Validating the Ontario Child Health Study Emotional Behavioural Scales-Brief Version (OCHS-EBS-B) in children with chronic physical illness.

BACKGROUND: A substantial proportion of children have a physical illness; these children commonly experience physical-mental comorbidity. To assess child mental health, brief scales that can be used in clinical and research settings are needed. This study assessed the validity and reliability of parent-reported Ontario Child Health Study Emotional Behavioural Scale-Brief Version (OCHS-EBS-B) scores. METHODS: Data come from a longitudinal study of children aged 2-16 years with a physical illness recruited from outpatient clinics at a pediatric hospital. Confirmatory factor analysis and McDonald's coefficient assessed the factor structure and internal consistency reliability of the OCHS-EBS-B, respectively. Point biserial correlations assessed agreement between the OCHS-EBS-B and Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), a structured diagnostic interview. The Wilcoxon rank sum test compared OCHS-EBS-B scores between children with versus without physical-mental comorbidity (known-group validity). RESULTS: The three-factor structure of the OCHS-EBS-B was replicated in this sample of children with physical illness (χ2 = 196.23(272), p < 0.001; CFI = 0.98; TLI = 0.98; SRMR = 0.06; RMSEA [90% CI] = 0.034 [0.027, 0.044]). It had excellent internal consistency reliability (ω = 0.86-0.92) and was moderately correlated with the MINI-KID (baseline: rpb = 0.43-0.51; 6 months: rpb = 0.55-0.65). OCHS-EBS-B scores were significantly higher among children with versus without physical-mental comorbidity. CONCLUSIONS: Findings confirm psychometric evidence that the OCHS-EBS-B is a valid and reliable measure of mental health in children with chronic physical illness. Its brevity and robust psychometric properties make the OCHS-EBS-B a strong candidate for routine use in integrated pediatric physical and mental health services.

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats.

BACKGROUND: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. METHODS: In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. RESULTS: Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. CONCLUSIONS: These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Rates of 30-day revisit to the emergency department among older adults living with dementia: a systematic review and meta-analysis.

OBJECTIVE: Older adults visit emergency departments (EDs) at higher rates than their younger counterparts. However, less is known about the rate at which older adults living with dementia visit and revisit EDs. We conducted a systematic review and meta-analysis to quantify the revisit rate to the ED among older adults living with a dementia diagnosis. METHODS: We searched MEDLINE, Embase, and CINAHL, as well as gray literature, to identify observational studies reporting on older adults living with dementia that revisited an ED within 30 days of a prior ED visit. We calculated pooled rates of 30-day revisit as percentages using random effects models, and conducted stratified analyses by study data source, study population, and study period. We assessed between-studies heterogeneity using the I2 statistic and considered [Formula: see text] > 50% to indicate substantial heterogeneity. All analyses were performed in R software. RESULTS: We identified six articles for inclusion. Percentages of 30-day ED revisit among older adults living with dementia ranged widely from 16.1% to 58.0%. The overall revisit rate of 28.6% showed significant heterogeneity. Between-studies heterogeneity across all stratified analyses was also high. By data source, 30-day revisit percentages were 52.3% (public hospitals) and 20.0% (administrative databases); by study population, revisit percentages were 33.5% (dementia as main population) and 19.8% (dementia as a subgroup). By study period, revisit percentages were 41.2% (5 years or greater) and 18.9% (5 years or less). CONCLUSION: Existing literature on ED revisits among older adults living with dementia highlights the medical complexities and challenges surrounding discharge and follow-up care that may cause these patients to seek ED care at an increased rate. ED personnel may play an important role in connecting patients and caregivers to more appropriate medical and social resources in order to deliver an efficient and more rounded approach to care.

RéSUMé: OBJECTIFS: Les personnes âgées se rendent aux services d'urgence (SU) à des taux plus élevés que leurs homologues plus jeunes. Cependant, on sait moins à quelle fréquence les personnes âgées vivant avec une démence se rendent et retournent aux SU. Nous avons mené une revue systématique et une méta-analyse pour quantifier le taux de retour aux SU chez les personnes âgées vivant avec un diagnostic de démence. MéTHODES: Nous avons effectué une recherche dans MEDLINE, Embase et CINAHL, ainsi que dans la littérature grise, pour identifier les études observationnelles rapportant sur les personnes âgées vivant avec une démence qui sont retournées aux SU dans les 30 jours suivant une visite antérieure aux SU. Nous avons calculé les taux de retour à 30 jours en pourcentage en utilisant des modèles à effets aléatoires, et nous avons effectué des analyses stratifiées selon la source des données de l'étude, la population de l'étude et la période de l'étude. Nous avons évalué l'hétérogénéité entre les études à l'aide de la statistique I2 et avons considéré I

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats.

Background: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. Methods: Neural recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. Results: Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared saline-exposed controls, but responses to tones and noise burst trains were unaltered. Conclusions: These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Ligand-Guided Investigation of a Series of Formamidine-Based Thiuram Disulfides as Potential Dual-Inhibitors of COX-1and COX-2.

A series of thiuram disulfides 1-6 which had been previously synthesized and characterized,[1] were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.

Computational studies of the properties and activities of selected trisubstituted benzimidazoles as potential antitubercular drugs inhibiting MTB-FtsZ polymerization.

Trisubstituted benzimidazoles (trisbenz) are significantly active against nonreplicating Mycobacterium tuberculosis (MTB) by inhibiting the polymerization of Filamentous Temperature Sensitive Mutant Z (FtsZ), an essential bacteria cell division protein. In-depth in-silico study of 5 of the most active trisubstituted benzimidazoles; trisbenz 1, 2, 3, 4 and 5, giving insight into their properties, such as stability, bioavailability, interactions with residues at the binding site of MTB-FtsZ and their influence on structural dynamics of the protein have been conducted. This was achieved through the application of in-silico methods including density functional theory (DFT) calculations, ADME properties calculations, molecular docking and molecular dynamics simulations. A DFT approach was applied to predict reactivity properties of potent FtsZ inhibitors, and the results reveal the relative reactivity of these inhibitors as bioactive moieties. The estimated ADME properties predicted all 5 compounds to be bioavailable and suitable for oral administration. Molecular docking, binding free energy, RMSD, RMSF, and hydrogen bond analysis confirmed these 5 compounds as potent MTB-FtsZ inhibitors. Although analyses proved these compounds to be bioactive and potent MTB-FtsZ inhibitors, however, trisbenz 1 appeared to be the most active against this protein while trisbenz 5 was the least active. This study further confirms the experimental study while also giving insight on the compounds mechanism of action and presents their bioavailability properties.

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb-FtsZ polymerisation through ligand-based virtual screening and molecular dynamics simulations.

Berberine, an active compound in the extract of golden seal (an age-long remedy for many infections) has been confirmed to be responsible for the extract's activity against multi-drug resistant strain of Mycobacterium tuberculosis. There is no available study that shows the exact target of berberine in M tuberculosis, although it is confirmed that berberine inhibits the polymerisation of filamentous temperature-sensitive mutant Z (FtsZ), an important bacteria cytokinesis protein, in Escherichia coli, suggesting that FtsZ could as well be the target of berberine in M tuberculosis. In this study, we carried out ligand-based virtual screening to identify analogues of berberine followed by molecular dynamics (MD) simulations of the complexes of Mtb-FtsZ with berberine (berb1) and the five selected analogues (berb9 [ZINC1709414], berb37 [ZINC238749993], berb38 [ZINC13509022], berb43 [ZINC14765594], and berb48 [ZINC238758595]). Post-MD analyses such as binding free energy, RMSD, RMSF, RoG and hydrogen bond lifetime analysis were used to understand the interactions between these ligands and the receptor. The results suggested that Mtb-FtsZ could likely be the target of berberine in M tuberculosis as it forms a stable complex coupled with a significantly high binding energy. The study also identified other potential inhibitors of MTB-FtsZ polymerisation. Berb38 specifically showed greater interaction with the residues at the binding site of the protein, forming a far more stable complex with the receptor than any of the other compounds under investigation, including berberine itself. ADME properties calculations also predicted all the ligands to be bioactive as orally administered drugs.

Drug repurposing: Fusidic acid as a potential inhibitor of M. tuberculosis FtsZ polymerization - Insight from DFT calculations, molecular docking and molecular dynamics simulations.

Filamentous Temperature Sensitive Mutant Z (FtsZ), an important cell division protein in bacteria, has been validated as a potential target for antibiotics development. Citric acid has been found to inhibit the polymerization of Mycobacterium tuberculosis (MTB) FtsZ and several other drugs have been predicted as potential inhibitors through a gene ontology-based drug repurposing approach. An in-depth study on four of the predicted drugs; Fusidic acid (FusA), l-tryptophan, Carbamic acid, and 2-(3-guanidinophenyl)-3-mercaptopropanoic acid, as potential inhibitors of MTB-FtsZ polymerization was conducted using Citric acid as reference compound. The applied in silico methods involve DFT calculations, molecular docking and molecular dynamics simulations. DFT approach was applied to evaluate selectivity and stability properties of the predicted drugs. Calculated parameters including non-linear optical properties, charge distribution and electrostatic potential analyses enabled selectivity prediction of these potential drugs. DFT-based descriptors revealed FusA as the most potent compound, even more reactive than the referenced compound, Citric acid, which is also supported from the molecular docking study. Parameters including MM/PBSA binding free energies, RMSD, RMSF, RoG and hydrogen bond analysis also support FusA as the best potential MTB-FtsZ polymerization inhibitor, that forms a stable complex with the protein and impose greatest level of rigidity to the protein.

Clinical evaluation of the therapeutic effectiveness of ethinyl oestradiol and oestrone sulphate on prolonged bleeding in women using depot medroxyprogesterone acetate for contraception. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-acting Systemic Agents for Fertility Regulation.

A placebo-controlled randomized clinical trial was conducted in six centres to compare the effects of a 14 day treatment with either 50 micrograms ethinyl oestradiol daily or 2.5 mg oestrone sulphate daily, on depot medroxyprogesterone acetate (DMPA)-induced prolonged bleeding. Out of 1035 women admitted to the study, 278 requested treatment and were given ethinyl oestradiol (n = 90), oestrone sulphate (n = 91) or placebo (n = 97). Ethinyl oestradiol was successful in stopping the bleeding episode in 93% of cases, compared with oestrone sulphate and placebo which had success rates of 76 and 74% respectively. However, the relative advantage of ethinyl oestradiol was marginal, with an average reduction of 1 bleeding day and 3 spotting days compared with the other two groups. Immediately after treatment, women given ethinyl oestradiol had less bleeding but a more unpredictable pattern than the other two groups. In the long term, there were no differences between the bleeding patterns or the discontinuation rates for any reason in the three groups, and the most important single reason for discontinuation in those groups remained 'menstrual problems'. In summary, the study showed that treatment of DMPA-induced prolonged bleeding with ethinyl oestradiol had a limited short-term effect but no beneficial effect on the acceptability of DMPA as a contraceptive method. Treatment with oestrone sulphate was no different from placebo.

PIP: The findings of a multicenter clinical trial challenge the practice of estrogen treatment of the prolonged or irregular vaginal bleeding associated with depot medroxyprogesterone acetate (DMPA) contraceptive use. Included in the study were 1035 DMPA users (mean age, 27 years) from Alexandria, Egypt; Bangkok, Thailand; Chiang Mai, Thailand; Jakarta, Indonesia; Karachi, Pakistan; and Manila, Philippines. 456 (44%) of these women experienced a bleeding episode lasting more than 7 days during their first 6 months of DMPA use. Of these, only 278 (61%) requested treatment. These 278 women were randomly allocated to receive 50 mcg of ethinyl estradiol (n = 90), 2.5 mg of estrone sulfate (n = 91), or placebo (n = 97) daily for 14 days. The treatment stopped the bleeding episode for 93% of women in the ethinyl estradiol group, 76% of those in the estrone sulfate group, and 74% of women receiving a placebo. The ethinyl estradiol advantage was marginal, however. On average, women treated with ethinyl estradiol had their bleeding episode shortened by 1 bleeding day and 3 spotting days. Immediately after treatment, women given ethinyl estradiol had less bleeding and spotting days than their counterparts in the 2 other groups, but demonstrated a more unpredictable pattern, including a greater range of lengths of bleeding/spotting-free intervals. Three months after treatment, there were no differences between the 3 groups in vaginal bleeding patterns.