human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Summary In patients with insulin-dependent diabetes mellitus ( IDDM ) good glycaemic control confers an enhanced risk of hypoglycaemia . Nocturnal hypoglycaemia occurs frequently and contributes to the syndrome of hypoglycaemia unawareness . In order to avoid nocturnal hypoglycaemia we substituted night-time continuous subcutaneous insulin infusion ( CSII ) therapy in 14 patients with well-controlled IDDM using a multiple injection regimen for the more variable bedtime NPH insulin . During a stepwise hypoglycaemic clamp we studied the effect of this regimen on counterregulatory hormonal responses , warning symptoms and cognitive function . In addition , we investigated the incidence of daytime hypoglycaemia and the acceptability of night-time CSII  treatment . CSII was associated with a lower frequency of hypoglycaemia ( mean ± SEM ) : 16.1 ± 3.1 vs 23.6 ± 3.3 ) episodes during the last 6 weeks of treatment , p = 0.03 ( CSII vs NPH ) ) with maintenance of good glycaemic control ( HbA1c 7.2 ± 0.2 vs 7.1 ± 0.2 % , p = 0.2 ) . Hypoglycaemic thresholds for the growth hormone response and for autonomic symptoms were lower for CSII treatment than for NPH treatment . Of 14 patients 6 decided to continue with the nocturnal CSII treatment . In conclusion , nocturnal CSII improves warning symptoms and counterregulatory hormonal responses to hypoglycaemia and is an acceptable treatment strategy for patients suffering from hypoglycaemia unawareness , as demonstrated in this acute feasibility study . [ Diabetologia ( 1998 ) 41 : 322–329 Currently , the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control . Quantifying these problems remains subjective . We have developed a scoring system for both hypoglycemia and glycemic lability , established normative data , and used them in patients who have undergone islet transplantation .  A composite hypoglycemic score ( HYPO score ) was devised based on the frequency , severity , and degree of unawareness of the hypoglycemia . In addition , using 4 weeks of glucose records , a lability index ( LI ) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability . A mean amplitude of glycemic excursions ( MAGE ) was also calculated based on 2 consecutive days of seven readings each day . These scores were determined in 100 r and omly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation . The mean age of the control diabetic subjects was 38.4 + /- 1.3 years ( + /-SE ) , with a duration of diabetes of 21.5 + /- 1.1 years . The median HYPO score in the control subjects was 143 ( 25th to 75th interquartile range : 46 - 423 ) . The LI in the diabetic control subjects was 223 ( 25th to 75th interquartile range : 130 - 329 mmol/l(2)/h.week(-1 ) ) . The LI correlated much more closely than the MAGE with the clinical assessment of lability . A HYPO score of > or = 1,047 ( 90th percentile ) or an LI > or = 433 mmol/l(2)/h.week(-1 ) ( 90th percentile ) indicated serious problems with hypoglycemia or glycemic lability , respectively . The islet transplant patients ( n = 51 ) were 42.1 + /- 1.4 years old , with a duration of diabetes of 25.7 + /- 1.4 years . Islet transplant patients had a mean HYPO score of 1,234 + /- 184 pretransplant , which was significantly higher than that of the control subjects ( P < 0.001 ) , which became negligible posttransplantation with the elimination of hypoglycemia . The median LI pretransplant was 497 mmol/l(2)/h.week(-1 ) ( 25th to 75th interquartile range : 330 - 692 ) , significantly higher than that of control subjects ( P < 0.001 ) , and fell to 40 ( 25th to 75th interquartile range : 14 - 83 ) within a month after the final transplant . In those who had lost graft function , the LI rose again . The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability , respectively , complement the clinical assessment of the problems with glucose control before islet transplantation , and will allow comparison of selection of subjects for transplants between centers OBJECTIVE To prospect ively evaluate the frequency and severity of hypoglycemic episodes in IDDM subjects who declare themselves to have reduced awareness of hypoglycemia , to vali date their self- design ations in their natural environment , and to determine objective ly the presence or absence of autonomic and neuroglycopenic symptoms associated with their low blood glucose ( BG ) levels . RESEARCH DESIGN AND METHODS A total of 78 insulin-dependent diabetes mellitus ( IDDM ) subjects ( mean age 38.3 ± 9.2 years ; duration of diabetes 19.3 ± 10.4 years ) completed two sets of assessment s separated by 6 months . The assessment s included reports of frequency and severity of low BG , symptoms associated with low BG , and a  BG symptom/estimation trial using a h and -held computer ( HHC ) . Diaries of hypoglycemic episodes were kept for the intervening 6 months  . HbA1 levels were determined at each assessment . RESULTS Of the subjects , 39 declared themselves as having reduced awareness of hypoglycemia ( reduced-awareness subjects ) . There were no differences between these reduced-awareness subjects and aware subjects with regard to age , sex , disease duration , insulin dose , or HbA1 . During the HHC trials , reduced-awareness subjects were significantly less accurate in detecting BG < 3.9 mmol/l ( 33.2 ± 47 vs. 47.6 ± 50 % detection , P = 0.001 ) and had significantly fewer autonomic ( 0.41 ± 0.82 vs. 1.08 ± 1.22 , P = 0.006 , reduced-awareness vs. aware ) and neuroglycopenic ( 0.44 ± 0.85 vs. 1.18 ± 1.32 , P = 0.004 , reduced-awareness vs. aware ) symptoms per subject . Prospect i ve diary records revealed that reduced-awareness subjects experienced more moderate ( 351 vs. 238 , P = 0.026 ) and severe ( 50 vs. 17 , P = 0.0062 ) hypoglycemic events . The second assessment results were similar to the first and verified the reliability of the data . CONCLUSIONS IDDM subjects who believe they have reduced awareness of hypoglycemia are generally correct . They have a history of more moderate and severe hypoglycemia , are less accurate at detecting BG < 3.9 mmol/l , and prospect ively experience more moderate and severe hypoglycemia than do aware subjects . Neither disease duration nor level of glucose control explains their reduced awareness of hypoglycemia . Reduced-awareness individuals may benefit from interventions design ed to teach them to recognize all of their potential early warning symptoms OBJECTIVE To determine the effect of blood glucose awareness training ( BGAT ) on epinephrine and symptom responses to hypoglycemia in patients with type 1 diabetes enrolled in an intensive diabetes treatment ( IDT ) program . RESEARCH DESIGN AND METHODS A total of 47 subjects with uncomplicated diabetes ( duration 9 + /- 3 years : HbA1c 9.0 + /- 1.2 % ; reference range 4 - 6 % ) enrolled in a 4-month outpatient IDT program were r and omized to classes in BGAT ( n = 25 ) ( BGAT group ) or cholesterol awareness ( n = 22 ) ( control group ) . Subjects underwent stepped hypoglycemic clamp studies before and at completion of IDT . Plasma glucose was lowered from 6.7 mmol/l ( baseline ) to 4.4 , 3.9 , 3.3 , 2.8 , and 2.2 mmol/l over 190 min . Symptoms , counterregulatory hormones , and ability of the subject to estimate their glucose level were assessed at each plateau . At home , subjects used a h and held computer to first estimate and then measure and record blood glucose levels for 70 trials over a 4-week period immediately before IDT and again immediately following the educational intervention . RESULTS HbA1c decreased in both BGAT group ( 9.1 + /- 1.4 to 7.9 + /- 1.1 % ; P < 0.001 ) and control group ( 9.0 + /- 1.1 to 7.8 + /- 0.8 % ; P < 0.001 ) ( NS between groups ) . Frequency of hypoglycemia ( < 3.9 mmol/l ) increased in both groups , from 0.45 + /- 0.06 to 0.69 + /- 0.07 episodes per day ( P < 0.001 ) in the BGAT group and from 0.50 + /- 0.08 to 0.68 + /- 0.06 episodes per day ( P < 0.05 ) in the control group NS between groups ) . Epinephrine responses after IDT were greater in the BGAT group ( repeated measure analysis of variance [ ANOVA ] , F = 3.5 , P < 0.05 ) . A separate analysis of subjects n = 26 ) most at risk for hypoglycemia ( HbA1c after IDT < 7.8 % or an HbA1c improvement of > 2 percentage points ) showed that frequency of hypoglycemia increased in both the groups : from 0.50 + /- 0.09 to 0.80 + /- 0.11 episodes per day ( P < 0.01 ) in the BGAT group ( n = 14 ) and from 0.43 + /- 0.11 to 0.75 + /- 0.07 episodes per day ( P < 0.05 ) in the control group ( n = 12 ) ( NS between groups ) . However , the epinephrine response in control subjects decreased with IDT while the response in the BGAT subjects was preserved ( repeated measure ANOVA , F = 4.4 , P < 0.02 ) . CONCLUSIONS BGAT is a useful intervention to decrease blunting of counterregulatory responses associated with improved glycemic control and may modify the severity of hypoglycemia associated with improved glycemic control in type 1 diabetes Aims /hypothesisThe aim of this study was to evaluate the implementation of a course teaching flexible , intensive insulin therapy on glycaemic control and severe hypoglycaemia in routine care . Methods This is a continuous quality -assurance project involving hospital diabetes centres . Every third year each centre re-examines 50 consecutive patients ( evaluation sample ) 1 year after participation in the course . Ninety-six diabetes centres in Germany participated and 9,583 patients with type 1 diabetes ( 190 evaluation sample s ) were re-examined between 1992 and 2004 . The intervention was a 5-day inpatient course for groups of up to ten patients with a fixed curriculum of education and training for dietary flexibility and insulin adjustment . The main outcome measures were HbA1c and severe hypoglycaemia . Results Mean baseline HbA1c was 8.1 % , and had decreased to 7.3 % at follow-up ; incidence of severe hypoglycaemia was 0.37 events per patient per year prior to intervention and 0.14 after intervention . In mixed-effects models adjusted for effects of centres , age and diabetes duration , the mean difference was −0.7 % ( 95 % CI −0.9 to −0.6 % , p<0.0001 ) for HbA1c and −0.21 events per patient per year ( 95 % CI −0.32 to −0.11 , p=0.0001 ) for severe hypoglycaemia , with similar results for evaluation sample s , with a maximum of 10 % of patients lost to follow-up . Before intervention , the incidence of severe hypoglycaemia was three-fold higher in the lowest quartile than in the highest quartile of HbA1c , whereas the risk was comparable across the range of HbA1c values after intervention . Conclusions /interpretationImplemented as part of a continuous quality -assurance programme the self-management programme is effective and safe in routine care . Improvement of glycaemic control can be achieved without increasing the risk of severe hypoglycaemia OBJECTIVE To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospect i ve assessment . RESEARCH DESIGN AND METHODS A prospect i ve study was undertaken for 12 months in 60 patients with type I diabetes : 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia . The two groups of 
    Output:
    
agent
These were able to reduce SH and improve glycemic control , with greater benefit from the latter two techniques in improving IAH .
Technological interventions ( insulin pump therapy , continuous glucose monitoring , and sensor-augmented pump ) reduced SH , improved glycemic control , and restored awareness when used in combination with structured education and frequent contact .
This review provides evidence for the effectiveness of a stepped-care approach in the management of patients with IAH  , initially with structured diabetes education in flexible insulin therapy , which may incorporate psychotherapeutic and behavioral therapies , progressing to diabetes technology , incorporating sensors and insulin pumps , in those with persisting need
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Summary In patients with insulin-dependent diabetes mellitus ( IDDM ) good glycaemic control confers an enhanced risk of hypoglycaemia . Nocturnal hypoglycaemia occurs frequently and contributes to the syndrome of hypoglycaemia unawareness . In order to avoid nocturnal hypoglycaemia we substituted night-time continuous subcutaneous insulin infusion ( CSII ) therapy in 14 patients with well-controlled IDDM using a multiple injection regimen for the more variable bedtime NPH insulin . During a stepwise hypoglycaemic clamp we studied the effect of this regimen on counterregulatory hormonal responses , warning symptoms and cognitive function . In addition , we investigated the incidence of daytime hypoglycaemia and the acceptability of night-time CSII  treatment . CSII was associated with a lower frequency of hypoglycaemia ( mean ± SEM ) : 16.1 ± 3.1 vs 23.6 ± 3.3 ) episodes during the last 6 weeks of treatment , p = 0.03 ( CSII vs NPH ) ) with maintenance of good glycaemic control ( HbA1c 7.2 ± 0.2 vs 7.1 ± 0.2 % , p = 0.2 ) . Hypoglycaemic thresholds for the growth hormone response and for autonomic symptoms were lower for CSII treatment than for NPH treatment . Of 14 patients 6 decided to continue with the nocturnal CSII treatment . In conclusion , nocturnal CSII improves warning symptoms and counterregulatory hormonal responses to hypoglycaemia and is an acceptable treatment strategy for patients suffering from hypoglycaemia unawareness , as demonstrated in this acute feasibility study . [ Diabetologia ( 1998 ) 41 : 322–329 Currently , the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control . Quantifying these problems remains subjective . We have developed a scoring system for both hypoglycemia and glycemic lability , established normative data , and used them in patients who have undergone islet transplantation .  A composite hypoglycemic score ( HYPO score ) was devised based on the frequency , severity , and degree of unawareness of the hypoglycemia . In addition , using 4 weeks of glucose records , a lability index ( LI ) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability . A mean amplitude of glycemic excursions ( MAGE ) was also calculated based on 2 consecutive days of seven readings each day . These scores were determined in 100 r and omly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation . The mean age of the control diabetic subjects was 38.4 + /- 1.3 years ( + /-SE ) , with a duration of diabetes of 21.5 + /- 1.1 years . The median HYPO score in the control subjects was 143 ( 25th to 75th interquartile range : 46 - 423 ) . The LI in the diabetic control subjects was 223 ( 25th to 75th interquartile range : 130 - 329 mmol/l(2)/h.week(-1 ) ) . The LI correlated much more closely than the MAGE with the clinical assessment of lability . A HYPO score of > or = 1,047 ( 90th percentile ) or an LI > or = 433 mmol/l(2)/h.week(-1 ) ( 90th percentile ) indicated serious problems with hypoglycemia or glycemic lability , respectively . The islet transplant patients ( n = 51 ) were 42.1 + /- 1.4 years old , with a duration of diabetes of 25.7 + /- 1.4 years . Islet transplant patients had a mean HYPO score of 1,234 + /- 184 pretransplant , which was significantly higher than that of the control subjects ( P < 0.001 ) , which became negligible posttransplantation with the elimination of hypoglycemia . The median LI pretransplant was 497 mmol/l(2)/h.week(-1 ) ( 25th to 75th interquartile range : 330 - 692 ) , significantly higher than that of control subjects ( P < 0.001 ) , and fell to 40 ( 25th to 75th interquartile range : 14 - 83 ) within a month after the final transplant . In those who had lost graft function , the LI rose again . The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability , respectively , complement the clinical assessment of the problems with glucose control before islet transplantation , and will allow comparison of selection of subjects for transplants between centers OBJECTIVE To prospect ively evaluate the frequency and severity of hypoglycemic episodes in IDDM subjects who declare themselves to have reduced awareness of hypoglycemia , to vali date their self- design ations in their natural environment , and to determine objective ly the presence or absence of autonomic and neuroglycopenic symptoms associated with their low blood glucose ( BG ) levels . RESEARCH DESIGN AND METHODS A total of 78 insulin-dependent diabetes mellitus ( IDDM ) subjects ( mean age 38.3 ± 9.2 years ; duration of diabetes 19.3 ± 10.4 years ) completed two sets of assessment s separated by 6 months . The assessment s included reports of frequency and severity of low BG , symptoms associated with low BG , and a  BG symptom/estimation trial using a h and -held computer ( HHC ) . Diaries of hypoglycemic episodes were kept for the intervening 6 months  . HbA1 levels were determined at each assessment . RESULTS Of the subjects , 39 declared themselves as having reduced awareness of hypoglycemia ( reduced-awareness subjects ) . There were no differences between these reduced-awareness subjects and aware subjects with regard to age , sex , disease duration , insulin dose , or HbA1 . During the HHC trials , reduced-awareness subjects were significantly less accurate in detecting BG < 3.9 mmol/l ( 33.2 ± 47 vs. 47.6 ± 50 % detection , P = 0.001 ) and had significantly fewer autonomic ( 0.41 ± 0.82 vs. 1.08 ± 1.22 , P = 0.006 , reduced-awareness vs. aware ) and neuroglycopenic ( 0.44 ± 0.85 vs. 1.18 ± 1.32 , P = 0.004 , reduced-awareness vs. aware ) symptoms per subject . Prospect i ve diary records revealed that reduced-awareness subjects experienced more moderate ( 351 vs. 238 , P = 0.026 ) and severe ( 50 vs. 17 , P = 0.0062 ) hypoglycemic events . The second assessment results were similar to the first and verified the reliability of the data . CONCLUSIONS IDDM subjects who believe they have reduced awareness of hypoglycemia are generally correct . They have a history of more moderate and severe hypoglycemia , are less accurate at detecting BG < 3.9 mmol/l , and prospect ively experience more moderate and severe hypoglycemia than do aware subjects . Neither disease duration nor level of glucose control explains their reduced awareness of hypoglycemia . Reduced-awareness individuals may benefit from interventions design ed to teach them to recognize all of their potential early warning symptoms OBJECTIVE To determine the effect of blood glucose awareness training ( BGAT ) on epinephrine and symptom responses to hypoglycemia in patients with type 1 diabetes enrolled in an intensive diabetes treatment ( IDT ) program . RESEARCH DESIGN AND METHODS A total of 47 subjects with uncomplicated diabetes ( duration 9 + /- 3 years : HbA1c 9.0 + /- 1.2 % ; reference range 4 - 6 % ) enrolled in a 4-month outpatient IDT program were r and omized to classes in BGAT ( n = 25 ) ( BGAT group ) or cholesterol awareness ( n = 22 ) ( control group ) . Subjects underwent stepped hypoglycemic clamp studies before and at completion of IDT . Plasma glucose was lowered from 6.7 mmol/l ( baseline ) to 4.4 , 3.9 , 3.3 , 2.8 , and 2.2 mmol/l over 190 min . Symptoms , counterregulatory hormones , and ability of the subject to estimate their glucose level were assessed at each plateau . At home , subjects used a h and held computer to first estimate and then measure and record blood glucose levels for 70 trials over a 4-week period immediately before IDT and again immediately following the educational intervention . RESULTS HbA1c decreased in both BGAT group ( 9.1 + /- 1.4 to 7.9 + /- 1.1 % ; P < 0.001 ) and control group ( 9.0 + /- 1.1 to 7.8 + /- 0.8 % ; P < 0.001 ) ( NS between groups ) . Frequency of hypoglycemia ( < 3.9 mmol/l ) increased in both groups , from 0.45 + /- 0.06 to 0.69 + /- 0.07 episodes per day ( P < 0.001 ) in the BGAT group and from 0.50 + /- 0.08 to 0.68 + /- 0.06 episodes per day ( P < 0.05 ) in the control group NS between groups ) . Epinephrine responses after IDT were greater in the BGAT group ( repeated measure analysis of variance [ ANOVA ] , F = 3.5 , P < 0.05 ) . A separate analysis of subjects n = 26 ) most at risk for hypoglycemia ( HbA1c after IDT < 7.8 % or an HbA1c improvement of > 2 percentage points ) showed that frequency of hypoglycemia increased in both the groups : from 0.50 + /- 0.09 to 0.80 + /- 0.11 episodes per day ( P < 0.01 ) in the BGAT group ( n = 14 ) and from 0.43 + /- 0.11 to 0.75 + /- 0.07 episodes per day ( P < 0.05 ) in the control group ( n = 12 ) ( NS between groups ) . However , the epinephrine response in control subjects decreased with IDT while the response in the BGAT subjects was preserved ( repeated measure ANOVA , F = 4.4 , P < 0.02 ) . CONCLUSIONS BGAT is a useful intervention to decrease blunting of counterregulatory responses associated with improved glycemic control and may modify the severity of hypoglycemia associated with improved glycemic control in type 1 diabetes Aims /hypothesisThe aim of this study was to evaluate the implementation of a course teaching flexible , intensive insulin therapy on glycaemic control and severe hypoglycaemia in routine care . Methods This is a continuous quality -assurance project involving hospital diabetes centres . Every third year each centre re-examines 50 consecutive patients ( evaluation sample ) 1 year after participation in the course . Ninety-six diabetes centres in Germany participated and 9,583 patients with type 1 diabetes ( 190 evaluation sample s ) were re-examined between 1992 and 2004 . The intervention was a 5-day inpatient course for groups of up to ten patients with a fixed curriculum of education and training for dietary flexibility and insulin adjustment . The main outcome measures were HbA1c and severe hypoglycaemia . Results Mean baseline HbA1c was 8.1 % , and had decreased to 7.3 % at follow-up ; incidence of severe hypoglycaemia was 0.37 events per patient per year prior to intervention and 0.14 after intervention . In mixed-effects models adjusted for effects of centres , age and diabetes duration , the mean difference was −0.7 % ( 95 % CI −0.9 to −0.6 % , p<0.0001 ) for HbA1c and −0.21 events per patient per year ( 95 % CI −0.32 to −0.11 , p=0.0001 ) for severe hypoglycaemia , with similar results for evaluation sample s , with a maximum of 10 % of patients lost to follow-up . Before intervention , the incidence of severe hypoglycaemia was three-fold higher in the lowest quartile than in the highest quartile of HbA1c , whereas the risk was comparable across the range of HbA1c values after intervention . Conclusions /interpretationImplemented as part of a continuous quality -assurance programme the self-management programme is effective and safe in routine care . Improvement of glycaemic control can be achieved without increasing the risk of severe hypoglycaemia OBJECTIVE To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospect i ve assessment . RESEARCH DESIGN AND METHODS A prospect i ve study was undertaken for 12 months in 60 patients with type I diabetes : 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia . The two groups of 
    Output:
    