6 Wentzel JJ, Gijsen FJ, Stergiopulos N, Serruys PW, Slager CJ, Krams R. Shear stress, vascular remo

Allogeneic Hematopoietic Stem Cell Transplantation for Inherited Disorders:Experience in a Single Center Olle Ringde´n,1,2,7Mats Remberger,1,2Britt-Marie Svahn,1Lisbeth Barkholt,1,2Jonas Mattsson,1,2Johan Aschan,1,3Katarina Le Blanc,1,2Britt Gustafsson,4Zuzana Hassan,1Brigitta Omazic,1,2Petter Svenberg,1,2,4Go¨ran Solders,5Ulrika von Do¨beln,6Jacek Winiarski,4Per Ljungman,3and Gunilla Malm4Background.Allogeneic hematopoietic stem cell transplantation(ASCT)is a possible cure for many inherited disorders.Methods.We report20years of experience in71patients.The disorders include7immunodeficiencies,21hemato-logical disorders,13histiocytic disorders,9mucopolysaccharoidoses,7metachromatic leukodystrophies(MLD),3adrenoleukodystrophies(ALD),2adrenomyeloneuropathy(AMN),6patients with Gaucher’s disease,1Sandhoff’sdisease,and2patients with aspartylglucosaminuria.Their median age was4(0-39)years.The donors were29HLA-identical related,27matched unrelated(MUD)and15HLA mismatches.Results.In recipients of HLA-identical sibling grafts,none developed acute GVHD grades II-IV as against22%in allothers.The overall cumulative incidence of chronic GVHD was17%.The5-year survival rates were93%,84%,and46%in recipients of grafts from HLA-identical siblings,MUD and HLA-mismatches,respectively.The overall10-yearsurvival rate was69%.All of the surviving patients with immunodeficiencies and hemoglobinopathies are well.Fourpatients with Hurler’s disease are also well,apart from skeletal problems.Five patients with Gaucher’s disease arebetween14and22years after the transplant.Two infants with MLD deteriorated,a girl with the juvenile form has stabledisease and one woman with the adult form has improved.Among four survivors with ALD/AMN,three are well andone has dementia.Two patients with aspartylglucosaminuria have stable disease.Conclusion.In patients with inborn errors of metabolism,ASCT gives a high survival rate using HLA-matched donors.Beneficial effects are seen in those who are transplanted early.Keywords:Bone marrow transplantation,Inborn errors of metabolism,Graft-versus-host disease,HLA matching.(Transplantation2006;81:718–725)O rgans,tissues,and hematopoietic stem cells have been used to replace enzyme-deficient cells for a variety of congenital metabolic disorders(1–6).Allogeneic hematopoi-etic stem cell transplantation(ASCT)can correct genetic dis-eases in two ways:by replacing genetically deranged or absent blood cells,or by implanting bone marrow cells that will de-liver a normal protein to the tissues of a defective host.Im-munodeficiencies,hematologic defects,lysosomal storage disorders,and peroxisomal diseases are among the diseases that can be treated,cured,or rearrested by ASCT(5–8).The first patients cured by ASCT had severe combined immuno-deficiencies(9,10)and are still alive after36years.Other immunodeficiencies cured by ASCT include the Wiskott-Al-drich syndrome Chediak-Higashi syndrome,chronic muco-cutaneous candidiasis and Kostmann’s agranulocytosis(11–15).Several hematological defects can also be cured by ASCT, such as Fanconi anemia,osteopetrosis,thalassemia major, infantile agranulocytosis,sickle cell disease,Blackfan Diamond anemia,Glanzmann’s thrombasthenia,chronic granulomatous disease,and congenital neutropenia(16–19).Histiocytic disor-ders cured by ASCT include familial hemophagocytic lympho-histiocytosis(FHL)and Langerhans’cell histiocytosis(20–21). In patients with mucopolysaccharoidosis ASCT is given to those with Hurler’s disease and Maroteaux-Lamy disease(6–8,22).A successful outcome from the treatment with ASCT has also been reported in the lipidosis Gaucher’s disease and metachromatic leukodystrophy(MLD)(23,24).Adrenoleukodystrophy(ALD), an X-linked,peroxisomal disorder,can be cured by the admin-istration of ASCT early in its course(7,25).Some of the rare disorders are hardly ever seen by most transplant physicians.Therefore,there are only a few reports from a single center.We here describe more than20years’experience in71patients treated with ASCT for inborn errors of metabolism.PATIENTS,MATERIAL AND METHODS PatientsIn this assessment of the value of the allogeneic hema-topoietic stem cell transplantation for metabolic disorders,This study was supported by grants from the Swedish Cancer Society(0070-B03-17XBC),the Children’s Cancer Foundation(03/039),the SwedishResearch Council(K2003-32X-05971-23A.),the Stockholm Cancer So-ciety,the Swedish Medical Society,and Karolinska Institutet.1Center for Allogeneic Stem Cell Transplantation,Karolinska Institutet,Karolinska University Hospital Huddinge,Stockholm,Sweden.2Division of Clinical Immunology,Karolinska Institutet,Karolinska Uni-versity Hospital Huddinge,Stockholm,Sweden.3Department of Hematology,Karolinska Institutet,Karolinska UniversityHospital Huddinge,Stockholm,Sweden.4Department of Pediatrics,Karolinska Institutet,Karolinska UniversityHospital Huddinge,Stockholm,Sweden.5Department of Neurology,Karolinska Institutet,Karolinska UniversityHospital Huddinge,Stockholm,Sweden.6Department of Clinical Chemistry,Karolinska Institutet,Karolinska Uni-versity Hospital Huddinge,Stockholm,Sweden.7Address correspondence to:Olle Ringde´n,M.D.,Ph.D.,Division of ClinicalImmunology,F79,Karolinska University Hospital Huddinge,SE-14186Stockholm,Sweden.E-mail:Olle.Ringden@labmed.ki.se.Received19May2005.Revision requested4July2005.Accepted28July2005.The publisher apologizes for the delay of the publication of this article.Copyright©2006by Lippincott Williams&WilkinsISSN0041-1337/06/8105-718DOI:10.1097/01.tp.0000181457.43146.36718Transplantation•Volume81,Number5,March15,2006we studied:1)7patients with immunodeficiencies [severecombined immunodeficiencies (5),Wiskott-Aldrich syn-drome (2)];2)21patients with severe hematologic defects [Fanconi anemia (10),thalassemia major (6),chronic granu-lomatous disease (3),osteopetrosis (1),sickle-cell disease (1)];3)13patients with histiocytic disorders [familial he-mophagocytic lymphohistiocytosis (FHL)(11),Langerhans’cell histiocytotis (2)];4)9patients with lysosomal disorders[mucopolysaccharoidoses Hurler’s disease (6),Sanfilippo’s syndrome (2),Maroteaux-Lamy syndrome (1)];5)12pa-tients with leukodystrophies [metachromatic leukodystrophy (MLD;7),adrenoleukodystrophy (ALD;3),adrenomyeloneu-ropathy (AMN;2)];and 6)9patients with glucoprotein disor-ders [Gaucher’s disease (6),aspartylglucosaminuria (2siblings),Sandhoff’s disease (1)].Various characteristics of the 71patients and their donors are given in Table 1.TABLE 1.Patient and donor characteristicsCharacteristicn (range)Recipient age,median years 4(0–39)ImmunodeficienciesSevere combined immunodeficiencies 5Wiskott-Aldrich syndrome 2Hematological disorders Fanconi anemia 10Thalassemia major6Chronic granulomatous disease 3Osteopetrosis 1Sickle-cell disease 1Histiocytic disordersFamilial hemophagocytic lymphohistiocytosis 11Langerhans’cell histiocytosis 2Mucopolysaccharoidoses Hurler’s disease6Sanfilippo’s syndrome2Maroteaux-Lamy syndrome 1LeukodystrophiesMetachromatic leukodystrophy 7Adrenoleukodystrophy 5Glucoprotein disorders Gaucher’s disease6Aspartylglucosaminuria 2Sandhoff’s disease 1Sex (male/female)41/30Donor age,median years 29(0–50)Donor sex (male/female)34/37ConditioningBusulfan ϩcyclophosphamide (Cy)51Cy ϩtotal lymphoid irradiation/thoracoabdominal irradiation 5Cy ϩtotal body irradiation4Fractionated total body irradiation 4Fludarabin ϩcyclophosphamide 6Fludarabin ϩbusulfan1Anti-T-cell globulin pretransplant 50Type of donorHLA-identical sibling 25Related HLA-compatible 4Related HLA-mismatch7HLA-A,-B,-DRB1identical unrelated 27Major mismatch unrelated 5Subtype mismatch unrelated 3Nucleated cell dose3.4(0.03–80)ϫ108/kgCD34cell dose ϫ106/kg7.9(0.4–46.0)Cytomegalovirus serology in donor/recipient aϩ/ϩ27–/ϩ8ϩ/–17–/–15aSerology missing in two patients and three donors.©2006Lippincott Williams &Wilkins 719Ringde ´n et al.DonorsAmong the donors were25HLA-identical siblings,4related HLA matched donors and7related major mis-matched donors.The unrelated donors included27HLA-A,-B,-DR␤1identical donors,5with major HLA mismatches and3with subtype mismatches.Genomic HLA class II typinghas been used since1991.The HLA class I typing was serolog-ical until September1999.Bone marrow grafts were given to58patients,peripheral blood stem cell grafts to10,cord bloodto3,2of whom also received bone marrow. ConditioningMost patients were conditioned with busulfan in a doseof80mg/m2(4–5mg/kg)for four consecutive days(day-9today-6),followed by cyclophosphamide2g/m2(50–70mg/kg)for four days(day-5to day-2),using Shaw et al.’s pro-tocol(26).The patients with FHL were given300mg/m2ofvepesid before this treatment.Three patients were condi-tioned with cyclophosphamide50mg/kg for four consecutivedays,followed by total body irradiation(TBI)of8Gy,withthe lungs shielded to receive no more than6Gy.The eyes andgonads were also shielded.In a girl with Hurler’s disease,thesame dose of cyclophosphamide was combined with7.5GyTBI and in three recipients of unrelated grafts,this dose wascombined with fractionated TBI,3Gy for four consecutivedays.Fludarabin50mg/m2/day for six days was combinedwith busulfan,total dose8mg/kg in one patient,and withcyclophosphamide120mg/kg in five patients.Anti-T-cellglobulin(ATG)was given to50patients during conditioningto prevent rejection and graft-versus-host disease(GVHD)(27).T-cell-depleted grafts were given to four recipients ofmismatched bone marrow(28).Prophylaxis and Treatment against Graft-versus-Host DiseaseThe most commonly used immunosuppressive proto-col included cyclosporine and four doses of methotrexate(29,30).Four patients who underwent ASCT for metabolic disor-ders transplanted during the early1980s received cyclospor-ine alone.In two patients,methotrexate was replaced byprednisolone and in six with mycophenolate mofetil.Fourrecent patients received prograf combined with rapamune(31).Cyclosporine trough levels during the first three monthsafter transplant were between200–300ng/ml in whole blood.The dose was tapered after12months and discontinued aftertwo years in the absence of chronic GVHD.Grade I acuteGVHD was treated with prednisolone2mg/kg/day for a weekand thereafter tapered(30).Supportive CareAll patients were kept in reversed isolation during thepancytopenic phase.They stayed in the isolation rooms to-gether with a relative.When the absolute neutrophil counts(ANC)exceeded0.2–0.5ϫ109/l for two days,the isolationwas discontinued.Granulocyte colony-stimulating factor(5␮g/kg/day i.v.)was given to25patients from day10after transplant until ANC wasϾ0.5ϫ109/l for two consecutive days.After engraftment,all patients were treated with co-trimoxazole for at least six months as prophylaxis against pneumocystis carinii infection.The supportive care has been described elsewhere in detail(30,32).Treatment of Cytomegalovirus InfectionPreemptive therapy has been used since1990to dealwith cytomegalovirus(CMV)infection.The patients receivedeither ganciclovir5mg/kg twice daily or foscarnet90mg/kgtwice daily for two weeks.If the polymerase chain reaction(PCR)test turned negative,the CMV therapy was discontin-ued;otherwise,the therapy was continued once a day until anegative PCR was found(33).CMV disease was initiallytreated with foscarnet(34).After1988,patients with CMVpneumonia were given ganciclovir in combination with in-travenous immunoglobulin.Patients with other types ofCMV disease were treated with either ganciclovir or foscarnetwithout immunoglobulin(33).StatisticsThe results were analyzed as of4December2004.Transplant-related mortality(TRM),grades II–IV acuteGVHD and chronic GVHD rates were estimated using a non-parametric estimator of cumulative incidence curves.Analy-ses were performed using the cmprsk package(developed byGray,June2001),Splus6.2software and Statistica software.RESULTSEngraftmentSeven patients rejected their grafts.A2-year-old girlwith Hurler’s disease rejected an HLA-mismatched graft andwas regrafted,but died of cardiomyopathy(35).Two patientswith Sanfilippo’s A and C disease,respectively,rejected theirgrafts,but were not retransplanted because we later learnedthat this disease is not cured by ASCT(8).The patient withSanfilippo’s A disease died of pneumonia5months afterASCT.The patient with Sanfilippo’s C disease is alive andmentally retarded14years after ASCT.A1-year-old boy withHurler’s disease received an HLA-mismatched unrelatedgraft,which was rejected.He underwent a retransplant,en-grafted but died of cardiac arrest nine months later.A1-year-old girl with a T-cell defect rejected a mismatched transplantfrom her father and died of interstitial pneumonia twomonths after the transplant.A6-year-old boy with Gaucherdisease received an HLA-mismatched graft from his father,which was rejected.He was treated with ceredase(36).A39-year-old male with AMN showed threatening rejection onchimerism tests.He was regrafted with the same donor afterconditioning with fludarabin and treatment with ATG.Hebecame a complete donor chimera.None of the recipients ofHLA-identical sibling grafts had rejection.The first sign of engraftment(WBCϾ0.2ϫ109/l)wasseen at a median of13days after the transplant,but no laterthan on day24.The time to reach ANCϾ0.5ϫ109/l was amedian of18(range9-30)days.The time to platelets Ͼ30ϫ109/l,without the need for platelet transfusions,oc-curred at a median of20(0–210)days after the transplant.Platelet transfusions were given at a median of6(0–70)units,erythrocyte transfusions at a median of3(0–44)units andgranulocyte transfusions for uncontrolled infections or se-vere mucositis were given to8patients.InfectionsBacteremia was diagnosed during the first months in37/71(52%)of the patients.It was caused by Coagulase neg-720Transplantation•Volume81,Number5,March15,2006ative staphylococcus in 19,alpha streptococcus in 13,Staph-ylococcus aureus in 3and other bacteria in 2.CMV infection (viral culture or detection of CMV DNA or RNA)was diagnosed in 25patients (36%).Four de-veloped CMV disease,two had interstitial pneumonitis and two enteritis.Graft-versus-Host DiseaseAmong 69evaluable patients,33had no signs of acute GVHD.A grade I skin rash was diagnosed in 27patients,which responded to prednisolone treatment.Among the re-cipients of sibling grafts,no patient developed more than grade I acute GVHD (n ϭ29).In contrast,the recipients of grafts from HLA-A,-B and -DRB1identical unrelated do-nors,6/27developed acute GVHD grades II–III with a cumu-lative incidence of 22%(Fig.1A).Among the recipients of HLA-mismatched transplants,3/15developed grades II–III acute GVHD with a cumulative incidence of 20%.The overall cumulative incidence of chronic GVHD was 17%.The prob-ability of chronic GVHD was similar in the recipients of sib-ling grafts,matched unrelated donor grafts,and mismatched grafts (Fig.1B).Transplant-Related Mortality RatesThe overall TRM was 17%at 5years and 22%at 10years.Among the HLA-identical sibling transplants,the 5-year TRM was 7%,as compared to 12%,using MUD do-nors and 48%,using HLA-mismatched donors (Fig.2).Survival RatesSurvival rates were 79%at 5years and 69%at 10years (Fig.3A).Among the patients receiving grafts from HLA-identical siblings or HLA-compatible related donors (n ϭ29),the 5-year survival rate was 93%(Fig.3B).The corresponding figure was 84%in the recipients of HLA-A,-B and –DR iden-tical unrelated grafts,and in those receiving mismatched grafts,it was 46%.Therefore,in patients with FHL,all three with HLA-identical related donors are alive,as compared to 3/5with MUD and 1/3receiving mismatched grafts.Patients receiving Ͼ3.4ϫ108nucleated bone marrow cells/kg had a 5-year survival of 91%,compared to 63%in those receiving Ͻ3.4ϫ108nucleated cells/kg (P ϭ0.12).Four patients died of progressive disease such as Sand-hoff’s disease,FHL and ALD,four of pneumonia and two of CMV interstitial pneumonitis.The other causes of death in-cluded:septicemia (1),invasive fungal infection (1),veno-occlusive disease (1),secondary malignancy (1),acute (2)and chronic (1)GVHD.Secondary TumorsA 28-year-old man with Fanconi anemia died of cancer of the tounge two years after ASCT.One patient with Lang-erhans’cell histiocytosis developed squamous cell cancer un-der his tongue,which was successfully removed seven years after ASCT (37).He has had no recurrence 13years afterresection.FIGURE 1.Cumulative incidence and times to acute (A)and chronic (B)GVHD in recipients of related HLA-identical stem cell grafts (sibs,n ϭ29),recipients of HLA-A,-B,-DRB1identical grafts from HLA-matched unrelated donors (MUD,n ϭ27)and recipients of grafts from HLA-mismatched re-lated or unrelated donors (MM,n ϭ15).FIGURE 2.Cumulative incidence of transplant-related mortality (TRM)in recipients of grafts from HLA-identical related donors (sibs),HLA-matched unrelated donors and HLA-mismatched related and unrelated donors (MM).The 5-year TRM rates are given in the figure.©2006Lippincott Williams &Wilkins 721Ringde ´n et al.Well-being of Surviving PatientsThe four surviving patients with immunodeficiencies are well with no late infections.One boy with a T-cell defect,who was two years of age at the time of ASCT,is now 20years old and has normal T-cell responses to phytohemagglutinine,concanavalin A,OKT3,protein A of staph.Aureus and in mixed lymphocyte cultures.A woman gave birth to a healthy child 19years after ASCT.All 17surviving patients with he-matological disorders are well between two and 14years after the transplant.Seven FHL patients are alive and well.A 4-year-old boy with FHL has 80-90%recipient CD3ϩ,19ϩand 33ϩcells in his blood,despite two donor lymphocyte infusions.He feels well two years after ASCT.One 20-year-old woman underwent ASCT for FHL at the age of 6years.She has given birth to a healthy child who is now 1year old,and she is pregnant again.One patient with Langerhans’cell histiocytosis is on chelative treatment for high ferritin levels and has hyperpig-mentation five years after ASCT.The other patient is well after 20years (37).Four patients with mucopolysaccharoidosis type 1,and Hurler’s disease grafted before 20months of age are now be-tween 6months and 3years after transplantation.The oldest child,6years of age,has normal mental development and will start in an ordinary main-stream school.Before transplanta-tion,he underwent a shunt operation for hydrocephalus.Af-ter it,he required surgery for kyphoscoliosis.Another child is 4.5years of age.He has poor hearing,needs a hearing aid in his left ear and is deaf in his right.His mental development is delayed by one year.After transplantation,operations were performed first on his tethered spinal cord,then on the ten-dons of his right heel and kyphoscoliosis.He now walks and runs normally for his age.Both patients showed rapid nor-malization of their glucosaminoglucans in urine after ASCT.The third child is 3.5years of age.She is normally developed for her age.She had a congenital hip luxation and underwent surgery for this after transplantation.The fourth child is 2years old.She was given enzyme replacement therapy three weeks before transplantation.She needed a retransplantation after two months because of recipient lymphocyte chimer-ism.L-iduronidase activity is 4.2␮kat/kg protein,which is within the heterozygote range.Her mental development re-sembles that of her healthy twin brother,but she cannot yet walk without support.Among the four long-term survivors with Gaucher’s disease,the longest one had the transplant 22years ago (36).She suffers from mild obstructive bronchiolitis and for the past two years has required treatment for seizures.Two pa-tients are well 17and 18years after ASCT,respectively.One boy has kyphosis and is also being treated for seizures 14years after ASCT.A boy grafted at 18months of age for late infantile MLD has been deteriorating since he had the transplant 11years ago.One girl with early juvenile MLD,who had a transplant at 8years of age,became worse after transplantation.She lost some gross motor functions,and showed a deterioration in speech and mental ability at follow-up three years later (38).The disease then stabilized.Now,12years after the transplant,she is enrolled in a high-school,can speak,read and write.She needs a wheel chair for transport and cannot walk without support.Her favorite sport is riding horses.The IQ of a 28-year-old woman with slowly progressive adult onset MLD has improved since her transplant 11years ago (39).Her disease is stable.The aryl sulfatase A level is normal,15(ref value 9–19)␮kat/kg protein.Two adult patients with more advanced late juvenile onset MLD at the time of transplant have continued to deteriorate slowly 5and 3years after the transplant,respec-tively.One has moderate chronic GVHD of the liver,which requires immunosuppressive therapy.A boy with ALD underwent a transplant at the age of six when he had no clinical symptoms,but showed progressive lesions on MRI.He is healthy apart from Addison’s disease 12years after the transplant.Another boy with ALD,who re-ceived a transplant at the age of 10when he had frontal lesions on MRI,is still alive,but developed dementia 12years later.His older brother developed early symptoms and was given a transplant at 34years of age;he is doing well 7months after the transplant.One man with severe progressive AMN,but no signs of cerebral engagement,39years of age at the timeofFIGURE 3.The overall 5-year survival rates in patients with inborn errors of metabolism.Survival rates in recipi-ents of stem cell grafts from HLA-identical siblings and HLA-identical related donors (sibs,n ϭ29),recipients of grafts from matched unrelated donors (MUD,n ϭ27)and HLA-mismatched related or unrelated donors (MM,n ϭ15).722Transplantation •Volume 81,Number 5,March 15,2006the transplant,is alive and well four years after retransplanta-tion.Two siblings with aspartylglucosaminuria and fairly advanced disease at the age of5and10years,respectively, underwent transplantation using unrelated donors(40).No increase in the severity of the disease has occurred and their condition remains stable seven years after the transplant.DISCUSSIONAllogeneic hematopoietic stem cell transplantation is the only possible cure or method of stopping the progression of the disease in most of these inherited disorders(5–8).Our experience with this method,using HLA-identical siblings and matched unrelated donors,seems very encouraging as judged by a low TRM and low incidences of acute and chronic GVHD(Figs.1and2).The low incidence of acute GVHD may partly be due to early therapy using prednisolone for grade I acute GVHD.TRM is commonly associated with acute GVHD.None of the patients who were given grafts from HLA-identical siblings developed severe acute GVHD and TRM was therefore low.However,the probability of acute GVHD was similar,using matched unrelated donors or mismatched donors,but the TRM was higher in those with mismatched donors.This is partly because4/15patients with mismatched grafts had a rejection.HLA mismatching is also associated with an increase in the risk of infections.Many of the patients receiving mismatched grafts succumbed due to infections.The probability of chronic GVHD was low,with a cumulative incidence of only17%,regardless of the HLA match of the donor(Fig.2).This is because most of the pa-tients were children and they run a relatively low risk of de-veloping chronic GVHD(41).Moreover,we continued im-munosuppressive prophylaxis with cyclosporine during the first1.5to2years after the transplant.This probably also contributed to the low incidence of chronic GVHD.It has long been known that severe combined immuno-deficiencies,and Wiskott-Aldrich syndrome are cured by ASCT,which transfers immunocompetent cells from a healthy donor(9–15).Since these patients lack immunity, rejection has not been a major problem,but failures have occurred due to infections and GVHD.Their immunoin-competence permits the use of haploidentical related donors and prevents the development of GVHD by using T-cell-de-pleted grafts(42).However,ASCT with haploidentical trans-plants or mismatched unrelated grafts results in a poorer sur-vival rate than with HLA-identical siblings(Fig.3B).This accords with the findings of the European Group for Blood and Marrow Transplantation(EBMT)for immunodeficien-cies who reported a survival rate of less than50%,using hap-loidentical donors(15).Unrelated donors are now being used more frequently.With the donor pools available today—more than9million volunteer donors worldwide—a well-matched donor can be found for almost90%of the patients. With better immunosuppression,which includes condition-ing with ATG and genomic tissue typing,the results have steadily improved(27,30).In our most recent series using unrelated donors for inborn errors of metabolism,the5-year survival rate was85%(43).Therefore,if an HLA-identical sibling or a related donor is not available,a well-matched unrelated donor is better than a mismatched transplant.However,if the patient has an unusual HLA type,a cord blood transplant may be the best option(44)because the risk of GVHD is lower than with bone marrow grafts,which per-mits the use of one or two major HLA antigen mismatches.In this study,we used cord blood transplants only in three pa-tients,two from HLA-identical siblings and combined with bone marrow grafts.All three are alive and well.Hematological disorders such as Fanconi anemia, thalassemia major,etc.,can be successfully treated with ASCT,especially if an HLA-identical sibling donor is used (16–19).In patients with thalassemia major,transplantation should preferable be done before six years of age and too many transfusions,which may result in liver cirrhosis and immunization.In such patients,the vast experience of Luca-relli and co-workers showed that the long-term survival rate is about90%(19).Rejection of the transplant has been the main problem.All our six patients with thalassemia major who received grafts from related HLA-identical donors are alive and well between2and16years after the transplant. Thalassemia major is commoner in the Mediterranean coun-tries and our patients emigrated from these areas to Sweden.The histiocytic disorders,FHL and Langerhans’cell histiocytosis seem to be cured by ASCT(20,21,37,45).This has been the subject of much dispute,but,the first patient who underwent ASCT for Langerhans’cell histiocytosis has been free of disease for20years after the transplantation.MPS I or Hurler’s disease is the mucopolysaccharide form now recommended for transplantation,apart from the very rare MPS VI,Maroteaux-Lamy.Our first two patients with Hurler’s disease rejected their HLA mismatched grafts, underwent retransplantation,but died of complications.The four most recent patients who received grafts from unrelated donors are alive.The L-iduronidase levels are normal,hepa-tomegaly and cornea clouding have normalized,but their skeletal problems required surgery in accord with the experi-ence of Peters and co-workers(22).Among the seven patients with MLD,two with the in-fantile form became worse.The first patient with advanced disease was transplanted16years ago.It was not then known that this disorder would become worse despite donor enzyme replacement.The other patient with very mild symptoms when transplanted is still alive12years later.He is severely handicapped,but had a much slower course than expected, and is a joy for his parents.Among the remaining patients, one girl with the juvenile form in an early stage now has stable disease12years after the transplant;she has a fairly good quality of life(38).The transplantation in the first adult onset MLD patient was even more rewarding,because she im-proved afterwards(39).However,in two other adult patients with more advanced late juvenile onset MLD at the time of the transplant,the disease has become severer and the trans-plantation may not have benefited them.It therefore seems that in the adult and late juvenile forms,like the juvenile form of MLD,the transplant should be done early when the pa-tients have only a few symptoms.We did the first successful bone marrow transplanta-tion for Gaucher’s disease(23).Bone marrow transplantation seemed to reverse all symptoms of the disease and resulted in normal mental development,a growth spurt,normalization of the liver size,among other improvements(36).Today,©2006Lippincott Williams&Wilkins723Ringde´n et al.。

DESY02-096ISSN0418-9833 July2002Search for Excited Electrons at HERAH1CollaborationAbstractA search for excited electron(e∗)production is described in which the electroweak decayse∗→eγ,e∗→eZ and e∗→νW are considered.The data used correspond to anintegrated luminosity of120pb−1taken in e±p collisions from1994to2000with the H1detector at HERA at centre-of-mass energies of300and318GeV.No evidence for a signalis found.Mass dependent exclusion limits are derived for the ratio of the couplings to thecompositeness scale,f/Λ.These limits extend the excluded region to higher masses thanhas been possible in previous direct searches for excited electrons.To be submitted toPhysics Letters BC.Adloff33,V.Andreev24,B.Andrieu27,T.Anthonis4,A.Astvatsatourov35,A.Babaev23,J.B¨a hr35,P.Baranov24,E.Barrelet28,W.Bartel10,S.Baumgartner36,J.Becker37,M.Beckingham21,A.Beglarian34,O.Behnke13,A.Belousov24,Ch.Berger1,T.Berndt14,ot26,J.B¨o hme10,V.Boudry27,W.Braunschweig1,V.Brisson26,H.-B.Br¨o ker2,D.P.Brown10,D.Bruncko16,F.W.B¨u sser11,A.Bunyatyan12,34,A.Burrage18,G.Buschhorn25, L.Bystritskaya23,A.J.Campbell10,S.Caron1,F.Cassol-Brunner22,D.Clarke5,C.Collard4, J.G.Contreras7,41,Y.R.Coppens3,J.A.Coughlan5,M.-C.Cousinou22,B.E.Cox21,G.Cozzika9,J.Cvach29,J.B.Dainton18,W.D.Dau15,K.Daum33,39,M.Davidsson20,B.Delcourt26,N.Delerue22,R.Demirchyan34,A.De Roeck10,43,E.A.De Wolf4,C.Diaconu22,J.Dingfelder13,P.Dixon19,V.Dodonov12,J.D.Dowell3,A.Droutskoi23,A.Dubak25,C.Duprel2,G.Eckerlin10,D.Eckstein35,V.Efremenko23,S.Egli32,R.Eichler32, F.Eisele13,E.Eisenhandler19,M.Ellerbrock13,E.Elsen10,M.Erdmann10,40,e,W.Erdmann36, P.J.W.Faulkner3,L.Favart4,A.Fedotov23,R.Felst10,J.Ferencei10,S.Ferron27,M.Fleischer10,P.Fleischmann10,Y.H.Fleming3,G.Fl¨u gge2,A.Fomenko24,I.Foresti37,J.Form´a nek30,G.Franke10,G.Frising1,E.Gabathuler18,K.Gabathuler32,J.Garvey3,J.Gassner32,J.Gayler10,R.Gerhards10,C.Gerlich13,S.Ghazaryan4,34,L.Goerlich6,N.Gogitidze24,C.Grab36,V.Grabski34,H.Gr¨a ssler2,T.Greenshaw18,G.Grindhammer25, T.Hadig13,D.Haidt10,L.Hajduk6,J.Haller13,B.Heinemann18,G.Heinzelmann11,R.C.W.Henderson17,S.Hengstmann37,H.Henschel35,R.Heremans4,G.Herrera7,44,I.Herynek29,M.Hildebrandt37,M.Hilgers36,K.H.Hiller35,J.Hladk´y29,P.H¨o ting2,D.Hoffmann22,R.Horisberger32,A.Hovhannisyan34,S.Hurling10,M.Ibbotson21,C¸.˙Is¸sever7, M.Jacquet26,M.Jaffre26,L.Janauschek25,X.Janssen4,V.Jemanov11,L.J¨o nsson20,C.Johnson3,D.P.Johnson4,M.A.S.Jones18,H.Jung20,10,D.Kant19,M.Kapichine8,M.Karlsson20,O.Karschnick11,J.Katzy10,F.Keil14,N.Keller37,J.Kennedy18,I.R.Kenyon3, C.Kiesling25,P.Kjellberg20,M.Klein35,C.Kleinwort10,T.Kluge1,G.Knies10,B.Koblitz25, S.D.Kolya21,V.Korbel10,P.Kostka35,S.K.Kotelnikov24,R.Koutouev12,A.Koutov8,J.Kroseberg37,K.Kr¨u ger10,T.Kuhr11,mb3,ndon19,nge35,ˇs toviˇc ka35,30,ycock18,E.Lebailly26,A.Lebedev24,B.Leißner1,R.Lemrani10,V.Lendermann10,S.Levonian10,B.List36,E.Lobodzinska10,6,B.Lobodzinski6,10,A.Loginov23,N.Loktionova24,V.Lubimov23,S.L¨u ders37,D.L¨u ke7,10,L.Lytkin12,N.Malden21,E.Malinovski24,S.Mangano36,R.Maraˇc ek25,P.Marage4,J.Marks13,R.Marshall21,H.-U.Martyn1,J.Martyniak6,S.J.Maxfield18,D.Meer36,A.Mehta18,K.Meier14,A.B.Meyer11,H.Meyer33,J.Meyer10,S.Michine24,S.Mikocki6,stead18, S.Mohrdieck11,M.N.Mondragon7,F.Moreau27,A.Morozov8,J.V.Morris5,K.M¨u ller37, P.Mur´ın16,42,V.Nagovizin23,B.Naroska11,J.Naumann7,Th.Naumann35,P.R.Newman3, F.Niebergall11,C.Niebuhr10,O.Nix14,G.Nowak6,M.Nozicka30,B.Olivier10,J.E.Olsson10, D.Ozerov23,V.Panassik8,C.Pascaud26,G.D.Patel18,M.Peez22,E.Perez9,A.Petrukhin35, J.P.Phillips18,D.Pitzl10,R.P¨o schl26,I.Potachnikova12,B.Povh12,J.Rauschenberger11,P.Reimer29,B.Reisert25,C.Risler25,E.Rizvi3,P.Robmann37,R.Roosen4,A.Rostovtsev23, S.Rusakov24,K.Rybicki6,D.P.C.Sankey5,S.Sch¨a tzel13,J.Scheins10,F.-P.Schilling10,P.Schleper10,D.Schmidt33,D.Schmidt10,S.Schmidt25,S.Schmitt10,M.Schneider22,L.Schoeffel9,A.Sch¨o ning36,T.Sch¨o rner25,V.Schr¨o der10,H.-C.Schultz-Coulon7,C.Schwanenberger10,K.Sedl´a k29,F.Sefkow37,V.Shekelyan25,I.Sheviakov24,1L.N.Shtarkov24,Y.Sirois27,T.Sloan17,P.Smirnov24,Y.Soloviev24,D.South21,V.Spaskov8, A.Specka27,H.Spitzer11,R.Stamen7,B.Stella31,J.Stiewe14,I.Strauch10,U.Straumann37, S.Tchetchelnitski23,G.Thompson19,P.D.Thompson3,F.Tomasz14,D.Traynor19,P.Tru¨o l37, G.Tsipolitis10,38,I.Tsurin35,J.Turnau6,J.E.Turney19,E.Tzamariudaki25,A.Uraev23,M.Urban37,ik24,S.Valk´a r30,A.Valk´a rov´a30,C.Vall´e e22,P.Van Mechelen4,A.Vargas Trevino7,S.Vassiliev8,Y.Vazdik24,C.Veelken18,A.Vest1,A.Vichnevski8,K.Wacker7,J.Wagner10,R.Wallny37,B.Waugh21,G.Weber11,D.Wegener7,C.Werner13,N.Werner37, M.Wessels1,G.White17,S.Wiesand33,T.Wilksen10,M.Winde35,G.-G.Winter10,Ch.Wissing7,M.Wobisch10,E.-E.Woehrling3,E.W¨u nsch10,A.C.Wyatt21,J.ˇZ´aˇc ek30,J.Z´a leˇs´a k30,Z.Zhang26,A.Zhokin23,F.Zomer26,and M.zur Nedden251I.Physikalisches Institut der RWTH,Aachen,Germany a2III.Physikalisches Institut der RWTH,Aachen,Germany a3School of Physics and Space Research,University of Birmingham,Birmingham,UK b4Inter-University Institute for High Energies ULB-VUB,Brussels;Universiteit Antwerpen (UIA),Antwerpen;Belgium c5Rutherford Appleton Laboratory,Chilton,Didcot,UK b6Institute for Nuclear Physics,Cracow,Poland d7Institut f¨u r Physik,Universit¨a t Dortmund,Dortmund,Germany a8Joint Institute for Nuclear Research,Dubna,Russia9CEA,DSM/DAPNIA,CE-Saclay,Gif-sur-Yvette,France10DESY,Hamburg,Germany11Institut f¨u r Experimentalphysik,Universit¨a t Hamburg,Hamburg,Germany a12Max-Planck-Institut f¨u r Kernphysik,Heidelberg,Germany13Physikalisches Institut,Universit¨a t Heidelberg,Heidelberg,Germany a14Kirchhoff-Institut f¨u r Physik,Universit¨a t Heidelberg,Heidelberg,Germany a15Institut f¨u r experimentelle und Angewandte Physik,Universit¨a t Kiel,Kiel,Germany16Institute of Experimental Physics,Slovak Academy of Sciences,Koˇs ice,Slovak Republic e,f 17School of Physics and Chemistry,University of Lancaster,Lancaster,UK b18Department of Physics,University of Liverpool,Liverpool,UK b19Queen Mary and Westfield College,London,UK b20Physics Department,University of Lund,Lund,Sweden g21Physics Department,University of Manchester,Manchester,UK b22CPPM,CNRS/IN2P3-Univ Mediterranee,Marseille-France23Institute for Theoretical and Experimental Physics,Moscow,Russia l24Lebedev Physical Institute,Moscow,Russia e25Max-Planck-Institut f¨u r Physik,M¨u nchen,Germany26LAL,Universit´e de Paris-Sud,IN2P3-CNRS,Orsay,France27LPNHE,Ecole Polytechnique,IN2P3-CNRS,Palaiseau,France28LPNHE,Universit´e s Paris VI and VII,IN2P3-CNRS,Paris,France29Institute of Physics,Academy of Sciences of the Czech Republic,Praha,Czech Republic e,i 30Faculty of Mathematics and Physics,Charles University,Praha,Czech Republic e,i31Dipartimento di Fisica Universit`a di Roma Tre and INFN Roma3,Roma,Italy232Paul Scherrer Institut,Villigen,Switzerland33Fachbereich Physik,Bergische Universit¨a t Gesamthochschule Wuppertal,Wuppertal, Germany34Yerevan Physics Institute,Yerevan,Armenia35DESY,Zeuthen,Germany36Institut f¨u r Teilchenphysik,ETH,Z¨u rich,Switzerland j37Physik-Institut der Universit¨a t Z¨u rich,Z¨u rich,Switzerland j38Also at Physics Department,National Technical University,Zografou Campus,GR-15773 Athens,Greece39Also at Rechenzentrum,Bergische Universit¨a t Gesamthochschule Wuppertal,Germany40Also at Institut f¨u r Experimentelle Kernphysik,Universit¨a t Karlsruhe,Karlsruhe,Germany 41Also at Dept.Fis.Ap.CINVESTAV,M´e rida,Yucat´a n,M´e xico k42Also at University of P.J.ˇSaf´a rik,Koˇs ice,Slovak Republic43Also at CERN,Geneva,Switzerland44Also at Dept.Fis.CINVESTAV,M´e xico City,M´e xico ka Supported by the Bundesministerium f¨u r Bildung und Forschung,FRG,under contract numbers05H11GUA/1,05H11PAA/1,05H11PAB/9,05H11PEA/6,05H11VHA/7and 05H11VHB/5b Supported by the UK Particle Physics and Astronomy Research Council,and formerly by the UK Science and Engineering Research Councilc Supported by FNRS-FWO-Vlaanderen,IISN-IIKW and IWTd Partially Supported by the Polish State Committee for Scientific Research,grant no.2P0310318and SPUB/DESY/P03/DZ-1/99and by the German Bundesministerium f¨u r Bildung und Forschunge Supported by the Deutsche Forschungsgemeinschaftf Supported by VEGA SR grant no.2/1169/2001g Supported by the Swedish Natural Science Research Councili Supported by the Ministry of Education of the Czech Republic under the projectsINGO-LA116/2000and LN00A006,by GAUK grant no173/2000j Supported by the Swiss National Science Foundationk Supported by CONACyTl Partially Supported by Russian Foundation for Basic Research,grant no.00-15-965843Among the unexplained features of the Standard Model(SM)of particle physics is the exis-tence of three distinct generations of fermions and the hierarchy of their masses.One possible explanation for this is fermion substructure,with the constituents of the known fermions being strongly bound together by a new,as yet undiscovered force[1,2].A natural consequence of these models would be the existence of excited states of the known leptons and quarks.Assum-ing a compositeness scale in the TeV region,one would naively expect that the excited fermions have masses in the same energy region.However,the dynamics of the constituent level are un-known,so the lowest excited states could have masses of the order of only a few hundred GeV. Electron1-proton interactions at very high energies provide an excellent environment in which to search for excited fermions of thefirst generation.These excited electrons(e∗)could be singly produced through t-channelγand Z boson exchange.Their production cross-section and par-tial decay widths have been calculated using an effective Lagrangian[3,4]which depends on a compositeness mass scaleΛand on weight factors f and f′describing the relative coupling strengths of the excited lepton to the SU(2)L and U(1)Y gauge bosons,respectively.In this model the excited electron can decay to an electron or a neutrino via the radiation of a gauge boson(γ,W,Z)with branching ratios determined by the e∗mass and the coupling parameters f and f′.In most analyses[5–7]the assumption is made that these coupling parameters are of comparable strength and only the relationships f=+f′or f=−f′are considered.If a relationship between f and f′is assumed,the production cross-section and partial decay widths depend on two parameters only,namely the e∗mass and the ratio f/Λ.In this paper excited electrons are searched for in three samples of data taken by the H1 experiment from1994to2000with a total integrated luminosity of120pb−1.Thefirst sample consists of e+p data accumulated from1994to1997at positron and proton beam energies of27.5GeV and820GeV respectively,and corresponds to an integrated luminosity of37pb−1.A search for excited electrons using this sample of data has been previously published[8].The strategy for the selection of events has been modified from the procedures described in[8]to optimize the sensitivity to higher e∗masses.The two other samples were taken from1998 to2000with an electron or positron beam energy of27.5GeV and a proton beam energy of 920GeV.The integrated luminosities of the e−p and e+p samples are15pb−1and68pb−1, pared to previous H1results[8]the analysis presented here benefits from an increase in luminosity by a factor of more than three and an increase of the centre-of-mass energy from300GeV to318GeV.We search for all electroweak decays e∗→eγ,e∗→eZ and e∗→νW,considering the subsequent Z and W hadronic decay modes only.This leads tofinal states containing an electron and a photon,an electron and jets or jets with missing transverse energy induced by the neutrinos escaping from the detector.The Standard Model backgrounds which could mimic such signatures are neutral current Deep Inelastic Scattering(NC DIS),charged current Deep Inelastic Scattering(CC DIS),QED Compton scattering(or Wide Angle Bremsstrahlung W AB),photoproduction processes(γp)and lepton pair production via the two photon fusion process(γγ).The determination of the contribution of NC DIS processes is performed using two MonteCarlo samples which employ different models of QCD radiation.Thefirst was produced withthe DJANGO[9]event generator which includes QEDfirst order radiative corrections based onHERACLES[10].QCD radiation is implemented using ARIADNE[11]based on the ColourDipole Model[12].This sample,with an integrated luminosity of more than10times the exper-imental luminosity,is chosen to estimate the NC DIS contribution in the e∗→eγanalysis.The second sample was generated with the program RAPGAP[13],in which QEDfirst order radia-tive corrections are implemented as described above.RAPGAP includes the leading order QCDmatrix element and higher order radiative corrections are modelled by leading-log parton show-ers.This sample is used to determine potential NC DIS background in the e∗→νW֒→q¯q and e∗→eZ֒→q¯q searches,as RAPGAP describes better this particular phase space domain[8]. For both samples the parton densities in the proton are taken from the MRST[14]parametriza-tion which includes constraints from DIS measurements at HERA up to squared momentum transfers Q2=5000GeV2[15–18].Hadronisation is performed in the Lund string fragmenta-tion scheme using JETSET[19].The modelling of the CC DIS process is performed using the DJANGO program with MRST structure functions.While inelastic W AB is treated using the DJANGO generator,elastic and quasi-elastic W AB is simulated with the W ABGEN[20]event generator.Direct and resolvedγp processes including prompt photon production are generated with the PYTHIA[21]event generator.Finally theγγprocess is produced using the LPAIR generator[22].For the calculation of the e∗production cross-section and to determine the efficiencies,events have been generated with the COMPOS[23]generator based on the cross-section for-mulae given in reference[3]and the partial decay widths stated in reference[4].Initial stateradiation of a photon from the incoming electron is included.This generator uses the narrowwidth approximation(NW A)for the calculation of the production cross section and takes intoaccount the natural width for the e∗decay.For all values of f/Λrelevant to this analysis thisassumption is valid even at high e∗masses where the natural width of the e∗is of the order ofthe experimental resolution.To give an example,for M e∗=250GeV this resolution is equal to7GeV,10GeV,and12GeV for the eγ,eZ andνW decay modes,respectively.All Monte Carlo samples are subjected to a detailed simulation of the response of the H1detector.The detector components of the H1experiment[24]most relevant for this analysis arebriefly described in the following.Surrounding the interaction region is a system of drift andproportional chambers which covers the polar angle2range7◦<θ<176◦.The tracking sys-tem is surrounded by afinely segmented liquid argon(LAr)calorimeter covering the polar angle√range4◦<θ<154◦[25]with energy resolutions ofσE/E≃12%/E⊕2%for hadrons,obtained in test beam measurements[26,27].The tracking system and calorimeters are surrounded by a superconducting solenoid and an iron yoke instrumented with streamer tubes.Backgrounds not related to e+p or e−p collisions are rejected by requiring that a primary interaction vertex be reconstructed within±35cm of the nominal vertex position,by usingfilters based on the event topology and by requiring an event time which is consistent with the interaction time.Electromagnetic clusters are required to havemore than95%of their energy in the electromagnetic part of the calorimeter and to be isolated from other particles[28].They are further differentiated into electron and photon candidates using the tracking chambers.Jets with a minimum transverse momentum of5GeV are recon-structed from the hadronicfinal state using a cone algorithm adapted from the LUCELL schemein the JETSET package[19].Missing transverse energy(E misst )is reconstructed using the vec-tor sum of energy depositions in the calorimeter cells.The analysis presented in this paper is described extensively in[29].The e∗→eγchannel is characterized by two electromagnetic clusters in thefinal state. The main sources of background are the W AB process,NC DIS with photon radiation or a high energyπ0in a jet and the production of electron pairs viaγγfusion.Candidate events are selected with two electromagnetic clusters in the LAr calorimeter of transverse energy greater than20GeV and15GeV,respectively,and with a polar angle between0.1and2.2radians. The sum of the energies of the two clusters has to be greater than100GeV.If this sum is below 200GeV,the background is further suppressed by rejecting events with a total transverse energy of the two electromagnetic clusters lower than75GeV or with more than two tracks spatially associated to one of the clusters.The numbers of events passing the analysis cuts for the SM background processes and for the data in each of the three samples are given in Table1.About half of the background originates from NC DIS events with most of the remainder being due to W AB events.The efficiency for selecting the signal varies from85%for an e∗mass of150GeV to72%for an e∗mass of250GeV.As in all other channels the efficiencies are derived using samples of1000e∗events generated at different e∗masses.The various sources of systematic error are discussed later.Distributions of the invariant mass of the candidate electron-photon pairs of the three data samples together and for the SM expectation are shown in Fig.1a.Sample e−p920GeVChannel SM background SM background SM background e∗→eγ7.2±1.0±0.1 4.0±0.7±0.215.6±1.7±0.4 e∗→eZ֒→q¯q7.1±2.1±2.8 5.6±0.4±1.225.3±1.9±5.5 e∗→νW֒→q¯q 2.4±0.2±0.7 3.9±0.2±0.7 6.1±0.4±1.5 Table1:Number of candidate events observed in the three decay channels with the correspond-ing SM expectation and the uncertainties on the expectation(statistical and systematic error).The e∗→eZ֒→q¯q channel is characterized by an electromagnetic cluster with an associated track and two high transverse energy jets.The analysis for this channel uses a sample of events with at least two jets with a transverse energy above17GeV and16GeV,respectively,and an electron candidate with a transverse energy E e t>20GeV.These two jets and the electron must have polar angles smaller than2.2radians.Furthermore,to avoid possible double counting of events from the e∗→eγchannel,events with two electromagnetic clusters with transverse energies above10GeV and a total energy of the two clusters greater than100GeV are removed. The main SM contribution is NC DIS as photoproduction events do not yield a significant rate of electron candidates with large E e t.For20GeV<E e t<65GeV,a cut is made on the602468101214161820invariant mass (GeV)e v e n t s0510152025invariant mass (GeV)e v e n t s 012345678910invariant mass (GeV)e v e n t s Figure 1:Invariant mass spectra of candidate (a)eγpairs for the e ∗→eγanalysis,(b)elec-tron and two jets for the e ∗→eZ analysis and (c)neutrino and two jets for the e ∗→νW anal-ysis.Solid points correspond to the data and the histogram to the total expectation from different SM processes.electron polar angle.This ranges from θe <1.35for E e t =20GeV to θe <2.2radians for E e t =65GeV and depends linearly on E e t .The dijet invariant mass has to be in the range −15<M jj −M Z <7GeV .If there are more than two jets,the pair with invariant mass closest to the nominal Z boson mass is chosen as the Z candidate.The two jets chosen are ordered such that E jet 1t >E jet 2t .In many SM events the direction of jet 2is close to the proton direction.To ensure that this jet is well measured,an additional cut on its polar angle,θjet 2>0.2radians,7is applied if its transverse momentum is lower than30GeV.For an electron transverse energy 65GeV<E e t<85GeV two jets with an invariant mass M jj>M Z−30GeV are required. At very high transverse energy,E e t>85GeV,the contribution from NC DIS is very low and no further cuts on M jj are needed.The number of events which remain in the data after these cuts are summarized in Table1and compared with the expected SM contribution(mostly NC DIS events).The efficiency for selecting the signal varies from44%for an e∗mass of150GeV to 62%for an e∗mass of250GeV.Distributions of the invariant mass of the electron and the two jets are shown in Fig.1b for data and for the SM expectation.The e∗→νW֒→q¯q channel is characterized by two jets and missing transverse energy E miss t. The main background originates from CC DIS events with a moderate contribution from photo-production,whereas the NC DIS contribution is suppressed for large E misst .The analysis startsfrom a sample of events with at least two jets with transverse energies above17GeV and16GeV,missing transverse energy E misst >20GeV and no isolated electromagnetic cluster withtransverse energy above10GeV.The jets must have a polar angle below2.2radians.Jets in which the most energetic track enters the boundary region between two calorimeter modules and central jets(θ>0.5radians)are required to contain more than two tracks.This cut re-moves NC DIS events in which the scattered electron is misidentified as a jet.Only events with S=V apevents in a mass interval that varies with the width of the expected signal.At M e ∗=150GeV ,a width of the mass interval of 30GeV is chosen for the e ∗→eγdecay mode and 60GeV is chosen for the decay channels with two jets.Systematic uncertainties are taken into account as in [8].The limits on the product of the e ∗production cross-section and the decay branching ratio are shown in Fig.2.As stated in the introduction,most experiments give f/Λlimits under the assumptions f =+f ′and f =−f ′.The H1limits for each decay channel and after combi-nation of all decay channels are given as a function of the e ∗mass in Fig.3a,for the assumption f =+f ′.With this hypothesis the main contribution comes from the e ∗→eγchannel.The values of the limits for f/Λvary between 5×10−4and 10−2GeV −1for an e ∗mass ranging from 130GeV to 275GeV .These results improve significantly the previously published H1limits for e +p [8]collisions.The LEP experiments [5,6]and the ZEUS collaboration [7]have also reported on excited electron searches.Their limits are shown in Fig.3b.The LEP 2experiments have shown results in two mass domains.In direct searches for excited electrons limits up to a mass of about 200GeV are given.Above 200GeV their results are derived from indirect searches only.The H1limit extends the excluded region to higher masses than reached in previous direct searches.Figure 2:Upper limits at 95%confi-dence level on the product of the pro-duction cross-section σand the decaybranching ratio BR for excited elec-trons e ∗in the various electroweakdecay channels,e ∗→eγ(dashed line),e ∗→eZ ֒→q ¯q (dotted-dashedline)and e ∗→νW ֒→q ¯q (dotted line)as a function of the excited electronmass.The signal efficiencies used tocompute these limits have been deter-mined with events generated under theassumption f =+f ′.1010110e * mass (GeV)σ*B R (p b )More generally,limits on f/Λas a function of f ′/f are shown in Fig.4for three e ∗masses (150,200and 250GeV ).It is worth noting that excited electrons have vanishing electromag-netic coupling for f =−f ′.In this case the e ∗is produced through pure Z boson exchange.As a consequence the production cross-section for excited electrons at HERA is much smaller in the f =−f ′case than in the f =+f ′case.For e ∗masses between 150and 250GeV the ratio910101010e* mass (GeV)f /Λ (G e V -1)10101010e* mass (GeV)f /Λ (G e V -1)Figure 3:Exclusion limits on the coupling f/Λat 95%confidence level as a function of the mass of excited electrons with the assumption f =+f ′.(a)Limit for each decay channele ∗→eγ(dashed line),e ∗→eZ ֒→q ¯q (thick dotted-dashed line),e ∗→νW ֒→q ¯q (dotted line)and for the combination of the three channels (full line).It must be noted that a part of the data included in the present result were used to obtain the previous H1limit [8].(b)Comparison of this analysis with ZEUS results [7](dashed line)and LEP 2results on direct searches [5](dotted-dashed line)and on indirect searches [6](dotted line).of the cross-sections for f =+f ′and f =−f ′varies between 170and 900.For high e ∗masses and some values of the couplings,no limits are given because the natural width of the e ∗would become extremely large.In summary,a search for excited electron production was performed using all the e +p and e −p data accumulated by H1between 1994and 2000.No indication of a signal was found.New limits have been established as a function of the couplings and the excited electron mass for the conventional relationship between the couplings f =+f ′.The dependence of the f/Λlimit on the ratio f ′/f has been shown for the first time at HERA.The data presented here restrict excited electrons to higher mass values than has been possible previously in direct searches.We are grateful to the HERA machine group whose outstanding efforts have made and continue to make this experiment possible.We thank the engineers and technicians for their work in constructing and now maintaining the H1detector,our funding agencies for financial support,the DESY technical staff for continual assistance and the DESY directorate for the hospitality which they extend to the non-DESY members of the collaboration.10Figure 4:Exclusion lim-its on the coupling f/Λat 95%confidence level as a function of the ratio f ′/f for three different masses of the e ∗:150GeV (full line),200GeV (dotted line)and 250GeV (dashed line).10101010f //ff / Λ (G e V -1)References[1]H.Harari,Phys.Rep.104(1984)159.[2]F.Boudjema,A.Djouadi and J.L.Kneur,Z.Phys.C 57(1993)425.[3]K.Hagiwara,D.Zeppenfeld and S.Komamiya,Z.Phys.C 29(1985)115.[4]U.Baur,M.Spira and P.M.Zerwas,Phys.Rev.D 42(1990)815.[5]G.Abbiendi et al.[OPAL Collaboration],CERN-EP/2002-043,arXiv:hep-ex/0206061.Submitted to Phys.Lett.B [6]P.Abreu et al.[DELPHI Collaboration],Eur.Phys.J.C 8(1999)41[hep-ex/9811005].[7]S.Chekanov et al.[ZEUS Collaboration],DESY-01-132arXiv:hep-ex/0109018.[8]C.Adloff et al.,[H1Collaboration],Eur.Phys.J.C 17(2000)567[hep-ex/0007035].[9]G.A.Schuler and H.Spiesberger,in:Proceedings of Physics at HERA ,Hamburg 1991,V ol.3,pp.1419-1432.[10]A.Kwiatkowski,H.Spiesberger and H.J.M¨o hring,mun.69(1992)155.11[11]L.L¨o nnblad,mun.71(1992)15.[12]B.Andersson,G.Gustafson,L.L¨o nnblad and U.Pettersson,Z.Phys.C43(1989)625.[13]H.Jung,mun.86(1995)147.[14]A.D.Martin,R.G.Roberts,W.J.Stirling and R.S.Thorne,Eur.Phys.J.C4(1998)463.[hep-ph/9803445].[15]S.Aid et al.,[H1Collaboration],Nucl.Phys.B470(1996)3[hep-ex/9603004].[16]C.Adloff et al.,[H1Collaboration],Nucl.Phys.B497(1997)3[hep-ex/9703012].[17]M.Derrick et al.,[ZEUS Collaboration],Z.Phys.C69(1996)607[hep-ex/9510009].[18]M.Derrick et al.,[ZEUS Collaboration],Z.Phys.C72(1996)399[hep-ex/9607002].[19]T.Sj¨o strand,hep-ph/9508391,LU-TP-95-20,CERN-TH-7112-93-REV,August1995.[20]C.Berger and P.Kandel,Proceedings of the Workshop Monte Carlo generators for HERAPhysics,Hamburg1998-1999,pp.596-600,[hep-ph/9906541].[21]T.Sj¨o strand,mun.82(1994)74.[22]S.P.Baranov,O.D¨u nger,H.Shooshtari and J.A.Vermaseren,Proceedings of Physics atHERA,Hamburg1991,vol.3,pp.1478-1482.[23]T.K¨o hler,Proceedings of Physics at HERA,Hamburg1991,vol.3,pp.1526-1541.[24]I.Abt et al.,[H1Collaboration],Nucl.Instrum.Meth.A386(1997)310;ibid.348.[25]B.Andrieu et al.,[H1Calorimeter Group],Nucl.Instrum.Meth.A336(1993)460.[26]B.Andrieu et al.,[H1Calorimeter Group],Nucl.Instrum.Meth.A350(1994)57.[27]B.Andrieu et al.[H1Calorimeter Group],Nucl.Instrum.Meth.A336(1993)499.[28]A.Sch¨o ning,Untersuchung von Prozessen mit virtuellen und reellen W±-Bosonen amH1-Detektor bei HERA,Ph.D.Thesis,University of Hamburg,1996.https://www-h1.desy.de/publications/theseslist.html[30]T.Carli,Proceedings of the Workshop Monte Carlo generators for HERA Physics1998-1999,pp.185-194,[hep-ph/9906541].[31]P.Bate,High Transverse Momentum2-jet and3-jet Cross-section Measurements in Pho-toproduction,Ph.D.Thesis,University of Manchester,1999.12。

本研究还将血清Ｌｐ－ＰＬＡ２、ＲＤＷ用于ＡＩＳ的诊断分析，ＲＯＣ曲线分析显示，二者联合应用诊断ＡＩＳ的ＡＵＣ达到０．９６１，明显高于单项指标应用，表明血清Ｌｐ－ＰＬＡ２联合ＲＤＷ对ＡＩＳ具有较高的诊断效能。

４　结论综上所述，Ｌｐ－ＰＬＡ２、ＲＤＷ均与ＡＩＳ的发生发展、病情严重程度关系密切，二者联合用于ＡＩＳ诊断中具有较高的诊断效能。

临床在诊疗疑似ＡＩＳ患者时可密切关注患者的Ｌｐ－ＰＬＡ２、ＲＤＷ水平，发挥其早期诊断、病情严重程度监测的积极作用，使患者获得最佳预后。

参考文献［１］　葛成东，张尊胜．脑白质高信号与急性缺血性脑卒中患者功能预后的相关性研究［Ｊ］．临床和实验医学杂志，２０１９，１８（２）：１９８－２０１．［２］　中国老年医学学会急诊医学分会，中华医学会急诊医学分会卒中学组，中国卒中学会急救医学分会．急性缺血性脑卒中急诊急救中国专家共识（２０１８版）［Ｊ］．中华急诊医学杂志，２０１８，２７（７）：７２１－７２８．［３］　Ｒｏｄｒｉｇｕｅｚ－ＣｏｌｏｎＳＭ，ＭｏＪ，ＤｕａｎＹ，ｅｔａｌ．Ｍｅｔａｂｏｌｉｃｓｙｎｄｒｏｍｅｃｌｕｓｔｅｒｓａｎｄｔｈｅｒｉｓｋｏｆｉｎｃｉｄｅｎｔｓｔｒｏｋｅ：ｔｈｅａｔｈｅｒｏｓｃｌｅｒｏｓｉｓｒｉｓｋｉｎｃｏｍｍｕｎｉ ｔｉｅｓ（ＡＲＩＣ）ｓｔｕｄｙ［Ｊ］．Ｓｔｒｏｋｅ，２００９，４０（１）：２００－２０５．［４］　ＲａｍａｗａｔＢ，ＳａｌｕｊａＡ，ＢｈａｔａｃｈａｒｊｅｅＪ，ｅｔａｌ．ＡｃｕｔｅＩｓｃｈｅｍｉｃＳｔｒｏｋｅｉｓＡｓｓｏｃｉａｔｅｄｗｉｔｈＩｎｃｒｅａｓｅｄＳｅｒｕｍＬｅｖｅｌｓｏｆＰｒｏ－ｉｎｆｌａｍｍａｔｏｒｙＣｙｔｏｋｉｎｅｓ［Ｊ］．ＩｎｄｉａｎＪＣｌｉｎＢｉｏｃｈｅｍ，２０２０，３６（６）：８－１０．［５］　姜旭，李云慧，万楠．急性缺血性脑卒中的发生与脂蛋白相关磷脂酶Ａ２的相关性分析［Ｊ］．中国实验诊断学，２０２０，２４（１０）：１６２７－１６３０．［６］　ＨｕＧＸ，ＺｈａｎｇＪ，ＴｉａｎＹＧ，ｅｔａｌ．ＤｉａｇｎｏｓｔｉｃｖａｌｕｅｏｆｊｏｉｎｔｄｅｔｅｃｔｉｏｎｏｆｈｏｍｏｃｙｓｔｅｉｎｅａｎｄＲＤＷＣＶｏｎａｃｕｔｅｍｙｏｃａｒｄｉａｌｉｎｆａｒｃｔｉｏｎ．［Ｊ］．ＥｕｒＲｅｖＭｅｄＰｈａｒｍＳｃｉ，２０１６，２０（１９）：４１２４－４１２８．［７］　张贵涛，朱天瑞，张凤，等．红细胞分布宽度在急性脑梗死动脉硬化评估中的应用［Ｊ］．中国老年学杂志，２０１７，３７（１）：５９．［８］　中华医学会神经病学分会，中华医学会神经病学分会脑血管病学组．中国急性缺血性脑卒中诊治指南２０１８［Ｊ］．中华神经科杂志，２０１８，５１（９）：６６６－６８２．［９］　王洁，于蕾，郭淮莲．颈动脉硬化斑块内新生血管的超声造影评价及其与脑梗死患者病情严重程度及预后的关系［Ｊ］．中风与神经疾病杂志，２０１９，２６（８）：６７６－６８０．［１０］ＳｒｉｖａｓｔａｖａＡ，ＭｃｍａｈｏｎＫＤ，ＳｔｅｐａｎａｕｓｋａｓＲ，ｅｔａｌ．Ｄｅｎｏｖｏｓｙｎｔｈｅｓｉｓａｎｄｆｕｎｃｔｉｏｎａｌａｎａｌｙｓｉｓｏｆｔｈｅｐｈｏｓｐｈａｔａｓｅ－ｅｎｃｏｄｉｎｇｇｅｎｅａｃＩ－ＢｏｆｕｎｃｕｌｔｕｒｅｄＡｃｔｉｎｏｂａｃｔｅｒｉａｆｒｏｍＬａｋｅＳｔｅｃｈｌｉｎ（ＮＥＧｅｒｍａｎｙ）［Ｊ］．ＩｎｔＭｉｃｒｏｂｉｏｌ，２０１６，１８（４）：３９－４７．［１１］陈志华，张梅，李镒冲，等．我国成年人血压水平与心脑血管疾病行为危险因素及其聚集关系分析［Ｊ］．中华流行病学杂志，２０１８，３９（５）：６４０－６４５．［１２］ＭａｇｎｕｓＢ，ＨａｎｓｓｏｎＧＫ．Ａｎｔｉ－ｉｎｆｌａｍｍａｔｏｒｙｔｈｅｒａｐｉｅｓｆｏｒａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ［Ｊ］．ＮａｔｕｒｅＲｅｖｉｅｗｓＣａｒｄｉｏｌｏｇｙ，２０１５，１２（４）：１９９－２１１．［１３］ＵｌｒｉｃｈＣ，ＴｒｏｊａｎｏｗｉｃｚＢ，ＦｉｅｄｌｅｒＲ，ｅｔａｌ．ＤｉｆｆｅｒｅｎｔｉａｌＥｘｐｒｅｓｓｉｏｎｏｆＬｉｐｏｐｒｏｔｅｉｎ－ＡｓｓｏｃｉａｔｅｄＰｈｏｓｐｈｏｌｉｐａｓｅＡ２ｉｎＭｏｎｏｃｙｔｅＳｕｂｓｅｔｓ：ＩｍｐａｃｔｏｆＵｒｅｍｉａａｎｄＡｔｈｅｒｏｓｃｌｅｒｏｓｉｓ［Ｊ］．Ｎｅｐｈｒｏｎ，２０１７，１３５（３）：２３１－２４１．［１４］Ｂｏｎｎｅｆｏｎｔ－ＲｏｕｓｓｅｌｏｔＤ．Ｌｐ－ＰＬＡ２，ａｂｉｏｍａｒｋｅｒｏｆｖａｓｃｕｌａｒｉｎｆｌａｍｍａｔｉｏｎａｎｄｖｕｌｎｅｒａｂｉｌｉｔｙｏｆａｔｈｅｒｏｓｃｌｅｒｏｓｉｓｐｌａｑｕｅｓ［Ｊ］．ＡｎｎＰｈａｒｍＦｒ，２０１６，７４（３）：１９０－１９７．［１５］张晓红，刘向 ．脂蛋白相关磷脂酶Ａ２与心血管疾病的关系［Ｊ］．标记免疫分析与临床，２０１９，１２（５）：８９２－８９６．［１６］ＫｉｔａｍｕｒａＪ，ＵｅｎｏＨ，ＮａｇａｉＭ，ｅｔａｌ．ＢｌｏｏｄＰｒｅｓｓｕｒｅＶａｒｉａｂｉｌｉｔｙｉｎＡｃｕｔｅＩｓｃｈｅｍｉｃＳｔｒｏｋｅ：ＩｎｆｌｕｅｎｃｅｏｆＩｎｆａｒｃｔＬｏｃａｔｉｏｎｉｎｔｈｅＩｎｓｕｌａｒＣｏｒｔｅｘ［Ｊ］．ＥｕｒＮｅｕｒｏｌ，２０１８，７９（１－２）：９０－９９．［１７］刘希奇，李孝庆，姚彦，等．急性脑梗死患者血清ＣＸＣＬ１６ＧＤＦ１５Ｌｐ－ＰＬＡ２水平变化及临床意义［Ｊ］．河北医学，２０１９，２５（３）：５８０－５８４．［１８］Ｓｚｙｇｕｌａ－ＪｕｒｋｉｅｗｉｃｚＢ，ＳｚｃｚｕｒｅｋＷ，ＳｋｒｚｙｐｅｋＭ，ｅｔａｌ．ＲｅｄＢｌｏｏｄＣｅｌｌＤｉｓｔｒｉｂｕｔｉｏｎＷｉｄｔｈｉｎＥｎｄ－ＳｔａｇｅＨｅａｒｔＦａｉｌｕｒｅＰａｔｉｅｎｔｓＩｓＩｎｄｅ ｐｅｎｄｅｎｔｌｙＡｓｓｏｃｉａｔｅｄＷｉｔｈＡｌｌ－ＣａｕｓｅＭｏｒｔａｌｉｔｙＡｆｔｅｒＯｒｔｈｏｔｏｐｉｃＨｅａｒｔＴｒａｎｓｐｌａｎｔａｔｉｏｎ［Ｊ］．ＴｒａｎｓｐｌａｎｔＰｒｏｃｅｅｄ，２０１８，５０（７）：２０９５－２０９９．［１９］ＥｍｉｒｏｇｌｕＮ，ＣｅｎｇｉｚＦＰ，ＡＧＢａｈａｌ ，ｅｔａｌ．ＲｅｄＢｌｏｏｄＣｅｌｌＤｉｓｔｒｉｂｕｔｉｏｎＷｉｄｔｈａｎｄＮｅｕｔｒｏｐｈｉｌ－ｔｏ－ＬｙｍｐｈｏｃｙｔｅＲａｔｉｏｉｎＰａｔｉｅｎｔｓｗｉｔｈＣｕｔａｎｅ ｏｕｓＶａｓｃｕｌｉｔｉｓ［Ｊ］．ＡｎｎＣｌｉｎＬａｂＳｃｉ，２０１７，４７（２）：１６２－１６５．［２０］Ｇａｒｒｏｔｅ－ＦｉｌｈｏＳ，Ｂｅｒｎａｒｄｉｎｏ－ＮｅｔｏＭ，Ｐｅｎｈａ－ＳｉｌｖａＮ．ＩｎｆｌｕｅｎｃｅｏｆＥｒｙｔｈｒｏｃｙｔｅＭｅｍｂｒａｎｅＳｔａｂｉｌｉｔｙｉｎＡｔｈｅｒｏｓｃｌｅｒｏｓｉｓ［Ｊ］．ＣｕｒｒＡｔｈｅｒＲｅｐ，２０１７，１９（４）：１７．［２１］张茜，王萌，赖惠英，等．红细胞分布宽度对老年急性缺血性脑卒中患者的早期诊断价值［Ｊ］．中华老年医学杂志，２０２０，３９（５）：４９７－５００．（收稿日期：２０２１－１２－０６） ＤＯＩ：１０．３９６９／ｊ．ｉｓｓｎ．１６７１－４６９５．２０２２．０４．００６ 文章编号：１６７１－４６９５（２０２２）０４－０３５６－０５信迪利单抗联合盐酸安罗替尼用于晚期非小细胞肺癌疗效研究操思源　宋文灿　陶正平　（池州市人民医院肿瘤科　安徽　池州　２４７１００）基金项目：安徽省自然科学基金项目（编号：１４０８０８５ＭＧ１４６） 【摘要】　目的　探讨信迪利单抗联合盐酸安罗替尼用于晚期非小细胞肺癌疗效研究。

ISSN: 1524-4539Copyright © 2010 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online72514Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TXDOI: 10.1161/CIRCULATIONAHA.110.9708892010;122;S640-S656Circulation HoekCallaway, Brett Cucchiara, Jeffrey D. Ferguson, Thomas D. Rea and Terry L. VandenMark S. Link, Laurie J. Morrison, Robert E. O'Connor, Michael Shuster, Clifton W. Marc D. Berg, John E. Billi, Brian Eigel, Robert W. Hickey, Monica E. Kleinman,Neumar, Mary Ann Peberdy, Jeffrey M. Perlman, Elizabeth Sinz, Andrew H. Travers, Farhan Bhanji, Diana M. Cave, Edward C. Jauch, Peter J. Kudenchuk, Robert W.Schexnayder, Robin Hemphill, Ricardo A. Samson, John Kattwinkel, Robert A. Berg, John M. Field, Mary Fran Hazinski, Michael R. Sayre, Leon Chameides, Stephen M. Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Part 1: Executive Summary: 2010 American Heart Association Guidelines for/cgi/content/full/122/18_suppl_3/S640located on the World Wide Web at:The online version of this article, along with updated information and services, is/reprints Reprints: Information about reprints can be found online atjournalpermissions@ 410-528-8550. E-mail:Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters/subscriptions/Subscriptions: Information about subscribing to Circulation is online atPart1:Executive Summary2010American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care John M.Field,Co-Chair*;Mary Fran Hazinski,Co-Chair*;Michael R.Sayre;Leon Chameides; Stephen M.Schexnayder;Robin Hemphill;Ricardo A.Samson;John Kattwinkel;Robert A.Berg;Farhan Bhanji;Diana M.Cave;Edward C.Jauch;Peter J.Kudenchuk;Robert W.Neumar;Mary Ann Peberdy;Jeffrey M.Perlman;Elizabeth Sinz;Andrew H.Travers;Marc D.Berg; John E.Billi;Brian Eigel;Robert W.Hickey;Monica E.Kleinman;Mark S.Link;Laurie J.Morrison; Robert E.O’Connor;Michael Shuster;Clifton W.Callaway;Brett Cucchiara;Jeffrey D.Ferguson;Thomas D.Rea;Terry L.Vanden HoekT he publication of the2010American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care marks the50th anniversary of modern CPR.In1960Kouwenhoven,Knickerbocker,and Jude documented14patients who survived cardiac arrest with the application of closed chest cardiac massage.1That same year,at the meeting of the Maryland Medical Society in Ocean City,MD,the combination of chest compressions and rescue breathing was introduced.2Two years later,in1962, direct-current,monophasic waveform defibrillation was de-scribed.3In1966the American Heart Association(AHA) developed the first cardiopulmonary resuscitation(CPR) guidelines,which have been followed by periodic updates.4 During the past50years the fundamentals of early recogni-tion and activation,early CPR,early defibrillation,and early access to emergency medical care have saved hundreds of thousands of lives around the world.These lives demonstrate the importance of resuscitation research and clinical transla-tion and are cause to celebrate this50th anniversary of CPR. Challenges remain if we are to fulfill the potential offered by the pioneer resuscitation scientists.We know that there is a striking disparity in survival outcomes from cardiac arrest across systems of care,with some systems reporting5-fold higher survival rates than others.5–9Although technology, such as that incorporated in automated external defibrillators (AEDs),has contributed to increased survival from cardiac arrest,no initial intervention can be delivered to the victim of cardiac arrest unless bystanders are ready,willing,and able to act.Moreover,to be successful,the actions of bystanders and other care providers must occur within a system that coordi-nates and integrates each facet of care into a comprehensive whole,focusing on survival to discharge from the hospital.This executive summary highlights the major changes and most provocative recommendations in the2010AHA Guide-lines for CPR and Emergency Cardiovascular Care(ECC). The scientists and healthcare providers participating in a comprehensive evidence evaluation process analyzed the sequence and priorities of the steps of CPR in light of current scientific advances to identify factors with the greatest potential impact on survival.On the basis of the strength of the available evidence,they developed recommendations to support the interventions that showed the most promise. There was unanimous support for continued emphasis on high-quality CPR,with compressions of adequate rate and depth,allowing complete chest recoil,minimizing inter-ruptions in chest compressions and avoiding excessive ventilation.High-quality CPR is the cornerstone of a system of care that can optimize outcomes beyond return of spontaneous circulation(ROSC).Return to a prior quality of life and functional state of health is the ultimate goal of a resuscitation system of care.The2010AHA Guidelines for CPR and ECC are based on the most current and comprehensive review of resuscitation litera-ture ever published,the2010ILCOR International Consensus on CPR and ECC Science With Treatment Recommendations.10 The2010evidence evaluation process included356resuscita-tion experts from29countries who reviewed,analyzed,evalu-ated,debated,and discussed research and hypotheses through in-person meetings,teleconferences,and online sessions(“web-inars”)during the36-month period before the2010Consensus Conference.The experts produced411scientific evidence re-views on277topics in resuscitation and emergency cardiovas-cular care.The process included structured evidence evaluation, analysis,and cataloging of the literature.It also included rigor-The American Heart Association requests that this document be cited as follows:Field JM,Hazinski MF,Sayre MR,Chameides L,Schexnayder SM, Hemphill R,Samson RA,Kattwinkel J,Berg RA,Bhanji F,Cave DM,Jauch EC,Kudenchuk PJ,Neumar RW,Peberdy MA,Perlman JM,Sinz E,Travers AH,Berg MD,Billi JE,Eigel B,Hickey RW,Kleinman ME,Link MS,Morrison LJ,O’Connor RE,Shuster M,Callaway CW,Cucchiara B,Ferguson JD,Rea TD,Vanden Hoek TL.Part1:executive summary:2010American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.Circulation.2010;122(suppl3):S640–S656.*Co-chairs and equal first co-authors.(Circulation.2010;122[suppl3]:S640–S656.)©2010American Heart Association,Inc.Circulation is available at DOI:10.1161/CIRCULATIONAHA.110.970889ous disclosure and management of potential conflicts of interest, which are detailed in Part2:“Evidence Evaluation and Man-agement of Potential and Perceived Conflicts of Interest.”The recommendations in the2010Guidelines confirm the safety and effectiveness of many approaches,acknowledge ineffectiveness of others,and introduce new treatments based on intensive evidence evaluation and consensus of experts. These new recommendations do not imply that care using past guidelines is either unsafe or ineffective.In addition,it is important to note that they will not apply to all rescuers and all victims in all situations.The leader of a resuscitation attempt may need to adapt application of these recommenda-tions to unique circumstances.New Developments in Resuscitation ScienceSince2005A universal compression-ventilation ratio of30:2performed by lone rescuers for victims of all ages was one of the most controversial topics discussed during the2005International Consensus Conference,and it was a major change in the2005 AHA Guidelines for CPR and ECC.11In2005rates of survival to hospital discharge from witnessed out-of-hospital sudden cardiac arrest due to ventricular fibrillation(VF)were low,averagingՅ6%worldwide with little improvement in the years immediately preceding the2005conference.5Two studies published just before the2005International Consen-sus Conference documented poor quality of CPR performed in both out-of-hospital and in-hospital resuscitations.12,13The changes in the compression-ventilation ratio and in the defibrillation sequence(from3stacked shocks to1shock followed by immediate CPR)were recommended to mini-mize interruptions in chest compressions.11–13There have been many developments in resuscitation science since2005,and these are highlighted below. Emergency Medical Services Systems andCPR QualityEmergency medical services(EMS)systems and healthcare providers should identify and strengthen“weak links”in the Chain of Survival.There is evidence of considerable regional variation in the reported incidence and outcome from cardiac arrest within the United States.5,14This evidence supports the importance of accurately identifying each instance of treated cardiac arrest and measuring outcomes and suggests additional opportunities for improving survival rates in many communities. Recent studies have demonstrated improved outcome from out-of-hospital cardiac arrest,particularly from shockable rhythms,and have reaffirmed the importance of a stronger emphasis on compressions of adequate rate and depth,allowing complete chest recoil after each compression,minimizing interrup-tions in compressions and avoiding excessive ventilation.15–22 Implementation of new resuscitation guidelines has been shown to improve outcomes.18,20–22A means of expediting guidelines implementation(a process that may take from18 months to4years23–26)is needed.Impediments to implemen-tation include delays in instruction(eg,time needed to produce new training materials and update instructors and providers),technology upgrades(eg,reprogramming AEDs), and decision making(eg,coordination with allied agencies and government regulators,medical direction,and participa-tion in research).Documenting the Effects of CPR Performance by Lay RescuersDuring the past5years there has been an effort to simplify CPR recommendations and emphasize the fundamental importance of high-quality rge observational studies from investiga-tors in member countries of the Resuscitation Council of Asia (the newest member of ILCOR)27,28–30and other studies31,32 have provided important information about the positive impact of bystander CPR on survival after out-of-hospital cardiac arrest. For most adults with out-of-hospital cardiac arrest,bystander CPR with chest compression only(Hands-Only CPR)appears to achieve outcomes similar to those of conventional CPR(com-pressions with rescue breathing).28–32However,for children, conventional CPR is superior.27CPR QualityMinimizing the interval between stopping chest compressions and delivering a shock(ie,minimizing the preshock pause) improves the chances of shock success33,34and patient sur-vival.33–35Data downloaded from CPR-sensing and feedback-enabled defibrillators provide valuable information to resus-citation teams,which can improve CPR quality.36These data are driving major changes in the training of in-hospital resuscitation teams and out-of-hospital healthcare providers. In-Hospital CPR RegistriesThe National Registry of CardioPulmonary Resuscitation (NRCPR)37and other large databases are providing new infor-mation about the epidemiology and outcomes of in-hospital resuscitation in adults and children.8,38–44Although observa-tional in nature,registries provide valuable descriptive informa-tion to better characterize cardiac arrest and resuscitation out-comes as well as identify areas for further research. Deemphasis on Devices and Advanced Cardiovascular Life Support Drugs During Cardiac ArrestAt the time of the2010International Consensus Conference there were still insufficient data to demonstrate that any drugs or mechanical CPR devices improve long-term outcome after cardiac arrest.45Clearly further studies,adequately powered to detect clinically important outcome differences with these interventions,are needed.Importance of Post–Cardiac Arrest Care Organized post–cardiac arrest care with an emphasis on multidisciplinary programs that focus on optimizing hemo-dynamic,neurologic,and metabolic function(including ther-apeutic hypothermia)may improve survival to hospital dis-charge among victims who achieve ROSC following cardiac arrest either in-or out-of-hospital.46–48Although it is not yet possible to determine the individual effect of many of these therapies,when bundled as an integrated system of care,their deployment may well improve outcomes.Therapeutic hypothermia is one intervention that has been shown to improve outcome for comatose adult victims of Field et al Part1:Executive Summary S641witnessed out-of-hospital cardiac arrest when the presenting rhythm was VF.49,50Since2005,two nonrandomized studies with concurrent controls as well as other studies using historic controls have indicated the possible benefit of hypo-thermia following in-and out-of-hospital cardiac arrest from all other initial rhythms in adults.46,51–56Hypothermia has also been shown to be effective in improving intact neurologic survival in neonates with hypoxic-ischemic encephalopa-thy,57–61and the results of a prospective multicenter pediatric study of therapeutic hypothermia after cardiac arrest are eagerly awaited.Many studies have attempted to identify comatose post–cardiac arrest patients who have no prospect for meaningful neurologic recovery,and decision rules for prognostication of poor outcome have been proposed.62Therapeutic hypother-mia changes the specificity of prognostication decision rules that were previously established from studies of post–cardiac arrest patients not treated with hypothermia.Recent reports have documented occasional good outcomes in post–cardiac arrest patients who were treated with therapeutic hypother-mia,despite neurologic exam or neuroelectrophysiologic studies that predicted poor outcome.63,64Education and ImplementationThe quality of rescuer education and frequency of retraining are critical factors in improving the effectiveness of resusci-tation.65–83Ideally retraining should not be limited to2-year intervals.More frequent renewal of skills is needed,with a commitment to maintenance of certification similar to that embraced by many healthcare-credentialing organizations. Resuscitation interventions are often performed simulta-neously,and rescuers must be able to work collaboratively to minimize interruptions in chest compressions.Teamwork and leadership skills continue to be important,particularly for advanced cardiovascular life support(ACLS)and pediatric advanced life support(PALS)providers.36,84–89 Community and hospital-based resuscitation programs should systematically monitor cardiac arrests,the level of resuscitation care provided,and outcome.The cycle of measurement,interpretation,feedback,and continuous qual-ity improvement provides fundamental information necessary to optimize resuscitation care and should help to narrow the knowledge and clinical gaps between ideal and actual resus-citation performance.Highlights of the2010GuidelinesThe Change From“A-B-C”to“C-A-B”The newest development in the2010AHA Guidelines for CPR and ECC is a change in the basic life support(BLS)sequence of steps from“A-B-C”(Airway,Breathing,Chest compressions)to “C-A-B”(Chest compressions,Airway,Breathing)for adults and pediatric patients(children and infants,excluding newly borns).Although the experts agreed that it is important to reduce time to first chest compressions,they were aware that a change in something as established as the A-B-C sequence would require re-education of everyone who has ever learned CPR.The 2010AHA Guidelines for CPR and ECC recommend this change for the following reasons:●The vast majority of cardiac arrests occur in adults,and the highest survival rates from cardiac arrest are reported among patients of all ages with witnessed arrest and a rhythm of VF or pulseless ventricular tachycardia(VT).In these patients the critical initial elements of CPR are chest compressions and early defibrillation.90●In the A-B-C sequence chest compressions are often delayed while the responder opens the airway to give mouth-to-mouth breaths or retrieves a barrier device or other ventilation equipment.By changing the sequence to C-A-B,chest compressions will be initiated sooner and ventilation only minimally delayed until completion of the first cycle of chest compressions(30compressions should be accomplished in approximately18seconds).●Fewer than50%of persons in cardiac arrest receive bystander CPR.There are probably many reasons for this,but one impediment may be the A-B-C sequence,which starts with the procedures that rescuers find most difficult:opening the airway and delivering rescue breaths.Starting with chest compressions might ensure that more victims receive CPR and that rescuers who are unable or unwilling to provide ventilations will at least perform chest compressions.●It is reasonable for healthcare providers to tailor the sequence of rescue actions to the most likely cause of arrest.For example,if a lone healthcare provider sees a victim suddenly collapse,the provider may assume that the victim has suffered a sudden VF cardiac arrest;once the provider has verified that the victim is unresponsive and not breathing or is only gasping,the provider should immediately activate the emergency response system,get and use an AED,and give CPR.But for a presumed victim of drowning or other likely asphyxial arrest the priority would be to provide about5cycles(about2minutes)of conventional CPR(including rescue breathing)before ac-tivating the emergency response system.Also,in newly born infants,arrest is more likely to be of a respiratory etiology,and resuscitation should be attempted with the A-B-C sequence unless there is a known cardiac etiology. Ethical IssuesThe ethical issues surrounding resuscitation are complex and vary across settings(in-or out-of-hospital),providers(basic or advanced),and whether to start or how to terminate CPR.Recent work suggests that acknowledgment of a verbal do-not-attempt-resuscitation order(DNAR)in addition to the current stan-dard—a written,signed,and dated DNAR document—may decrease the number of futile resuscitation attempts.91,92This is an important first step in expanding the clinical decision rule pertaining to when to start resuscitation in out-of-hospital car-diac arrest.However,there is insufficient evidence to support this approach without further validation.When only BLS-trained EMS personnel are available, termination of resuscitative efforts should be guided by a validated termination of resuscitation rule that reduces the transport rate of attempted resuscitations without compro-mising the care of potentially viable patients.93Advanced life support(ALS)EMS providers may use the same termination of resuscitation rule94–99or a derived nonvali-dated rule specific to ALS providers that when applied willS642Circulation November2,2010decrease the number of futile transports to the emergency department(ED).95,97–100Certain characteristics of a neonatal in-hospital cardiac arrest are associated with death,and these may be helpful in guiding physicians in the decision to start and stop a neonatal resuscitation attempt.101–104There is more variability in ter-minating resuscitation rates across systems and physicians when clinical decision rules are not followed,suggesting that these validated and generalized rules may promote uniformity in access to resuscitation attempts and full protocol care.105 Offering select family members the opportunity to be present during the resuscitation and designating staff within the team to respond to their questions and offer comfort may enhance the emotional support provided to the family during cardiac arrest and after termination of a resuscitation attempt. Identifying patients during the post–cardiac arrest period who do not have the potential for meaningful neurologic recovery is a major clinical challenge that requires further research.Caution is advised when considering limiting care or withdrawing life-sustaining therapy.Characteristics or test results that are predictive of poor outcome in post–cardiac arrest patients not treated with therapeutic hypothermia may not be as predictive of poor outcome after administration of therapeutic hypothermia. Because of the growing need for transplant tissue and organs,all provider teams who treat postarrest patients should also plan and implement a system of tissue and organ donation that is timely, effective,and supportive of family members for the subset of patients in whom brain death is confirmed or for organ donation after cardiac arrest.Resuscitation research is challenging.It must be scientifically rigorous while confronting ethical,regulatory,and public rela-tions concerns that arise from the need to conduct such research with exception to informed consent.Regulatory requirements, community notification,and consultation requirements often impose expensive and time-consuming demands that may not only delay important research but also render it cost-prohibitive, with little significant evidence that these measures effectively address the concerns about research.106–109Basic Life SupportBLS is the foundation for saving lives following cardiac arrest.Fundamental aspects of adult BLS include immediate recognition of sudden cardiac arrest and activation of the emergency response system,early performance of high-quality CPR,and rapid defibrillation when appropriate.The 2010AHA Guidelines for CPR and ECC contain several important changes but also have areas of continued emphasis based on evidence presented in prior years.Key Changes in the2010AHA Guidelines for CPRand ECC●The BLS algorithm has been simplified,and“Look,Listen and Feel”has been removed from the algorithm.Performance of these steps is inconsistent and time consuming.For this reason the2010AHA Guidelines for CPR and ECC stress immediate activation of the emergency response system and starting chest compressions for any unresponsive adult victim with no breathing or no normal breathing(ie,only gasps).●Encourage Hands-Only(compression only)CPR for the untrained lay rescuer.Hands-Only CPR is easier to perform by those with no training and can be more readily guided by dispatchers over the telephone.●Initiate chest compressions before giving rescue breaths(C-A-B rather than A-B-C).Chest compressions can be started immediately,whereas positioning the head,attaining a seal for mouth-to-mouth rescue breathing,or obtaining or assembling a bag-mask device for rescue breathing all take time.Begin-ning CPR with30compressions rather than2ventilations leads to a shorter delay to first compression.●There is an increased focus on methods to ensure that high-quality CPR is performed.Adequate chest compres-sions require that compressions be provided at the appro-priate depth and rate,allowing complete recoil of the chest after each compression and an emphasis on minimizing any pauses in compressions and avoiding excessive ventilation. Training should focus on ensuring that chest compressions are performed correctly.The recommended depth of com-pression for adult victims has increased from a depth of11⁄2 to2inches to a depth of at least2inches.●Many tasks performed by healthcare providers during resus-citation attempts,such as chest compressions,airway man-agement,rescue breathing,rhythm detection,shock delivery, and drug administration(if appropriate),can be performed concurrently by an integrated team of highly trained rescuers in appropriate settings.Some resuscitations start with a lone rescuer who calls for help,resulting in the arrival of additional team members.Healthcare provider training should focus on building the team as each member arrives or quickly delegat-ing roles if multiple rescuers are present.As additional personnel arrive,responsibilities for tasks that would ordi-narily be performed sequentially by fewer rescuers may now be delegated to a team of providers who should perform them simultaneously.Key Points of Continued Emphasis for the2010AHA Guidelines for CPR and ECC●Early recognition of sudden cardiac arrest in adults is based on assessing responsiveness and the absence of normal breathing.Victims of cardiac arrest may initially have gasping respirations or even appear to be having a seizure. These atypical presentations may confuse a rescuer,caus-ing a delay in calling for help or beginning CPR.Training should focus on alerting potential rescuers to the unusual presentations of sudden cardiac arrest.●Minimize interruptions in effective chest compressions until ROSC or termination of resuscitative efforts.Any unnecessary interruptions in chest compressions(including longer than necessary pauses for rescue breathing)de-creases CPR effectiveness.●Minimize the importance of pulse checks by healthcare providers.Detection of a pulse can be difficult,and even highly trained healthcare providers often incorrectly assess the presence or absence of a pulse when blood pressure is abnormally low or absent.Healthcare providers should take no more than10seconds to determine if a pulse is present. Chest compressions delivered to patients subsequently found not to be in cardiac arrest rarely lead to significant Field et al Part1:Executive Summary S643injury.110The lay rescuer should activate the emergency response system if he or she finds an unresponsive adult. The lay rescuer should not attempt to check for a pulse and should assume that cardiac arrest is present if an adult suddenly collapses,is unresponsive,and is not breathing or not breathing normally(ie,only gasping).CPR Techniques and DevicesAlternatives to conventional manual CPR have been devel-oped in an effort to enhance perfusion during resuscitation from cardiac arrest and to improve pared with conventional CPR,these techniques and devices typically require more personnel,training,and equipment,or apply to a specific setting.Some alternative CPR techniques and devices may improve hemodynamics or short-term survival when used by well-trained providers in selected patients. Several devices have been the focus of recent clinical trials. Use of the impedance threshold device(ITD)improved ROSC and short-term survival when used in adults with out-of-hospital cardiac arrest,but there was no significant improvement in either survival to hospital discharge or neurologically-intact survival to discharge.111One multicenter,prospective,randomized con-trolled trial112,112a comparing load-distributing band CPR(Auto-pulse)with manual CPR for out-of-hospital cardiac arrest demonstrated no improvement in4-hour survival and worse neurologic outcome when the device was used.More research is needed to determine if site-specific factors113or experience with deployment of the device114influence effectiveness of the load-distributing band CPR device.Case series employing me-chanical piston devices have reported variable degrees of success.115–119To prevent delays and maximize efficiency,initial training, ongoing monitoring,and retraining programs should be offered on a frequent basis to providers using CPR devices. To date,no adjunct has consistently been shown to be superior to standard conventional(manual)CPR for out-of-hospital BLS,and no device other than a defibrillator has consistently improved long-term survival from out-of-hospital cardiac arrest.Electrical TherapiesThe2010AHA Guidelines for CPR and ECC have been updated to reflect new data on the use of pacing in bradycar-dia,and on cardioversion and defibrillation for tachycardic rhythm disturbances.Integration of AEDs into a system of care is critical in the Chain of Survival in public places outside of hospitals.To give the victim the best chance of survival,3actions must occur within the first moments of a cardiac arrest120:activation of the EMS system,121provision of CPR,and operation of a defibrillator.122One area of continued interest is whether delivering a longer period of CPR before defibrillation improves out-comes in cardiac arrest.In early studies,survival was im-proved when1.5to3minutes of CPR preceded defibrillation for patients with cardiac arrest ofϾ4to5minutes duration prior to EMS arrival.123,124However,in2more recent randomized controlled trials,CPR performed before defibril-lation did not improve outcome.125,126IfՆ2rescuers are present CPR should be performed while a defibrillator is being obtained and readied for use.The1-shock protocol for VF has not been changed. Evidence has accumulated that even short interruptions in CPR are harmful.Thus,rescuers should minimize the interval between stopping compressions and delivering shocks and should resume CPR immediately after shock delivery. Over the last decade biphasic waveforms have been shown to be more effective than monophasic waveforms in cardio-version and defibrillation.127–135However,there are no clin-ical data comparing one specific biphasic waveform with another.Whether escalating or fixed subsequent doses of energy are superior has not been tested with different wave-forms.However,if higher energy levels are available in the device at hand,they may be considered if initial shocks are unsuccessful in terminating the arrhythmia.In the last5to10years a number of randomized trials have compared biphasic with monophasic cardioversion in atrial fibrillation.The efficacy of shock energies for cardioversion of atrial fibrillation is waveform-specific and can vary from120to 200J depending on the defibrillator manufacturer.Thus,the recommended initial biphasic energy dose for cardioversion of atrial fibrillation is120to200J using the manufacturer’s recommended setting.136–140If the initial shock fails,providers should increase the dose in a stepwise fashion.Cardiover-sion of adult atrial flutter and other supraventricular tachycardias generally requires less energy;an initial energy of50J to100J is often sufficient.140If the initial shock fails,providers should increase the dose in a stepwise fashion.141Adult cardioversion of atrial fibrilla-tion with monophasic waveforms should begin at200J and increase in a stepwise fashion if not successful. Transcutaneous pacing has also been the focus of several recent trials.Pacing is not generally recommended for pa-tients in asystolic cardiac arrest.Three randomized controlled trials142–144indicate no improvement in rate of admission to hospital or survival to hospital discharge when paramedics or physicians attempted pacing in patients with cardiac arrest due to asystole in the prehospital or hospital(ED)setting. However,it is reasonable for healthcare providers to be prepared to initiate pacing in patients with bradyarrhythmias in the event the heart rate does not respond to atropine or other chronotropic(rate-accelerating)drugs.145,146 Advanced Cardiovascular Life SupportACLS affects multiple links in the Chain of Survival,including interventions to prevent cardiac arrest,treat cardiac arrest,and improve outcomes of patients who achieve ROSC after cardiac arrest.The2010AHA Guidelines for CPR and ECC continue to emphasize that the foundation of successful ACLS is good BLS, beginning with prompt high-quality CPR with minimal interrup-tions,and for VF/pulseless VT,attempted defibrillation within minutes of collapse.The new fifth link in the Chain of Survival and Part9:“Post–Cardiac Arrest Care”(expanded from a subsection of the ACLS part of the2005AHA Guidelines for CPR and ECC)emphasize the importance of comprehensive multidisciplinary care that begins with recognition of cardiac arrest and continues after ROSC through hospital discharge and beyond.Key ACLS assessments and interventions provide anS644Circulation November2,2010。