Radiation dose analysis of computed tomography coronary angiography in Children with Kawasaki disease

BACKGROUND There is evolving role of computed tomography coronary angiography(CTCA)in non-invasive evaluation of coronary artery abnormalities in children with Kawasaki disease(KD).Despite this,there is lack of data on radiation dose in this group of children undergoing CTCA.AIM To audit the radiation dose of CTCA in children with KD.METHODS Study(December 2013-February 2018)was performed on dual source CT scanner using adaptive prospective electrocardiography-triggering.The dose length product(DLP in milligray-centimeters-mGy.cm)was recorded.Effective radiation dose(millisieverts-mSv)was calculated by applying appropriate age adjusted conversion factors as per recommendations of International Commission on Radiological Protection.Radiation dose was compared across the groups(0-1,1-5,5-10,and>10 years).RESULTS Eighty-five children(71 boys,14 girls)with KD underwent CTCA.The median age was 5 years(range,2 mo-11 years).Median DLP and effective dose was 21 mGy.cm,interquartile ranges(IQR)=15(13,28)and 0.83 mSv,IQR=0.33(0.68,1.01)respectively.Mean DLP increased significantly across the age groups.Mean effective dose in infants(0.63 mSv)was significantly lower than the other age groups(1-5 years 0.85 mSv,5-10 years 1.04 mSv,and>10 years 1.38 mSv)(P<0.05).There was no significant difference in the effective dose between the other groups of children.All the CTCA studies were of diagnostic quality.No child required a repeat examination.CONCLUSION CTCA is feasible with submillisievert radiation dose in most children with KD.Thus,CTCA has the potential to be an important adjunctive imaging modality in children with KD.

Controversies in diagnosis and management of Kawasaki disease

Kawasaki disease(KD) is a common medium vessel systemic vasculitis that usually occurs in small children. It has a predilection for the coronary arteries, but other medium sized arteries can also be involved. The etiology of this disorder remains a mystery. Though typical presentation of KD is quite characteristic, it may also present as incomplete or atypical disease in which case the diagnosis can be very challenging. As both incomplete and atypical forms of KD can be associated with serious coronary artery complications, the pediatrician can ill afford to miss these diagnoses. The American Heart Association has enunciated consensus guidelines to facilitate the clinical diagnosis and treatment of this condition. However, there are still several issues that remain controversial. Intravenous immunoglobulin remains the cornerstone of management but several other treatment modalities, especially glucocorticoids, are increasingly finding favour. We review here some of the contemporary issues, and the controversies thereon, pertaining to management of KD.

Adipocytokine profile in children with Kawasaki disease at a mean follow-up period of 5.5 years: A study from North India

BACKGROUND Kawasaki disease(KD)is an acute self-limited vasculitis with a predilection for coronary arteries.Children with KD may have altered lipid metabolism and abnormal lipid profiles that may last for prolonged periods.However,there is a paucity of literature on the role of adipocytokines in KD.AIM To estimate the levels of adipocytokines(adiponectin,leptin and resistin)during the convalescent phase of KD.METHODS Twenty children,who had KD at least three years earlier,were enrolled in this study.In addition,20 healthy controls were also enrolled.Clinical and laboratory profiles of patients were obtained from hospital records.Serum adiponectin,leptin and resistin levels were estimated by enzyme-linked immunosorbent assay.RESULTS Mean age of the patients in the study group was 10.15±3 years and the male:female ratio was 1.5:1.Median serum resistin levels in patients with KD(27.77 ng/mL;[IQR:18.66,48.90])were decreased compared to controls(21.20 ng/mL;[IQR:14.80,27.00])(P=0.04).Median serum leptin levels in cases and controls were 1.83 ng/mL;(IQR:1.13,3.80),and 1.10 ng/mL;(IQR:0.41,2.88),respectively(P=0.09).Median serum adiponectin levels were similar in both cases(12.20μg/mL;[IQR:9.76,17.97])and controls(13.95μg/mL;[IQR:11.17,22.58]);(P=0.18).There was no significant difference in all 3 adipocytokines between children with(4/20)and without coronary artery abnormalities(16/20).CONCLUSION Serum resistin levels were significantly elevated in patients with KD during the convalescent phase compared to controls.Serum leptin levels appeared to be higher in patients with KD,although the difference was not statistically significant.Adiponectin levels were similar in both cases and controls.Raised resistin and leptin levels may partially explain lipid perturbations observed during the convalescent phase of KD.

Platelets in Kawasaki disease:Is this only a numbers game or something beyond?

Kawasaki disease(KD)is a medium vessel vasculitis with predilection to cause coronary artery abnormalities.KD is now the most common cause of acquired heart disease in developed countries.Thrombocytosis is consistently found in patients with KD,usually in 2nd to 3rd week of illness.Thrombocytopenia has occasionally been reported in the acute phase of KD.An increase or decrease in platelet number in patients with KD was initially considered to be a benign phenomenon.However,recent literature on platelet biology in KD has suggested that platelets are not only increasing but are rather activated.This phenomenon has been found to increase the risk of thrombosis in these patients.Similarly a fall in platelet counts during acute stage of KD has also been found to be associated with increased severity of disease.In this review,we update on the current best understanding about pathogenic role of platelets in patients with KD.

Recent advances in chronic granulomatous disease

Chronic granulomatous disease(CGD)is an inherited defect of phagocyte function due to defective NADPH oxidase.Patients with CGD are not able to effectively clear the infections because of the defect in the phagocyte production of oxygen free radicals and are prone to recurrent bacterial and fungal infections.Inflammatory complications are also noted in CGD such as colitis,non-infective granulomas causing gastrointestinal or urinary tract obstruction,hemophagocytic lymphohistiocytosis,and arthritis.Studies on toll-like receptor pathways and neutrophil extracellular traps in CGD have shed light on the role of NADPH oxidase in the innate immunity and pathogenesis of infections in CGD.Some reports also indicate a reduction of memory B cells and defective production of functional antibodies in CGD.Though the exact mechanisms for non-infective inflammatory complications in CGD are not yet clear,studies on efferocytosis and defective autophagy with inflammasome activation have made a substantial contribution to our understanding of the pathogenesis of inflammation in CGD.We also discuss the clinical and molecular features of p40phox defects and a newer genetic defect,EROS.Clinical phenotypes of X-linked carriers of CYBB are also discussed.

An updated review on activated PI3 kinase delta syndrome(APDS)

Activated Phosphoinositide 3-kinase d syndrome(APDS)is a newly recognised primary immunodeficiency disease.It has currently been a hot topic of clinical research and new data are emerging regarding its pathogenesis,clinical manifestations and treatment.Patients with APDS syndrome have significant autoimmune manifestations and lymphoproliferation.It is important to differentiate APDS from the usual polygenic CVID in view of the availability of targeted therapy like mTOR inhibitors such as Rapamycin and selective PI3Kd inhibitors.We provide a comprehensive review on this interesting disorder focusing light on its etiology,genetic research and emerging therapy.

Recent advances in elucidating the genetics of common variable immunodeficiency

Common variable immunodeficiency disorders(CVID),a heterogeneous group of inborn errors of immunity,is the most common symptomatic primary immunodeficiency disorder.Patients with CVID have highly variable clinical presentation.With the advent of whole genome sequencing and genome wide association studies(GWAS),there has been a remarkable improvement in understanding the genetics of CVID.This has also helped in understanding the pathogenesis of CVID and has drastically improved the management of these patients.A multiomics approach integrating the DNA sequencing along with RNA sequencing,proteomics,epigenetic and metabolomics profile is the need of the hour to unravel specific CVID associated disease pathways and novel therapeutic targets.In this review,we elaborate various techniques that have helped in understanding the genetics of CVID.

Genetics on early onset inflammatory bowel disease:An update

Inflammatory bowel disease(IBD)is more common in adults than in children.Onset of IBD before 17 years of age is referred as pediatric onset IBD and is further categorized as very early onset IBD(VEO-IBD)for children who are diagnosed before 6 years of age,infantile IBD who had the disease before 2 years of age and neonatal onset IBD for children less than 28 days of life.Children presenting with early onset disease may have a monogenic basis.Knowledge and awareness of the clinical manifestations facilitates early evaluation and diagnosis.Next generation sequencing is helpful in making the genetic diagnosis.Treatment of childhood IBD is difficult;targeted therapies and hematopoietic stem cell transplantation form the mainstay.In this review we aim to summarize the genetic defects associated with IBD phenotype.We describe genetic location and functions of various genetic defect associated with VEO-IBD with their key clinical manifestations.We also provide clinical clues to suspect these conditions and approaches to the diagnosis of these disorders and suitable treatment options.

An updated review on phenocopies of primary immunodeficiency diseases

Primary immunodeficiency diseases(PIDs)refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections,autoimmunity and increased risk of malignancies.These group of disorders present with clinical manifestations similar to PIDs with known genetic defects but have either no genetic defect or have a somatic mutation and thus have been labelled as“Phenocopies of PIDs”.These diseases have been further subdivided into those associated with somatic mutations and those associated with presence of auto-antibodies against various cytokines.In this review,we provide an update on clinical manifestations,diagnosis and management of these diseases.

Genetics of severe combined immunodeficiency

Severe Combined Immunodeficiency(SCID)is an inherited group of rare,lifethreatening disorders due to the defect in T cell development and function.Clinical manifestations are characterised by recurrent and severe bacterial,viral,and fungal opportunistic infections that start from early infancy period.Haematopoietic stem cell transplantation(HSCT)is the treatment of choice.The pattern of inheritance of SCID may be X-linked or autosomal recessive.Though the diagnosis of SCID is usually established by flow cytometry-based tests,genetic diagnosis is often needed for genetic counselling,prognostication,and modification of pre-transplant chemotherapeutic agents.This review aims to highlight the genetic aspects of SCID.

Leukocyte adhesion defect:Where do we stand circa 2019?

Migration of polymorphonuclear leukocytes from bloodstream to the site of inflammation is an important event required for surveillance of foreign antigens.This trafficking of leukocytes from bloodstream to the tissue occurs in several distinct steps and involves several adhesion molecules.Defect in adhesion of leukocytes to vascular endothelium affecting their subsequent migration to extravascular space gives rise to a group of rare primary immunodeficiency diseases(PIDs)known as Leukocyte Adhesion Defects(LAD).Till date,four classes of LAD are discovered with LAD I being the most common form.LAD I is caused by loss of function of common chain,cluster of differentiation(CD)18 of β2 integrin family.These patients suffer from life-threatening bacterial infections and in its severe form death usually occurs in childhood without bone marrow transplantation.LAD II results from a general defect in fucose metabolism.These patients suffer from less severe bacterial infections and have growth and mental retardation.Bombay blood group phenotype is also observed in these patients.LAD III is caused by abnormal integrin activation.LAD III patients suffer from severe bacterial and fungal infections.Patients frequently show delayed detachment of umbilical cord,impaired wound healing and increased tendency to bleed.LAD IV is the most recently described class.It is caused by defects in β2 and α4β1 integrins which impairs lymphocyte adhesion.LAD IV patients have monogenic defect in cystic-fibrosis-transmembraneconductance-regulator(CFTR)gene,resulting in cystic fibrosis.Pathophysiology and genetic etiology of all LAD syndromes are discussed in detail in this paper.

An update on the genetics and pathogenesis of hereditary angioedema

Hereditary angioedema(HAE)is an uncommon genetic disorder characterized by recurrent episodes of edema involving subcutaneous tissue and submucosa.The pathogenesis of HAE reflects an intricate coordinated regulation of components of complement,kinin and hemostatic pathway.Till date,mutations in 4 different genes have been identified to cause HAE which includes serine protease inhibitor G1(SERPING1),factor XII(F12),plasminogen(PLG)and angiopoietin 1(ANGPT 1).These mutations lead to increased bradykinin 2 receptor mediated signalling via increased production of bradykinin except mutations in ANGPT1 gene that disturbs the cytoskeletal assembly of vascular endothelial cells.In this review we aim to summarize the recent advances in the pathogenesis and genetics of HAE.We also provide an overview of possible future prospects in the identification of new genetic defects in HAE.

Current status and prospects of primary immunodeficiency diseases in Asia

Primary Immunodeficiency Diseases(PIDs)are increasingly being reported across the World.Several advances have been made in the diagnostic and therapeutic research related to PIDs.With increasing awareness,the field of PIDs has rapidly evolved in Asia as well.In this review,we summarize the progress that has been made in the field of PIDs in Asian countries;major limitations and challenges faced by the clinicians working in this field in Asia;difference in spectrum of PIDs in Asia from rest of the World;current state of diagnostic and treatment facilities available in various countries in Asia and the future prospects of these diseases in the continent.

Application of artificial intelligence in clinical diagnosis and treatment:an overview of systematic reviews

Objective This study aimed to summarize the characteristics and methodological quality of systematic reviews on the application of artificial intelligence(AI)in clinical diagnosis and treatment.Methods We systematically searched seven English-and Chinese-language literature databases to identify sys-tematic reviews on the application of AI,deep learning,or machine learning in the diagnosis and treatment of any disease published in 2020.We evaluated the methodological quality of the included systematic reviews using“A Measurement tool for the assessment of multiple systematic reviews”(AMSTAR).We also conducted meta-analyses on the diagnostic accuracy of AI on selected disease categories with a large number of included studies and low clinical heterogeneity.Results A total of 40 systematic reviews reporting 1,083 original studies were included,covering 31 diseases from 11 groups of diseases.Eleven systematic reviews were related to neoplasms and nine were systematic reviews related to diseases of the digestive system.We selected digestive system diseases for the meta-analysis.The pooled sensitivities(with 95%confidence interval(CI))of AI to assist the diagnosis of helicobacter pylori,gastrointestinal ulcers,hemorrhage,esophageal tumors,gastric tumors,and intestinal tumors(with 95%CI)were 0.91(0.83-0.95),0.99(0.76-1.00),0.95(0.83-0.99),0.90(0.85-0.93),0.90(0.82-0.95),and 0.93(0.88-0.96),respectively,and the pooled specificities were 0.82(0.77-0.87),0.97(0.86-1.00),1.00(0.99-1.00),0.80(0.71-0.87),0.93(0.87-0.97),and 0.89(0.85-0.92),respectively.The AMSTAR items“the list of included studies”(n=39,97.5%)and“the characteristics of the included studies”(n=39,97.5%)had the highest compliance among the reviews;the compliance was relatively low to the items“the consideration of publication status”(n=1,2.5%),“the consideration of scientific quality”(n=19,47.5%),“data synthesis methods”(n=18,45.0%),and“the evaluation of publication bias”(n=13,32.5%).Conclusions The main subjects of systematic reviews on AI applications in clinical diagnosis and treatment pub-lished in 2020 were diseases of the digestive system and neoplasms.The methodological quality of the systematic reviews on AI needs to be improved,paying particular attention to publication bias and the rigorous evaluation of the quality of the included studies.

Analysis of COVID-19 Guideline Quality and Change of Recommendations:A Systematic Review

Background.Hundreds of coronavirus disease 2019(COVID-19)clinical practice guidelines(CPGs)and expert consensus statements have been developed and published since the outbreak of the epidemic.However,these CPGs are of widely variable quality.So,this review is aimed at systematically evaluating the methodological and reporting qualities of COVID-19 CPGs,exploring factors that may influence their quality,and analyzing the change of recommendations in CPGs with evidence published.Methods.We searched five electronic databases and five websites from 1 January to 31 December 2020 to retrieve all COVID-19 CPGs.The assessment of the methodological and reporting qualities of CPGs was performed using the AGREE II instrument and RIGHT checklist.Recommendations and evidence used to make recommendations in the CPGs regarding some treatments for COVID-19(remdesivir,glucocorticoids,hydroxychloroquine/chloroquine,interferon,and lopinavir-ritonavir)were also systematically assessed.And the statistical inference was performed to identify factors associated with the quality of CPGs.Results.We included a total of 92 COVID-19 CPGs developed by 19 countries.Overall,the RIGHT checklist reporting rate of COVID-19 CPGs was 33.0%,and the AGREE II domain score was 30.4%.The overall methodological and reporting qualities of COVID-19 CPGs gradually improved during the year 2020.Factors associated with high methodological and reporting qualities included the evidence-based development process,management of conflicts of interest,and use of established rating systems to assess the quality of evidence and strength of recommendations.The recommendations of only seven(7.6%)CPGs were informed by a systematic review of evidence,and these seven CPGs have relatively high methodological and reporting qualities,in which six of them fully meet the Institute of Medicine(IOM)criteria of guidelines.Besides,a rapid advice CPG developed by the World Health Organization(WHO)of the seven CPGs got the highest overall scores in methodological(72.8%)and reporting qualities(83.8%).Many CPGs covered the same clinical questions(it refers to the clinical questions on the effectiveness of treatments of remdesivir,glucocorticoids,hydroxychloroquine/chloroquine,interferon,and lopinavirritonavir in COVID-19 patients)and were published by different countries or organizations.Although randomized controlled trials and systematic reviews on the effectiveness of treatments of remdesivir,glucocorticoids,hydroxychloroquine/chloroquine,interferon,and lopinavir-ritonavir for patients with COVID-19 have been published,the recommendations on those treatments still varied greatly across COVID-19 CPGs published in different countries or regions,which may suggest that the CPGs do not make sufficient use of the latest evidence.Conclusions.Both the methodological and reporting qualities of COVID-19 CPGs increased over time,but there is still room for further improvement.The lack of effective use of available evidence and management of conflicts of interest were the main reasons for the low quality of the CPGs.The use of formal rating systems for the quality of evidence and strength of recommendations may help to improve the quality of CPGs in the context of the COVID-19 pandemic.During the pandemic,we suggest developing a living guideline of which recommendations are supported by a systematic review for it can facilitate the timely translation of the latest research findings to clinical practice.We also suggest that CPG developers should register the guidelines in a registration platform at the beginning for it can reduce duplication development of guidelines on the same clinical question,increase the transparency of the development process,and promote cooperation among guideline developers all over the world.Since the International Practice Guideline Registry Platform has been created,developers could register guidelines prospectively and internationally on this platform.

Primary Immune Deficiencies e A rapidly emerging area of basic and clinical research

In this special issue of Genes&Diseases,Primary Immune Deficiencies(PIDs)are the main focus.This is an exciting and a rapidly emerging field of basic and clinical immunology wherein upwards of 400 clinical conditions,with approximately 350 defined mutations,are now recognized.Contrary to common perception,PIDs as a group are not uncommon.Epidemiologic studies show that population prevalence of PIDs is approximately 1:2000.Statistical extrapolations of this figure would suggest that in a large country like China or India,approximately 1 million individuals would be expected to have a PID.However,at present because of lack of awareness of these conditions amongst both the laity as well as medical professionals,majority of these patients remain undiagnosed and untreated in many developing countries.This is clearly unfortunate.

Investigation and evaluation of randomized controlled trials for interventions involving artificial intelligence

Objective Complete and transparent reporting is of critical importance for randomized controlled trials(RCTs).The present study aimed to determine the reporting quality and methodological quality of RCTs for interventions involving artificial intelligence(AI)and their protocols.Methods We searched MEDLINE(via PubMed),Embase,Web of Science,CBMdisc,Wanfang Data,and CNKI from January 1,2016,to November 11,2020,to collect RCTs involving AI.We also extracted the protocol of each included RCT if it could be obtained.CONSORT-AI(Consolidated Standards of Reporting Trials-Artificial Intelligence)statement and Cochrane Collaboration’s tool for assessing risk of bias(ROB)were used to evaluate the reporting quality and methodological quality,respectively,and SPIRIT-AI(The Standard Protocol Items:Recommendations for Interventional Trials-Artificial Intelligence)statement was used to evaluate the reporting quality of the protocols.The associations of the reporting rate of CONSORT-AI with the publication year,journal’s impact factor(IF),number of authors,sample size,and first author’s country were analyzed univariately using Pearson’s chi-squared test,or Fisher’s exact test if the expected values in any of the cells were below 5.The compliance of the retrieved protocols to SPIRIT-AI was presented descriptively.Results Overall,29 RCTs and three protocols were considered eligible.The CONSORT-AI items“title and abstract”and“interpretation of results”were reported by all RCTs,with the items with the lowest reporting rates being“funding”(0),“implementation”(3.5%),and“harms”(3.5%).The risk of bias was high in 13(44.8%)RCTs and not clear in 15(51.7%)RCTs.Only one RCT(3.5%)had a low risk of bias.The compliance was not significantly different in terms of the publication year,journal’s IF,number of authors,sample size,or first author’s country.Ten of the 35 SPIRIT-AI items(funding,participant timeline,allocation concealment mechanism,implementation,data management,auditing,declaration of interests,access to data,informed consent materials and biological specimens)were not reported by any of the three protocols.Conclusions The reporting and methodological quality of RCTs involving AI need to be improved.Because of the limited availability of protocols,their quality could not be fully judged.Following the CONSORT-AI and SPIRIT-AI statements and with appropriate guidance on the risk of bias when designing and reporting AI-related RCTs can promote standardization and transparency.