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: Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures Background — Whether physical activity reduces the impact of obesity on the risk of acute coronary events is much debated . However , little is known about the role of other potentially modifiable lifestyle factors in combination with obesity . Methods and Results — We followed up 54 783 women and men from the prospect i ve Danish Diet , Cancer and Health study who were 50 to 64 years at baseline ( 1993 to 1997 ) and free of coronary artery disease and cancer . During a median of 7.7 years , 1127 incident cases of acute coronary syndrome ( ACS ) occurred . After multivariable adjustments , each unit of body mass index was associated with a 5 % and 7 % higher risk of ACS among women and men , respectively ( both P<0.0001 for trend ) . Overweight ( body mass index , 25 to 29.9 kg/m2 ) and obesity ( body mass index ≥30 kg/m2 ) were associated with a higher risk of ACS among the physically active and inactive , in nonsmokers and smokers , and among those who adhered more or less to a heart-healthy dietary pattern . Obese individuals who were active 1 to 3.5 h/wk had a lower risk than sedentary , obese individuals . In addition , obese nonsmokers had a lower risk than obese smokers . Adherence to a healthy diet  was associated with a lower risk of ACS ; however , the relative risk was not different among obese individuals with the most healthy diet versus obese individuals with a less healthy diet . Conclusions — Obesity confers an elevated risk of ACS in both healthy and less healthy subgroups of lifestyle behaviors . Adherence to healthy lifestyle behaviors was associated with a lower risk even among obese individuals Editors ' Notes Context Whether there is added benefit from performing the same amount of exercise at a higher intensity is unclear . Contribution In this 24-week study , participants r and omly assigned to complete the same total amount of exercise at higher or lower intensities had similar reductions in waist circumference and weight .  High-intensity exercise alone improved 2-hour glucose tolerance and led to the greatest increase in cardiorespiratory fitness . Caution The importance of improved 2-hour glucose tolerance in participants without diabetes is unclear . Implication For the same amount of exercise , higher-intensity exercise may not result in greater reduction in waist circumference or weight but may provide benefits in glucose tolerance and cardiorespiratory fitness . The high prevalence of obesity and associated type 2 diabetes mellitus among adults presents a major public health challenge ( 1 ) . Physical inactivity is a significant determinant of obesity , and most adults in the United States are inactive ( 2 ) . Although progress has been made to eluci date the effects of exercise as a strategy for reducing obesity and related glucose tolerance , the specific exercise exposures required to achieve optimal benefit continue to be the source of considerable uncertainty and debate . Implicit within current guidelines for physical activity and health is the observation that 75 minutes of weekly high-intensity exercise is equivalent to 150 minutes of weekly lower-intensity exercise ( 3 , 4 ) . Therefore , guidelines suggest that there are no added health benefits of high-intensity exercise other than the shorter time frame needed to expend the appropriate amount of energy . Thus , the benefits of engaging in high-intensity exercise are attributed to the greater amount of energy expenditure per unit of time and do not relate to intensity per se ( 3 ) . The scientific committee report from which current guidelines were developed recognized that many unanswered issues exist in response to the question of how much of what type of activity is appropriate for a given health outcome , and acknowledged that future investigations need to evaluate the effects of exercise intensity at fixed amounts of energy expenditure . We therefore performed a r and omized clinical trial to investigate the separate effects of habitual exercise differing in amount and intensity on abdominal obesity and glucose tolerance . We studied abdominally obese adults because they are at substantially increased risk for morbidity ( 5 ) and mortality ( 6 ) and because it is estimated that 60 % of men and 45 % of women between the ages of 35 and 65 years in the United States are abdominally obese ( 7 ) . Methods Setting and Participants Details of the trial design and methods are published ( 8) . We conducted a 24-week , single-center , parallel-group , r and omized , controlled trial between 2009 to 2013 . Potential participants were excluded if they reported a history of heart disease , stroke , or any condition that would prevent them from engaging in exercise ; were already engaging in 2 or more planned exercise sessions per week ; or were diabetic . All participants provided informed consent before participation . The study was approved by the Queen 's University Health Sciences Research Ethics Board , Kingston , Ontario , Canada . Interventions Participants were r and omly assigned to 1 of the following groups : control ( no exercise ) or 5 sessions per week of low-amount , low-intensity exercise ( LALI ) ( 180 and 300 kcal/session for women and men , respectively , at 50 % of maximum oxygen consumption [ V̇o 2peak ] ) ; high-amount , low-intensity exercise ( HALI ) ( 360 and 600 kcal/session for women and men , respectively , at 50 % of V̇o 2peak ) ; or high-amount , high-intensity exercise ( HAHI ) ( 360 and 600 kcal/session for women and men , respectively , at 75 % of V̇o 2peak ) . Exercise Interventions All participants performed walk/jog exercise consistent with consensus recommendations on a treadmill for the time required to achieve the desired amount of exercise ( energy expenditure in kilocalories per session , relative to V̇o 2peak ) 5 times per week for 24 weeks . Using the heart rate and V̇o 2 data obtained from the baseline exercise test , we assigned the target heart rate associated with a V̇o 2peak of approximately 50 % ( LALI and HALI ) and approximately 75 % ( HAHI ) for each participant . At these exercise intensities , the energy expenditure targets ( exercise amount ) for women and men , respectively , were 180 and 300 kcal for the LALI group and 360 and 600 kcal for the HALI and HAHI groups . Follow-up exercise tests to measure V̇o 2peak were performed at weeks 4 , 8 , and 16 to verify the relationship between heart rate and V̇o 2 . Continual adjustment of the heart rateV̇o 2 relationship accounted for improvement in cardiorespiratory fitness ( CRF ) , which alters the time required to achieve the prescribed exercise amount ( for example , energy expenditure ) . Heart rate was monitored continuously for all exercise participants at every session to ensure adherence to the prescribed exercise intensity . All exercise sessions were supervised , and all exercise participants were asked not to engage in any structured exercise outside of the supervised sessions . Nonexercise Control Group Participants in the control group were asked to maintain their level of physical activity throughout the trial and received diet composition advice similar to that received in the exercise groups . Daily Physical Activity Unsupervised physical activity was monitored using ActiGraph GT3X accelerometers for 1-week periods at baseline and at 8 , 16 , and 25 weeks . Participants were required to wear the accelerometer for at least 4 days each period . Established accelerometer cut points were used to estimate physical activity and sedentary time ( 9 ) . Dietary Regimen During a 1-week baseline period , participants were instructed to maintain baseline body weight by monitoring their calorie intake and recording their daily consumption of self-selected foods . During the intervention , participants were instructed to maintain the calorie intake targets measured during baseline . All participants were prescribed a balanced diet and were asked to su bmi t daily dietary intake records during the intervention . Two weeks of records for all groups were analyzed using a computerized program to assess the accuracy of self-reported records . Outcomes and Follow-up Primary outcome variables were waist circumference ( WC ) , which was measured at the superior edge of the iliac crest ( 10 ) at baseline and at 8 (  exercise groups only ) , 16 , and 24 weeks , and 2-hour glucose level , which was measured in response to a 2-hour , 75-g oral glucose tolerance test between 36 and 48 hours after the last exercise session at baseline and at 16 and 24 weeks ( 8) . Secondary outcomes included CRF ( V̇o 2peak ) assessed by using st and ard open-circuit spirometry techniques with a mass flow sensor ( SensorMedics ) during a grade d exercise test in which participants walked on a treadmill at a self-selected speed at 0 elevation for 3 minutes , after which the incline was increased every 2 minutes until the participant stopped voluntarily . Levels of glucose , triglycerides , high- and low-density lipoprotein cholesterol , and insulin and blood pressure were measured using established procedures ( 8) . The Matsuda index ( an indication of insulin sensitivity ) was calculated as follows : ( 10000/[{fasting glucose levelfasting insulin level}{mean glucose levelmean insulin level during the oral glucose tolerance test}]1/2 ) ( 11 ) . There were separate assessment and intervention personnel , and all assessment personnel were blinded to participant r and omization assignment . Sample Size and Power Sample size was determined for WC and 2-hour glucose level on the basis of reduction after treatment . Previous trials suggested that exercise-induced weight loss of approximately 6 % was associated with WC reductions of 6.9 cm ( SD , 2.6 ) in men ( 12 ) and 6.5 cm ( SD , 2.6 ) in women ( 13 ) . For 2-hour glucose level , mean reductions of 0.70 mmol/L ( SD , 1.9 ) ( 12.6 mg/dL [ SD , 34.2 ] ) and 0.94 mmol/L ( SD , 0.7 ) ( 16.9 mg/dL [ SD , 12.6 ] ) were seen in men and women , respectively ( 12 , 13 ) . The sample size calculation incorporated the larger SDs for WC and 2-hour glucose level . The sample -size formula ( equation 13 of Overall and Doyle [ 14 ] ) relevant to the repeated- measures analysis of variance design was applied . The formula is based on a simple 2-group comparison of the pretreatment and posttreatment outcome changes , and it accounts for the correlation between the pretreatment and posttreatment outcome variables . With a correlation of 0.7 between pretreatment and posttreatment glucose tolerance and WC , and allowance for a dropout rate of 30 % , a sample of 40 men or women with 28 completers in each treatment group gives more than 85 % power to detect a mean difference of 2 cm in WC and a mean difference of 1.9 mmol/L ( 34.2 mg/dL ) in glucose tolerance between any 2 treatment groups . R and omization Participants were r and omly assigned to the 4 groups using the method of permuted blocks , with r and om block sizes of 4 , 8 , or 12 within strata . R and omization was stratified by sex and age , with a fifth stratum for the few couples participating to ensure that they were r and omly assigned to the same treatment . The computer-generated r and omization list was maintained by an independent statistician otherwise uninvolved in the study and was concealed from study personnel until the time of r and omization . After baseline data collection , the study coordinator contacted the statistician by e-mail to obtain treatment assignment . Statistical Analysis Analyses were done on an intention-to-treat basis ( 15 ) . All r and omly assigned participants were included in the analyses . Differences in continuous and categorical variables between dropouts and participants who completed the study were examined by using a 2-tailed t test and a chi-square test , respectively . For WC , 2-hour glucose level , CONTEXT Deciphering the early processes occurring in adipose tissue during weight gain is a major issue for underst and ing the development of fat mass and obesity . Experimental overfeeding in humans is a unique situation to tackle these events . OBJECTIVE Our aim was to identify the pathways involved in sc adipose tissue remodeling during the initial phase of weight gain . RESEARCH DESIGN AND METHODS Forty-four healthy men were involved in an overfeeding protocol with a lipid-enriched diet ( + 760 kcal/d ) for 2 months .  Subcutaneous abdominal adipose tissue biopsies were taken for histology , transcriptomics , and Western blotting in 
    Output:
    
agent
We argue that despite inconsistencies in the definition , patterns across studies clearly show that healthy obesity is a state of intermediate disease risk .
Expert commentary : Given the current state of population -level evidence , we conclude that obesity and metabolic dysfunction are inseparable and that healthy obesity is best viewed only as a state of relative health but not of absolute health .
***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: Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures Background — Whether physical activity reduces the impact of obesity on the risk of acute coronary events is much debated . However , little is known about the role of other potentially modifiable lifestyle factors in combination with obesity . Methods and Results — We followed up 54 783 women and men from the prospect i ve Danish Diet , Cancer and Health study who were 50 to 64 years at baseline ( 1993 to 1997 ) and free of coronary artery disease and cancer . During a median of 7.7 years , 1127 incident cases of acute coronary syndrome ( ACS ) occurred . After multivariable adjustments , each unit of body mass index was associated with a 5 % and 7 % higher risk of ACS among women and men , respectively ( both P<0.0001 for trend ) . Overweight ( body mass index , 25 to 29.9 kg/m2 ) and obesity ( body mass index ≥30 kg/m2 ) were associated with a higher risk of ACS among the physically active and inactive , in nonsmokers and smokers , and among those who adhered more or less to a heart-healthy dietary pattern . Obese individuals who were active 1 to 3.5 h/wk had a lower risk than sedentary , obese individuals . In addition , obese nonsmokers had a lower risk than obese smokers . Adherence to a healthy diet  was associated with a lower risk of ACS ; however , the relative risk was not different among obese individuals with the most healthy diet versus obese individuals with a less healthy diet . Conclusions — Obesity confers an elevated risk of ACS in both healthy and less healthy subgroups of lifestyle behaviors . Adherence to healthy lifestyle behaviors was associated with a lower risk even among obese individuals Editors ' Notes Context Whether there is added benefit from performing the same amount of exercise at a higher intensity is unclear . Contribution In this 24-week study , participants r and omly assigned to complete the same total amount of exercise at higher or lower intensities had similar reductions in waist circumference and weight .  High-intensity exercise alone improved 2-hour glucose tolerance and led to the greatest increase in cardiorespiratory fitness . Caution The importance of improved 2-hour glucose tolerance in participants without diabetes is unclear . Implication For the same amount of exercise , higher-intensity exercise may not result in greater reduction in waist circumference or weight but may provide benefits in glucose tolerance and cardiorespiratory fitness . The high prevalence of obesity and associated type 2 diabetes mellitus among adults presents a major public health challenge ( 1 ) . Physical inactivity is a significant determinant of obesity , and most adults in the United States are inactive ( 2 ) . Although progress has been made to eluci date the effects of exercise as a strategy for reducing obesity and related glucose tolerance , the specific exercise exposures required to achieve optimal benefit continue to be the source of considerable uncertainty and debate . Implicit within current guidelines for physical activity and health is the observation that 75 minutes of weekly high-intensity exercise is equivalent to 150 minutes of weekly lower-intensity exercise ( 3 , 4 ) . Therefore , guidelines suggest that there are no added health benefits of high-intensity exercise other than the shorter time frame needed to expend the appropriate amount of energy . Thus , the benefits of engaging in high-intensity exercise are attributed to the greater amount of energy expenditure per unit of time and do not relate to intensity per se ( 3 ) . The scientific committee report from which current guidelines were developed recognized that many unanswered issues exist in response to the question of how much of what type of activity is appropriate for a given health outcome , and acknowledged that future investigations need to evaluate the effects of exercise intensity at fixed amounts of energy expenditure . We therefore performed a r and omized clinical trial to investigate the separate effects of habitual exercise differing in amount and intensity on abdominal obesity and glucose tolerance . We studied abdominally obese adults because they are at substantially increased risk for morbidity ( 5 ) and mortality ( 6 ) and because it is estimated that 60 % of men and 45 % of women between the ages of 35 and 65 years in the United States are abdominally obese ( 7 ) . Methods Setting and Participants Details of the trial design and methods are published ( 8) . We conducted a 24-week , single-center , parallel-group , r and omized , controlled trial between 2009 to 2013 . Potential participants were excluded if they reported a history of heart disease , stroke , or any condition that would prevent them from engaging in exercise ; were already engaging in 2 or more planned exercise sessions per week ; or were diabetic . All participants provided informed consent before participation . The study was approved by the Queen 's University Health Sciences Research Ethics Board , Kingston , Ontario , Canada . Interventions Participants were r and omly assigned to 1 of the following groups : control ( no exercise ) or 5 sessions per week of low-amount , low-intensity exercise ( LALI ) ( 180 and 300 kcal/session for women and men , respectively , at 50 % of maximum oxygen consumption [ V̇o 2peak ] ) ; high-amount , low-intensity exercise ( HALI ) ( 360 and 600 kcal/session for women and men , respectively , at 50 % of V̇o 2peak ) ; or high-amount , high-intensity exercise ( HAHI ) ( 360 and 600 kcal/session for women and men , respectively , at 75 % of V̇o 2peak ) . Exercise Interventions All participants performed walk/jog exercise consistent with consensus recommendations on a treadmill for the time required to achieve the desired amount of exercise ( energy expenditure in kilocalories per session , relative to V̇o 2peak ) 5 times per week for 24 weeks . Using the heart rate and V̇o 2 data obtained from the baseline exercise test , we assigned the target heart rate associated with a V̇o 2peak of approximately 50 % ( LALI and HALI ) and approximately 75 % ( HAHI ) for each participant . At these exercise intensities , the energy expenditure targets ( exercise amount ) for women and men , respectively , were 180 and 300 kcal for the LALI group and 360 and 600 kcal for the HALI and HAHI groups . Follow-up exercise tests to measure V̇o 2peak were performed at weeks 4 , 8 , and 16 to verify the relationship between heart rate and V̇o 2 . Continual adjustment of the heart rateV̇o 2 relationship accounted for improvement in cardiorespiratory fitness ( CRF ) , which alters the time required to achieve the prescribed exercise amount ( for example , energy expenditure ) . Heart rate was monitored continuously for all exercise participants at every session to ensure adherence to the prescribed exercise intensity . All exercise sessions were supervised , and all exercise participants were asked not to engage in any structured exercise outside of the supervised sessions . Nonexercise Control Group Participants in the control group were asked to maintain their level of physical activity throughout the trial and received diet composition advice similar to that received in the exercise groups . Daily Physical Activity Unsupervised physical activity was monitored using ActiGraph GT3X accelerometers for 1-week periods at baseline and at 8 , 16 , and 25 weeks . Participants were required to wear the accelerometer for at least 4 days each period . Established accelerometer cut points were used to estimate physical activity and sedentary time ( 9 ) . Dietary Regimen During a 1-week baseline period , participants were instructed to maintain baseline body weight by monitoring their calorie intake and recording their daily consumption of self-selected foods . During the intervention , participants were instructed to maintain the calorie intake targets measured during baseline . All participants were prescribed a balanced diet and were asked to su bmi t daily dietary intake records during the intervention . Two weeks of records for all groups were analyzed using a computerized program to assess the accuracy of self-reported records . Outcomes and Follow-up Primary outcome variables were waist circumference ( WC ) , which was measured at the superior edge of the iliac crest ( 10 ) at baseline and at 8 (  exercise groups only ) , 16 , and 24 weeks , and 2-hour glucose level , which was measured in response to a 2-hour , 75-g oral glucose tolerance test between 36 and 48 hours after the last exercise session at baseline and at 16 and 24 weeks ( 8) . Secondary outcomes included CRF ( V̇o 2peak ) assessed by using st and ard open-circuit spirometry techniques with a mass flow sensor ( SensorMedics ) during a grade d exercise test in which participants walked on a treadmill at a self-selected speed at 0 elevation for 3 minutes , after which the incline was increased every 2 minutes until the participant stopped voluntarily . Levels of glucose , triglycerides , high- and low-density lipoprotein cholesterol , and insulin and blood pressure were measured using established procedures ( 8) . The Matsuda index ( an indication of insulin sensitivity ) was calculated as follows : ( 10000/[{fasting glucose levelfasting insulin level}{mean glucose levelmean insulin level during the oral glucose tolerance test}]1/2 ) ( 11 ) . There were separate assessment and intervention personnel , and all assessment personnel were blinded to participant r and omization assignment . Sample Size and Power Sample size was determined for WC and 2-hour glucose level on the basis of reduction after treatment . Previous trials suggested that exercise-induced weight loss of approximately 6 % was associated with WC reductions of 6.9 cm ( SD , 2.6 ) in men ( 12 ) and 6.5 cm ( SD , 2.6 ) in women ( 13 ) . For 2-hour glucose level , mean reductions of 0.70 mmol/L ( SD , 1.9 ) ( 12.6 mg/dL [ SD , 34.2 ] ) and 0.94 mmol/L ( SD , 0.7 ) ( 16.9 mg/dL [ SD , 12.6 ] ) were seen in men and women , respectively ( 12 , 13 ) . The sample size calculation incorporated the larger SDs for WC and 2-hour glucose level . The sample -size formula ( equation 13 of Overall and Doyle [ 14 ] ) relevant to the repeated- measures analysis of variance design was applied . The formula is based on a simple 2-group comparison of the pretreatment and posttreatment outcome changes , and it accounts for the correlation between the pretreatment and posttreatment outcome variables . With a correlation of 0.7 between pretreatment and posttreatment glucose tolerance and WC , and allowance for a dropout rate of 30 % , a sample of 40 men or women with 28 completers in each treatment group gives more than 85 % power to detect a mean difference of 2 cm in WC and a mean difference of 1.9 mmol/L ( 34.2 mg/dL ) in glucose tolerance between any 2 treatment groups . R and omization Participants were r and omly assigned to the 4 groups using the method of permuted blocks , with r and om block sizes of 4 , 8 , or 12 within strata . R and omization was stratified by sex and age , with a fifth stratum for the few couples participating to ensure that they were r and omly assigned to the same treatment . The computer-generated r and omization list was maintained by an independent statistician otherwise uninvolved in the study and was concealed from study personnel until the time of r and omization . After baseline data collection , the study coordinator contacted the statistician by e-mail to obtain treatment assignment . Statistical Analysis Analyses were done on an intention-to-treat basis ( 15 ) . All r and omly assigned participants were included in the analyses . Differences in continuous and categorical variables between dropouts and participants who completed the study were examined by using a 2-tailed t test and a chi-square test , respectively . For WC , 2-hour glucose level , CONTEXT Deciphering the early processes occurring in adipose tissue during weight gain is a major issue for underst and ing the development of fat mass and obesity . Experimental overfeeding in humans is a unique situation to tackle these events . OBJECTIVE Our aim was to identify the pathways involved in sc adipose tissue remodeling during the initial phase of weight gain . RESEARCH DESIGN AND METHODS Forty-four healthy men were involved in an overfeeding protocol with a lipid-enriched diet ( + 760 kcal/d ) for 2 months .  Subcutaneous abdominal adipose tissue biopsies were taken for histology , transcriptomics , and Western blotting in 
    Output:
    