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approximately , one - third of patients with symptomatic vte manifests pe , whereas two - thirds manifest dvt alone . both dvt and pe can be clinically silent ( asymptomatic ) and hence not suspected . if undiagnosed , asymptomatic vte can lead to chronic venous disease or recurrent vte and long - term debilitating sequelae such as postthrombotic syndrome and chronic thromboembolic pulmonary hypertension . vte is not only disabling but also prolongs hospital stay and increases the cost of treatment . along with myocardial infarction and arrhythmia ( due to electrolyte imbalance ) , pe is one of the commonest causes of sudden unexplained deaths in hospitalized patients . it is estimated that 20 million cases of lower extremity dvt occur in the usa alone . the prevailing notion that the incidence of vte in asians is less than that in the western population has been disproved by recent studies . the incidence of postoperative dvt in indian patients undergoing major lower limb surgery is as high ( 43.2% and 60% patients in the groups with and without prophylaxis , respectively ) as seen in the western world . given the growing burden of vte in india and lack of substantial indian data on characteristics of vte patients , use of diagnostics tools , prophylaxis , treatment options , and clinical outcomes in vte , there was a need to systematically collect such data . data on patient characteristics , clinical outcomes , predictors of mortality in acute dvt , management strategies and temporal trends in vte . the intent was to collect and provide data that would reflect actual day - to - day clinical practice , rather than results of highly controlled clinical trials with restricted study populations and imposed experimental intervention . consecutive medical records of inpatients and outpatients between january 2006 and december 2010 , meeting eligibility criteria ( confirmed diagnosis of acute or acute - on - chronic dvt by doppler ultrasound scan and/or pe by chest computed tomography scan , pulmonary angiography or v / q scan ) were identified and collected from the general medical records and/or radiology departments at each of the three participating hospitals . hospital data were used to obtain the total number of patients who were annually registered at the hospital from 2006 to 2010 . data were processed and analyzed using sas ( version 9.1 , statistical analysis system ) . for the purpose of analysis , acute - on - chronic descriptive statistics were used to present patient characteristics , management strategies , and clinical outcomes of patients . annual incidence rates ( 95% ci ) of vte per 100,000 hospital registrations over a period of 5 years were reported for each site . fisher 's exact test was used to determine differences in the incidence of acute dvt ( pe ) over the years 20062010 . armitage trend test was used to examine the direction ( positive or negative ) of the trend . as primary analyses the remaining 41% ( 393/949 ) medical records were not included because they did not satisfy the inclusion criteria . data from seven patients were excluded as there was no radiologically confirmed diagnosis of pe . a total of 64% ( 352/549 ) patients had acute dvt without pe , 23% ( 124/549 ) had acute dvt with pe , and 13% ( 73/549 ) had pe . eighty - seven percent ( 476/549 ) of patients had acute dvt ( pe ) , and 36% ( 197/549 ) had pe ( acute dvt ) [ figure 1 ] . overall distribution of venous thromboembolism patients ( n = 549 ) a total of 21% ( 115/549 ) of patients visited the hospitals directly without being referred by a physician . venous thromboembolism patients referred from different medical specialties ( n=434 ) the demographic characteristics of the vte patients are mentioned in table 2 . demographic characteristics of venous thromboembolism patients ( n=549 ) a total of 182 patients had evidence of one risk factor , 126 had evidence of two risk factors , 70 had evidence of three risk factors and 31 had four or more risk factors recorded . patients undergoing orthopedic surgery constituted 22% ( 33/152 ) of all surgical patients [ table 3 ] . risk factors for venous thromboembolism based on a review of the available records , 157 patients had a single co - morbidity , 81 had two co - morbidities , 23 had three co - morbidities , and 16 had four or more co - morbidities . ( myocardial infarction , heart failure , chronic obstructive pulmonary disease , ventilator dependency , sepsis , or pneumonia ) [ table 4 ] . co - morbidities in venous thromboembolism patients of the 476 patients with dvt , 2% ( 9 ) had upper extremity dvt , 97% ( 462 ) had lower extremity dvt and the site of dvt was not known in 5 patients . a total of 31% ( 143/462 ) patients had dvt in the right limb , 54% ( 249/462 ) in the left limb and 9% ( 41/462 ) in both limbs ( site not known in 29 patients ) . of the 462 patients with lower extremity dvt , 61% had proximal dvt , 13% had distal dvt , and 7% had proximal and distal dvt . a total of 39% ( 215/549 ) patients were diagnosed with vte during their hospital stay , 54% ( 296/549 ) were admitted to hospital with a diagnosis of vte , and 7% ( 38/549 ) were diagnosed and continued to be managed in the outpatient department [ figure 2 ] . place of detection of venous thromboembolism ( n = 549 ) duration of hospitalization after diagnosis of venous thromboembolism a smaller proportion of patients ( 15% ; 81/549 ) was diagnosed with vte during the postoperative period . figure 3 shows the proportion of patients with vte at different time points during the postoperative period . of those diagnosed beyond 6 weeks , 21% ( 3/14 ) had orthopedic surgery ( hip fracture surgery ) . diagnosis of venous thromboembolism during the postoperative period ( n = 81 ) the most common ( 73% ) symptom was swelling of the limb among patients with vte [ table 6 ] . symptoms in venous thromboembolism patients in merely 4% of all the patients , dvt was also confirmed by venography . pe was confirmed by pulmonary angiography in 27% of all the patients [ table 7 ] . . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . five percent ( 25/515 ) of patients were recommended lmwh alone , and 76% ( 393/515 ) were recommended either warfarin or acenocoumarol alone for long - term anticoagulation . the median duration of initial anticoagulation was 5 days while that of long - term anticoagulation was 180 days ( 6 months ) . anticoagulants were needed to be stopped because of bleeding in only 2% ( 9/515 ) patients . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . however , a formal site - wise statistical analysis could not be performed to analyse trends in the incidence rates in acute dvt ( pe ) and pe alone as there were zero observations in some instances . incidence of acute deep vein thrombosis ( with or without pulmonary embolism ) over a 5 years period ( 20062010 ) at three sites demographic characteristics of venous thromboembolism patients ( n=549 ) a total of 182 patients had evidence of one risk factor , 126 had evidence of two risk factors , 70 had evidence of three risk factors and 31 had four or more risk factors recorded . patients undergoing orthopedic surgery constituted 22% ( 33/152 ) of all surgical patients [ table 3 ] . risk factors for venous thromboembolism based on a review of the available records , 157 patients had a single co - morbidity , 81 had two co - morbidities , 23 had three co - morbidities , and 16 had four or more co - morbidities . ( myocardial infarction , heart failure , chronic obstructive pulmonary disease , ventilator dependency , sepsis , or pneumonia ) [ table 4 ] . 2% ( 9 ) had upper extremity dvt , 97% ( 462 ) had lower extremity dvt and the site of dvt was not known in 5 patients . a total of 31% ( 143/462 ) patients had dvt in the right limb , 54% ( 249/462 ) in the left limb and 9% ( 41/462 ) in both limbs ( site not known in 29 patients ) . of the 462 patients with lower extremity dvt , 61% had proximal dvt , 13% had distal dvt , and 7% had proximal and distal dvt . a total of 39% ( 215/549 ) patients were diagnosed with vte during their hospital stay , 54% ( 296/549 ) were admitted to hospital with a diagnosis of vte , and 7% ( 38/549 ) were diagnosed and continued to be managed in the outpatient department [ figure 2 ] . place of detection of venous thromboembolism ( n = 549 ) duration of hospitalization after diagnosis of venous thromboembolism a smaller proportion of patients ( 15% ; 81/549 ) was diagnosed with vte during the postoperative period . figure 3 shows the proportion of patients with vte at different time points during the postoperative period . of those diagnosed beyond 6 weeks diagnosis of venous thromboembolism during the postoperative period ( n = 81 ) the most common ( 73% ) symptom was swelling of the limb among patients with vte [ table 6 ] . a total of 182 patients had evidence of one risk factor , 126 had evidence of two risk factors , 70 had evidence of three risk factors and 31 had four or more risk factors recorded . patients undergoing orthopedic surgery constituted 22% ( 33/152 ) of all surgical patients [ table 3 ] . based on a review of the available records , 157 patients had a single co - morbidity , 81 had two co - morbidities , 23 had three co - morbidities , and 16 had four or more co - morbidities . ( myocardial infarction , heart failure , chronic obstructive pulmonary disease , ventilator dependency , sepsis , or pneumonia ) [ table 4 ] . of the 476 patients with dvt , 2% ( 9 ) had upper extremity dvt , 97% ( 462 ) had lower extremity dvt and the site of dvt was not known in 5 patients . a total of 31% ( 143/462 ) patients had dvt in the right limb , 54% ( 249/462 ) in the left limb and 9% ( 41/462 ) in both limbs ( site not known in 29 patients ) . of the 462 patients with lower extremity dvt , 61% had proximal dvt , 13% had distal dvt , and 7% had proximal and distal dvt . a total of 39% ( 215/549 ) patients were diagnosed with vte during their hospital stay , 54% ( 296/549 ) were admitted to hospital with a diagnosis of vte , and 7% ( 38/549 ) were diagnosed and continued to be managed in the outpatient department [ figure 2 ] . place of detection of venous thromboembolism ( n = 549 ) duration of hospitalization after diagnosis of venous thromboembolism a smaller proportion of patients ( 15% ; 81/549 ) was diagnosed with vte during the postoperative period . figure 3 shows the proportion of patients with vte at different time points during the postoperative period . of those diagnosed beyond 6 weeks diagnosis of venous thromboembolism during the postoperative period ( n = 81 ) the most common ( 73% ) symptom was swelling of the limb among patients with vte [ table 6 ] pe was confirmed by pulmonary angiography in 27% of all the patients [ table 7 ] . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . five percent ( 25/515 ) of patients were recommended lmwh alone , and 76% ( 393/515 ) were recommended either warfarin or acenocoumarol alone for long - term anticoagulation . the median duration of initial anticoagulation was 5 days while that of long - term anticoagulation was 180 days ( 6 months ) . anticoagulants were needed to be stopped because of bleeding in only 2% ( 9/515 ) patients . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . however , a formal site - wise statistical analysis could not be performed to analyse trends in the incidence rates in acute dvt ( pe ) and pe alone as there were zero observations in some instances . incidence of acute deep vein thrombosis ( with or without pulmonary embolism ) over a 5 years period ( 20062010 ) at three sites pe was confirmed by pulmonary angiography in 27% of all the patients [ table 7 ] . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . five percent ( 25/515 ) of patients were recommended lmwh alone , and 76% ( 393/515 ) were recommended either warfarin or acenocoumarol alone for long - term anticoagulation . the median duration of initial anticoagulation was 5 days while that of long - term anticoagulation was 180 days ( 6 months ) . anticoagulants were needed to be stopped because of bleeding in only 2% ( 9/515 ) patients . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . however , a formal site - wise statistical analysis could not be performed to analyse trends in the incidence rates in acute dvt ( pe ) and pe alone as there were zero observations in some instances . incidence of acute deep vein thrombosis ( with or without pulmonary embolism ) over a 5 years period ( 20062010 ) at three sites to our knowledge , this is the first multicenter , retrospective registry in india involving patients with vte that reflect real - world clinical practice . in contrast with the western data in which vte is predominantly a disease of older age , 44% patients in our study were between 40 and 59 years of age while 34% were below 40 years , particularly those with pe . in a study from north india , men constituted 70% of our registry , more than those reported from vellore registry ( 48% ) , but similar to those reported in the endorse ( epidemiologic international day for the evaluation of patients at risk for vte in the acute hospital care setting ) study ( 69% ) . one of the reasons for this could be significantly high levels of homocysteine ( thrombophilia marker ) in males as compared to females as reported in an indian study . fewer indian women use oral contraceptives and postmenopausal hormone replacement therapy , which are known to be risk factors for thrombosis . this is supported by the fact that only 1% of women in this registry reported the use of oral contraceptives , and none reported use of hormonal replacement therapy . a total of 28% of the overall referrals were from cardiologists . the majority ( 82% ) of the referrals were from medical rather than surgical ( 15% ) specialties as against a referral rate of 93% from surgeons at vellore . our finding complements that from the endorse study in which 55% of the medical patients at risk of vte had cardiovascular disease . majority ( 53% ) of patients in our study had co - morbid cardiovascular disease including diabetes mellitus ; it is possible that these patients visited a cardiologist for their cardiovascular ailment ( s ) and were then referred by the cardiologist to vascular disease specialist ( investigator ) . most ( 89% ) of these patients had swelling of the ( lower ) limb . it is possible that these patients may not have felt the need to visit a specialist for a symptom like swelling of limb , instead visited their family physician . it is very encouraging to know that family physicians suspected dvt in these situations and referred the patient to a specialist . patients with a history of vte are about 8 times more likely to develop a new episode during a subsequent high - risk period compared with patients without a history of dvt or pe . prior history of dvt was the most ( 34% ) common risk factor in patients who had only dvt , whereas past history of pe , trauma , and immobilization for more than 3 days were the most common risk factors in patients who had only pe . our results ( major lower limb surgery as a risk factor in 3% patients ) appear to be consistent with those reported in the endorse study , which reported dvt in 4.4% patients undergoing major lower limb surgery . other studies from india have reported a dvt incidence rate ranging from 8% to 20% in major lower limb surgery . however , in our study , only 7% of patients had malignancy as a predisposing factor . among the malignancies , genitourinary cancer had the highest incidence ( 45% ) . hypertension ( 25% ) was the most common co - morbidity followed by diabetes mellitus ( 19% ) in this patient population . in addition , obesity ( 11% ) was a common risk factor in dvt complicated by pe . our findings support an asian ( korean ) study that demonstrated prevalence of the metabolic syndrome in 48% patients with vte . co - morbid neurological disease ( other than stroke ) and ventilator dependency were also commonly found in patients with dvt ( 10% ) and pe ( 11% ) respectively . both these conditions immobilize patients for prolonged periods of time , predisposing them to vte . venography and pulmonary angiography are the gold standard for diagnosis of dvt and pe respectively . in our study , venography was used in just 4% patients and pulmonary angiography in less than one - third of the patients . perhaps the relatively high cost of these tests and limited availability of such procedures may be the limiting factors . overall , most ( 93% ) patients were managed as inpatients ( 39% diagnosed with vte during hospital stay and 54% admitted to hospital with a diagnosis of vte ) . a mean duration of hospitalization of 79 days after diagnosis of vte is supported by published data . in selected low - risk patients , outpatient treatment of dvt and pe may be considered . this approach was observed in a small proportion ( 7% ) of patients who were managed on an outpatient basis , nearly all ( 97% ) of whom had only dvt . the reported prevalence of postsurgical vte in our study ( 15% ) was half of that ( 30% ) reported in vellore registry . this could be explained by higher referral rate from surgeons at vellore compared to that of our sites . most ( 40% ; 32/81 ) dvt cases were diagnosed between 2 and 6 postoperative weeks , but pe in most cases ( 70% ; 7/10 ) was diagnosed during the first postoperative week . we notice that acute dvt complicated by pe was less ( 6% ; 7/124 ) frequently diagnosed during the postoperative period as against 18% ( 64/352 ) and 14% ( 10/73 ) of acute dvt alone and pe alone , respectively . the use and duration of anticoagulants in our registry appears to be consistent with the american college of chest physicians treatment guidelines , which recommend at least 5 days of initial anticoagulation with parenteral anticoagulation ( lmwh , fondaparinux , intravenous ufh , or subcutaneous ufh ) and at least 3 months of long - term anticoagulation treatment with vitamin k antagonist . bleeding is the most serious complication of anticoagulation treatment and is a major concern for clinicians particularly as the patient 's age advances . in this registry , anticoagulant treatment was needed to be stopped because of bleeding in only 2% of the study population . the prospective reite registry has reported a rate of 3% for major / fatal bleeds . thus , the fear of bleeding complications , which decreases the use of anticoagulant treatment , appears to be minimal . dvt complicated by pe ( 60% ) and pe alone ( 75% ) were more frequently shifted to intensive care unit than those who had dvt alone ( 25% ) . similar to published data in which hospital readmission rate for vte was 5% for primary and 14% for secondary diagnosis , we report a hospital readmission rate of 6% ; however we do not know the cause for readmission . the death rate was 7% among those diagnosed with vte during hospital stay as against a rate of 1% among those who were hospitalized with a diagnosis of vte . over 90% of patients treated on an outpatient basis obtained symptomatic relief with treatment . in our study , the hospital discharge rate ( 97% ) was more than triple and death rate was a quarter of that reported by pandey et al . ( hospital discharge rate 31% and death rate 16% ) at a university hospital in delhi . our data show a significant increase in acute dvt ( pe ) from 2006 to 2010 . this can be explained by the increased awareness of vte in india as well as the advent of better diagnostic modalities , such as duplex ultrasonography becoming more readily available and accepted . although there was no significant change in the number of pe cases from 2006 to 2010 , the burden of pe is almost double ( 13% of all vte ) of 7% , rate reported at christian medical college , vellore during a 10-year period from 1996 to 2005 . our finding is consistent with a study from north india that reported a 16% incidence of pe in adult medical autopsies . this study has the expected limitations of any retrospective review including the availability of complete records for all patients , although a robust review of the data on medical charts was conducted . controlling for bias and confounders is difficult as there is no randomization and no blinding . follow - up data of patients after hospital discharge were not available . in cases of death , further , the clinic charts reviewed in this study included a mix of those from vascular surgery and hematology departments , limiting the generalizability of the study results . despite these limitations , this study provides large amount of useful information in a short span of time on patient characteristics , clinical outcomes , management strategies , and temporal trends in vte , based on real world data that reflect actual day - to - day clinical practice over a period of 5 years across three sites in india . we believe that this information will serve as a guide in the optimal implementation of vte prophylaxis and treatment , to improve patient outcomes and to decrease the occurrence of vte in india . real world data reflecting actual day - to - day clinical practice in vte over a period of 5 years across three sites in india showed that vte is not uncommon in indian patients and that acute dvt was responsible for the substantial burden of vte . we believe that this information will serve as a guide in the optimal implementation of vte prophylaxis and treatment , to improve patient outcomes and to decrease the occurrence of vte in india . liesel c. dsilva is and dr . sadhna j. joglekar was full - time employee of glaxosmithkline pharmaceuticals limited .

background and aim : there is lack of substantial indian data on venous thromboembolism ( vte ) . the aim of this study was to provide real - world information on patient characteristics , management strategies , clinical outcomes , and temporal trends in vte.subjects and methods : multicentre retrospective registry involving 549 medical records of patients with confirmed diagnosis of vte ( deep vein thrombosis [ dvt ] confirmed by doppler ultrasonography ; pulmonary embolism [ pe ] by computed tomography , pulmonary angiography and/or v / q scan ) from 2006 to 2010 at three indian tertiary care hospitals.results:acute dvt without pe , acute dvt with pe , and pe alone were reported in 64% ( 352/549 ) , 23% ( 124/549 ) , and 13% ( 73/549 ) patients , respectively . mean age was 47 ( 16 ) years , and 70% were males . h / o dvt ( 34% ) , surgery including orthopedic surgery ( 28% ) , trauma ( 16% ) , and immobilization > 3 days ( 14% ) were the most common risk factors for vte . hypertension ( 25% ) , diabetes ( 19% ) , and neurological disease ( other than stroke ) ( 8% ) were the most common co - morbidities . most ( 94% ) were treated with heparin alone ( 82% ) or fondaparinux ( 2% ) for initial anticoagulation ; low molecular weight heparin alone ( 5% ) or warfarin / acenocoumarol ( 76% ) for long - term anticoagulation . anticoagulant treatment was stopped because of bleeding in 2% ( 9/515 ) patients . mortality was 7% among patients diagnosed with vte during hospital stay versus 1% in those hospitalized with diagnosed vte . the annual incidence of dvt ( pe ) increased from 2006 to 2010.conclusion:acute dvt alone was responsible for the substantial burden of vte in indian patients . bleeding was not the limiting factor for anticoagulant treatment in most patients .

Introduction Subjects and Methods Results Demographics and characteristics of venous thromboembolism patients Risk factors for venous thromboembolism patients Co-morbidities in venous thromboembolism patients Clinical presentation of venous thromboembolism Management strategies for venous thromboembolism patients Diagnostic tools for venous thromboembolism Anticoagulant treatment in venous thromboembolism Annual incidence of acute deep venous thrombosis including the trend over a period of 5 years Discussion Conclusion None Financial support and sponsorship Conflicts of interest

given the growing burden of vte in india and lack of substantial indian data on characteristics of vte patients , use of diagnostics tools , prophylaxis , treatment options , and clinical outcomes in vte , there was a need to systematically collect such data . data on patient characteristics , clinical outcomes , predictors of mortality in acute dvt , management strategies and temporal trends in vte . consecutive medical records of inpatients and outpatients between january 2006 and december 2010 , meeting eligibility criteria ( confirmed diagnosis of acute or acute - on - chronic dvt by doppler ultrasound scan and/or pe by chest computed tomography scan , pulmonary angiography or v / q scan ) were identified and collected from the general medical records and/or radiology departments at each of the three participating hospitals . for the purpose of analysis , acute - on - chronic descriptive statistics were used to present patient characteristics , management strategies , and clinical outcomes of patients . a total of 64% ( 352/549 ) patients had acute dvt without pe , 23% ( 124/549 ) had acute dvt with pe , and 13% ( 73/549 ) had pe . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . of those diagnosed beyond 6 weeks diagnosis of venous thromboembolism during the postoperative period ( n = 81 ) the most common ( 73% ) symptom was swelling of the limb among patients with vte [ table 6 ] pe was confirmed by pulmonary angiography in 27% of all the patients [ table 7 ] . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . incidence of acute deep vein thrombosis ( with or without pulmonary embolism ) over a 5 years period ( 20062010 ) at three sites to our knowledge , this is the first multicenter , retrospective registry in india involving patients with vte that reflect real - world clinical practice . prior history of dvt was the most ( 34% ) common risk factor in patients who had only dvt , whereas past history of pe , trauma , and immobilization for more than 3 days were the most common risk factors in patients who had only pe . despite these limitations , this study provides large amount of useful information in a short span of time on patient characteristics , clinical outcomes , management strategies , and temporal trends in vte , based on real world data that reflect actual day - to - day clinical practice over a period of 5 years across three sites in india . real world data reflecting actual day - to - day clinical practice in vte over a period of 5 years across three sites in india showed that vte is not uncommon in indian patients and that acute dvt was responsible for the substantial burden of vte .

approximately , one - third of patients with symptomatic vte manifests pe , whereas two - thirds manifest dvt alone . both dvt and pe can be clinically silent ( asymptomatic ) and hence not suspected . if undiagnosed , asymptomatic vte can lead to chronic venous disease or recurrent vte and long - term debilitating sequelae such as postthrombotic syndrome and chronic thromboembolic pulmonary hypertension . vte is not only disabling but also prolongs hospital stay and increases the cost of treatment . along with myocardial infarction and arrhythmia ( due to electrolyte imbalance ) , pe is one of the commonest causes of sudden unexplained deaths in hospitalized patients . the prevailing notion that the incidence of vte in asians is less than that in the western population has been disproved by recent studies . the incidence of postoperative dvt in indian patients undergoing major lower limb surgery is as high ( 43.2% and 60% patients in the groups with and without prophylaxis , respectively ) as seen in the western world . given the growing burden of vte in india and lack of substantial indian data on characteristics of vte patients , use of diagnostics tools , prophylaxis , treatment options , and clinical outcomes in vte , there was a need to systematically collect such data . consecutive medical records of inpatients and outpatients between january 2006 and december 2010 , meeting eligibility criteria ( confirmed diagnosis of acute or acute - on - chronic dvt by doppler ultrasound scan and/or pe by chest computed tomography scan , pulmonary angiography or v / q scan ) were identified and collected from the general medical records and/or radiology departments at each of the three participating hospitals . hospital data were used to obtain the total number of patients who were annually registered at the hospital from 2006 to 2010 . annual incidence rates ( 95% ci ) of vte per 100,000 hospital registrations over a period of 5 years were reported for each site . fisher 's exact test was used to determine differences in the incidence of acute dvt ( pe ) over the years 20062010 . armitage trend test was used to examine the direction ( positive or negative ) of the trend . demographic characteristics of venous thromboembolism patients ( n=549 ) a total of 182 patients had evidence of one risk factor , 126 had evidence of two risk factors , 70 had evidence of three risk factors and 31 had four or more risk factors recorded . patients undergoing orthopedic surgery constituted 22% ( 33/152 ) of all surgical patients [ table 3 ] . risk factors for venous thromboembolism based on a review of the available records , 157 patients had a single co - morbidity , 81 had two co - morbidities , 23 had three co - morbidities , and 16 had four or more co - morbidities . ( myocardial infarction , heart failure , chronic obstructive pulmonary disease , ventilator dependency , sepsis , or pneumonia ) [ table 4 ] . co - morbidities in venous thromboembolism patients of the 476 patients with dvt , 2% ( 9 ) had upper extremity dvt , 97% ( 462 ) had lower extremity dvt and the site of dvt was not known in 5 patients . a total of 31% ( 143/462 ) patients had dvt in the right limb , 54% ( 249/462 ) in the left limb and 9% ( 41/462 ) in both limbs ( site not known in 29 patients ) . of the 462 patients with lower extremity dvt , 61% had proximal dvt , 13% had distal dvt , and 7% had proximal and distal dvt . a total of 39% ( 215/549 ) patients were diagnosed with vte during their hospital stay , 54% ( 296/549 ) were admitted to hospital with a diagnosis of vte , and 7% ( 38/549 ) were diagnosed and continued to be managed in the outpatient department [ figure 2 ] . place of detection of venous thromboembolism ( n = 549 ) duration of hospitalization after diagnosis of venous thromboembolism a smaller proportion of patients ( 15% ; 81/549 ) was diagnosed with vte during the postoperative period . figure 3 shows the proportion of patients with vte at different time points during the postoperative period . of those diagnosed beyond 6 weeks , 21% ( 3/14 ) had orthopedic surgery ( hip fracture surgery ) . diagnosis of venous thromboembolism during the postoperative period ( n = 81 ) the most common ( 73% ) symptom was swelling of the limb among patients with vte [ table 6 ] . symptoms in venous thromboembolism patients in merely 4% of all the patients , dvt was also confirmed by venography . pe was confirmed by pulmonary angiography in 27% of all the patients [ table 7 ] . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . the median duration of initial anticoagulation was 5 days while that of long - term anticoagulation was 180 days ( 6 months ) . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . however , a formal site - wise statistical analysis could not be performed to analyse trends in the incidence rates in acute dvt ( pe ) and pe alone as there were zero observations in some instances . incidence of acute deep vein thrombosis ( with or without pulmonary embolism ) over a 5 years period ( 20062010 ) at three sites demographic characteristics of venous thromboembolism patients ( n=549 ) a total of 182 patients had evidence of one risk factor , 126 had evidence of two risk factors , 70 had evidence of three risk factors and 31 had four or more risk factors recorded . patients undergoing orthopedic surgery constituted 22% ( 33/152 ) of all surgical patients [ table 3 ] . risk factors for venous thromboembolism based on a review of the available records , 157 patients had a single co - morbidity , 81 had two co - morbidities , 23 had three co - morbidities , and 16 had four or more co - morbidities . ( myocardial infarction , heart failure , chronic obstructive pulmonary disease , ventilator dependency , sepsis , or pneumonia ) [ table 4 ] . 2% ( 9 ) had upper extremity dvt , 97% ( 462 ) had lower extremity dvt and the site of dvt was not known in 5 patients . a total of 31% ( 143/462 ) patients had dvt in the right limb , 54% ( 249/462 ) in the left limb and 9% ( 41/462 ) in both limbs ( site not known in 29 patients ) . of the 462 patients with lower extremity dvt , 61% had proximal dvt , 13% had distal dvt , and 7% had proximal and distal dvt . a total of 39% ( 215/549 ) patients were diagnosed with vte during their hospital stay , 54% ( 296/549 ) were admitted to hospital with a diagnosis of vte , and 7% ( 38/549 ) were diagnosed and continued to be managed in the outpatient department [ figure 2 ] . place of detection of venous thromboembolism ( n = 549 ) duration of hospitalization after diagnosis of venous thromboembolism a smaller proportion of patients ( 15% ; 81/549 ) was diagnosed with vte during the postoperative period . figure 3 shows the proportion of patients with vte at different time points during the postoperative period . of those diagnosed beyond 6 weeks diagnosis of venous thromboembolism during the postoperative period ( n = 81 ) the most common ( 73% ) symptom was swelling of the limb among patients with vte [ table 6 ] . a total of 182 patients had evidence of one risk factor , 126 had evidence of two risk factors , 70 had evidence of three risk factors and 31 had four or more risk factors recorded . patients undergoing orthopedic surgery constituted 22% ( 33/152 ) of all surgical patients [ table 3 ] . based on a review of the available records , 157 patients had a single co - morbidity , 81 had two co - morbidities , 23 had three co - morbidities , and 16 had four or more co - morbidities . ( myocardial infarction , heart failure , chronic obstructive pulmonary disease , ventilator dependency , sepsis , or pneumonia ) [ table 4 ] . of the 476 patients with dvt , 2% ( 9 ) had upper extremity dvt , 97% ( 462 ) had lower extremity dvt and the site of dvt was not known in 5 patients . a total of 31% ( 143/462 ) patients had dvt in the right limb , 54% ( 249/462 ) in the left limb and 9% ( 41/462 ) in both limbs ( site not known in 29 patients ) . of the 462 patients with lower extremity dvt , 61% had proximal dvt , 13% had distal dvt , and 7% had proximal and distal dvt . a total of 39% ( 215/549 ) patients were diagnosed with vte during their hospital stay , 54% ( 296/549 ) were admitted to hospital with a diagnosis of vte , and 7% ( 38/549 ) were diagnosed and continued to be managed in the outpatient department [ figure 2 ] . place of detection of venous thromboembolism ( n = 549 ) duration of hospitalization after diagnosis of venous thromboembolism a smaller proportion of patients ( 15% ; 81/549 ) was diagnosed with vte during the postoperative period . figure 3 shows the proportion of patients with vte at different time points during the postoperative period . of those diagnosed beyond 6 weeks diagnosis of venous thromboembolism during the postoperative period ( n = 81 ) the most common ( 73% ) symptom was swelling of the limb among patients with vte [ table 6 ] pe was confirmed by pulmonary angiography in 27% of all the patients [ table 7 ] . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . five percent ( 25/515 ) of patients were recommended lmwh alone , and 76% ( 393/515 ) were recommended either warfarin or acenocoumarol alone for long - term anticoagulation . the median duration of initial anticoagulation was 5 days while that of long - term anticoagulation was 180 days ( 6 months ) . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . incidence of acute deep vein thrombosis ( with or without pulmonary embolism ) over a 5 years period ( 20062010 ) at three sites pe was confirmed by pulmonary angiography in 27% of all the patients [ table 7 ] . heparin ( low molecular weight heparin [ lmwh]/unfractionated heparin [ ufh ] ) alone , a combination of heparin ( lmwh / ufh ) and oral anticoagulant ( warfarin ) , and fondaparinux sodium alone were recommended to 82% ( 420/515 ) , 13% ( 66/515 ) , and 2% ( 12/515 ) patients , respectively as initial anticoagulation . five percent ( 25/515 ) of patients were recommended lmwh alone , and 76% ( 393/515 ) were recommended either warfarin or acenocoumarol alone for long - term anticoagulation . the median duration of initial anticoagulation was 5 days while that of long - term anticoagulation was 180 days ( 6 months ) . clinical outcomes in patients diagnosed with venous thromboembolism during hospital stay clinical outcomes in patients admitted to hospital with a diagnosis of venous thromboembolism the annual incidence of acute dvt ( pe ) increased from 2006 to 2010 at all the three sites [ figure 4 ] . incidence of acute deep vein thrombosis ( with or without pulmonary embolism ) over a 5 years period ( 20062010 ) at three sites to our knowledge , this is the first multicenter , retrospective registry in india involving patients with vte that reflect real - world clinical practice . in contrast with the western data in which vte is predominantly a disease of older age , 44% patients in our study were between 40 and 59 years of age while 34% were below 40 years , particularly those with pe . in a study from north india , men constituted 70% of our registry , more than those reported from vellore registry ( 48% ) , but similar to those reported in the endorse ( epidemiologic international day for the evaluation of patients at risk for vte in the acute hospital care setting ) study ( 69% ) . one of the reasons for this could be significantly high levels of homocysteine ( thrombophilia marker ) in males as compared to females as reported in an indian study . fewer indian women use oral contraceptives and postmenopausal hormone replacement therapy , which are known to be risk factors for thrombosis . this is supported by the fact that only 1% of women in this registry reported the use of oral contraceptives , and none reported use of hormonal replacement therapy . a total of 28% of the overall referrals were from cardiologists . our finding complements that from the endorse study in which 55% of the medical patients at risk of vte had cardiovascular disease . majority ( 53% ) of patients in our study had co - morbid cardiovascular disease including diabetes mellitus ; it is possible that these patients visited a cardiologist for their cardiovascular ailment ( s ) and were then referred by the cardiologist to vascular disease specialist ( investigator ) . most ( 89% ) of these patients had swelling of the ( lower ) limb . prior history of dvt was the most ( 34% ) common risk factor in patients who had only dvt , whereas past history of pe , trauma , and immobilization for more than 3 days were the most common risk factors in patients who had only pe . our results ( major lower limb surgery as a risk factor in 3% patients ) appear to be consistent with those reported in the endorse study , which reported dvt in 4.4% patients undergoing major lower limb surgery . other studies from india have reported a dvt incidence rate ranging from 8% to 20% in major lower limb surgery . however , in our study , only 7% of patients had malignancy as a predisposing factor . among the malignancies , genitourinary cancer had the highest incidence ( 45% ) . in addition , obesity ( 11% ) was a common risk factor in dvt complicated by pe . in our study , venography was used in just 4% patients and pulmonary angiography in less than one - third of the patients . a mean duration of hospitalization of 79 days after diagnosis of vte is supported by published data . in selected low - risk patients , outpatient treatment of dvt and pe may be considered . the reported prevalence of postsurgical vte in our study ( 15% ) was half of that ( 30% ) reported in vellore registry . this could be explained by higher referral rate from surgeons at vellore compared to that of our sites . we notice that acute dvt complicated by pe was less ( 6% ; 7/124 ) frequently diagnosed during the postoperative period as against 18% ( 64/352 ) and 14% ( 10/73 ) of acute dvt alone and pe alone , respectively . the use and duration of anticoagulants in our registry appears to be consistent with the american college of chest physicians treatment guidelines , which recommend at least 5 days of initial anticoagulation with parenteral anticoagulation ( lmwh , fondaparinux , intravenous ufh , or subcutaneous ufh ) and at least 3 months of long - term anticoagulation treatment with vitamin k antagonist . bleeding is the most serious complication of anticoagulation treatment and is a major concern for clinicians particularly as the patient 's age advances . in this registry , anticoagulant treatment was needed to be stopped because of bleeding in only 2% of the study population . thus , the fear of bleeding complications , which decreases the use of anticoagulant treatment , appears to be minimal . similar to published data in which hospital readmission rate for vte was 5% for primary and 14% for secondary diagnosis , we report a hospital readmission rate of 6% ; however we do not know the cause for readmission . over 90% of patients treated on an outpatient basis obtained symptomatic relief with treatment . in our study , the hospital discharge rate ( 97% ) was more than triple and death rate was a quarter of that reported by pandey et al . our data show a significant increase in acute dvt ( pe ) from 2006 to 2010 . although there was no significant change in the number of pe cases from 2006 to 2010 , the burden of pe is almost double ( 13% of all vte ) of 7% , rate reported at christian medical college , vellore during a 10-year period from 1996 to 2005 . our finding is consistent with a study from north india that reported a 16% incidence of pe in adult medical autopsies . despite these limitations , this study provides large amount of useful information in a short span of time on patient characteristics , clinical outcomes , management strategies , and temporal trends in vte , based on real world data that reflect actual day - to - day clinical practice over a period of 5 years across three sites in india . real world data reflecting actual day - to - day clinical practice in vte over a period of 5 years across three sites in india showed that vte is not uncommon in indian patients and that acute dvt was responsible for the substantial burden of vte . we believe that this information will serve as a guide in the optimal implementation of vte prophylaxis and treatment , to improve patient outcomes and to decrease the occurrence of vte in india .

the need for magnetic resonance imaging ( mri ) in patients with an implanted pacemaker or implantable cardioverter - defibrillator ( icd ) is a growing clinical issue . it is estimated that as many as 75% of active cardiac device recipients will become indicated for mri . currently , the vast majority of such devices are contraindicated for use with an mri . in european heart rhythm association survey , published recently for non - mri - certified icds ( 0.51.5 t field strength ) , the totally subcutaneous icd ( s - icd ) system , an implantable defibrillator with no leads that touch the heart , has recently been demonstrated to be a safe and effective defibrillator option for patients at risk for sudden cardiac death . it provides shock therapy and post - shock pacing therapy , but no long - term bradycardia pacing . although it has been shown as an alternative to the standard transvenous icd , its compatibility with mri remains unclear . various types of clinical mri systems currently use a superconductive magnet that creates a static magnetic field strength , typically 1.5 or 3 t. the use of mri with most pacemakers and icds is considered a contraindication due to potential hazards , including heating of the electrode that resides in or on the heart , damage to myocardium , elevation of pacing thresholds , unintended induction of ventricular tachycardia ( vt ) or ventricular fibrillation ( vf ) , pacing inhibition , permanent device malfunction , and distortion of the mri scan . recently , mr - conditional. mr - conditional indicates a lack of known hazards in a specified mri environment with specified conditions of use . due to the variety of mri scanners and scanning protocols , it is not practical to test even a single device under all conditions . hence , mr - conditional labelling dictates that the device is safe for use under certain scanning conditions , as well as how the cardiac device should be programmed before an exposure to the magnetic field in a mri scanner . the literature , although limited , provides some guidance for imaging patients with implanted pacemakers or icds that do not have mr - conditional labelling . this single - centre prospective non - controlled study describes the first use of mri in patients with an implanted s - icd . patients with implanted s - icd systems ( boston scientific sqrx model 1010 and q - trak model 3010 ) were enrolled for mri testing over a period of 18 months . the s - icd system implanted in this patient cohort was composed of a can implanted in a left mid - lateral pocket and a para - sternal subcutaneous electrode . the s - icd is currently not certified for use with an mri ; therefore , the ethics committee of homolka hospital , prague , czech republic approved our clinical study . patients with newly implanted s - icd systems ( < 6 weeks ) were excluded , and none of the patients had any intravascular leads . the patients were randomized for either a cardiac , brain , cervical , or lumbar spinal scan . one of the subjects underwent an additional knee examination , due to reported chronic pain . a total of 15 patients were enrolled into this study ( 12 males and three females , aged 2283 years , mean 53 years . subjects in our cohort ( table 1 ) underwent a total of 22 mri scans between 6 june 2012 and 24 december 2013 . in total , five brain scans , three cardiac scans , 12 lumbar scans , one knee , and one cervical spine scan were conducted ( table 2 ) . however , in one patient a minor disc protrusion was found , in other mri revealed stenosis of intervertebral foramen which was causing radicular pain of the nerve root l4 and based on this examination the patient was referred to ct - navigated periradicular therapy . table 1summary of patient anatomical data and scan locations , along with noted clinical eventsidagesexbmidgef , % indication for s - icdheating0164f20.5hcmp / vfs85secondary preventionnone0283m30.0post - mi / smvts post - catheter ablation/35secondary prevention ( post - transvenous icd extraction)none0331m25.3arvc / d / smvts68secondary preventionin - tolerable re - scanned0458m23.6post - mi / post - cabg30primary preventionnone0577m25.5post - mi30primary preventionnone0663m27.0post - mi30primary preventionnone0768m23.7post - mi / vfs / vts60secondary prevention post - transvenous icd extraction / svc occlusiontolerable0822m29.4brugada sy / vfs68secondary preventionin - tolerable re - scanned0959m27.1dcmp / vfs / post - mitral valve surgery/60secondary prev./post - transvenous icd extractionnone1041f24.6arvc / d70primary preventionnone1123f21.5lqts / vf60secondary preventionnone1266m36.9post - mi / vf / post - cabg50secondary prevention / post - repeat transvenous icd extractiontolerable1348m22.9dcmp(non - compaction)/vfs35secondary preventionnone1470m29systolic dysfunction of lv35primary preventionnone1526m33brugada sy65primary preventionnonehcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . table 2parmeters of s - icd and patient sensation during individual mri scansscan # idbody partheating sensationsshock zone ( b.p.m.)condit . shock zone ( b.p.m.)bat % episode num.101brainnone2302101001202brainnone240220861303l spinein - tolerable240220831403brainnone240220831504brainnone220190691605l spinenone220210541706l spinenone240220681807l spinetolerable240220582908l spinein - tolerablenananana1008brainnonenananana1108l spinenone2302108411209heartnone2402208911310l spinenone2301807911410heartnonenananana1511heartnone2301909711612l spinetolerable2001709721712l spinenone2001709421813c spinenone23019010041913l spinenone23019010042014l spinenone2301908612115kneenone25021010012215l spinenone2502101001s - icd parameters acquired prior- and post - mri were without any change , therefore only one value is presented.indices : na , not available ; l spine , lumbar spine ; c spine , cervical spine . summary of patient anatomical data and scan locations , along with noted clinical events hcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . parmeters of s - icd and patient sensation during individual mri scans s - icd parameters acquired prior- and post - mri were without any change , therefore only one value is presented . indices : na , not available ; l spine , lumbar spine ; c spine , cervical spine . studies were performed using a siemens avanto 1.5 t mri scanner ( vb17 software , quantum gradient coils ) . all scans were run in normal operating mode , which is limited to 2 w / kg whole body averaged specific absorption rate ( sar ) . clinically relevant mri sequences were used for evaluation ( see table 3 ) . table 3types of pulse sequences typically used for imaging of respective anatomical areasscan locationscan sequencesflairdwiflashfsehastesestirtruefispbrainxxxxheartxxxxcervical spinexxkneexxxxlumbar spinexxflair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession.fse sequence caused heating in subjects with a thermistor probe during lumbar spine examination ( see the text for details ) . types of pulse sequences typically used for imaging of respective anatomical areas flair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession . fse sequence caused heating in subjects with a thermistor probe during lumbar spine examination ( see the text for details ) . patients were asked to report immediately any pain , torqueing movement , or heating sensation in the area of the pocket or the electrode by pressing an emergency bulb . furthermore , all patients were questioned immediately following the mri procedure to ascertain any discomfort in the vicinity of the can or electrode . pulse oximetry and standard lead electrocardiogram ( ecg ) if discomfort occurred , the patient was asked if the scan could be repeated at a later time using a revised scan sequence or the subject was again randomized for another anatomical area . since none of the components of the s - icd system are on or in the heart , heating near or around however , heating near the electrode or can with the s - icd system may still cause serious patient discomfort . therefore , along with education of subjects , each patient was instrumented by taping an oesophageal temperature probe ( beta - therm model g22k7mcd8 ) on the skin over the mid - lateral implant site to record any temperature excursions that might be correlated to patient symptoms of heating / discomfort near the pocket . to minimize the risk of inappropriate therapy , the s - icd system was programmed to therapy each s - icd system was evaluated prior to and immediately after the scan to verify proper functioning , including interrogation , sensing , and battery voltage . after the completion of the mri , long - term regular clinical follow - up and checking of the device were performed . patients with implanted s - icd systems ( boston scientific sqrx model 1010 and q - trak model 3010 ) were enrolled for mri testing over a period of 18 months . the s - icd system implanted in this patient cohort was composed of a can implanted in a left mid - lateral pocket and a para - sternal subcutaneous electrode . the s - icd is currently not certified for use with an mri ; therefore , the ethics committee of homolka hospital , prague , czech republic approved our clinical study . patients with newly implanted s - icd systems ( < 6 weeks ) were excluded , and none of the patients had any intravascular leads . the patients were randomized for either a cardiac , brain , cervical , or lumbar spinal scan . one of the subjects underwent an additional knee examination , due to reported chronic pain . a total of 15 patients were enrolled into this study ( 12 males and three females , aged 2283 years , mean 53 years . subjects in our cohort ( table 1 ) underwent a total of 22 mri scans between 6 june 2012 and 24 december 2013 . in total , five brain scans , three cardiac scans , 12 lumbar scans , one knee , and one cervical spine scan were conducted ( table 2 ) . however , in one patient a minor disc protrusion was found , in other mri revealed stenosis of intervertebral foramen which was causing radicular pain of the nerve root l4 and based on this examination the patient was referred to ct - navigated periradicular therapy . table 1summary of patient anatomical data and scan locations , along with noted clinical eventsidagesexbmidgef , % indication for s - icdheating0164f20.5hcmp / vfs85secondary preventionnone0283m30.0post - mi / smvts post - catheter ablation/35secondary prevention ( post - transvenous icd extraction)none0331m25.3arvc / d / smvts68secondary preventionin - tolerable re - scanned0458m23.6post - mi / post - cabg30primary preventionnone0577m25.5post - mi30primary preventionnone0663m27.0post - mi30primary preventionnone0768m23.7post - mi / vfs / vts60secondary prevention post - transvenous icd extraction / svc occlusiontolerable0822m29.4brugada sy / vfs68secondary preventionin - tolerable re - scanned0959m27.1dcmp / vfs / post - mitral valve surgery/60secondary prev./post - transvenous icd extractionnone1041f24.6arvc / d70primary preventionnone1123f21.5lqts / vf60secondary preventionnone1266m36.9post - mi / vf / post - cabg50secondary prevention / post - repeat transvenous icd extractiontolerable1348m22.9dcmp(non - compaction)/vfs35secondary preventionnone1470m29systolic dysfunction of lv35primary preventionnone1526m33brugada sy65primary preventionnonehcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . table 2parmeters of s - icd and patient sensation during individual mri scansscan # idbody partheating sensationsshock zone ( b.p.m.)condit . shock zone ( b.p.m.)bat % episode num.101brainnone2302101001202brainnone240220861303l spinein - tolerable240220831403brainnone240220831504brainnone220190691605l spinenone220210541706l spinenone240220681807l spinetolerable240220582908l spinein - tolerablenananana1008brainnonenananana1108l spinenone2302108411209heartnone2402208911310l spinenone2301807911410heartnonenananana1511heartnone2301909711612l spinetolerable2001709721712l spinenone2001709421813c spinenone23019010041913l spinenone23019010042014l spinenone2301908612115kneenone25021010012215l spinenone2502101001s - icd parameters acquired prior- and post - mri were without any change , therefore only one value is presented.indices : na , not available ; l spine , lumbar spine ; c spine , cervical spine . summary of patient anatomical data and scan locations , along with noted clinical events hcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . parmeters of s - icd and patient sensation during individual mri scans s - icd parameters acquired prior- and post - mri were without any change , therefore only one value is presented . indices : na , not available ; l spine , lumbar spine ; c spine , cervical spine . studies were performed using a siemens avanto 1.5 t mri scanner ( vb17 software , quantum gradient coils ) . all scans were run in normal operating mode , which is limited to 2 w / kg whole body averaged specific absorption rate ( sar ) . clinically relevant mri sequences were used for evaluation ( see table 3 ) . table 3types of pulse sequences typically used for imaging of respective anatomical areasscan locationscan sequencesflairdwiflashfsehastesestirtruefispbrainxxxxheartxxxxcervical spinexxkneexxxxlumbar spinexxflair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession.fse sequence caused heating in subjects with a thermistor probe during lumbar spine examination ( see the text for details ) . types of pulse sequences typically used for imaging of respective anatomical areas flair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession . fse sequence caused heating in subjects with a thermistor probe during lumbar spine examination ( see the text for details ) . patients were asked to report immediately any pain , torqueing movement , or heating sensation in the area of the pocket or the electrode by pressing an emergency bulb . furthermore , all patients were questioned immediately following the mri procedure to ascertain any discomfort in the vicinity of the can or electrode . pulse oximetry and standard lead electrocardiogram ( ecg ) if discomfort occurred , the patient was asked if the scan could be repeated at a later time using a revised scan sequence or the subject was again randomized for another anatomical area . since none of the components of the s - icd system are on or in the heart , heating near or around the electrode can not harm the myocardium . however , heating near the electrode or can with the s - icd system may still cause serious patient discomfort . therefore , along with education of subjects , each patient was instrumented by taping an oesophageal temperature probe ( beta - therm model g22k7mcd8 ) on the skin over the mid - lateral implant site to record any temperature excursions that might be correlated to patient symptoms of heating / discomfort near the pocket . to minimize the risk of inappropriate therapy , the s - icd system was programmed to therapy each s - icd system was evaluated prior to and immediately after the scan to verify proper functioning , including interrogation , sensing , and battery voltage . after the completion of the mri , the s - icd system was reprogrammed to original settings . long - term regular clinical follow - up and checking of the device were performed . no anomalies were noted via pulse oximetry or ecg during the scans for any of the patients . eleven of 15 patients reported no sensation or pain from heating of the can , two of 15 patients reported feeling some heating , and two patients reported intolerable heating ( see table 2 ) . in patients with intolerable heating , the scan was halted within seconds and changed to a scan of the brain , which proceeded without incident . patient reports of heating in the vicinity of the can occurred only during lumbar scans with a thermistor probe ; no such reports occurred during scans of the brain , cardiac area , cervical spine , or without the probe . in two cases where heating in the vicinity of the can was reported by the patient , the scan sequence was altered to reduce the intensity of radiofrequency ( rf ) field exposure by reducing the turbo factor ( e.g. from 21 to 7 ) , increasing the repetition time ( e.g. to > 4000 ms ) , and reducing the flip angle ( e.g. from 170 to 120 ) . the target values were chosen arbitrarily to maintain image contrast ( flip angle ) and keep scan time at reasonable limits ( turbo factor and repetition time ) . less heating was noted by patients after these modifications to the scan parameters were made . 03 ) was observed to have a skin lesion , appearing to be a circular rash or ulcer on the surface of the skin over the can , approximately 35 mm in diameter . the cause of this skin anomaly is not known ; it was later noted to have fully healed at a follow - up 10 days after the scan . to ascertain the effect of heating due to the instrumented thermistor catheter , the two patients who experienced the heating ( examinations 9 and 16 , see table 2 ) were rescanned several weeks later without the thermistor catheter in place ( examinations 11 and 17 ) . first , modified sequence ( with even lower amount of energy deposited in the tissue ) was used , which caused no heating . as no sensation was reported by the subjects , they were asked to report even a minimal discomfort , and the lumbar scans were performed using the same settings that resulted in heating with the thermistor catheter in place in the first imaging session . the results of the rescans revealed that no heating was felt by the patients when the thermistor catheter was absent . there were no noted changes to battery voltage , ability to detect the qrs signal or stored diagnostic data . pacing thresholds can not be assessed by the s - icd system , so this was not evaluated . none of the patients reported any pulling or twisting of the can or pain from heating of the s - icd electrode . for scans of the brain , lumbar spine , knee , and cervical spine , no effect from image artefact was noted in the anatomical area of interest . however , for scans of the cardiac area , image artefact was noted to interfere with the ability to see parts of the left ventricle , though the right ventricle of the heart was unaffected and could be imaged usefully . this was due to the can and not the electrode ( see figure 1 ) , modifications to the protocol for the lumbar spine resulted in a lower signal - to - noise ratio ; however , the images remain in diagnostic quality ( see figure 2 ) . figure 1kinetic study in four - chamber view : the systolic ( a and c ) and diastolic ( b and d ) images of cine sequences , four - chamber view . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . in ssfp kinetic study , an inflow of dark blood from the left pulmonary veins was seen . it could be caused by s - icd but also by metallic ring in mitral annulus . the spoiled gradient echo ( gre ) sequence ( c and d ) is better , but an artefact at the lateral wall is obvious . figure 2lumbar spine imaging with icd : low sar t2 fse sequence ( upper image ) compared with normal t2 fse in the same subject ( lower image , for the scanning parameters see the discussion section ) . kinetic study in four - chamber view : the systolic ( a and c ) and diastolic ( b and d ) images of cine sequences , four - chamber view . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . in ssfp kinetic study , an inflow of dark blood from the left pulmonary veins was seen . it could be caused by s - icd but also by metallic ring in mitral annulus . the spoiled gradient echo ( gre ) sequence ( c and d ) is better , but an artefact at the lateral wall is obvious . lumbar spine imaging with icd : low sar t2 fse sequence ( upper image ) compared with normal t2 fse in the same subject ( lower image , for the scanning parameters see the discussion section ) . there were no noted changes to battery voltage , ability to detect the qrs signal or stored diagnostic data . pacing thresholds can not be assessed by the s - icd system , so this was not evaluated . none of the patients reported any pulling or twisting of the can or pain from heating of the s - icd electrode . for scans of the brain , lumbar spine , knee , and cervical spine , no effect from image artefact was noted in the anatomical area of interest . however , for scans of the cardiac area , image artefact was noted to interfere with the ability to see parts of the left ventricle , though the right ventricle of the heart was unaffected and could be imaged usefully . this was due to the can and not the electrode ( see figure 1 ) , modifications to the protocol for the lumbar spine resulted in a lower signal - to - noise ratio ; however , the images remain in diagnostic quality ( see figure 2 ) . figure 1kinetic study in four - chamber view : the systolic ( a and c ) and diastolic ( b and d ) images of cine sequences , four - chamber view . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . in ssfp kinetic study , an inflow of dark blood from the left pulmonary veins was seen . it could be caused by s - icd but also by metallic ring in mitral annulus . the spoiled gradient echo ( gre ) sequence ( c and d ) is better , but an artefact at the lateral wall is obvious . figure 2lumbar spine imaging with icd : low sar t2 fse sequence ( upper image ) compared with normal t2 fse in the same subject ( lower image , for the scanning parameters see the discussion section ) . kinetic study in four - chamber view : the systolic ( a and c ) and diastolic ( b and d ) images of cine sequences , four - chamber view . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . in ssfp kinetic study , an inflow of dark blood from the left pulmonary veins was seen . it could be caused by s - icd but also by metallic ring in mitral annulus . the spoiled gradient echo ( gre ) sequence ( c and d ) is better , but an artefact at the lateral wall is obvious . lumbar spine imaging with icd : low sar t2 fse sequence ( upper image ) compared with normal t2 fse in the same subject ( lower image , there are several reports in the current literature about mr - conditional pacemakers from several companies , but very limited reports about mr - conditional icds . biotronik announced in late 2011 release of their first mr - compatible icd device and defibrillator leads pro mri , but in the conditions of use excluded scanning of the torso and focused more on the extremities examination . in european heart rhythm association survey , 60% of centres did not implant any mri - certified icds , 34.3% implanted < 10 icd devices , and only 5.6% implanted 10 and more icds ; one - fifth of responders stated that mri - certified icds should be implanted in all patients but lack of reimbursement was indicated as a possible obstacle to implant more mri - certified pacemakers / icds by 47.1% of responding centres . none of the components of the s - icd system are on or in the heart . the s - icd depends less upon being in direct contact with the myocardium to function and instead uses far - field sensing and stimulation to provide the shock and post - shock pacing therapy . as a consequence , unlike transvenous systems heating near or around the electrode can not harm the myocardium , which could present with possible safety consequences such as an elevation in pacing thresholds or scarring of the myocardium , but it may still cause serious patient discomfort . because the s - icd is larger than modern transvenous icd 's , there may be more potential for the can to experience heating due to the magnetic gradient or rf field . we report results from what we believe is the first experience of mri scanning in patients with an implanted s - icd and in various anatomical areas . overall , mri was performed safely in all patients , which is in contrast to the current literature with mri imaging in patients with electrical - active devices which are not mri - conditional . in our study , the primary clinically significant event attributable to the mri scan was the occurrence of heating in the area of the pocket in the four patients that underwent lumbar scans . it was not known if this was due to the s - icd can itself or an artefact of the thermistor catheter used to measure skin temperature over the pocket . this required a revision of our protocol , which was to re - scan two of the patients who complained of heating . re - scanning of these patients without the thermistor probe resulted in no complaints of heating , so it is assumed that the thermistor catheter itself heated during the lumbar scans and caused the discomfort . as further evidence , all the heating complaints occurred during rf - intensive scan sequences ( namely fast spin echo ) with the temperature probe located axially near the centre of the bore , where rf fields are the highest . the thermistor catheter is constructed of insulated conductive cables connected to electrodes and should couple to the rf fields efficiently , causing heating at the electrodes and pain or damage on the surface of the skin where the probe was placed over the s - icd can . if the heating was due to the s - icd can itself , it would more likely occur during gradient - intensive scan sequences ( which can generate eddy currents on can surfaces and internal components ) and at locations in the bore where there are high gradient fields , such as near the bore edges . however , when the patient was scanned with gradient - intensive scan sequences ( e.g. flair dwi ) and with the s - icd system in high gradient field locations in the bore ( e.g. such as during a brain scan ) , patients did not detect any heating or discomfort . in addition , the subcutaneous lead , which was not instrumented with a thermistor catheter , never resulted in any heating sensation noted by the patient , even when exactly the same sequence that resulted in heating in the first session was used . the use of mri - compatible temperature monitors such as fibre optic temperature probes would have provided better confirmation of possible skin temperature elevation and would not have been affected by the rf fields . for cardiac imaging , the main problem to solve is metallic artefact , especially on the gradient - echo sequences . like in research performed by nazarian et al . , several scan protocols were used to see if any yielded different effects or reduced the qualitative extent of artefact . gradient mode was changed from normal to whisper , resulting in slower ramping of the field and therefore diminishing the changes of the magnetic field in time . artefacts when present were limited to blurring of the left ventricle during cardiac scans and most yielded clinically useful information . standard interrogation of the s - icd revealed no adverse effects upon the functioning of the system . while no adverse effects upon the post - scan s - icd device function were noted , not all possible scanning protocols were tested . it should be noted that , four of the s - icd 's were exposed to repeat mri scans without adverse effects to device function . in addition , because the s - icd does not provide long - term bradycardia pacing , it is assumed that pacemaker - dependent patients would not be implanted with this system . the inhibition of the pacemaker function during the scanning sequence and possible pacing threshold changes are a unique concern in patients implanted with transvenous icds . this study included only 15 patients and 22 scans done on the same 1.5 t mri scanner . thus , even these preliminary results should only be applied to 1.5 t mri scanners ( similarly as reported in the present literature for other implantable devices ) . device functionality was tested immediately after the scan but not for long - term effects . in addition , not all device functions were tested although the s - icd system does have a beeper / interrogation warning if battery levels or memory irregularities occur . however , patients were scheduled for regular check - up and no defect of the device was observed in following 725 months ( mean observation time 18 months ) . delayed enhancement mri for determining cardiac scarring was also not tested . also , there are other anatomical areas that were not evaluated , such as shoulder and knees . this study included only 15 patients and 22 scans done on the same 1.5 t mri scanner . thus , even these preliminary results should only be applied to 1.5 t mri scanners ( similarly as reported in the present literature for other implantable devices ) . device functionality was tested immediately after the scan but not for long - term effects . in addition , not all device functions were tested although the s - icd system does have a beeper / interrogation warning if battery levels or memory irregularities occur . however , patients were scheduled for regular check - up and no defect of the device was observed in following 725 months ( mean observation time 18 months ) . delayed enhancement mri for determining cardiac scarring was also not tested . also , there are other anatomical areas that were not evaluated , such as shoulder and knees . while more data are required to support a claim of mri - conditional , this study is the study to demonstrate the feasibility of exposing s - icd patients to mri using the scanning and monitor protocol described , with some precautionary measures including : ( i ) programming the device therapy off ; ( ii ) limiting the sar to 2.0 w / kg ; ( iii ) continuous monitoring of the patients pulse oximetry and ecg by qualified personnel and especially for any feelings of heating ; ( iv ) evaluate device function post scan ; ( v ) availability of full resuscitation facilities at the mri site . given the variables of different mri scanners , the decision to perform mri on patients with an implanted s - icd system should be balanced against the potential risks . in our study , the only heating was very likely introduced by not fully mri - compatible thermometer probe ; subjects rescanned without the probe did not report any abnormalities during the scan of any body area listed ( brain , cervical and lumbar spine , heart , and knee ) . this study was supported by iga mz r nt12094/2011 , research project charles university in prague , prvouk p34 and unce 204010/2012 . funding to pay the open access publication charges for this article was provided by iga mz r nt12094/2011 .

aimsour aim was to evaluate the potential for safely imaging patients with a new type of implantable cardioverter - defibrillator called the subcutaneous implantable cardioverter - defibrillator ( s - icd ) in a 1.5 t magnetic resonance imaging ( mri ) scanner . with the increasing number of patients with cardiac implantable devices who are indicated for mri , there is a growing need for establishing mri compatibility of cardiac implantable devices.methods and resultspatients with implanted s - icd systems underwent one or more types of anatomical mri scans . the s - icd was programmed off and patients were monitored throughout the imaging procedure . device function was evaluated pre- and post - scan . patients were asked to report immediately any pain , torqueing movement , or heating sensation in the area of the pocket or electrode . fifteen patients underwent a total of 22 examinations at 1.5 t. scans included brain , spine , knee , and heart . two patients were re - scanned due to complaints of heating over the can during lumbar scans , which was caused by a thermistor probe placed on the skin to measure skin temperature . all the remaining scans occurred without incident . no evidence of device malfunction was observed.conclusionthis study is the first to domonstrate the feasibility of exposing s - icd patients to mri using the scanning and monitoring protocol described . more data are required to support s - icd as a mri conditional device .

Introduction Methods Patient selection Magnetic resonance imaging Device assessment Results Subcutaneous implantable cardioverter-defibrillator status Image artefacts Discussion Limitations Conclusions Funding

the need for magnetic resonance imaging ( mri ) in patients with an implanted pacemaker or implantable cardioverter - defibrillator ( icd ) is a growing clinical issue . various types of clinical mri systems currently use a superconductive magnet that creates a static magnetic field strength , typically 1.5 or 3 t. the use of mri with most pacemakers and icds is considered a contraindication due to potential hazards , including heating of the electrode that resides in or on the heart , damage to myocardium , elevation of pacing thresholds , unintended induction of ventricular tachycardia ( vt ) or ventricular fibrillation ( vf ) , pacing inhibition , permanent device malfunction , and distortion of the mri scan . patients with implanted s - icd systems ( boston scientific sqrx model 1010 and q - trak model 3010 ) were enrolled for mri testing over a period of 18 months . patients with newly implanted s - icd systems ( < 6 weeks ) were excluded , and none of the patients had any intravascular leads . patients were asked to report immediately any pain , torqueing movement , or heating sensation in the area of the pocket or the electrode by pressing an emergency bulb . since none of the components of the s - icd system are on or in the heart , heating near or around however , heating near the electrode or can with the s - icd system may still cause serious patient discomfort . to minimize the risk of inappropriate therapy , the s - icd system was programmed to therapy each s - icd system was evaluated prior to and immediately after the scan to verify proper functioning , including interrogation , sensing , and battery voltage . patients with implanted s - icd systems ( boston scientific sqrx model 1010 and q - trak model 3010 ) were enrolled for mri testing over a period of 18 months . patients with newly implanted s - icd systems ( < 6 weeks ) were excluded , and none of the patients had any intravascular leads . patients were asked to report immediately any pain , torqueing movement , or heating sensation in the area of the pocket or the electrode by pressing an emergency bulb . to minimize the risk of inappropriate therapy , the s - icd system was programmed to therapy each s - icd system was evaluated prior to and immediately after the scan to verify proper functioning , including interrogation , sensing , and battery voltage . patient reports of heating in the vicinity of the can occurred only during lumbar scans with a thermistor probe ; no such reports occurred during scans of the brain , cardiac area , cervical spine , or without the probe . as no sensation was reported by the subjects , they were asked to report even a minimal discomfort , and the lumbar scans were performed using the same settings that resulted in heating with the thermistor catheter in place in the first imaging session . for scans of the brain , lumbar spine , knee , and cervical spine , no effect from image artefact was noted in the anatomical area of interest . for scans of the brain , lumbar spine , knee , and cervical spine , no effect from image artefact was noted in the anatomical area of interest . because the s - icd is larger than modern transvenous icd 's , there may be more potential for the can to experience heating due to the magnetic gradient or rf field . in our study , the primary clinically significant event attributable to the mri scan was the occurrence of heating in the area of the pocket in the four patients that underwent lumbar scans . it was not known if this was due to the s - icd can itself or an artefact of the thermistor catheter used to measure skin temperature over the pocket . this required a revision of our protocol , which was to re - scan two of the patients who complained of heating . the thermistor catheter is constructed of insulated conductive cables connected to electrodes and should couple to the rf fields efficiently , causing heating at the electrodes and pain or damage on the surface of the skin where the probe was placed over the s - icd can . in addition , the subcutaneous lead , which was not instrumented with a thermistor catheter , never resulted in any heating sensation noted by the patient , even when exactly the same sequence that resulted in heating in the first session was used . it should be noted that , four of the s - icd 's were exposed to repeat mri scans without adverse effects to device function . while more data are required to support a claim of mri - conditional , this study is the study to demonstrate the feasibility of exposing s - icd patients to mri using the scanning and monitor protocol described , with some precautionary measures including : ( i ) programming the device therapy off ; ( ii ) limiting the sar to 2.0 w / kg ; ( iii ) continuous monitoring of the patients pulse oximetry and ecg by qualified personnel and especially for any feelings of heating ; ( iv ) evaluate device function post scan ; ( v ) availability of full resuscitation facilities at the mri site .

it is estimated that as many as 75% of active cardiac device recipients will become indicated for mri . currently , the vast majority of such devices are contraindicated for use with an mri . in european heart rhythm association survey , published recently for non - mri - certified icds ( 0.51.5 t field strength ) , the totally subcutaneous icd ( s - icd ) system , an implantable defibrillator with no leads that touch the heart , has recently been demonstrated to be a safe and effective defibrillator option for patients at risk for sudden cardiac death . it provides shock therapy and post - shock pacing therapy , but no long - term bradycardia pacing . although it has been shown as an alternative to the standard transvenous icd , its compatibility with mri remains unclear . various types of clinical mri systems currently use a superconductive magnet that creates a static magnetic field strength , typically 1.5 or 3 t. the use of mri with most pacemakers and icds is considered a contraindication due to potential hazards , including heating of the electrode that resides in or on the heart , damage to myocardium , elevation of pacing thresholds , unintended induction of ventricular tachycardia ( vt ) or ventricular fibrillation ( vf ) , pacing inhibition , permanent device malfunction , and distortion of the mri scan . recently , mr - conditional. mr - conditional indicates a lack of known hazards in a specified mri environment with specified conditions of use . due to the variety of mri scanners and scanning protocols , it is not practical to test even a single device under all conditions . hence , mr - conditional labelling dictates that the device is safe for use under certain scanning conditions , as well as how the cardiac device should be programmed before an exposure to the magnetic field in a mri scanner . the literature , although limited , provides some guidance for imaging patients with implanted pacemakers or icds that do not have mr - conditional labelling . the s - icd system implanted in this patient cohort was composed of a can implanted in a left mid - lateral pocket and a para - sternal subcutaneous electrode . the s - icd is currently not certified for use with an mri ; therefore , the ethics committee of homolka hospital , prague , czech republic approved our clinical study . patients with newly implanted s - icd systems ( < 6 weeks ) were excluded , and none of the patients had any intravascular leads . the patients were randomized for either a cardiac , brain , cervical , or lumbar spinal scan . one of the subjects underwent an additional knee examination , due to reported chronic pain . a total of 15 patients were enrolled into this study ( 12 males and three females , aged 2283 years , mean 53 years . subjects in our cohort ( table 1 ) underwent a total of 22 mri scans between 6 june 2012 and 24 december 2013 . in total , five brain scans , three cardiac scans , 12 lumbar scans , one knee , and one cervical spine scan were conducted ( table 2 ) . however , in one patient a minor disc protrusion was found , in other mri revealed stenosis of intervertebral foramen which was causing radicular pain of the nerve root l4 and based on this examination the patient was referred to ct - navigated periradicular therapy . table 1summary of patient anatomical data and scan locations , along with noted clinical eventsidagesexbmidgef , % indication for s - icdheating0164f20.5hcmp / vfs85secondary preventionnone0283m30.0post - mi / smvts post - catheter ablation/35secondary prevention ( post - transvenous icd extraction)none0331m25.3arvc / d / smvts68secondary preventionin - tolerable re - scanned0458m23.6post - mi / post - cabg30primary preventionnone0577m25.5post - mi30primary preventionnone0663m27.0post - mi30primary preventionnone0768m23.7post - mi / vfs / vts60secondary prevention post - transvenous icd extraction / svc occlusiontolerable0822m29.4brugada sy / vfs68secondary preventionin - tolerable re - scanned0959m27.1dcmp / vfs / post - mitral valve surgery/60secondary prev./post - transvenous icd extractionnone1041f24.6arvc / d70primary preventionnone1123f21.5lqts / vf60secondary preventionnone1266m36.9post - mi / vf / post - cabg50secondary prevention / post - repeat transvenous icd extractiontolerable1348m22.9dcmp(non - compaction)/vfs35secondary preventionnone1470m29systolic dysfunction of lv35primary preventionnone1526m33brugada sy65primary preventionnonehcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . table 2parmeters of s - icd and patient sensation during individual mri scansscan # idbody partheating sensationsshock zone ( b.p.m. summary of patient anatomical data and scan locations , along with noted clinical events hcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . table 3types of pulse sequences typically used for imaging of respective anatomical areasscan locationscan sequencesflairdwiflashfsehastesestirtruefispbrainxxxxheartxxxxcervical spinexxkneexxxxlumbar spinexxflair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession.fse sequence caused heating in subjects with a thermistor probe during lumbar spine examination ( see the text for details ) . types of pulse sequences typically used for imaging of respective anatomical areas flair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession . furthermore , all patients were questioned immediately following the mri procedure to ascertain any discomfort in the vicinity of the can or electrode . since none of the components of the s - icd system are on or in the heart , heating near or around however , heating near the electrode or can with the s - icd system may still cause serious patient discomfort . therefore , along with education of subjects , each patient was instrumented by taping an oesophageal temperature probe ( beta - therm model g22k7mcd8 ) on the skin over the mid - lateral implant site to record any temperature excursions that might be correlated to patient symptoms of heating / discomfort near the pocket . to minimize the risk of inappropriate therapy , the s - icd system was programmed to therapy each s - icd system was evaluated prior to and immediately after the scan to verify proper functioning , including interrogation , sensing , and battery voltage . the s - icd system implanted in this patient cohort was composed of a can implanted in a left mid - lateral pocket and a para - sternal subcutaneous electrode . the s - icd is currently not certified for use with an mri ; therefore , the ethics committee of homolka hospital , prague , czech republic approved our clinical study . patients with newly implanted s - icd systems ( < 6 weeks ) were excluded , and none of the patients had any intravascular leads . the patients were randomized for either a cardiac , brain , cervical , or lumbar spinal scan . one of the subjects underwent an additional knee examination , due to reported chronic pain . a total of 15 patients were enrolled into this study ( 12 males and three females , aged 2283 years , mean 53 years . subjects in our cohort ( table 1 ) underwent a total of 22 mri scans between 6 june 2012 and 24 december 2013 . in total , five brain scans , three cardiac scans , 12 lumbar scans , one knee , and one cervical spine scan were conducted ( table 2 ) . however , in one patient a minor disc protrusion was found , in other mri revealed stenosis of intervertebral foramen which was causing radicular pain of the nerve root l4 and based on this examination the patient was referred to ct - navigated periradicular therapy . table 1summary of patient anatomical data and scan locations , along with noted clinical eventsidagesexbmidgef , % indication for s - icdheating0164f20.5hcmp / vfs85secondary preventionnone0283m30.0post - mi / smvts post - catheter ablation/35secondary prevention ( post - transvenous icd extraction)none0331m25.3arvc / d / smvts68secondary preventionin - tolerable re - scanned0458m23.6post - mi / post - cabg30primary preventionnone0577m25.5post - mi30primary preventionnone0663m27.0post - mi30primary preventionnone0768m23.7post - mi / vfs / vts60secondary prevention post - transvenous icd extraction / svc occlusiontolerable0822m29.4brugada sy / vfs68secondary preventionin - tolerable re - scanned0959m27.1dcmp / vfs / post - mitral valve surgery/60secondary prev./post - transvenous icd extractionnone1041f24.6arvc / d70primary preventionnone1123f21.5lqts / vf60secondary preventionnone1266m36.9post - mi / vf / post - cabg50secondary prevention / post - repeat transvenous icd extractiontolerable1348m22.9dcmp(non - compaction)/vfs35secondary preventionnone1470m29systolic dysfunction of lv35primary preventionnone1526m33brugada sy65primary preventionnonehcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . table 2parmeters of s - icd and patient sensation during individual mri scansscan # idbody partheating sensationsshock zone ( b.p.m. summary of patient anatomical data and scan locations , along with noted clinical events hcmp , hypertrophic cardiomyopathy ; smvt , sustained monomorphic ventricular tachycardia ; mi , myocardial infarction ; arvc , arrhythmogenic right ventricular cardiomyopathy ; cabg , coronary artery by - pass graft ; lqts , long qt syndrom . table 3types of pulse sequences typically used for imaging of respective anatomical areasscan locationscan sequencesflairdwiflashfsehastesestirtruefispbrainxxxxheartxxxxcervical spinexxkneexxxxlumbar spinexxflair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession.fse sequence caused heating in subjects with a thermistor probe during lumbar spine examination ( see the text for details ) . types of pulse sequences typically used for imaging of respective anatomical areas flair , fluid attenuated inversion recovery ; dwi , diffusion weighted imaging ; flash , fast low angle shot ; fse , fast spin echo ; haste , half acquisition single - shot turbo spin echo ; se , spin echo ; stir , short tau inversion recovery ; truefisp , true fast imaging with steady - state precession . however , heating near the electrode or can with the s - icd system may still cause serious patient discomfort . therefore , along with education of subjects , each patient was instrumented by taping an oesophageal temperature probe ( beta - therm model g22k7mcd8 ) on the skin over the mid - lateral implant site to record any temperature excursions that might be correlated to patient symptoms of heating / discomfort near the pocket . to minimize the risk of inappropriate therapy , the s - icd system was programmed to therapy each s - icd system was evaluated prior to and immediately after the scan to verify proper functioning , including interrogation , sensing , and battery voltage . after the completion of the mri , the s - icd system was reprogrammed to original settings . long - term regular clinical follow - up and checking of the device were performed . in patients with intolerable heating , the scan was halted within seconds and changed to a scan of the brain , which proceeded without incident . the cause of this skin anomaly is not known ; it was later noted to have fully healed at a follow - up 10 days after the scan . to ascertain the effect of heating due to the instrumented thermistor catheter , the two patients who experienced the heating ( examinations 9 and 16 , see table 2 ) were rescanned several weeks later without the thermistor catheter in place ( examinations 11 and 17 ) . first , modified sequence ( with even lower amount of energy deposited in the tissue ) was used , which caused no heating . none of the patients reported any pulling or twisting of the can or pain from heating of the s - icd electrode . this was due to the can and not the electrode ( see figure 1 ) , modifications to the protocol for the lumbar spine resulted in a lower signal - to - noise ratio ; however , the images remain in diagnostic quality ( see figure 2 ) . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . pacing thresholds can not be assessed by the s - icd system , so this was not evaluated . none of the patients reported any pulling or twisting of the can or pain from heating of the s - icd electrode . for scans of the brain , lumbar spine , knee , and cervical spine , no effect from image artefact was noted in the anatomical area of interest . this was due to the can and not the electrode ( see figure 1 ) , modifications to the protocol for the lumbar spine resulted in a lower signal - to - noise ratio ; however , the images remain in diagnostic quality ( see figure 2 ) . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . the steady - state free precession ( ssfp ) sequence ( a and b ) shows more artefacts . it could be caused by s - icd but also by metallic ring in mitral annulus . lumbar spine imaging with icd : low sar t2 fse sequence ( upper image ) compared with normal t2 fse in the same subject ( lower image , there are several reports in the current literature about mr - conditional pacemakers from several companies , but very limited reports about mr - conditional icds . biotronik announced in late 2011 release of their first mr - compatible icd device and defibrillator leads pro mri , but in the conditions of use excluded scanning of the torso and focused more on the extremities examination . in european heart rhythm association survey , 60% of centres did not implant any mri - certified icds , 34.3% implanted < 10 icd devices , and only 5.6% implanted 10 and more icds ; one - fifth of responders stated that mri - certified icds should be implanted in all patients but lack of reimbursement was indicated as a possible obstacle to implant more mri - certified pacemakers / icds by 47.1% of responding centres . none of the components of the s - icd system are on or in the heart . this required a revision of our protocol , which was to re - scan two of the patients who complained of heating . the thermistor catheter is constructed of insulated conductive cables connected to electrodes and should couple to the rf fields efficiently , causing heating at the electrodes and pain or damage on the surface of the skin where the probe was placed over the s - icd can . if the heating was due to the s - icd can itself , it would more likely occur during gradient - intensive scan sequences ( which can generate eddy currents on can surfaces and internal components ) and at locations in the bore where there are high gradient fields , such as near the bore edges . however , when the patient was scanned with gradient - intensive scan sequences ( e.g. flair dwi ) and with the s - icd system in high gradient field locations in the bore ( e.g. in addition , the subcutaneous lead , which was not instrumented with a thermistor catheter , never resulted in any heating sensation noted by the patient , even when exactly the same sequence that resulted in heating in the first session was used . the use of mri - compatible temperature monitors such as fibre optic temperature probes would have provided better confirmation of possible skin temperature elevation and would not have been affected by the rf fields . standard interrogation of the s - icd revealed no adverse effects upon the functioning of the system . while no adverse effects upon the post - scan s - icd device function were noted , not all possible scanning protocols were tested . this study included only 15 patients and 22 scans done on the same 1.5 t mri scanner . device functionality was tested immediately after the scan but not for long - term effects . device functionality was tested immediately after the scan but not for long - term effects . while more data are required to support a claim of mri - conditional , this study is the study to demonstrate the feasibility of exposing s - icd patients to mri using the scanning and monitor protocol described , with some precautionary measures including : ( i ) programming the device therapy off ; ( ii ) limiting the sar to 2.0 w / kg ; ( iii ) continuous monitoring of the patients pulse oximetry and ecg by qualified personnel and especially for any feelings of heating ; ( iv ) evaluate device function post scan ; ( v ) availability of full resuscitation facilities at the mri site . in our study , the only heating was very likely introduced by not fully mri - compatible thermometer probe ; subjects rescanned without the probe did not report any abnormalities during the scan of any body area listed ( brain , cervical and lumbar spine , heart , and knee ) .

most adults with autoimmune diabetes non - insulin - requiring at diagnosis become so within 36 years ( 1 , 2 ) . the optimal treatment for this second largest group of patients with diabetes is still unknown ( 37 ) . adult patients with autoimmune diabetes usually have larger remaining -cell mass at diagnosis and many develop -cell destruction more slowly . latent autoimmune diabetes in adults ( lada ) is therefore a suitable group for evaluating new therapies in autoimmune diabetes and may also serve as a model for intervention in classical type 1 diabetes ( 3 , 4 , 69 ) . the incidence of autoimmune diabetes is about equal in almost all age groups ( 10 , 11 ) . abrupt onset , often with ketoacidosis , is most frequent during childhood , a more modest onset is more frequent in adolescents and younger adults , and among adults and elders a slowly progressive onset , termed lada , is frequent ( 3 , 4 , 11 , 12 ) . classical type 1 diabetes and lada patients often have normal c - peptide levels at diagnosis , but further progressive decline occurs after onset , and insulin dependency occurs almost inevitably ( 3 , 4 , 8 , 9 , 13 ) . most trials in early type 1 diabetes have been performed in children , whose remaining -cell mass is limited , and short - term evaluation of intervention may be difficult also due to not infrequently occurring remission periods ( 14 , 15 ) . no therapy has yet been demonstrated to promote long - term insulin independency ( 3 , 5 , 7 , 16 ) . rodent studies have demonstrated potential positive effects of insulin treatment ( 17 , 18 ) . a pilot study of small doses of insulin versus sulphonylurea ( su ) to ten ica - positive patients with slowly progressive -cell failure favoured insulin for the preservation of c - peptide ( 19 ) . c - peptide is the outcome measure of choice of -cell function in trials of autoimmune diabetes ( 20 ) . even modest preservation of -cell function has been demonstrated to have positive effects on the frequency of hypoglycaemic events , and on the prevalence of retinopathy ( 21 ) . to investigate the effect of early insulin treatment in lada patients , for 3 years , on residual -cell function and metabolic control , compared with a group initially treated with diet and/or oral hypoglycaemic agents ( oha ) . adults , aged 30 years , diagnosed with diabetes in lund and kronoberg counties in southern sweden , non - insulin - requiring at diagnosis and positive to at least one of gadabs and/or icas were eligible for participation . two thirds had to be excluded due to mental conditions or severe physical illness , but also unwillingness to risk the early start of insulin injections . the majority of the patients were randomised into two groups , in blocks of eight , by pre - prepared closed envelopes kept at the two hospital policlinics . however complete strict randomisation was not possible , as some patients refused randomisation to possible insulin treatment before it was unavoidable . there were 20 patients in the intervention group ( i ) , treated with insulin from baseline , starting with 26 units intermediate - acting insulin at night ; and 17 patients in the control group ( c ) who received regular treatment with dietoha , mostly metformin , and some su ( 5/17 ; 30% ) . for both the groups , goals for glucose levels were in accordance with general guidelines ( fasting plasma glucose ( fpg ) 4.57 , preprandial pg 57 and postprandial decisions to increase treatment in doses , number of doses and addition of ohas or insulin were at the discretion of the treating physician . if two doses / day of intermediate - acting insulin or mix - insulin were not satisfactory , doses of direct or rapid - acting insulin before meals were added , resulting in 14 doses / day . glucagon - stimulation tests were performed at baseline and after 12 , 24 and 36 months during annual policlinic visits at the two research clinics . after an overnight fast , c - peptide was determined before and 6 min after i.v . c - peptide was analysed by commercial ria ( md315 , euro - diagnostica ab , malm , sweden ) , total variation ( sum of intra - and inter - assay variations ) 7% , reference range 0.251.0 c - peptide level , to reflect a preserved normal -cell function , was arbitrarily set at 0.5 nmol / l . icas were analysed with immunofluorescence assay , with detection limit 9 jdf - u , sensitivity 100% and specificity 88% . gadabs were analysed with radioimmuno - precipitation with lower reference limit at an index of 0.08 , corresponding to 21 who - u / ml , sensitivity 70% and specificity 100% . all analyses were standardised according to the diabetes antibody standardization program ( 25 , 26 ) . metabolic control was assessed by hbalc ( mono - s ) , and values were converted to dcct standard ( 27 ) . regarding the metabolic syndrome , complete information was available regarding only body mass index ( bmi ) and prevalence of hypertension , defined as blood pressure > 140/80 mmhg at the baseline visit , or taking antihypertensive medication . all subjects provided informed consent . analyses were carried out according to intention - to - treat . for comparisons between the groups , student 's t - test , or fisher 's exact test and the mann c - peptide and hbalc at baseline and after 12 , 24 , and 36 months were analysed with repeated measures anova using time as covariate ; for three - group analyses , anova with bonferroni correction was performed where appropriate . risk factors and relations were analysed in several models with simple , multiple , linear and logistic regressions ( forward stepwise , wald ) . spss software , version 17.0 ( chicago , il , usa ) , was used . analyses were carried out according to intention - to - treat . for comparisons between the groups , student 's t - test , or fisher 's exact test and the mann c - peptide and hbalc at baseline and after 12 , 24 , and 36 months were analysed with repeated measures anova using time as covariate ; for three - group analyses , anova with bonferroni correction was performed where appropriate . risk factors and relations were analysed in several models with simple , multiple , linear and logistic regressions ( forward stepwise , wald ) . spss software , version 17.0 ( chicago , il , usa ) , was used . for the baseline characteristics of the groups , see table 1 . there were no significant gender differences in the whole study , except that in the control group there were only men with hypertension ( p=0.03 ) . most subjects were overweight since both the i and c groups had mean bmi27 kg / m . median duration of diabetes at inclusion in the study was 5.0 ( quartiles 3.09.0 ) months . in both the groups , 90% of the patients , 18/20 in i and 15/17 in c , completed 36 months of follow - up . the conventionally treated ( c ) , 30% ( 5/17 ) started insulin treatment due to clinical necessity within 6612182430 months . for the levels of glucagon - stimulated c - peptide , see table 2 and fig . c - peptide levels were unchanged for four patients , increased by mean 0.73 ( 0.5 ) nmol / l for six and declined in all others after 36 months . mean glucagon - stimulated c - peptide decreased significantly in both the groups during the 36 months ( p<0.0001 ) . there was a significant time trend for the decrease in c - peptide of 0.17 nmol / l per year ( p=0.03 ) over 36 months without any significant difference between the groups . in repeated measures , anova with time as covariate , that analyses the changes in c - peptide over time with the levels at baseline taken into account , no differences could be found regarding mean - stimulated c - peptide at any time point , although with the mann whitney u test the difference in c - peptide at baseline ( cp0 ) was significant , p=0.03 . there were large variations in c - peptide levels between different individuals , at all time points , within both the groups ( p<0.0001 ) , explaining all the variation between them ( fig . cp0 explained 43% of level of c - peptide at 36 months ( cp36 ) , r 0.43 ( p<0.0001 ) . furthermore , age was the only other factor that had a weak and non - significant influence on cp36 , explaining about 5% of cp36 , r 0.049 ( p=0.2 ) . gender , baseline or end - of - study values of bmi , titres of gadab or ica , hbalc or diabetes duration before the study start did not influence c - peptide at end - of - study . it was 86% ( 13/15 ) in c , and 61% ( 11/18 ) in i ( p=0.13 ) . the odds ratio ( or ) for having a cp36 0.5 nmol / l was 2.4 for every increase in cp0 with 0.10 nmol / l ( p=0.02 ) , and 1.06 for each increase in baseline age by 1 year ( p=0.03 ) . if corrected for cp0 and age , the two factors found to have any influence on cp36 , the insulin treated had a non - significant or of 2.5 ( 0.04184 ) of having a cp36 of 0.5 the results of levels of fasting c - peptide ( fcp ) , when comparing the two treatment groups ( data not shown ) , were in accordance with the described results of stimulated c - peptide . among the controls , the level of hbalc had increased significantly at 36 months from 7.0 ( 1.3)% to 7.5 ( 1.5)% ( p=0.006 ) ( fig . , there was no significant difference between hbalc at baseline , 7.3 ( 1.3)% , and after 36 months , 7.2 ( 0.7)% ( p=0.6 ) ( fig . 2 ) . for the levels of hbalc at baseline and during follow - up , see table 2 and fig . the differences between the groups in absolute levels of hbalc were not significant either at baseline or after 12 , 24 or 36 months . the levels of hbalc were not influenced by age , gender , bmi , antibody prevalences or titres or c - peptide levels . at baseline , prevalences of gadab were 94% , ica 67% , 72% had both antibodies , 22% gadab only and 6% only ica , with no significant differences between the two treatment groups . of the 32 patients whose ia-2a status was known , 7 ( 22% ) were positive , all of them were also positive to gadab and all but one was positive to ica , meaning that 75% of all were positive to at least two antibodies . at baseline , mean indexes of gadab were 0.78 ( 0.39 ) in i , 0.78 ( 0.48 ) in c ( ns ) and mean ica titres were 29.4 ( 40 ) in i , 72.4 ( 119 ) jdf - u in c ( ns ) . at baseline , there were no significant differences in the prevalences of any of the three antibodies between the two treatment groups or between genders , different ages , duration of diabetes before study start or levels of bmi or hbalc . neither were there any significant differences between the groups in titres of gadab or ica after 12 , 24 or 36 months . the titres of gadab or ica were not related to patient age , gender , bmi , diabetes duration , treatment or hbalc at baseline or during the follow - up . c - peptide at baseline or 36 months was not influenced by baseline titre of gadab , ica or ia-2a . no episodes of major hypoglycaemia were reported for any of the patients , and only a few minor ones . mean weight at baseline was 77.4 ( 14.5 , range 57.8110 ) kg in group i , and 83.0 ( 17.8 , range 50.8117 ) kg in group c ( ns ) ; at end - of - study 79.3 ( 12.4 , 57.7101 ) kg in i , 82.3 ( 14.8 , range 50.4115 ) kg in c ( ns ) . mean weight change during the study was 2.5 ( 4.8 , range 8.8 to + 9.3 ) kg in i ; 1.0 ( 10.5 , range 27.3 to + 16.4 ) kg in c ( ns ) . for the three groups , those treated with insulin from baseline , those never treated with insulin and those who were originally treated with dietoha , but had to start insulin treatment during the study , the influences of age , bmi , hbalc , diabetes duration before study start or antibody titres were analysed , with no significant findings except for the influence of cp0 on cp36 . the tests for all the relevant parameters were also carried out with the 37 patients divided into groups of ever- versus never - insulin treated ( during the study ) , again with no significant results ( p=0.120.87 ) , apart from the significant influence of cp0 on cp36 ( p<0.0001 ) . for the levels of glucagon - stimulated c - peptide , see table 2 and fig . c - peptide levels were unchanged for four patients , increased by mean 0.73 ( 0.5 ) nmol / l for six and declined in all others after 36 months . mean glucagon - stimulated c - peptide decreased significantly in both the groups during the 36 months ( p<0.0001 ) . there was a significant time trend for the decrease in c - peptide of 0.17 nmol / l per year ( p=0.03 ) over 36 months without any significant difference between the groups . in repeated measures , anova with time as covariate , that analyses the changes in c - peptide over time with the levels at baseline taken into account , no differences could be found regarding mean - stimulated c - peptide at any time point , although with the mann whitney u test the difference in c - peptide at baseline ( cp0 ) was significant , p=0.03 . there were large variations in c - peptide levels between different individuals , at all time points , within both the groups ( p<0.0001 ) , explaining all the variation between them ( fig . cp0 explained 43% of level of c - peptide at 36 months ( cp36 ) , r 0.43 ( p<0.0001 ) . furthermore , age was the only other factor that had a weak and non - significant influence on cp36 , explaining about 5% of cp36 , r 0.049 ( p=0.2 ) . gender , baseline or end - of - study values of bmi , titres of gadab or ica , hbalc or diabetes duration before the study start did not influence c - peptide at end - of - study . it was 86% ( 13/15 ) in c , and 61% ( 11/18 ) in i ( p=0.13 ) . the odds ratio ( or ) for having a cp36 0.5 nmol / l was 2.4 for every increase in cp0 with 0.10 nmol / l ( p=0.02 ) , and 1.06 for each increase in baseline age by 1 year ( p=0.03 ) . if corrected for cp0 and age , the two factors found to have any influence on cp36 , the insulin treated had a non - significant or of 2.5 ( 0.04184 ) of having a cp36 of 0.5 the results of levels of fasting c - peptide ( fcp ) , when comparing the two treatment groups ( data not shown ) , were in accordance with the described results of stimulated c - peptide . among the controls , the level of hbalc had increased significantly at 36 months from 7.0 ( 1.3)% to 7.5 ( 1.5)% ( p=0.006 ) ( fig . , there was no significant difference between hbalc at baseline , 7.3 ( 1.3)% , and after 36 months , 7.2 ( 0.7)% ( p=0.6 ) ( fig . 2 ) . for the levels of hbalc at baseline and during follow - up , see table 2 and fig . 2 . the differences between the groups in absolute levels of hbalc were not significant either at baseline or after 12 , 24 or 36 months . the levels of hbalc were not influenced by age , gender , bmi , antibody prevalences or titres or c - peptide levels . at baseline , prevalences of gadab were 94% , ica 67% , 72% had both antibodies , 22% gadab only and 6% only ica , with no significant differences between the two treatment groups . of the 32 patients whose ia-2a status was known , 7 ( 22% ) were positive , all of them were also positive to gadab and all but one was positive to ica , meaning that 75% of all were positive to at least two antibodies . at baseline , mean indexes of gadab were 0.78 ( 0.39 ) in i , 0.78 ( 0.48 ) in c ( ns ) and mean ica titres were 29.4 ( 40 ) in i , 72.4 ( 119 ) jdf - u in c ( ns ) . at baseline , there were no significant differences in the prevalences of any of the three antibodies between the two treatment groups or between genders , different ages , duration of diabetes before study start or levels of bmi or hbalc . neither were there any significant differences between the groups in titres of gadab or ica after 12 , 24 or 36 months . the titres of gadab or ica were not related to patient age , gender , bmi , diabetes duration , treatment or hbalc at baseline or during the follow - up . c - peptide at baseline or 36 months was not influenced by baseline titre of gadab , ica or ia-2a . no episodes of major hypoglycaemia were reported for any of the patients , and only a few minor ones . mean weight at baseline was 77.4 ( 14.5 , range 57.8110 ) kg in group i , and 83.0 ( 17.8 , range 50.8117 ) kg in group c ( ns ) ; at end - of - study 79.3 ( 12.4 , 57.7101 ) kg in i , 82.3 ( 14.8 , range 50.4115 ) kg in c ( ns ) . mean weight change during the study was 2.5 ( 4.8 , range 8.8 to + 9.3 ) kg in i ; 1.0 ( 10.5 , range 27.3 to + 16.4 ) kg in c ( ns ) . for the three groups , those treated with insulin from baseline , those never treated with insulin and those who were originally treated with dietoha , but had to start insulin treatment during the study , the influences of age , bmi , hbalc , diabetes duration before study start or antibody titres were analysed , with no significant findings except for the influence of cp0 on cp36 . the tests for all the relevant parameters were also carried out with the 37 patients divided into groups of ever- versus never - insulin treated ( during the study ) , again with no significant results ( p=0.120.87 ) , apart from the significant influence of cp0 on cp36 ( p<0.0001 ) . few prospective intervention studies have been conducted in lada patients and there is still no general agreement on the best treatment aimed to preserve -cell function ( 57 , 16 ) . there has not been any general consensus definition of lada , which complicates comparisons and pooling of results . the most common denominators are adult age , positivity to at least one pancreatic autoantibody , and non - insulin dependency at diagnosis ( 4 ) . age , bmi , duration of diabetes and of insulin independency , which of the antibodies that were analysed , gadab titres and the expression of the essential outcome variable c - peptide vary ( 2 , 4 , 5 , 2830 ) . a cochrane review also noted the heterogeneity between studies , and the conclusion about early insulin treatment was uncertain ( 5 ) . our study included patients aged 30 years , non - insulin dependent at the times of diagnosis and inclusion and positive to at least one pancreatic autoantibody , for 75% two antibodies , thereby fulfilling the main criteria for lada ( 4 ) . the results of the study indicated that none of the baseline parameters , except initial c - peptide level , significantly influenced the outcome , eliminating the importance of several criteria in comparisons with other studies . in other studies , patients aged > 65 years have often been excluded , but lada exists also in these older age groups ( 11 ) . the decline in residual -cell function was progressive for the majority of our lada patients , as is usual in autoimmune diabetes ( 4 , 8 , 13 , 16 ) . we observed great variation in the rates and magnitudes of -cell loss between patients and between different time periods during the study , with no consistent patterns . mechanisms such as more step - wise losses due to , for instance , partial remissions might explain this ( 15 ) . the decline in c - peptide was irrespective of age , gender , bmi , antibody titres , hbalc or treatment modality . the lack of influence of bmi , age , diabetes duration and baseline hbalc on disease progression was also seen in a non - interventional observation study of lada that followed 13 ab - positive patients by stimulated c - peptide for 2 years ( 16 ) . similar to ukpds , we found no association between gadab levels and disease progress ( 31 ) , in contrast to observational studies that described this ( 30 , 32 ) . we could not , in a number of regression analyses , define any other factor besides cp0 that significantly influenced the level of cp36 . the significance of initial c - peptide level was also demonstrated in a large swedish study of new - onset 1534 year olds and in the tokyo intervention study ( 28 , 33 ) . the length of our study may explain that some patients with initially higher levels of c - peptide , overrepresented in the control group , by 36 months had not yet lost enough -cell function to be clinically insulin dependent . some antibody - positive patients were described to take up to 12 years to become insulin dependent , but practically all eventually did ( 34 ) . a significant beneficial effect of early insulin treatment on the preservation of -cell function could not be demonstrated , but level of hbalc after 36 months was better preserved in the insulin treated , in keeping with observations by chaillous et al . incidentally , the shape of the curve of the development of hbalc levels over time for the conventionally treated group in our study had a likeness to that observed in the ukpds ( 35 ) . our study , as most prospective intervention studies of lada , was not large . the tokyo study , with 60 patients , found a preference for insulin treatment versus su , possibly due to the differences in treatment , but longer duration of diabetes , up to 5 years without insulin before inclusion , rendering a selection of patients with better endogenous insulin production from the start , would have excluded those who progressed earlier to insulin dependence , so the trial population differed from ours ( 28 ) . baseline level of c - peptide was an important independent predictor of the ability to preserve a sufficient amount of c - peptide over time , just as in our study . many reports end with a general recommendation of insulin treatment in lada , but the evidence has not been compelling , as concluded by the 2007 cochrane review , which scrutinised seven insulin intervention studies in lada , two insulin versus su , the rest insulin alone versus different combinations of insulin+oha ( 5 ) . ukpds recorded hbalc , weight and treatment , randomised to insulin versus su , and found that 60% of the su treated were insulin dependent after 2 years ( 36 ) . one conclusion was that su might promote insulin dependency and apart from not recommending su the cochrane review found no preference for any special type of treatment for the lada group ( 5 ) . in our study after 3 years , 65% of the conventionally treated patients were not yet treated with insulin . in contrast to both ukpds and the tokyo study , only 30% of our control patients were treated with su , which could be of importance for -cell function . in another study , of 54 patients in four groups , the insulin treated , all with low fcp , 0.3 nmol , received either insulin alone or combined with rosiglitazone ( rgz ) , and the oha treated , all with fcp > 0.3 to our knowledge , this study is the first prospective controlled european intervention study of treatment in lada . differences in defining the lada population regarding age , diabetes duration before start of intervention , antibody prevalences and gadab titres , bmi and , not least , baseline levels of c - peptide , if available , have contributed to difficulties in interpreting and comparing the results of the few existing lada intervention studies ( 4 , 5 , 28 , 29 , 37 ) . in this study , none of these factors , except baseline level of c - peptide , significantly affected the outcome . the similar findings also seen in trials of classical type 1 diabetes and of prevention of autoimmune diabetes in high - risk individuals substantiate the observation of the influence of initial level of c - peptide on outcome level ( 38 , 39 ) . we also saw a non - significant or favouring insulin treatment for preservation of -cell function , indicating the possibility that a larger study population and/or a longer period of follow - up might demonstrate significant preference for early insulin treatment also regarding -cell function . this study indicated that early insulin treatment in lada patients lead to better preservation of level of metabolic control , and that it was safe and well tolerated . the decline in c - peptide was progressive irrespective of age , gender , bmi , hbalc levels and antibody titres . only baseline level of c - peptide significantly influenced c - peptide level after 3 years . m landin - olsson has received a part - time professorship sponsored by novo - nordisk scandinavia . the other authors have no dualities of interest in relation to this article . the work was financed by the healthcare regions of skane and kronoberg , southern sweden ; lund university funding of clinical research ( alf ) ; and the swedish council of medical research .

objectivesthe optimal treatment of latent autoimmune diabetes in adults ( lada ) is not established . we explored whether early insulin treatment , which has shown beneficial effects in rodents and in human pilot studies , would result in better preservation of -cell function or metabolic control , compared with conventional treatment.subjects and methodsglucagon - stimulated c - peptide and hbalc were evaluated at baseline and after 12 , 24 and 36 months in 37 patients recently diagnosed with diabetes , aged 30 years , non - insulin - requiring and gadab and/or ica positive . twenty patients received early insulin and 17 received conventional treatment ( dietoral hypoglycaemic agents ( oha ) , metformin , some and/or sulfonylurea ) and insulin when necessary.resultslevel of metabolic control , hbalc , was preserved in the early insulin treated , while it significantly deteriorated in the conventionally treated . there was no significant difference between the groups in c - peptide after 12 , 24 or 36 months , or in the decline of c - peptide . only baseline c - peptide predicted a c - peptide of 0.5 nmol / l at 36 months . gender , body mass index , antibody titres or hbalc did not influence the levels of c - peptide or hbalc at baseline or end - of - study , or the decline in c - peptide . among the dietoha - treated , 5/17 ( 30% ) developed insulin dependency during the follow - up . no major hypoglycaemic events occurred.conclusionsearly insulin treatment in lada leads to better preservation of metabolic control and was safe . superior preservation of c - peptide could not be significantly demonstrated . only baseline level of c - peptide significantly influenced c - peptide level after 3 years . further studies exploring the best treatment in lada are warranted .

Introduction Objective Subjects and methods Statistical analyses Results -Cell function Metabolic control Autoimmunity Adverse events Three-group analysis and ever- versus never-insulin treated Discussion Further considerations Conclusions Declaration of interest Funding

to investigate the effect of early insulin treatment in lada patients , for 3 years , on residual -cell function and metabolic control , compared with a group initially treated with diet and/or oral hypoglycaemic agents ( oha ) . adults , aged 30 years , diagnosed with diabetes in lund and kronoberg counties in southern sweden , non - insulin - requiring at diagnosis and positive to at least one of gadabs and/or icas were eligible for participation . glucagon - stimulation tests were performed at baseline and after 12 , 24 and 36 months during annual policlinic visits at the two research clinics . c - peptide was analysed by commercial ria ( md315 , euro - diagnostica ab , malm , sweden ) , total variation ( sum of intra - and inter - assay variations ) 7% , reference range 0.251.0 c - peptide level , to reflect a preserved normal -cell function , was arbitrarily set at 0.5 nmol / l . for comparisons between the groups , student 's t - test , or fisher 's exact test and the mann c - peptide and hbalc at baseline and after 12 , 24 , and 36 months were analysed with repeated measures anova using time as covariate ; for three - group analyses , anova with bonferroni correction was performed where appropriate . for comparisons between the groups , student 's t - test , or fisher 's exact test and the mann c - peptide and hbalc at baseline and after 12 , 24 , and 36 months were analysed with repeated measures anova using time as covariate ; for three - group analyses , anova with bonferroni correction was performed where appropriate . there was a significant time trend for the decrease in c - peptide of 0.17 nmol / l per year ( p=0.03 ) over 36 months without any significant difference between the groups . gender , baseline or end - of - study values of bmi , titres of gadab or ica , hbalc or diabetes duration before the study start did not influence c - peptide at end - of - study . if corrected for cp0 and age , the two factors found to have any influence on cp36 , the insulin treated had a non - significant or of 2.5 ( 0.04184 ) of having a cp36 of 0.5 the results of levels of fasting c - peptide ( fcp ) , when comparing the two treatment groups ( data not shown ) , were in accordance with the described results of stimulated c - peptide . , there was no significant difference between hbalc at baseline , 7.3 ( 1.3)% , and after 36 months , 7.2 ( 0.7)% ( p=0.6 ) ( fig . the differences between the groups in absolute levels of hbalc were not significant either at baseline or after 12 , 24 or 36 months . neither were there any significant differences between the groups in titres of gadab or ica after 12 , 24 or 36 months . there was a significant time trend for the decrease in c - peptide of 0.17 nmol / l per year ( p=0.03 ) over 36 months without any significant difference between the groups . gender , baseline or end - of - study values of bmi , titres of gadab or ica , hbalc or diabetes duration before the study start did not influence c - peptide at end - of - study . if corrected for cp0 and age , the two factors found to have any influence on cp36 , the insulin treated had a non - significant or of 2.5 ( 0.04184 ) of having a cp36 of 0.5 the results of levels of fasting c - peptide ( fcp ) , when comparing the two treatment groups ( data not shown ) , were in accordance with the described results of stimulated c - peptide . , there was no significant difference between hbalc at baseline , 7.3 ( 1.3)% , and after 36 months , 7.2 ( 0.7)% ( p=0.6 ) ( fig . the differences between the groups in absolute levels of hbalc were not significant either at baseline or after 12 , 24 or 36 months . neither were there any significant differences between the groups in titres of gadab or ica after 12 , 24 or 36 months . the titres of gadab or ica were not related to patient age , gender , bmi , diabetes duration , treatment or hbalc at baseline or during the follow - up . the decline in c - peptide was irrespective of age , gender , bmi , antibody titres , hbalc or treatment modality . a significant beneficial effect of early insulin treatment on the preservation of -cell function could not be demonstrated , but level of hbalc after 36 months was better preserved in the insulin treated , in keeping with observations by chaillous et al . this study indicated that early insulin treatment in lada patients lead to better preservation of level of metabolic control , and that it was safe and well tolerated . only baseline level of c - peptide significantly influenced c - peptide level after 3 years .

the optimal treatment for this second largest group of patients with diabetes is still unknown ( 37 ) . adult patients with autoimmune diabetes usually have larger remaining -cell mass at diagnosis and many develop -cell destruction more slowly . latent autoimmune diabetes in adults ( lada ) is therefore a suitable group for evaluating new therapies in autoimmune diabetes and may also serve as a model for intervention in classical type 1 diabetes ( 3 , 4 , 69 ) . the incidence of autoimmune diabetes is about equal in almost all age groups ( 10 , 11 ) . abrupt onset , often with ketoacidosis , is most frequent during childhood , a more modest onset is more frequent in adolescents and younger adults , and among adults and elders a slowly progressive onset , termed lada , is frequent ( 3 , 4 , 11 , 12 ) . most trials in early type 1 diabetes have been performed in children , whose remaining -cell mass is limited , and short - term evaluation of intervention may be difficult also due to not infrequently occurring remission periods ( 14 , 15 ) . no therapy has yet been demonstrated to promote long - term insulin independency ( 3 , 5 , 7 , 16 ) . rodent studies have demonstrated potential positive effects of insulin treatment ( 17 , 18 ) . a pilot study of small doses of insulin versus sulphonylurea ( su ) to ten ica - positive patients with slowly progressive -cell failure favoured insulin for the preservation of c - peptide ( 19 ) . c - peptide is the outcome measure of choice of -cell function in trials of autoimmune diabetes ( 20 ) . to investigate the effect of early insulin treatment in lada patients , for 3 years , on residual -cell function and metabolic control , compared with a group initially treated with diet and/or oral hypoglycaemic agents ( oha ) . adults , aged 30 years , diagnosed with diabetes in lund and kronoberg counties in southern sweden , non - insulin - requiring at diagnosis and positive to at least one of gadabs and/or icas were eligible for participation . there were 20 patients in the intervention group ( i ) , treated with insulin from baseline , starting with 26 units intermediate - acting insulin at night ; and 17 patients in the control group ( c ) who received regular treatment with dietoha , mostly metformin , and some su ( 5/17 ; 30% ) . for both the groups , goals for glucose levels were in accordance with general guidelines ( fasting plasma glucose ( fpg ) 4.57 , preprandial pg 57 and postprandial decisions to increase treatment in doses , number of doses and addition of ohas or insulin were at the discretion of the treating physician . glucagon - stimulation tests were performed at baseline and after 12 , 24 and 36 months during annual policlinic visits at the two research clinics . c - peptide was analysed by commercial ria ( md315 , euro - diagnostica ab , malm , sweden ) , total variation ( sum of intra - and inter - assay variations ) 7% , reference range 0.251.0 c - peptide level , to reflect a preserved normal -cell function , was arbitrarily set at 0.5 nmol / l . for comparisons between the groups , student 's t - test , or fisher 's exact test and the mann c - peptide and hbalc at baseline and after 12 , 24 , and 36 months were analysed with repeated measures anova using time as covariate ; for three - group analyses , anova with bonferroni correction was performed where appropriate . for comparisons between the groups , student 's t - test , or fisher 's exact test and the mann c - peptide and hbalc at baseline and after 12 , 24 , and 36 months were analysed with repeated measures anova using time as covariate ; for three - group analyses , anova with bonferroni correction was performed where appropriate . most subjects were overweight since both the i and c groups had mean bmi27 kg / m . median duration of diabetes at inclusion in the study was 5.0 ( quartiles 3.09.0 ) months . for the levels of glucagon - stimulated c - peptide , see table 2 and fig . in repeated measures , anova with time as covariate , that analyses the changes in c - peptide over time with the levels at baseline taken into account , no differences could be found regarding mean - stimulated c - peptide at any time point , although with the mann whitney u test the difference in c - peptide at baseline ( cp0 ) was significant , p=0.03 . gender , baseline or end - of - study values of bmi , titres of gadab or ica , hbalc or diabetes duration before the study start did not influence c - peptide at end - of - study . it was 86% ( 13/15 ) in c , and 61% ( 11/18 ) in i ( p=0.13 ) . the odds ratio ( or ) for having a cp36 0.5 nmol / l was 2.4 for every increase in cp0 with 0.10 nmol / l ( p=0.02 ) , and 1.06 for each increase in baseline age by 1 year ( p=0.03 ) . if corrected for cp0 and age , the two factors found to have any influence on cp36 , the insulin treated had a non - significant or of 2.5 ( 0.04184 ) of having a cp36 of 0.5 the results of levels of fasting c - peptide ( fcp ) , when comparing the two treatment groups ( data not shown ) , were in accordance with the described results of stimulated c - peptide . among the controls , the level of hbalc had increased significantly at 36 months from 7.0 ( 1.3)% to 7.5 ( 1.5)% ( p=0.006 ) ( fig . , there was no significant difference between hbalc at baseline , 7.3 ( 1.3)% , and after 36 months , 7.2 ( 0.7)% ( p=0.6 ) ( fig . for the levels of hbalc at baseline and during follow - up , see table 2 and fig . the differences between the groups in absolute levels of hbalc were not significant either at baseline or after 12 , 24 or 36 months . at baseline , prevalences of gadab were 94% , ica 67% , 72% had both antibodies , 22% gadab only and 6% only ica , with no significant differences between the two treatment groups . of the 32 patients whose ia-2a status was known , 7 ( 22% ) were positive , all of them were also positive to gadab and all but one was positive to ica , meaning that 75% of all were positive to at least two antibodies . at baseline , mean indexes of gadab were 0.78 ( 0.39 ) in i , 0.78 ( 0.48 ) in c ( ns ) and mean ica titres were 29.4 ( 40 ) in i , 72.4 ( 119 ) jdf - u in c ( ns ) . at baseline , there were no significant differences in the prevalences of any of the three antibodies between the two treatment groups or between genders , different ages , duration of diabetes before study start or levels of bmi or hbalc . neither were there any significant differences between the groups in titres of gadab or ica after 12 , 24 or 36 months . the titres of gadab or ica were not related to patient age , gender , bmi , diabetes duration , treatment or hbalc at baseline or during the follow - up . no episodes of major hypoglycaemia were reported for any of the patients , and only a few minor ones . mean weight at baseline was 77.4 ( 14.5 , range 57.8110 ) kg in group i , and 83.0 ( 17.8 , range 50.8117 ) kg in group c ( ns ) ; at end - of - study 79.3 ( 12.4 , 57.7101 ) kg in i , 82.3 ( 14.8 , range 50.4115 ) kg in c ( ns ) . mean weight change during the study was 2.5 ( 4.8 , range 8.8 to + 9.3 ) kg in i ; 1.0 ( 10.5 , range 27.3 to + 16.4 ) kg in c ( ns ) . for the three groups , those treated with insulin from baseline , those never treated with insulin and those who were originally treated with dietoha , but had to start insulin treatment during the study , the influences of age , bmi , hbalc , diabetes duration before study start or antibody titres were analysed , with no significant findings except for the influence of cp0 on cp36 . the tests for all the relevant parameters were also carried out with the 37 patients divided into groups of ever- versus never - insulin treated ( during the study ) , again with no significant results ( p=0.120.87 ) , apart from the significant influence of cp0 on cp36 ( p<0.0001 ) . for the levels of glucagon - stimulated c - peptide , see table 2 and fig . there was a significant time trend for the decrease in c - peptide of 0.17 nmol / l per year ( p=0.03 ) over 36 months without any significant difference between the groups . in repeated measures , anova with time as covariate , that analyses the changes in c - peptide over time with the levels at baseline taken into account , no differences could be found regarding mean - stimulated c - peptide at any time point , although with the mann whitney u test the difference in c - peptide at baseline ( cp0 ) was significant , p=0.03 . gender , baseline or end - of - study values of bmi , titres of gadab or ica , hbalc or diabetes duration before the study start did not influence c - peptide at end - of - study . it was 86% ( 13/15 ) in c , and 61% ( 11/18 ) in i ( p=0.13 ) . the odds ratio ( or ) for having a cp36 0.5 nmol / l was 2.4 for every increase in cp0 with 0.10 nmol / l ( p=0.02 ) , and 1.06 for each increase in baseline age by 1 year ( p=0.03 ) . if corrected for cp0 and age , the two factors found to have any influence on cp36 , the insulin treated had a non - significant or of 2.5 ( 0.04184 ) of having a cp36 of 0.5 the results of levels of fasting c - peptide ( fcp ) , when comparing the two treatment groups ( data not shown ) , were in accordance with the described results of stimulated c - peptide . among the controls , the level of hbalc had increased significantly at 36 months from 7.0 ( 1.3)% to 7.5 ( 1.5)% ( p=0.006 ) ( fig . , there was no significant difference between hbalc at baseline , 7.3 ( 1.3)% , and after 36 months , 7.2 ( 0.7)% ( p=0.6 ) ( fig . at baseline , prevalences of gadab were 94% , ica 67% , 72% had both antibodies , 22% gadab only and 6% only ica , with no significant differences between the two treatment groups . at baseline , mean indexes of gadab were 0.78 ( 0.39 ) in i , 0.78 ( 0.48 ) in c ( ns ) and mean ica titres were 29.4 ( 40 ) in i , 72.4 ( 119 ) jdf - u in c ( ns ) . at baseline , there were no significant differences in the prevalences of any of the three antibodies between the two treatment groups or between genders , different ages , duration of diabetes before study start or levels of bmi or hbalc . neither were there any significant differences between the groups in titres of gadab or ica after 12 , 24 or 36 months . the titres of gadab or ica were not related to patient age , gender , bmi , diabetes duration , treatment or hbalc at baseline or during the follow - up . mean weight at baseline was 77.4 ( 14.5 , range 57.8110 ) kg in group i , and 83.0 ( 17.8 , range 50.8117 ) kg in group c ( ns ) ; at end - of - study 79.3 ( 12.4 , 57.7101 ) kg in i , 82.3 ( 14.8 , range 50.4115 ) kg in c ( ns ) . mean weight change during the study was 2.5 ( 4.8 , range 8.8 to + 9.3 ) kg in i ; 1.0 ( 10.5 , range 27.3 to + 16.4 ) kg in c ( ns ) . for the three groups , those treated with insulin from baseline , those never treated with insulin and those who were originally treated with dietoha , but had to start insulin treatment during the study , the influences of age , bmi , hbalc , diabetes duration before study start or antibody titres were analysed , with no significant findings except for the influence of cp0 on cp36 . the tests for all the relevant parameters were also carried out with the 37 patients divided into groups of ever- versus never - insulin treated ( during the study ) , again with no significant results ( p=0.120.87 ) , apart from the significant influence of cp0 on cp36 ( p<0.0001 ) . the most common denominators are adult age , positivity to at least one pancreatic autoantibody , and non - insulin dependency at diagnosis ( 4 ) . age , bmi , duration of diabetes and of insulin independency , which of the antibodies that were analysed , gadab titres and the expression of the essential outcome variable c - peptide vary ( 2 , 4 , 5 , 2830 ) . a cochrane review also noted the heterogeneity between studies , and the conclusion about early insulin treatment was uncertain ( 5 ) . our study included patients aged 30 years , non - insulin dependent at the times of diagnosis and inclusion and positive to at least one pancreatic autoantibody , for 75% two antibodies , thereby fulfilling the main criteria for lada ( 4 ) . the results of the study indicated that none of the baseline parameters , except initial c - peptide level , significantly influenced the outcome , eliminating the importance of several criteria in comparisons with other studies . in other studies , patients aged > 65 years have often been excluded , but lada exists also in these older age groups ( 11 ) . mechanisms such as more step - wise losses due to , for instance , partial remissions might explain this ( 15 ) . the lack of influence of bmi , age , diabetes duration and baseline hbalc on disease progression was also seen in a non - interventional observation study of lada that followed 13 ab - positive patients by stimulated c - peptide for 2 years ( 16 ) . we could not , in a number of regression analyses , define any other factor besides cp0 that significantly influenced the level of cp36 . the length of our study may explain that some patients with initially higher levels of c - peptide , overrepresented in the control group , by 36 months had not yet lost enough -cell function to be clinically insulin dependent . some antibody - positive patients were described to take up to 12 years to become insulin dependent , but practically all eventually did ( 34 ) . a significant beneficial effect of early insulin treatment on the preservation of -cell function could not be demonstrated , but level of hbalc after 36 months was better preserved in the insulin treated , in keeping with observations by chaillous et al . incidentally , the shape of the curve of the development of hbalc levels over time for the conventionally treated group in our study had a likeness to that observed in the ukpds ( 35 ) . our study , as most prospective intervention studies of lada , was not large . the tokyo study , with 60 patients , found a preference for insulin treatment versus su , possibly due to the differences in treatment , but longer duration of diabetes , up to 5 years without insulin before inclusion , rendering a selection of patients with better endogenous insulin production from the start , would have excluded those who progressed earlier to insulin dependence , so the trial population differed from ours ( 28 ) . baseline level of c - peptide was an important independent predictor of the ability to preserve a sufficient amount of c - peptide over time , just as in our study . many reports end with a general recommendation of insulin treatment in lada , but the evidence has not been compelling , as concluded by the 2007 cochrane review , which scrutinised seven insulin intervention studies in lada , two insulin versus su , the rest insulin alone versus different combinations of insulin+oha ( 5 ) . ukpds recorded hbalc , weight and treatment , randomised to insulin versus su , and found that 60% of the su treated were insulin dependent after 2 years ( 36 ) . one conclusion was that su might promote insulin dependency and apart from not recommending su the cochrane review found no preference for any special type of treatment for the lada group ( 5 ) . in our study after 3 years , 65% of the conventionally treated patients were not yet treated with insulin . in contrast to both ukpds and the tokyo study , only 30% of our control patients were treated with su , which could be of importance for -cell function . in another study , of 54 patients in four groups , the insulin treated , all with low fcp , 0.3 nmol , received either insulin alone or combined with rosiglitazone ( rgz ) , and the oha treated , all with fcp > 0.3 to our knowledge , this study is the first prospective controlled european intervention study of treatment in lada . differences in defining the lada population regarding age , diabetes duration before start of intervention , antibody prevalences and gadab titres , bmi and , not least , baseline levels of c - peptide , if available , have contributed to difficulties in interpreting and comparing the results of the few existing lada intervention studies ( 4 , 5 , 28 , 29 , 37 ) . in this study , none of these factors , except baseline level of c - peptide , significantly affected the outcome . the similar findings also seen in trials of classical type 1 diabetes and of prevention of autoimmune diabetes in high - risk individuals substantiate the observation of the influence of initial level of c - peptide on outcome level ( 38 , 39 ) . we also saw a non - significant or favouring insulin treatment for preservation of -cell function , indicating the possibility that a larger study population and/or a longer period of follow - up might demonstrate significant preference for early insulin treatment also regarding -cell function . only baseline level of c - peptide significantly influenced c - peptide level after 3 years . m landin - olsson has received a part - time professorship sponsored by novo - nordisk scandinavia . the other authors have no dualities of interest in relation to this article . the work was financed by the healthcare regions of skane and kronoberg , southern sweden ; lund university funding of clinical research ( alf ) ; and the swedish council of medical research .

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Introduction Materials and Methods Results Discussion Conclusions

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"Introduction\nMaterials and methods\nResults\nDiscussion\nCritique on model 2\nReverse tandem activ(...TRUNCATED)

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"INTRODUCTION\nMATERIALS AND METHODS\nSubjects\nLaparoscopic Endometrioma Resection Surgery\nControl(...TRUNCATED)

"long gonadotropin releasing hormone agonist ( gnrh - a ) and gnrh antagonist ( gnrh - ant ) protoco(...TRUNCATED)

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"mycotic keratitis is a severe problem in most of the developing countries whereas specific antifung(...TRUNCATED)

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1. Introduction 2. Patients and Methods 3. Results 4. Discussion 5. Recommendation

"the study was conducted from the first of january 2011 to the end of december 2013 at the outpatien(...TRUNCATED)

"mycotic keratitis is a severe problem in most of the developing countries whereas specific antifung(...TRUNCATED)

"every year , more than 9 million babies die in utero or in the first few weeks of life , and the ma(...TRUNCATED)

" backgroundthe harmful effects of medication and licit substance use during pregnancy may potential(...TRUNCATED)

"Introduction\nMaterials and methods\nPopulation and data collection\nDefinitions and classification(...TRUNCATED)

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"female mice ( c57bl/6j strain ) 6 to 8 weeks old were obtained from jackson laboratory ( bar harbor(...TRUNCATED)

" purposetoll - like receptor 4 ( tlr4 ) alerts cells to the presence of bacteria by initiating an i(...TRUNCATED)

"Materials and Methods\nMice\nMurine Model of Dry Eye\nLPS Treatment\nRNA Isolation\nPCR\nProtein Is(...TRUNCATED)

"in the cell culture studies , 5 tlr4ko mice and 7 c57bl/6j mice\nmice were exposed to desiccating s(...TRUNCATED)

"all studies adhered to the association for research in vision and ophthalmology statement for use o(...TRUNCATED)

"diabetes mellitus is a growing public health concern , presently affecting 25.8 million or 8.3% of (...TRUNCATED)

" insulin resistance and a progressive decline in functional -cell mass are hallmarks of developing (...TRUNCATED)

1. Introduction 2. Methods 3. Results 4. Discussion

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