 0.002]. Conclusions: Combining each of hsa-miR-21-5p, hsa-miR-155-5p, and hsa-miR-199a-5p with AFP made it possible to identify HCC development in the LC patients’ cohort with higher sensitivity than using AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios are potential HCC molecular markers for AFP-negative HCC patients. hsa-miR-21-5p was linked, clinically and via in silico proof, to insulin metabolism, inflammation, dyslipidemia, and tumorigenesis in the HCC patients’ group as well as for an upregulated independent risk factor for the emergence of HCC from LC in the CHCV patients.

Purpose The authors aim to investigate the altered monocytes subsets distribution in liver cirrhosis (LC) and subsequent hepatocellular carcinoma (HCC) in association with the expression level of plasma Homo sapiens (has)-miR-21-5p and hsa-miR-155-5p. A step toward non-protein coding (nc) RNA precision medicine based on the immune perturbation manifested as altered monocytes distribution, on top of LC and HCC. Methods Seventy-nine patients diagnosed with chronic hepatitis C virus (CHCV) infection with LC were enrolled in the current study. Patients were sub-classified into LC group without HCC ( n  = 40), LC with HCC ( n  = 39), and 15 apparently healthy controls. Monocyte subsets frequencies were assessed by flow cytometry. Real-time quantitative PCR was used to measure plasma hsa-miR-21-5p and hsa-miR-155-5p expression. Results Hsa-miR-21-5p correlated with intermediate monocytes ( r  = 0.30, p  = 0.007), while hsa-miR-155-5p negatively correlated with non-classical monocytes ( r  = − 0.316, p  = 0.005). ROC curve analysis revealed that combining intermediate monocytes frequency and hsa-miR-21 yielded sensitivity = 79.5%, specificity = 75%, and AUC = 0.84. In comparison, AFP yielded a lower sensitivity = 69% and 100% specificity with AUC = 0.85. Logistic regression analysis proved that up-regulation of intermediate monocytes frequency and hsa-miR-21-5p were independent risk factors for LC progression to HCC, after adjustment for co-founders. Conclusion Monocyte subsets differentiation in HCC was linked to hsa-miR-21-5p and hsa-miR-155-5p. Combined up-regulation of intermediate monocytes frequency and hsa-miR-21-5p expression could be considered a sensitive indicator of LC progression to HCC. Circulating intermediate monocytes and hsa-miR-21-5p were independent risk factors for HCC evolution, clinically and in silico proved. Graphical abstract

Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers ( Abcc3 and Abcc4 ). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29 , were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms.

Fluorophore-coupled bile acids (BA) represent an important tool for intravital analysis of BA flux in animal models of cholestatic diseases. However, addition of a fluorophore to a BA may alter transport properties. We developed and validated a 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole-coupled taurocholic acid (3β-NBD-TCA) as a probe for intravital analysis of BA homeostasis. We compared transport of 3β-NBD-TCA to [3H]-TCA in HEK293 cells stably expressing the mouse hepatic or renal BA carriers mNtcp or mAsbt, respectively. We also studied distribution kinetics intravitally in livers and kidneys of anesthetized wildtype and mOatp1a/1b cluster knockout mice (OatpKO) with and without administration of the Ntcp inhibitor Myrcludex B and the ASBT inhibitor AS0369. In vitro, 3β-NBD-TCA and [3H]-TCA showed comparable concentration- and time-dependent transport via mNtcp and mAsbt as well as similar inhibition kinetics for Myrcludex B and AS0369. Intravital analysis in the livers of wildtype and OatpKO mice revealed contribution of both mNtcp and mOatp1a/1b in the 3β-NBD-TCA uptake from the sinusoidal blood into hepatocytes. Combined deletion of mOatp1a/1b and inhibition of mNtcp by Myrcludex B blocked the uptake of 3β-NBD-TCA from sinusoidal blood into hepatocytes. This led to an increase of 3β-NBD-TCA signal in the systemic circulation including renal capillaries, followed by strong enrichment in a subpopulation of proximal renal tubular epithelial cells (TEC). The enrichment of 3β-NBD-TCA in TEC was strongly reduced by the systemic ASBT inhibitor AS0369. NBD-coupled TCA has similar transport kinetics as [3H]-TCA and can be used as a tool to study hepatorenal BA transport. See also the graphical abstract(Fig. 1).