Development of a simple tool for diagnosis and initial approach to hypertension and pre-hypertension in children and youth

Background: Hypertension and pre-hypertension in children and adolescents are frequently missed despite current screening recommendations and the potential benefit for early diagnosis and intervention. Difficulty in interpretation of office blood pressure readings in children has been partially blamed for the significant under-diagnosis of childhood hypertension. The objective of our group was to develop and evaluate a simple tool designed to assist primary health care physicians to interpret office blood pressure readings in children and adolescents. Methods: A multi-disciplinary advisory group in our institution undertook the development of a diagnostic tool based on currently accepted gold standard parameters. Input from Family Physicians and Pediatricians was used in the design process. The tool was then distributed among Family Physicians in our catchment area and evaluated with a post-distribution survey. Results: A laminated one page summary of pediatric blood pressure parameters and initial approach to pediatric hypertension was created and distributed. Feedback from primary care physicians was mostly positive and supportive of this initiative. Conclusions: Innovating and simplifying the screening process for hypertension and pre-hypertension in childhood may promote early detection and intervention however the effect of such initiatives on the rate of diagnosis of pediatric hypertension will need to be tested prospectively by appropriately designed studies.

How completely are randomized controlled trials of non-pharmacological interventions following concussion reported? A systematic review

Purpose:The study aimed to examine the reporting completeness of randomized controlled trials(RCTs)of non-pharmacological interventions following concussion.Methods:We searched MEDLINE,Embase,PsycInfo,CINAHL,and Web of Science up to May 2022.Two reviewers independently screened studies and assessed reporting completeness using the Template for Intervention Description and Replication(TIDieR),Consensus on Exercise Reporting Template(CERT),and international Consensus on Therapeutic Exercise aNd Training(i-CONTENT)checklists.Additional information was sought my study authors where reporting was incomplete.Risk of bias(ROB)was assessed with the Cochrane ROB-2 Tool.RCTs examining non-pharmacological interventions following concussion.Results:We included 89 RCTs(n=53 high ROB)examining 11 different interventions for concussion:sub-symptom threshold aerobic exercise,cervicovestibular therapy,physical/cognitive rest,vision therapy,education,psychotherapy,hyperbaric oxygen therapy,transcranial magnetic stimulation,blue light therapy,osteopathic manipulation,and head/neck cooling.Median scores were:TIDieR 9/12(75%;interquartile range(IQR)=5;range:5-12),CERT 17/19(89%;IQR=2;range:10-19),and i-CONTENT 6/7(86%;IQR=1;range:5-7).Percentage of studies completely reporting all items was TIDieR 35%(31/89),CERT 24%(5/21),and i-CONTENT 10%(2/21).Studies were more completely reported after publication of TIDieR(t_(87)=2.08;p=0.04)and CERT(t_(19)=2.72;p=0.01).Reporting completeness was not strongly associated with journal impact factor(TIDieR:rs=0.27;p=0.01;CERT:r_(s)=-0.44;p=0.06;i-CONTENT:r_(s)=-0.17;p=0.48)or ROB(TIDieR:rs=0.11;p=0.31;CERT:rs=0.04;p=0.86;i-CONTENT:rs=0.12;p=0.60).Conclusion:RCTs of non-pharmacological interventions following concussion demonstrate moderate to good reporting completeness,but are often missing key components,particularly modifications,motivational strategies,and qualified supervisor.Reporting completeness improved after TIDieR and CERT publication,but publication in highly cited journals and low ROB do not guarantee reporting completeness.

Current methods for the maturation of induced pluripotent stem cellderived cardiomyocytes

Induced pluripotent stem cells(iPSCs) were first generated by Yamanaka and colleagues over a decade ago. Since then, iPSCs have been successfully differentiated into many distinct cell types, enabling tissue-, disease-, and patientspecific in vitro modelling. Cardiovascular disease is the greatest cause of mortality worldwide but encompasses rarer disorders of conduction and myocardial function for which a cellular model of study is ideal. Although methods to differentiate iPSCs into beating cardiomyocytes(iPSC-CMs) have recently been adequately optimized and commercialized, the resulting cells remain largely immature with regards to their structure and function,demonstrating fetal gene expression, disorganized morphology, reliance on predominantly glycolytic metabolism and contractile characteristics that differ from those of adult cardiomyocytes. As such, disease modelling using iPSC-CMs may be inaccurate and of limited utility. However, this limitation is widely recognized, and numerous groups have made substantial progress in addressing this problem. This review highlights successful methods that have been developed for the maturation of human iPSC-CMs using small molecules,environmental manipulation and 3-dimensional(3 D) growth approaches.

Herpes Zoster in Childhood

Herpes zoster is caused by reactivation of latent varicella-zoster virus that resides in a dorsal root ganglion. Herpes zoster can develop at any time after a primary infection or varicella vaccination. The incidence among children is approximately 110 per 100,000 person-years. Clinically, herpes zoster is characterized by a painful, unilateral vesicular eruption in a restricted dermatomal distribution. In young children, herpes zoster has a predilection for areas supplied by the cervical and sacral dermatomes. Herpes zoster tends to be milder in children than that in adults. Also, vaccine-associated herpes zoster is milder than herpes zoster after wild-type varicella. The diagnosis of herpes zoster is mainly made clinically, based on a distinct clinical appearance. The most common complications are secondary bacterial infection, depigmentation, and scarring. Chickenpox may develop in susceptible individuals exposed to herpes zoster. Oral acyclovir should be considered for uncomplicated herpes zoster in immunocompetent children. Intravenous acyclovir is the treatment of choice for immunocompromised children who are at risk for disseminated disease. The medication should be administered ideally within 72 hours of rash onset.

Cellular models for human cardiomyopathy:What is the best option?

The genetic cardiomyopathies are a group of disorders related by abnormal myocardial structure and function.Although individually rare,these diseases collectively represent a significant health burden since they usually develop early in life and are a major cause of morbidity and mortality amongst affected children.The heterogeneity and rarity of these disorders requires the use of an appropriate model system in order to characterize the mechanism of disease and develop useful therapeutics since standard drug trials are infeasible.A common approach to study human disease involves the use of animal models,especially rodents,but due to important biological and physiological differences,this model system may not recapitulate human disease.An alternative approach for studying the metabolic cardiomyopathies relies on the use of cellular models which have most frequently been immortalized cell lines or patient-derived fibroblasts.However,the recent introduction of induced pluripotent stem cells(iPSCs),which have the ability to differentiate into any cell type in the body,is of great interest and has the potential to revolutionize the study of rare diseases.In this paper we review the advantages and disadvantages of each model system by comparing their utility for the study of mitochondrial cardiomyopathy with a particular focus on the use of iPSCs in cardiovascular biology for the modeling of rare genetic or metabolic diseases.

Late intervention in an asymptomatic pediatric patient with anomalous left coronary artery

Anomalous left coronary artery from the pulmonary artery(ALCAPA) is most commonly diagnosed within the first year of life with congestive heart failure symptomatology reflecting left ventricle(LV) dysfunction. The late diagnosis of ALCAPA is presented in a 5-yearold without significant LV dysfunction, mild LV dilatation and only mild mitral regurgitation that did not change significantly after surgery. The timing of surgical intervention in the late diagnosis of ALCAPA remains unclear despite risks of significant ongoing myocardial injury secondary to coronary artery hypoperfusion and progressive mitral valve dysfunction. Intervention in this case allows for revascularization which may reverse ventricular and valvular dysfunction.

Age dependent expression and distribution of nitric oxide (NO) synthase isoforms in the ovine kidney

The aim of the present study was to measure intrarenal spatial and temporal localization of all three nitric oxide synthase (NOS) isoforms in the developing ovine kidney. Reverse transcriptase-polymerase chain reaction (RT-PCR), Western Blot analyses, and in situ hybridization techniques were performed for NOS I -III isoforms in renal tissue obtained from sheep aged ~24 h, one, three, six, and 12 weeks post natally (N = 3). RT-PCR performed on cortical and medullary kidney tissue revealed the presence of all three NOS isoforms from day one to 12 weeks postnatally. NOS I and NOS II mRNA levels were greater in cortex compared to medulla during the first three weeks whereas NOS III mRNA levels were predominantly transcribed within the medulla. In all NOS isoforms, there was a decrease in cortical mRNA levels after three to six weeks. Protein levels confirmed the presence of all three NOS isoforms over the first three months of postnatal life. By demonstrating NOS isoform transcripts to be more abundant in the early post natal period, these findings may provide insight into the age dependent role of NO in modulating kidney function during ontogeny.

eTumorMetastasis:A Network-based Algorithm Predicts Clinical Outcomes Using Whole-exome Sequencing Data of Cancer Patients

Continual reduction in sequencing cost is expanding the accessibility of genome sequencing data for routine clinical applications.However,the lack of methods to construct machine learning-based predictive models using these datasets has become a crucial bottleneck for the application of sequencing technology in clinics.Here,we develop a new algorithm,eTumorMetastasis,which transforms tumor functional mutations into network-based profiles and identifies network operational gene(NOG)signatures.NOG signatures model the tipping point at which a tumor cell shifts from a state that doesn’t favor recurrence to one that does.We show that NOG signatures derived from genomic mutations of tumor founding clones(i.e.,the‘most recent common ancestor’of the cells within a tumor)significantly distinguish the recurred and non-recurred breast tumors as well as outperform the most popular genomic test(i.e.,Oncotype DX).These results imply that mutations of the tumor founding clones are associated with tumor recurrence and can be used to predict clinical outcomes.As such,predictive tools could be used in clinics to guide treatment routes.Finally,the concepts underlying the eTumorMetastasis pave the way for the application of genome sequencing in predictions for other complex genetic diseases.eTumorMetastasis pseudocode and related data used in this study are available at https://github.com/WangEdwinLab/eTumorMetastasis.

Profiling Chromatin Accessibility at Single-cell Resolution

How distinct transcriptional programs are enacted to generate cellular heterogeneity and plasticity,and enable complex fate decisions are important open questions.One key regulator is the cell’s epigenome state that drives distinct transcriptional programs by regulating chromatin accessibility.Genome-wide chromatin accessibility measurements can impart insights into regulatory sequences(in)accessible to DNA-binding proteins at a single-cell resolution.This review outlines molecular methods and bioinformatic tools for capturing cell-to-cell chromatin variation using single-cell assay for transposase-accessible chromatin using sequencing(scATAC-seq)in a scalable fashion.It also covers joint profiling of chromatin with transcriptome/proteome measurements,computational strategies to integrate multi-omic measurements,and predictive bioinformatic tools to infer chromatin accessibility from single-cell transcriptomic datasets.Methodological refinements that increase power for cell discovery through robust chromatin coverage and integrate measurements from multiple modalities will further expand our understanding of gene regulation during homeostasis and disease.