The Utility of Serial Echocardiography Parameters in Management of Newborns with Congenital Diaphragmatic Hernia (CDH) and Predictors of Mortality.

Ventricular dysfunction may be found in 40% of newborns with CDH, and is not only a predictor of disease severity, but also mortality and need for ECMO. We conducted this study to assess the utility of serial echocardiography in management of newborns with CDH and their survival outcomes. This is a retrospective study, wherein the demographic, clinical and echocardiographic data from our local CDH registry and hospital clinical database were analyzed to study the correlation of timed echocardiographic findings with mortality and other outcomes. Fourty-two newborns with CDH were admitted during the study period (M/F:19/23), with median gestation of 38 weeks (IQR:36-39) and birth weight of 2.83 kg (IQR 2.45-3.17). Thirty-one were left-sided, seven right, one central, and three bilateral hernias. Twelve infants (28%) died in early infancy. Three infants were excluded from analysis due to either palliation at birth or significant cardiac anomaly. A total of 137 echos from 39 infants were analyzed. Seventy percent of newborns who died and had an echo within the first 72 h, were noted to have suffered from moderate to severe PH. Birth weight < 2.8 kg, RVSP > 45.5 in the first 72 h and postoperative VIS > 23.5 and RSS > 4.3 were good predictors of mortality. Markers of elevated pulmonary pressures and cardiac function were useful in guiding therapy. Serial timed functional echocardiography (f-Echo) monitoring allows targeted therapy of patients with CDH. Birth weight, initial severity of pulmonary hypertension and postoperative RSS and VIS may be useful in predicting mortality.

Extraordinary Titer and Broad Anti-SARS-CoV-2 Neutralization Induced by Stabilized RBD Nanoparticles from Strain BA.5.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike is a primary target of neutralizing antibodies and a key component of licensed vaccines. Substantial mutations in RBD, however, enable current variants to escape immunogenicity generated by vaccination with the ancestral (WA1) strain. Here, we produce and assess self-assembling nanoparticles displaying RBDs from WA1 and BA.5 strains by using the SpyTag:SpyCatcher system for coupling. We observed both WA1- and BA.5-RBD nanoparticles to degrade substantially after a few days at 37 °C. Incorporation of nine RBD-stabilizing mutations, however, increased yield ~five-fold and stability such that more than 50% of either the WA1- or BA.5-RBD nanoparticle was retained after one week at 37 °C. Murine immunizations revealed that the stabilized RBD-nanoparticles induced ~100-fold higher autologous neutralization titers than the prefusion-stabilized (S2P) spike at a 2 µg dose. Even at a 25-fold lower dose where S2P-induced neutralization titers were below the detection limit, the stabilized BA.5-RBD nanoparticle induced homologous titers of 12,795 ID50 and heterologous titers against WA1 of 1767 ID50. Assessment against a panel of ß-coronavirus variants revealed both the stabilized BA.5-RBD nanoparticle and the stabilized WA1-BA.5-(mosaic)-RBD nanoparticle to elicit much higher neutralization breadth than the stabilized WA1-RBD nanoparticle. The extraordinary titer and high neutralization breadth elicited by stabilized RBD nanoparticles from strain BA.5 make them strong candidates for next-generation COVID-19 vaccines.

Staff perceptions and challenges of the single-family room design-Experience of a greenfield level4 neonatal intensive care unit in the Middle East.

AIM: This study was undertaken to specifically identify challenges associated with the popular single-family room (SFR) design in our new neonatal intensive care unit (NICU), so as to reap the full benefits of this architectural model. METHODS: A survey was sent to all 223, newly recruited staff on our NICU. Questions explored staff perceptions of family experience, safety and staff's experience of the SFR in comparison with the open bay model. RESULTS: We obtained a response rate of 66%. Most staff perceived SFR as having a positive impact on communication with families, privacy, feasibility for skin-to-skin contact, reduction in noise levels and family access to their baby. There were however concerns raised about patient safety and isolation of staff and families in the SFR architecture. Lack of opportunities to leave the patient room for breaks and increased physical demands were highlighted. Staff also felt physically and emotionally less well supported. CONCLUSION: Whilst the SFR configuration was felt to be beneficial for infants and families, staff shared their perceived concerns regarding infant safety and isolation and staff satisfaction, and implied modifications to workflows. The survey findings resulted in re-organisation of our staff numbers and communication systems and further facilitation of parent interactions in order to optimise benefits of SFR design.

A population study of clinically actionable genetic variation affecting drug response from the Middle East.

Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond.

Prescription Pattern and Off-Label Use of Antipsychotics in a Middle Eastern Population.

Background: Understanding the prescription pattern of medications in a population can help reveal the potential usage scenarios, including off-label prescriptions, and the need for precision medicine implementation. Therefore, the aim of this study was to assess the prescription pattern and off-label use of antipsychotics in the Qatari population. Methods: We performed a cross-sectional study of Qatari patients who received antipsychotic prescriptions from the major healthcare providers in the country during the 2-year period between June 2018 and May 2020. The number of patients, prescriptions dispensed, and clinical indications were collected and statistical analysis using chi-square test was conducted. Results: Among the 9,349 Qatari patients prescribed with antipsychotics during the study period, the majority were female (57%; p < 0.001) and were in the age categories 20-39 and 30-39 years (both 22%; p < 0.001). Among the 35,938 antipsychotic prescriptions dispensed, second-generation antipsychotics were the most highly prescribed (59%), specifically, quetiapine (16%) and olanzapine (12%), but the first-generation antipsychotic prochlorperazine (13%) was also highly prescribed. Most of the indications of antipsychotics (69%) were for off-label use such as for controlling chronic diseases, sleeping disorders, benign paroxysmal positional vertigo and irritable bowel syndrome. Conclusion: Non-mental health and off-label prescriptions of several antipsychotics were observed. Integration of this data with pharmacogenomic and clinical outcome data will help in determining the course of action for implementing personalized and precision medicine in the country and beyond.

Prescription Pattern of Antidepressants and the Potential for Personalized Medicine in the Qatari Population.

Studying the prescription pattern of medications will help in understanding potential unnecessary prescriptions, due to the trial-and-error method of prescribing, and the need for personalized medicine in a population. Therefore, in this study, our aim was to explore the prescribing pattern and off-label use of antidepressants in the Qatari population. We conducted a retrospective study of Qatari patients who received prescriptions for antidepressants from the major healthcare providers in Qatar, for a period of 24 months between June 2018 and May 2020. The number of patients, prescriptions, and diagnostic indications were analyzed. The chi-square test was used for identifying statistically significant association of the number of individuals prescribed with age category or gender. Of the 14,601 Qatari patients who were prescribed antidepressants, the majority were female (61%, p < 2.2 × 10-16), and were at or above 60 years of age (27%, p < 2.2 × 10-16). More numbers of selective serotonin reuptake inhibitors (SSRIs) (22,085 out of 48,031; 46%), were dispensed than other classes of antidepressants, with escitalopram (26%) at the top of the list. Preponderance of prescription of antidepressants for non-mental health diseases was observed. Population-level prescription trends, as we reported here, when combined with patient genetic variability and outcome data, will have the power to predict the potential for treatment failures and adverse effects of these medications in the population. We also recommend educating non-mental health prescribers about the adherence to evidence and guidelines to ensure patient safety while prescribing antidepressants.

Hydronephrosis Classifications: Has UTD Overtaken APD and SFU? A Worldwide Survey.

Objective: To collect baseline information on the ultrasonographic reporting preferences. Method: A 13-multiple choice questionnaire was designed and distributed worldwide among pediatric urologists, pediatric surgeons, and urologists. The statistical analysis of the survey data consisted of 3 steps: a univariate analysis, a bivariate and a multivariate analysis. Results: Three hundred eighty participants responded from all the continents. The bivariate analysis showed the significant differences in the geographical area, the years of experience and the volume of cases. Most of the physicians prefer the SFU and APD systems because of familiarity and simplicity (37 and 34%, respectively). Respondents noted that their imaging providers most often report findings utilizing the mild-moderate-severe system or the APD measurements (28 and 39%, respectively) except for North America (SFU in 50%). Multivariate analysis did not provide significant differences. Conclusion: Our study evaluates the opinions regarding the various pediatric hydronephrosis classification systems from a large number of specialists and demonstrates that there is no single preferred grading system. The greatest reported shortcoming of all the systems was the lack of universal utilization. The observations taken from this study may serve as basis for the construction of a common worldwide system. As APD and SFU are the preferred systems and the UTD a newer combination of both, it is possible that with time, UTD may become the universal language for reporting hydronephrosis. This time, based on the result of this survey, seems not arrived yet.

Circadian succession of molecular processes in living tissues.

BACKGROUND: Oscillations of different origin, period and amplitude play an important role in the regulation of cellular processes. Most widely studied is the circadian or approximately daily variation in gene expression activity. Timing of gene expression is controlled by internal molecular clock keeping steady periodic expression. In this study, we shift attention towards a broad range of periodically expressed genes involved in multiple cellular functions which may or may not be under direct control of the intrinsic circadian clock. Are all molecular functions represented in expressed genes at all times? Alternatively, are different molecular functions performed at different times? Is there a pattern of succession for molecular processes and functions throughout their daily activity period? RESULTS: To answer these questions, we re-analyzed a number of mouse circadian gene expression data available from public sources. These data represent the normal function of metabolically active peripheral tissues (white adipose tissue, brown adipose tissue, liver). We applied novel methods for the estimation of confidence in phase assignment to identify groups of synchronous genes peaking at the same time regardless of the amplitude or the absolute intensity of expression. Each synchronous group has been annotated to identify Gene Ontology (GO) terms and molecular pathways. Our analysis identified molecular functions specific to a particular time of the day in different tissues. CONCLUSION: Improved methodology for datamining allowed for the discovery of functions and biological pathways in groups of genes with synchronized peak expression time. In particular, such functions as oxidative phase of energy metabolism, DNA repair, mRNA processing, lipid biosynthesis and others are separated in time. This timewise compartmentalization is important for understanding the cellular circuitry and can be used to optimize the time of intervention with drug or genome medication.

The role of alternative Polyadenylation in regulation of rhythmic gene expression.

BACKGROUND: Alternative transcription is common in eukaryotic cells and plays important role in regulation of cellular processes. Alternative polyadenylation results from ambiguous PolyA signals in 3' untranslated region (UTR) of a gene. Such alternative transcripts share the same coding part, but differ by a stretch of UTR that may contain important functional sites. METHODS: The methodoogy of this study is based on mathematical modeling, analytical solution, and subsequent validation by datamining in multiple independent experimental data from previously published studies. RESULTS: In this study we propose a mathematical model that describes the population dynamics of alternatively polyadenylated transcripts in conjunction with rhythmic expression such as transcription oscillation driven by circadian or metabolic oscillators. Analysis of the model shows that alternative transcripts with different turnover rates acquire a phase shift if the transcript decay rate is different. Difference in decay rate is one of the consequences of alternative polyadenylation. Phase shift can reach values equal to half the period of oscillation, which makes alternative transcripts oscillate in abundance in counter-phase to each other. Since counter-phased transcripts share the coding part, the rate of translation becomes constant. We have analyzed a few data sets collected in circadian timeline for the occurrence of transcript behavior that fits the mathematical model. CONCLUSION: Alternative transcripts with different turnover rate create the effect of rectifier. This "molecular diode" moderates or completely eliminates oscillation of individual transcripts and stabilizes overall protein production rate. In our observation this phenomenon is very common in different tissues in plants, mice, and humans. The occurrence of counter-phased alternative transcripts is also tissue-specific and affects functions of multiple biological pathways. Accounting for this mechanism is important for understanding the natural and engineering the synthetic cellular circuits.

Optimal classifier for imbalanced data using Matthews Correlation Coefficient metric.

Data imbalance is frequently encountered in biomedical applications. Resampling techniques can be used in binary classification to tackle this issue. However such solutions are not desired when the number of samples in the small class is limited. Moreover the use of inadequate performance metrics, such as accuracy, lead to poor generalization results because the classifiers tend to predict the largest size class. One of the good approaches to deal with this issue is to optimize performance metrics that are designed to handle data imbalance. Matthews Correlation Coefficient (MCC) is widely used in Bioinformatics as a performance metric. We are interested in developing a new classifier based on the MCC metric to handle imbalanced data. We derive an optimal Bayes classifier for the MCC metric using an approach based on Frechet derivative. We show that the proposed algorithm has the nice theoretical property of consistency. Using simulated data, we verify the correctness of our optimality result by searching in the space of all possible binary classifiers. The proposed classifier is evaluated on 64 datasets from a wide range data imbalance. We compare both classification performance and CPU efficiency for three classifiers: 1) the proposed algorithm (MCC-classifier), the Bayes classifier with a default threshold (MCC-base) and imbalanced SVM (SVM-imba). The experimental evaluation shows that MCC-classifier has a close performance to SVM-imba while being simpler and more efficient.

COUSCOus: improved protein contact prediction using an empirical Bayes covariance estimator.

BACKGROUND: The post-genomic era with its wealth of sequences gave rise to a broad range of protein residue-residue contact detecting methods. Although various coevolution methods such as PSICOV, DCA and plmDCA provide correct contact predictions, they do not completely overlap. Hence, new approaches and improvements of existing methods are needed to motivate further development and progress in the field. We present a new contact detecting method, COUSCOus, by combining the best shrinkage approach, the empirical Bayes covariance estimator and GLasso. RESULTS: Using the original PSICOV benchmark dataset, COUSCOus achieves mean accuracies of 0.74, 0.62 and 0.55 for the top L/10 predicted long, medium and short range contacts, respectively. In addition, COUSCOus attains mean areas under the precision-recall curves of 0.25, 0.29 and 0.30 for long, medium and short contacts and outperforms PSICOV. We also observed that COUSCOus outperforms PSICOV w.r.t. Matthew's correlation coefficient criterion on full list of residue contacts. Furthermore, COUSCOus achieves on average 10% more gain in prediction accuracy compared to PSICOV on an independent test set composed of CASP11 protein targets. Finally, we showed that when using a simple random forest meta-classifier, by combining contact detecting techniques and sequence derived features, PSICOV predictions should be replaced by the more accurate COUSCOus predictions. CONCLUSION: We conclude that the consideration of superior covariance shrinkage approaches will boost several research fields that apply the GLasso procedure, amongst the presented one of residue-residue contact prediction as well as fields such as gene network reconstruction.

Confidence in Phase Definition for Periodicity in Genes Expression Time Series.

Circadian oscillation in baseline gene expression plays an important role in the regulation of multiple cellular processes. Most of the knowledge of circadian gene expression is based on studies measuring gene expression over time. Our ability to dissect molecular events in time is determined by the sampling frequency of such experiments. However, the real peaks of gene activity can be at any time on or between the time points at which samples are collected. Thus, some genes with a peak activity near the observation point have their phase of oscillation detected with better precision then those which peak between observation time points. Separating genes for which we can confidently identify peak activity from ambiguous genes can improve the analysis of time series gene expression. In this study we propose a new statistical method to quantify the phase confidence of circadian genes. The numerical performance of the proposed method has been tested using three real gene expression data sets.