Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as “true” P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function

Long-term survival of children born with congenital anomalies: A systematic review and meta-analysis of population-based studies.

BACKGROUND: Following a reduction in global child mortality due to communicable diseases, the relative contribution of congenital anomalies to child mortality is increasing. Although infant survival of children born with congenital anomalies has improved for many anomaly types in recent decades, there is less evidence on survival beyond infancy. We aimed to systematically review, summarise, and quantify the existing population-based data on long-term survival of individuals born with specific major congenital anomalies and examine the factors associated with survival. METHODS AND FINDINGS: Seven electronic databases (Medline, Embase, Scopus, PsycINFO, CINAHL, ProQuest Natural, and Biological Science Collections), reference lists, and citations of the included articles for studies published 1 January 1995 to 30 April 2020 were searched. Screening for eligibility, data extraction, and quality appraisal were performed in duplicate. We included original population-based studies that reported long-term survival (beyond 1 year of life) of children born with a major congenital anomaly with the follow-up starting from birth that were published in the English language as peer-reviewed papers. Studies on congenital heart defects (CHDs) were excluded because of a recent systematic review of population-based studies of CHD survival. Meta-analysis was performed to pool survival estimates, accounting for trends over time. Of 10,888 identified articles, 55 (n = 367,801 live births) met the inclusion criteria and were summarised narratively, 41 studies (n = 54,676) investigating eight congenital anomaly types (spina bifida [n = 7,422], encephalocele [n = 1,562], oesophageal atresia [n = 6,303], biliary atresia [n = 3,877], diaphragmatic hernia [n = 6,176], gastroschisis [n = 4,845], Down syndrome by presence of CHD [n = 22,317], and trisomy 18 [n = 2,174]) were included in the meta-analysis. These studies covered birth years from 1970 to 2015. Survival for children with spina bifida, oesophageal atresia, biliary atresia, diaphragmatic hernia, gastroschisis, and Down syndrome with an associated CHD has significantly improved over time, with the pooled odds ratios (ORs) of surviving per 10-year increase in birth year being OR = 1.34 (95% confidence interval [95% CI] 1.24-1.46), OR = 1.50 (95% CI 1.38-1.62), OR = 1.62 (95% CI 1.28-2.05), OR = 1.57 (95% CI 1.37-1.81), OR = 1.24 (95% CI 1.02-1.5), and OR = 1.99 (95% CI 1.67-2.37), respectively (p < 0.001 for all, except for gastroschisis [p = 0.029]). There was no observed improvement for children with encephalocele (OR = 0.98, 95% CI 0.95-1.01, p = 0.19) and children with biliary atresia surviving with native liver (OR = 0.96, 95% CI 0.88-1.03, p = 0.26). The presence of additional structural anomalies, low birth weight, and earlier year of birth were the most commonly reported predictors of reduced survival for any congenital anomaly type. The main limitation of the meta-analysis was the small number of studies and the small size of the cohorts, which limited the predictive capabilities of the models resulting in wide confidence intervals. CONCLUSIONS: This systematic review and meta-analysis summarises estimates of long-term survival associated with major congenital anomalies. We report a significant improvement in survival of children with specific congenital anomalies over the last few decades and predict survival estimates up to 20 years of age for those born in 2020. This information is important for the planning and delivery of specialised medical, social, and education services and for counselling affected families. This trial was registered on the PROSPERO database (CRD42017074675)

Understanding the newly observed Y(4008) by Belle

Very recently a new enhancement around 4.05 GeV was observed by Belle experiment. In this short note, we discuss some possible assignments for this enhancement, i.e. $\psi(3S)$ and $D^*\bar{D}^*$ molecular state. In these two assignments, Y(4008) can decay into $J/\psi\pi^0\pi^0$ with comparable branching ratio with that of $Y(4008)\to J/\psi\pi^+\pi^-$. Thus one suggests high energy experimentalists to look for Y(4008) in $J/\psi\pi^0\pi^0$ channel. Furthermore one proposes further experiments to search missing channel $D\bar{D}$, $D\bar{D}^*+h.c.$ and especially $\chi_{cJ}\pi^+\pi^-\pi^0$ and $\eta_c\pi^+\pi^-\pi^0$, which will be helpful to distinguish $\psi(3S)$ and $D^*\bar{D}^*$ molecular state assignments for this new enhancement.Comment: 4 pages, 5 figures. Typos correcte

Patient satisfaction with anaesthesia care: development of a psychometric questionnaire and benchmarking among six hospitals in Switzerland and Austria†‡

Background. We describe the development and comparison of a psychometric questionnaire on patient satisfaction with anaesthesia care among six hospitals. Methods. We used a rigorous protocol: generation of items, construction of the pilot questionnaire, pilot study, statistical analysis (construct validity, factor analysis, reliability analysis), compilation of the final questionnaire, main study, repeated analysis of construct validity and reliability. We compared the mean total problem score and the scores for the dimensions: ‘Information/Involvement in decision‐making', and ‘Continuity of personal care by anaesthetist'. The influence of potential confounding variables was tested (multiple linear regression). Results. The average problem score from all hospitals was 18.6%. Most problems are mentioned in the dimensions ‘Information/Involvement in decision‐making' (mean problem score: 30.9%) and ‘Continuity of personal care by anaesthetist' (mean problem score: 32.2%). The overall assessment of the quality of anaesthesia care was good to excellent in 98.7% of cases. The most important dimension was ‘Information/Involvement in decision‐making'. The mean total problem score was significantly lower for two hospitals than the total mean for all hospitals (significantly higher at two hospitals) (P<0.05). Amongst the confounding variables considered, age, sex, subjective state of health, type of anaesthesia and level of education had an influence on the total problem score and the two dimensions mentioned. There were only marginal differences with and without the influence of the confounding variables for the different hospitals. Conclusions. A psychometric questionnaire on patient satisfaction with anaesthesia care must cover areas such as patient information, involvement in decision‐making, and contact with the anaesthetist. The assessment using summed scores for dimensions is more informative than a global summed rating. There were significant differences between hospitals. Moreover, the high problem scores indicate a great potential for improvement at all hospitals. Br J Anaesth 2002; 89: 863-7

Focus Group Data Saturation: A New Approach to Data Analysis

The qualitative research “gold standard” for quality research is data saturation. The limited literature on reporting data saturation and transparency in qualitative research has supported an inconsistent research standard suggesting researchers have not adequately reported data saturation to promote transparency (O’Reilly & Parker, 2012). Confusion regarding how to analyze qualitative data to achieve data saturation, how to write clear qualitative research findings, and present these findings in a usable manner continues (Sandelowski & Leeman, 2012). A phenomenological asynchronous online focus group using WordPress® was employed to answer the research question. Based on the current literature on the topic of focus group data saturation, the study findings were analyzed by group, individual, and day of the study. Additionally, the data was presented in a chart format providing a visible approach to data analysis and saturation. Employing three different methods of data analysis to confirm saturation and transparency provides qualitative researchers with different approaches to data analysis for saturation and enhancement of trustworthiness. Placing data in a visual configuration provides an alternative method of presenting research findings. The data analysis methods presented are not meant to replace existing methods of achieving data saturation but to provide an alternate approach to achieving data saturation and reporting the findings in a clear, usable format

Fatal flaws in the UK asylum decision-making system: an analysis of Home Office refusal letters

The process of deciding who is in need of international protection is well established most western liberal democracies, and has been subject to critical scrutiny for decades. And yet asylum seekers remain vulnerable to serious and ongoing flaws in that system. In this paper, based on research conducted in Afghanistan 2012–2018, Schuster explores a number of shortcomings in the asylum decision-making process, specifically with regard to the rejection of claims from Afghans. The analysis of Reasons for Refusal Letters, allows Schuster to examine the use of key tools in that process (previous cases and country of origin reports). Schuster argues that the current adversarial approach, which seeks to prove an applicant is not credible or does not need protection, undermines the legitimacy of the asylum and risks refusing protection to those in need and or condemning others to years of damaging appeals before they are granted asylum. She concludes by arguing for a shift to a more investigative approach, one that seeks to identify those in need of protection, rather than to keep numbers low

Risk perception of arsenic exposure from rice intake in a UK population

In the UK, consumption of rice and rice-based products is on the rise but, notwithstanding public expressed concerns about such products as an exposure route for arsenic (e.g. BBC News report, 2017“Should I worry about arsenic in my rice?”) there are few, if any published data on public perceptions of risks associated with exposure to arsenic in rice. We therefore aimed to determine the risk perception of arsenic exposure from rice intake and factors that are associated with arsenic knowledge and whether or not this knowledge had an influence on rice consumption and cooking practices. A questionnaire, targeting participation of rice-eating ethnic minorities in Greater Manchester, UK, was administered to 184 participants. A multivariate generalized linear model was used to determine the factors associated with rice consumption behaviour, cooking practices, and risk perception. We show for the first time that the general population did not associate arsenic, which they perceive as toxic to health, with rice consumption. More than half of the participants knew about arsenic as a hazardous substance but less than ten percent knew that rice consumption could be an important route of arsenic exposure. Knowledge of arsenic was significantly lower in Asian/Asian British:Pakistanis (Pakistani) (OR: 0.006; 95% CI:0.00-0.03) and Asian/Asian British:Bangladeshis (Bangladeshi) (OR: 0.064; 95% CI:0.01-0.25) compared to White:English/Welsh/Scottish/Northern Irish/British (White British). Moreover, Bangladeshis consumed three times more rice (OR: 2.92; 95% CI:1.73-4.93) compared to White British. Overall higher rice consumption was not associated with higher knowledge of the nutritional value of rice. Rinsing rice before cooking, an effective arsenic removal technique, was practised by 93% of the participants, however the most popular cooking method was the use of adequate water (rice to water ratio of 1:2) but not excess water (rice to water ratio of > 1:4), the latter being more effective in removing arsenic. Better education, higher weekly expenditure on food and prior knowledge of arsenic hazard were all significant factors positively influencing a change in behaviour to reduce arsenic exposure from rice intake

Creating a population-based cohort of children born with and without congenital anomalies using birth data matched to hospital discharge databases in 11 European regions: Assessment of linkage success and data quality

Linking routinely collected healthcare administrative data is a valuable method for conducting research on morbidity outcomes, but linkage quality and accuracy needs to be assessed for bias as the data were not collected for research. The aim of this study was to describe the rates of linking data on children with and without congenital anomalies to regional or national hospital discharge databases and to evaluate the quality of the matched data. Eleven population-based EUROCAT registries participated in a EUROlinkCAT study linking data on children with a congenital anomaly and children without congenital anomalies (reference children) born between 1995 and 2014 to administrative databases including hospital discharge records. Odds ratios (OR), adjusted by region, were estimated to assess the association of maternal and child characteristics on the likelihood of being matched. Data on 102,654 children with congenital anomalies were extracted from 11 EUROCAT registries and 2,199,379 reference children from birth registers in seven regions. Overall, 97% of children with congenital anomalies and 95% of reference children were successfully matched to administrative databases. Information on maternal age, multiple birth status, sex, gestational age and birthweight were &gt;95% complete in the linked datasets for most regions. Compared with children born at term, those born at ≤27 weeks and 28-31 weeks were less likely to be matched (adjusted OR 0.23, 95% CI 0.21-0.25 and adjusted OR 0.75, 95% CI 0.70-0.81 respectively). For children born 32-36 weeks, those with congenital anomalies were less likely to be matched (adjusted OR 0.78, 95% CI 0.71-0.85) while reference children were more likely to be matched (adjusted OR 1.28, 95% CI 1.24-1.32). Children born to teenage mothers and mothers ≥35 years were less likely to be matched compared with mothers aged 20-34 years (adjusted ORs 0.92, 95% CI 0.88-0.96; and 0.87, 95% CI 0.86-0.89 respectively). The accuracy of linkage and the quality of the matched data suggest that these data are suitable for researching morbidity outcomes in most regions/countries. However, children born preterm and those born to mothers aged &lt;20 and ≥35 years are less likely to be matched. While linkage to administrative databases enables identification of a reference group and long-term outcomes to be investigated, efforts are needed to improve linkages to population groups that are less likely to be linked.</p

Antiasthmatic prescriptions in children with and without congenital anomalies: a population-based study.

OBJECTIVES: To explore the risk of being prescribed/dispensed medications for respiratory symptoms and breathing difficulties in children with and without congenital anomalies. DESIGN: A EUROlinkCAT population-based data linkage cohort study. Data on children with and without congenital anomalies were linked to prescription databases to identify children who did/did not receive antiasthmatic prescriptions. Data were analysed by age, European region, class of antiasthmatic, anomaly, sex, gestational age and birth cohort. SETTING: Children born 2000-2014 in six regions within five European countries. PARTICIPANTS: 60 662 children with congenital anomalies and 1 722 912 reference children up to age 10 years. PRIMARY OUTCOME MEASURE: Relative risks (RR) of >1 antiasthmatic prescription in a year, identified using Anatomical Therapeutic Chemical classification codes beginning with R03. RESULTS: There were significant differences in the prescribing of antiasthmatics in the six regions. Children with congenital anomalies had a significantly higher risk of being prescribed antiasthmatics (RR 1.41, 95% CI 1.35 to 1.48) compared with reference children. The increased risk was consistent across all regions and all age groups. Children with congenital anomalies were more likely to be prescribed beta-2 agonists (RR 1.71, 95% CI 1.60 to 1.83) and inhaled corticosteroids (RR 1.74, 95% CI 1.61 to 1.87). Children with oesophageal atresia, genetic syndromes and chromosomal anomalies had over twice the risk of being prescribed antiasthmatics compared with reference children. Children with congenital anomalies born <32 weeks gestational age were over twice as likely to be prescribed antiasthmatics than those born at term (RR 2.20, 95% CI 2.10 to 2.30). CONCLUSION: This study documents the additional burden of respiratory symptoms and breathing difficulties for children with congenital anomalies, particularly those born preterm, compared with children without congenital anomalies in the first 10 years of life. These findings are beneficial to clinicians and healthcare providers as they identify children with greater morbidity associated with respiratory symptoms, as indicated by antiasthmatic prescriptions