The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

Model informed precision medicine of Chinese herbal medicines formulas-A multi-scale mechanistic intelligent model

Recent trends suggest that Chinese herbal medicine formulas(CHM formulas)are promising treatments for complex diseases.To characterize the precise syndromes,precise diseases and precise targets of the precise targets between complex diseases and CHM formulas,we developed an artificial intelligence-based quantitative predictive algorithm(DeepTCM).DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling,molecular and theoretical levels of traditional Chinese medicine(TCM).As an example,our model simulated the optimal CHM formulas for the treatment of coronary heart disease(CHD)with depression,and through model sensitivity analysis,we calculated the balanced scoring of the formulas.Furthermore,we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions.Finally,we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice.This novel multiscale model opened up a new avenue to combine“disease syndrome”and“macro micro”system modeling to facilitate translational research in CHM formulas.

Research on the development methodology for clinical practice guidelines for organic integration of traditional Chinese medicine and Western medicine

Integrated traditional Chinese medicine(TCM)and Western medicine(WM)is a new medical science grounded in the knowledge bases of both TCM and WM,which then forms a unique modern medical system in China.Integrated TCM and WM has a long history in China,and has made important achievements in the process of clinical diagnosis and treatment.However,the methodological defects in currently published clinical practice guidelines(CPGs)limit its development.The organic integration of TCM and WM is a deeper integration of TCM and WM.To realize the progression of"integration"to"organic integration",a targeted and standardized guideline development methodology is needed.Therefore,the purpose of this study is to establish a standardized development procedure for clinical practice guidelines for the organic integration of TCM and WM to promote the systematic integration of TCM and WM research results into clinical practice guidelines in order to achieve optimal results as the whole is greater than the sum of the parts.

Bio-soft matter derived from traditional Chinese medicine:Characterizations of hierarchical structure,assembly mechanism,and beyond

Structural and functional explorations on bio-soft matter such as micelles,vesicles,nanoparticles,aggregates or polymers derived from traditional Chinese medicine(TCM)has emerged as a new topic in the field of TCM.The discovery of such cross-scaled bio-soft matter may provide a unique perspective for unraveling the new effective material basis of TCM as well as developing innovative medicine and biomaterials.Despite the rapid rise of TCM-derived bio-soft matter,their hierarchical structure and assembly mechanism must be unambiguously probed for a further in-depth understanding of their pharmacological activity.In this review,the current emerged TCM-derived bio-soft matter assembled from either small molecules or macromolecules is introduced,and particularly the unambiguous elucidation of their hierarchical structure and assembly mechanism with combined electron microscopic and spectroscopic techniques is depicted.The pros and cons of each technique are also discussed.The future challenges and perspective of TCM-derived bio-soft matter are outlined,particularly the requirement for their precise in situ structural determination is highlighted.

Regenerative medicine strategies for chronic complete spinal cord injury

Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases.While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable,most research in this field has focused on the early phase of incomplete injury.However,the majority of patients have chronic severe injuries;therefore,treatments for these situations are of fundamental importance.The reason why the treatment of complete spinal cord injury has not been studied is that,unlike in the early stage of incomplete spinal cord injury,there are various inhibitors of neural regeneration.Thus,we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies.First,we established a combination therapy of cell transplantation and drug-releasing scaffolds,which contributes to functional recovery after chronic complete transection spinal cord injury,but we found that functional recovery was limited and still needs further investigation.Here,for the further development of the treatment of chronic complete spinal cord injury,we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss,with reference to the literature,which combination of treatments is most effective in achieving functional recovery.

Bronchoalveolar lavage fluid assessment facilitates precision medicine for lung cancer

Lung cancer is the most common and fatal malignant disease worldwide and has the highest mortality rate among tumor-related causes of death.Early diagnosis and precision medicine can significantly improve the survival rate and prognosis of lung cancer patients.At present,the clinical diagnosis of lung cancer is challenging due to a lack of effective non-invasive detection methods and biomarkers,and treatment is primarily hindered by drug resistance and high tumor heterogeneity.Liquid biopsy is a method for detecting circulating biomarkers in the blood and other body fluids containing genetic information from primary tumor tissues.Bronchoalveolar lavage fluid(BALF)is a potential liquid biopsy medium that is rich in a variety of bioactive substances and cell components.BALF contains information on the key characteristics of tumors,including the tumor subtype,gene mutation type,and tumor environment,thus BALF may be used as a diagnostic supplement to lung biopsy.In this review,the current research on BALF in the diagnosis,treatment,and prognosis of lung cancer is summarized.The advantages and disadvantages of different components of BALF,including cells,cell-free DNA,extracellular vesicles,and micro RNA are introduced.In particular,the great potential of extracellular vesicles in precision diagnosis and detection of drug-resistant for lung cancer is highlighted.In addition,the performance of liquid biopsies with different body fluid sources in lung cancer detection are compared to facilitate more selective studies involving BALF,thereby promoting the application of BALF for precision medicine in lung cancer patients in the future.

Unveiling the anticancer effect of traditional Chinese herbal medicine

In this issue of World Journal of Gastroenterology,Huang et al reported that Calculus bovis(CB),a traditional Chinese herbal medicine,impedes the growth of liver cancers in vivo.Through further in vitro studies,they showed that CB suppressed the M2 polarization of tumor-associated macrophages by suppressing the Wnt signaling pathway,which consequently inhibited the growth of liver cancer.Although the effects of traditional Chinese herbal medicine are often not scientifically proven,Huang et al successfully identified the molecular mechanism involved in the anticancer effect of CB,and it is anticipated that the molecular mechanisms involved in the effects of other traditional Chinese herbal medicines will be scientifically elucidated,as demonstrated in this article.

Knee osteoarthritis:A review of animal models and intervention of traditional Chinese medicine

Background:Knee osteoarthritis(KOA)characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults.The pathophysiology of KOA remains poorly understood,as it involves complex mechanisms that result in the same outcome.Consequently,researchers are interested in studying KOA and require appropriate animal models for basic research.Chinese herbal compounds,which consist of multiple herbs with diverse pharmacological properties,possess characteristics such as multicomponent,multipathway,and multitarget effects.The potential benefits in the treatment of KOA continue to attract attention.Purpose:This study aims to provide a comprehensive overview of the advantages,limitations,and specific considerations in selecting different species and methods for KOA animal models.This will help researchers make informed decisions when choosing an animal model.Methods:Online academic databases(e.g.,PubMed,Google Scholar,Web of Science,and CNKI)were searched using the search terms“knee osteoarthritis,”“animal models,”“traditional Chinese medicine,”and their combinations,primarily including KOA studies published from 2010 to 2023.Results:Based on literature retrieval,this review provides a comprehensive overview of the methods of establishing KOA animal models;introduces the current status of advantages and disadvantages of various animal models,including mice,rats,rabbits,dogs,and sheep/goats;and presents the current status of methods used to establish KOA animal models.Conclusion:This study provides a review of the animal models used in recent KOA research,discusses the common modeling methods,and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Integration of traditional,complementary,and alternative medicine with modern biomedicine:the scientization,evidence,and challenges for integration of traditional Chinese medicine

Traditional medicine has garnered significant global recognition,with an estimated 80%of the global population using it.Therefore,it is essential to fully understand the integration of traditional medicines into current healthcare systems.This review aims to provide a comprehensive overview of the standard process to modernize traditional medicine scientifically in the context of modern biomedicine,further termed here as“scientization”.Specifically,we aim to summarize the advancements made in understanding the efficacy,effectiveness,and underlying mechanisms of herbal medicine.We also examined the transition from experience-to evidence-based medicine during acupuncture.Furthermore,we explore the development of universal safety and quality control standards.Finally,we discuss international trade and export markets for Chinese medical products.The development and integration of traditional medicine have allowed it to further improve human health,resulting in a more comprehensive health solution for the global population.

Inhibition of hepatitis B virus via selective apoptosis modulation by Chinese patent medicine Liuweiwuling Tablet

BACKGROUND Liuweiwuling Tablet(LWWL)is a Chinese patent medicine approved for the treatment of chronic inflammation caused by hepatitis B virus(HBV)infection.Previous studies have indicated an anti-HBV effect of LWWL,specifically in terms of antigen inhibition,but the underlying mechanism remains unclear.AIM To investigate the potential mechanism of action of LWWL against HBV.METHODS In vitro experiments utilized three HBV-replicating and three non-HBV-replicating cell lines.The in vivo experiment involved a hydrodynamic injectionmediated mouse model with HBV replication.Transcriptomics and metabolomics were used to investigate the underlying mechanisms of action of LWWL.RESULTS In HepG2.1403F cells,LWWL(0.8 mg/mL)exhibited inhibitory effects on HBV DNA,hepatitis B surface antigen and pregenomic RNA(pgRNA)at rates of 51.36%,24.74%and 50.74%,respectively.The inhibition rates of LWWL(0.8mg/mL)on pgRNA/covalently closed circular DNA in HepG2.1403F,HepG2.2.15 and HepG2.A64 cells were 47.78%,39.51%and 46.74%,respectively.Integration of transcriptomics and metabolomics showed that the anti-HBV effect of LWWL was primarily linked to pathways related to apoptosis(PI3K-AKT,CASP8-CASP3 and P53 pathways).Apoptosis flow analysis revealed that the apoptosis rate in the LWWL-treated group was significantly higher than in the control group(CG)among HBV-replicating cell lines,including HepG2.2.15(2.92%±1.01%vs 6.68%±2.04%,P<0.05),HepG2.A64(4.89%±1.28%vs 8.52%±0.50%,P<0.05)and HepG2.1403F(3.76%±1.40%vs 7.57%±1.35%,P<0.05)(CG vs LWWL-treated group).However,there were no significant differences in apoptosis rates between the non-HBV-replicating HepG2 cells(5.04%±0.74%vs 5.51%±1.57%,P>0.05),L02 cells(5.49%±0.80%vs 5.48%±1.01%,P>0.05)and LX2 cells(6.29%±1.54%vs 6.29%±0.88%,P>0.05).TUNEL staining revealed a significantly higher apoptosis rate in the LWWL-treated group than in the CG in the HBVreplicating mouse model,while no noticeable difference in apoptosis rates between the two groups was observed in the non-HBV-replicating mouse model.CONCLUSION Preliminary results suggest that LWWL exerts a potent inhibitory effect on wild-type and drug-resistant HBV,potentially involving selective regulation of apoptosis.These findings offer novel insights into the anti-HBV activities of LWWL and present a novel mechanism for the development of anti-HBV medications.

HHO optimized support vector machine classifier for traditional Chinese medicine syndrome differentiation of diabetic retinopathy

AIM:To develop a classifier for traditional Chinese medicine(TCM)syndrome differentiation of diabetic retinopathy(DR),using optimized machine learning algorithms,which can provide the basis for TCM objective and intelligent syndrome differentiation.METHODS:Collated data on real-world DR cases were collected.A variety of machine learning methods were used to construct TCM syndrome classification model,and the best performance was selected as the basic model.Genetic Algorithm(GA)was used for feature selection to obtain the optimal feature combination.Harris Hawk Optimization(HHO)was used for parameter optimization,and a classification model based on feature selection and parameter optimization was constructed.The performance of the model was compared with other optimization algorithms.The models were evaluated with accuracy,precision,recall,and F1 score as indicators.RESULTS:Data on 970 cases that met screening requirements were collected.Support Vector Machine(SVM)was the best basic classification model.The accuracy rate of the model was 82.05%,the precision rate was 82.34%,the recall rate was 81.81%,and the F1 value was 81.76%.After GA screening,the optimal feature combination contained 37 feature values,which was consistent with TCM clinical practice.The model based on optimal combination and SVM(GA_SVM)had an accuracy improvement of 1.92%compared to the basic classifier.SVM model based on HHO and GA optimization(HHO_GA_SVM)had the best performance and convergence speed compared with other optimization algorithms.Compared with the basic classification model,the accuracy was improved by 3.51%.CONCLUSION:HHO and GA optimization can improve the model performance of SVM in TCM syndrome differentiation of DR.It provides a new method and research idea for TCM intelligent assisted syndrome differentiation.

Chinese Medicine,Acupuncture and Science

Ever since the introduction of Western biomedicine into China, there has been friction between proponents of this new approach, and proponents of the traditional medical practices that had evolved over thousands of years in China. For the most part, this friction has been couched in the unexamined assumption that Western medicine is based on science, while Chinese medicine is not. This article will examine that assumption, which in this author’s opinion is unjustified and incorrect. Having practiced acupuncture for the past 50 years, after receiving my doctoral degrees in medicine and physiology, my thinking on this topic has also evolved over time. I will begin this article with some historical information that bears on the topic under discussion, followed by my personal ideas about how to resolve the confiicts that have arisen.

Introduction of Western Medicines into China and Improvement on Decoctions during Modern China

During the late Qing dynasty(1840 A.D.-1912 A.D.),a large quantity of Western medicines entered China,which continuously impacted the traditional Chinese medicine(TCM)market and revealed the shortcomings of Chinese medicines.Some personages in the TCM community followed the trend of learning from the West,and attempted to reform TCM,with the improvement on decoction becoming an important aspect of this effort.Through debates and trials,the improvement on decoction underwent three stages of conceptual evolution:“taking Chinese medicines as the foundation and referring to the dosage forms of Western medicines”,“introducing Western techniques to serve the preparation of decoctions”and“integrating the theories of TCM and Western medicine to improve decoctions”.The study highlights the effective complementarity between modern TCM and Western medicine in the field of pharmacy,and provides valuable experience and support for the reevaluation of the value of TCM in contemporary society.

Growth of Chinese Medicine in Iran: Past, Present, and Prospects

The international recognition of traditional Chinese medicine(TCM)has continuously increased,and that medical practice has gradually become incorporated into the medical systems of many nations.As an important country in the Belt and Road Initiative,Iran has enormous potential for cooperation with China in medical and health care.High-level officials of the two countries attach great importance to cooperation in both areas.Despite the recent rapid development of TCM in Iran,that medical practice still faces many problems;examples here are the lack of practitioners of TCM as well as the paucity of comprehensive cooperation among herbal medicine factories,publishing houses,traditional medicine colleges,and universities in the two countries.The present study collected and analyzed materials related to the practice of TCM in Iran;it made a deep examination of the current situation,problems,and development prospects regarding TCM in Iran with the aim of providing ideas and references to promote the international development of that form of medicine.Following an analysis of the development trends of TCM in Iran in recent years,it became evident that the prospects for TCM in that country are extensive,and the practice has excellent potential.

Use of artificial intelligence in the field of pain medicine

In this editorial we comment on the article“Potential and limitations of ChatGPT and generative artificial intelligence in medial safety education”published in the recent issue of the World Journal of Clinical Cases.This article described the usefulness of artificial intelligence(AI)in medial safety education.Herein,we focus specifically on the use of AI in the field of pain medicine.AI technology has emerged as a powerful tool,and is expected to play an important role in the healthcare sector and significantly contribute to pain medicine as further developments are made.AI may have several applications in pain medicine.First,AI can assist in selecting testing methods to identify causes of pain and improve diagnostic accuracy.Entry of a patient’s symptoms into the algorithm can prompt it to suggest necessary tests and possible diagnoses.Based on the latest medical information and recent research results,AI can support doctors in making accurate diagnoses and setting up an effective treatment plan.Second,AI assists in interpreting medical images.For neural and musculoskeletal disorders,imaging tests are of vital importance.AI can analyze a variety of imaging data,including that from radiography,computed tomography,and magnetic resonance imaging,to identify specific patterns,allowing quick and accurate image interpretation.Third,AI can predict the outcomes of pain treatments,contributing to setting up the optimal treatment plan.By predicting individual patient responses to treatment,AI algorithms can assist doctors in establishing a treatment plan tailored to each patient,further enhancing treatment effectiveness.For efficient utilization of AI in the pain medicine field,it is crucial to enhance the accuracy of AI decision-making by using more medical data,while issues related to the protection of patient personal information and responsibility for AI decisions will have to be addressed.In the future,AI technology is expected to be innovatively applied in the field of pain medicine.The advancement of AI is anticipated to have a positive impact on the entire medical field by providing patients with accurate and effective medical services.

The Making of a Health Profession:How Chinese Medicine Became a Nationally Registered Allied Health Profession in Australia

In 2012, traditional Chinese medicine(TCM) practitioners in Australia became nationally-registered allied health professionals in three categories: acupuncturist, Chinese herbal medicine practitioner, and Chinese herbal medicine dispenser. Australia was the first Western country to introduce national registration for Chinese medicine, followed by Portugal and, recently, New Zealand. The practice of TCM in Australia can be traced back to the beginning of Chinese immigration to Australia during the Victorian Gold Rush which began in the 1850s. The process which led to national registration commenced in the early 1970s with the establishment of the first acupuncture courses. Decades of gradual development of courses from unaccredited part-time diplomas to accredited bachelor degrees, and the development, by the profession, of national consensus on educational standards were essential elements in the process which led to registration. Professional associations, such as the Australian Acupuncture and Chinese Medicine Association Ltd.(AACMA), also developed a framework of professional selfregulation, including Codes of Ethics, Codes of Conduct, ongoing professional development requirements and Infection Control Guidelines, and provided leadership in the development of the profession. After decades of tribalism and division within the TCM profession, the National Academic Standards Committee brought almost all stakeholders together to reach a consensus on the Australian Guidelines for Traditional Chinese Medicine Education which were published by AACMA in 2001. Professional associations also collaborated on joint submissions to the government in support of registration, which was introduced first in the state of Victoria in 2000, and subsequently became national in 2012. Despite national registration, some barriers still remain, and professional associations continue to lobby the federal government for inclusion in Medicare, chronic disease management scheme, and Veterans Affairs.

Medcheck:A novel software for automated de-formulation of traditional Chinese medicine(TCM)prescriptions by liquid chromatography-mass spectrometry

Prescriptions are the main clinical application of traditional Chinese medicines(TCMs).Common forms include Chinese patent medicines,Kampo formulas,and hospital decoctions.A new pre-scription called“famous classical formulas”is recently developed and expected to boom in the market.Identifying constituent me-dicinal plants in prescriptions is critical for new drug development and quality control[1],which could avoid safety issues from adulteration or substandard ingredients,as seen in the notorious Longdan Xiegan Pill event.

Hepatitis B virus genotypes in precision medicine of hepatitis Brelated hepatocellular carcinoma:Where we are now

Hepatitis B virus(HBV)infection is a major player in chronic hepatitis B that may lead to the development of hepatocellular carcinoma(HCC).HBV genetics are diverse where it is classified into at least 9 genotypes(A to I)and 1 putative genotype(J),each with specific geographical distribution and possible different clinical outcomes in the patient.This diversity may be associated with the precision medicine for HBV-related HCC and the success of therapeutical approaches against HCC,related to different pathogenicity of the virus and host response.This Editorial discusses recent updates on whether the classification of HBV genetic diversity is still valid in terms of viral oncogenicity to the HCC and its precision medicine,in addition to the recent advances in cellular and molecular biology technologies.

Comparative efficacy and safety of Chinese patent medicines of iron deficiency anemia during pregnancy:A network meta-analysis

BACKGROUND Iron deficiency anemia(IDA)is a prevalent nutritional disorder during pregnancy.Clinical studies indicate that incorporating Chinese patent medicines(CPMs)with oral iron(OI)in treating IDA in pregnancy can reduce adverse effects and improve clinical outcomes.Nonetheless,the comparative efficacy of different CPMs remains unclear.AIM To assess the safety and effectiveness of different CPMs for treating IDA during pregnancy using network meta-analysis.METHODS We conducted a search for randomized controlled trials(RCTs)that combined CPM and OI for IDA treatment in pregnancy,spanning from 2013 to the present.Data analysis was performed using Rev Man 5.3 and Stata 14.0 on literature that satisfied the quality criteria.RESULTS The analysis included 45 RCTs,encompassing 4422 pregnant patients with IDA.Six CPMs were examined,including Shengxuebao Mixture,Shengxuening Tablets(SXN),Yiqi Weixue CPMs(YQWX),Jianpi Shengxue CPMs(JPSX),Yiqi Buxue Tablets,and Compound Hongyi Buxue Oral Liquid(FFHY).Findings indicated that FFHY+OI significantly improved the clinical effective rate.SXN+OI was most effective in boosting red blood cells counts and hemoglobin levels.YQWX+OI showed superior results in improving serum ferritin,and SXN+OI was most effective in increasing serum iron levels.JPSX+OI was optimal in reducing adverse pregnancy outcomes,while YQBX+OI effectively minimized adverse events.A cluster analysis suggested that SXN+OI could be the potentially optimal therapeutic regimen for IDA in pregnancy.CONCLUSION This study demonstrates that the combination of OI with CPMs offers better outcomes than OI alone.Based on clinical efficacy and other measured outcomes,SXN+OI emerges as the most effective treatment modality for improving the health of pregnant patients with IDA.

Chinese herbal medicine combined with Western medicine for Mycoplasma pneumoniae pneumonia in children:An overview of systematic reviews

Objective:To summarize the characteristics and evaluate the quality of the methodology and evidence within systematic reviews(SRs)of Chinese herbal medicine(CHM)for Mycoplasma pneumoniae pneumonia(MPP)inchildren.Methods:SRs of randomized controlled trials were searched using PubMed,the Cochrane Library,Embase,the Chinese National Knowledge Infrastructure Databases(CNKI),the Chinese Scientific Journals Database(VIP),Wanfang,and the SinoMed Database.SRs on the use of CHM alone or in combination with Western medications for MPP in children were included.The study compared the effects of Western medicine alone with those of CHM.The evidence quality using the A Measurement Tool to Assess Systematic Reviews(AMSTAR)2,the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)2020,and the Grading of Recommendations,Assessment,Development,and Evaluation(GRADE)criteria.The primary indicators were the total effective rate,fever subsidence time,and cough disappearance time.The secondary outcomes were pulmonary rale disappearance time,average hospitalization time,lung X-ray infiltrate disappearance time,immunological indices,and inflammatory cytokine levels.Results:Twelve relevant SRs were included;75%(9/12)were assessed as very low quality,and 25%(3/12)Were rated as low quality using the AMSTAR 2 criteria.According to the PRISMA 2020 checklist,the average SR score was 20.3 out of a 27 point maximum.In all SRs,CHM demonstrated improvement in symptoms and signs among children with MPP.The evidence quality using the GRADE criteria ranged from"very low"(>50%)to"moderate"(<5%).The most common downgrading factor was imprecision,followed by publication bias and inconsistency.Conclusion:This overview highlights the limited quality of the methodology and evidence of the included SRs.Although the included studies showed the beneficial effects of CHM on MPP in children,it was difficult to draw firm conclusions owing to methodological flaws.