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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."

These pediatric hypertension guidelines are an update to the 2004 "Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents." Significant changes in these guidelines include (1) the replacement of the term "prehypertension" with the term "elevated blood pressure," (2) new normative pediatric blood pressure (BP) tables based on normal-weight children, (3) a simplified screening table for identifying BPs needing further evaluation, (4) a simplified BP classification in adolescents ≥13 years of age that aligns with the forthcoming American Heart Association and American College of Cardiology adult BP guidelines, (5) a more limited recommendation to perform screening BP measurements only at preventive care visits, (6) streamlined recommendations on the initial evaluation and management of abnormal BPs, (7) an expanded role for ambulatory BP monitoring in the diagnosis and management of pediatric hypertension, and (8) revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy. These guidelines include 30 Key Action Statements and 27 additional recommendations derived from a comprehensive review of almost 15 000 published articles between January 2004 and July 2016. Each Key Action Statement includes level of evidence, benefit-harm relationship, and strength of recommendation. This clinical practice guideline, endorsed by the American Heart Association, is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.

BACKGROUND: Carotid-artery stenting and carotid endarterectomy are both options for treating carotid-artery stenosis, an important cause of stroke. METHODS: We randomly assigned patients with symptomatic or asymptomatic carotid stenosis to undergo carotid-artery stenting or carotid endarterectomy. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization. RESULTS: For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P=0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P=0.84) or sex (P=0.34). The 4-year rate of stroke or death was 6.4% with stenting and 4.7% with endarterectomy (hazard ratio, 1.50; P=0.03); the rates among symptomatic patients were 8.0% and 6.4% (hazard ratio, 1.37; P=0.14), and the rates among asymptomatic patients were 4.5% and 2.7% (hazard ratio, 1.86; P=0.07), respectively. Periprocedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P=0.18), for stroke (4.1% vs. 2.3%, P=0.01), and for myocardial infarction (1.1% vs. 2.3%, P=0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P=0.85). CONCLUSIONS: Among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the periprocedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy. (ClinicalTrials.gov number, NCT00004732.)

BACKGROUND: Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. METHODS: We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. RESULTS: We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). CONCLUSIONS: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).

Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU. m(-2). min(-1)) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m(2). Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis. In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied. Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI. Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients. Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs. -84% in control subjects; P = 0.003). Postabsorptive hepatic glucose production (HGP), measured by [6,6-(2)H(2)]glucose, was normal. In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs. 84% in control subjects (P = 0.002). Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulin-mediated suppression of HGP. There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status. Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis. We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance.

Objective. —To examine the association between the use of right heart catheterization (RHC) during the first 24 hours of care in the intensive care unit (ICU) and subsequent survival, length of stay, intensity of care, and cost of care. Design. —Prospective cohort study. Setting. —Five US teaching hospitals between 1989 and 1994. Subjects. —A total of 5735 critically ill adult patients receiving care in an ICU for 1 of 9 prespecified disease categories. Main Outcome Measures. —Survival time, cost of care, intensity of care, and length of stay in the ICU and hospital, determined from the clinical record and from the National Death Index. A propensity score for RHC was constructed using multivariable logistic regression. Case-matching and multivariable regression modeling techniques were used to estimate the association of RHC with specific outcomes after adjusting for treatment selection using the propensity score. Sensitivity analysis was used to estimate the potential effect of an unidentified or missing covariate on the results. Results. —By case-matching analysis, patients with RHC had an increased 30-day mortality (odds ratio, 1.24; 95% confidence interval, 1.03-1.49). The mean cost (25th, 50th, 75th percentiles) per hospital stay was $49300 ($17000, $30500, $56600) with RHC and $35700 ($11 300, $20600, $39200) without RHC. Mean length of stay in the ICU was 14.8 (5,9, 17) days with RHC and 13.0 (4,7, 14) days without RHC. These findings were all confirmed by multivariable modeling techniques. Subgroup analysis did not reveal any patient group or site for which RHC was associated with improved outcomes. Patients with higher baseline probability of surviving 2 months had the highest relative risk of death following RHC. Sensitivity analysis suggested that a missing covariate would have to increase the risk of death 6-fold and the risk of RHC 6-fold for a true beneficial effect of RHC to be misrepresented as harmful. Conclusion. —In this observational study of critically ill patients, after adjustment for treatment selection bias, RHC was associated with increased mortality and increased utilization of resources. The cause of this apparent lack of benefit is unclear. The results of this analysis should be confirmed in other observational studies. These findings justify reconsideration of a randomized controlled trial of RHC and may guide patient selection for such a study.

They selected references within their field of expertise and experience and graded the references according to the GRADE system. 1 The selection of references for the guideline was based on a validation of the appropriateness of the study design for the stated purpose, a relevant number of patients under study, and confidence in the participating centers and authors.References on original data were preferred and those that were found unsatisfactory in any of these respects were excluded from further evaluation.There may be limitations in this approach when recommendations are needed on rare problems or problems on which scant original data are available.In such cases, it may be necessary to rely on less-qualified references with a low grading.As a result of the important changes in the treatment of complications of cirrhosis (renal failure, infections, and variceal bleeding [VB]), studies performed more than 30 years ago have generally not been considered for these guidelines. Recommendation StrongFactors influencing the strength of recommendation included the quality of evidence, presumed patient-important outcomes, and costs. 1 Weak Variability in preferences and values, or more uncertainty.Recommendation is made with less certainty, higher costs, or resource consumption.

Research on hepatic encephalopathy is hampered by the imprecise definition of this disabling complication of liver disease. Under this light, the Organisation Mondiale de Gastroentérologie commissioned a Working Party to reach a consensus in this area and to present it at the 11th World Congress of Gastroenterology in Vienna (1998). The Working Party continued its work thereafter and now present their final report. In summary, the Working Party has suggested a modification of current nomenclature for clinical diagnosis of hepatic encephalopathy; proposed guidelines for the performance of future clinical trials in hepatic encephalopathy; and felt the need for a large study to redefine neuropsychiatric abnormalities in liver disease, which would allow the diagnosis of minimal (subclinical) encephalopathy to be made on firm statistical grounds. In the interim, it proposes the use of a psychometric hepatic encephalopathy score, based on the result of 5 neuropsychologic tests. Finally, the need for a careful evaluation of the newer neuroimaging modalities for the diagnosis of hepatic encephalopathy was stressed.

C-reactive protein (CRP) is a phylogenetically highly conserved plasma protein, with homologs in vertebrates and many invertebrates, that participates in the systemic response to inflammation. Its plasma concentration increases during inflammatory states, a characteristic that has long been employed for clinical purposes. CRP is a pattern recognition molecule, binding to specific molecular configurations that are typically exposed during cell death or found on the surfaces of pathogens. Its rapid increase in synthesis within hours after tissue injury or infection suggests that it contributes to host defense and that it is part of the innate immune response. Recently, an association between minor CRP elevation and future major cardiovascular events has been recognized, leading to the recommendation by the Centers for Disease Control and the American Heart Association that patients at intermediate risk of coronary heart disease might benefit from measurement of CRP. This review will largely focus on our current understanding of the structure of CRP, its ligands, the effector molecules with which it interacts, and its apparent functions.

Foot infections are a common and serious problem in persons with diabetes. Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence. Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations). This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation. Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy). Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation). Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs.

OBJECTIVE: To examine the association between the use of right heart catheterization (RHC) during the first 24 hours of care in the intensive care unit (ICU) and subsequent survival, length of stay, intensity of care, and cost of care. DESIGN: Prospective cohort study. SETTING: Five US teaching hospitals between 1989 and 1994. SUBJECTS: A total of 5735 critically ill adult patients receiving care in an ICU for 1 of 9 prespecified disease categories. MAIN OUTCOME MEASURES: Survival time, cost of care, intensity of care, and length of stay in the ICU and hospital, determined from the clinical record and from the National Death Index. A propensity score for RHC was constructed using multivariable logistic regression. Case-matching and multivariable regression modeling techniques were used to estimate the association of RHC with specific outcomes after adjusting for treatment selection using the propensity score. Sensitivity analysis was used to estimate the potential effect of an unidentified or missing covariate on the results. RESULTS: By case-matching analysis, patients with RHC had an increased 30-day mortality (odds ratio, 1.24; 95% confidence interval, 1.03-1.49). The mean cost (25th, 50th, 75th percentiles) per hospital stay was $49 300 ($17 000, $30 500, $56 600) with RHC and $35 700 ($11 300, $20 600, $39 200) without RHC. Mean length of stay in the ICU was 14.8 (5, 9, 17) days with RHC and 13.0 (4, 7, 14) days without RHC. These findings were all confirmed by multivariable modeling techniques. Subgroup analysis did not reveal any patient group or site for which RHC was associated with improved outcomes. Patients with higher baseline probability of surviving 2 months had the highest relative risk of death following RHC. Sensitivity analysis suggested that a missing covariate would have to increase the risk of death 6-fold and the risk of RHC 6-fold for a true beneficial effect of RHC to be misrepresented as harmful. CONCLUSION: In this observational study of critically ill patients, after adjustment for treatment selection bias, RHC was associated with increased mortality and increased utilization of resources. The cause of this apparent lack of benefit is unclear. The results of this analysis should be confirmed in other observational studies. These findings justify reconsideration of a randomized controlled trial of RHC and may guide patient selection for such a study.

In order to describe the outcomes of patients hospitalized with an acute exacerbation of severe chronic obstructive pulmonary disease (COPD) and determine the relationship between patient characteristics and length of survival, we studied a prospective cohort of 1,016 adult patients from five hospitals who were admitted with an exacerbation of COPD and a PaCO2 of 50 mm Hg or more. Patient characteristics and acute physiology were determined. Outcomes were evaluated over a 6 mo period. Although only 11% of the patients died during the index hospital stay, the 60-d, 180-d, 1-yr, and 2-yr mortality was high (20%, 33%, 43%, and 49%, respectively). The median cost of the index hospital stay was $7,100 ($4,100 to $16,000; interquartile range). The median length of the index hospital stay was 9 d (5 to 15 d). After discharge, 446 patients were readmitted 754 times in the next 6 mo. At 6 mo, only 26% of the cohort were both alive and able to report a good, very good, or excellent quality of life. Survival time was independently related to severity of illness, body mass index (BMI), age, prior functional status, PaO2/FI(O2), congestive heart failure, serum albumin, and the presence of cor pulmonale. Patients and caregivers should be aware of the likelihood of poor outcomes following hospitalization for exacerbation of COPD associated with hypercarbia.

Obesity is the most common medical condition in women of reproductive age. Obesity during pregnancy has short term and long term adverse consequences for both mother and child. Obesity causes problems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anomalies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of cesarean delivery and wound complications is increased. Postpartum, obese women have an increased risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of overweight or obese women gain more than recommended by Institute of Medicine gestational weight guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesity in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which increases the risk of childhood obesity. Although there is no unifying mechanism responsible for the adverse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and oxidative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysiology underlying these data and try to shed light on the specific underlying mechanisms.

BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

tricarboxylic acid cycle phosphoenolpyruvate carboxykinase phosphoenolpyruvate The oxidation of acetyl-CoA to CO2by the TCA1 cycle is the central process in energy metabolism. However, the TCA cycle also functions in biosynthetic pathways in which intermediates leave the cycle to be converted primarily to glucose, fatty acids, or non-essential amino acids. If TCA cycle anions are removed from the cycle they must be replaced to permit its continued function. This process is termed anaplerosis. Pyruvate carboxylase, which generates oxalacetate directly in the mitochondria, is the major anaplerotic enzyme. Conversely, 4- and 5-carbon intermediates enter the TCA cycle during the catabolism of amino acids. Because the TCA cycle cannot fully oxidize 4- and 5-carbon compounds, these intermediates must be removed from the cycle by a process termedcataplerosis. Cataplerosis may be linked to biosynthetic processes such as gluconeogenesis in the liver and kidney cortex, fatty acid synthesis in the liver, and glyceroneogenesis in adipose tissue. Cataplerotic enzymes present in many mammalian tissues include P-enolpyruvate carboxykinase (PEPCK), glutamate dehydrogenase, aspartate aminotransferase, and citrate lyase. In this review we have evaluated the roles of anaplerosis and cataplerosis in whole body metabolism. The expression anaplerotic sequences was a term used in biochemistry by Sir Hans Kornberg (1Kornberg H.L. Essays Biochem. 1966; 2: 1-31Crossref Scopus (359) Google Scholar) to describe a series of enzymatic reactions or pathways that replenish the pools of metabolic intermediates in the TCA cycle. These intermediates are critical for the functioning of the TCA cycle, the primary role of which is the oxidation of acetyl-CoA to carbon dioxide. The pool of TCA cycle intermediates is sufficient to sustain the oxidative carbon flux over a fairly wide range, so that during high energy consumption (e.g. exercise) or during lower energy consumption (e.g. fasting), there is not a large change in the pool size of TCA intermediates (2Graham T.E. Gibala M.J. Richter E.A. Galbo H. Kiens B. Saltin B. Skeletal Muscle Metabolism in Exercise and Diabetes. Plenum Press, New York1998: 271-286Google Scholar). However, in several physiological states, there is a large influx (anaplerosis) of 4- and 5-carbon intermediates into the TCA cycle. Because the TCA cycle cannot act as a carbon sink, anaplerosis must be coupled with the exit of intermediates from the cycle via cataplerosis. The importance of anaplerotic reactions for cellular metabolism is thus apparent. However, the coupling of this process with cataplerosis and the roles that both pathways play in the regulation of amino acid, glucose, and fatty acid metabolism have not been emphasized to a sufficient extent. The terms anaplerosis and cataplerosis describe reciprocal and correlative reactions involved in the function of the TCA cycle. The enzymatic steps in these processes have long been known, but the overall concept of a linkage between anaplerosis and cataplerosis should be underscored, because the balance between these two processes controls the entry and exit of TCA cycle anions. Anaplerotic and cataplerotic reactions are involved in the ultimate disposal of all metabolic intermediates. The metabolic role of anaplerosis and cataplerosis in amino acid metabolism varies with specific organs and is dependent on the nutritional/metabolic status of the individual. During feeding, the intestine is an important site of catabolism of enterally derived amino acids, whereas in the starved state amino acid catabolism occurs primarily in the kidney, liver, and muscle. The catabolism of amino acids produces gluconeogenic or ketogenic precursors (Table I). The disposal of gluconeogenic anions in the TCA cycle employs anaplerotic and cataplerotic pathways for their terminal oxidation. The only known pathway for the terminal oxidation of leucine is through acetoacetate to acetyl-CoA and subsequent oxidation in the TCA cycle. However, other amino acids also have for their disposal alternate ketogenic pathways for terminal oxidation. Thus, the ketogenic amino acids from proteolysis can be terminally oxidized in muscle, whereas the gluconeogenic amino acids are dependent upon anaplerosis and cataplerosis for conversion to glucose in the liver and kidney before oxidation to CO2 and H2O.Table IMetabolic fates of amino acids in the TCA cycle1. Amino acids converted to pyruvate Alanine, serine, glycine, threonine, cysteine, tryptophan2. Amino acids converted to oxaloacetate Aspartate, asparagine3. Amino acids converted to α-ketoglutarate Glutamate, glutamine, proline, histidine, arginine4. Amino acids converted to fumarate Phenylalanine, tyrosine5. Amino acids converted to succinyl-CoA Methionine, isoleucine, valine6. Amino acids converted to acetyl-CoA Leucine, isoleucine, lysine, phenylalanine, tyrosine, tryptophan, threonine Open table in a new tab The first reaction of the TCA cycle, citrate synthase, catalyzes the condensation of oxalacetate with acetyl-CoA; the oxalacetate is subsequently regenerated by the reactions of the cycle and condenses with another molecule of acetyl-CoA. However, the TCA cycle also functions in biosynthetic processes in which intermediates are removed from the cycle; this necessitates anaplerotic reactions to replenish TCA cycle intermediates to ensure its continued function. Pyruvate carboxylase, which synthesizes oxalacetate from pyruvate in the mitochondrial matrix, is the archetypical anaplerotic enzyme. The activity of this enzyme is high in many tissues (e.g. 10–12 units/g of liver); acetyl-CoA is a positive allosteric regulator of the enzyme. Anaplerosis is obligatory during both gluconeogenesis and lipogenesis when malate (gluconeogenesis) or citrate (lipogenesis) leaves the mitochondria and is further metabolized to form glucose or fatty acids, respectively. If intermediates can be added to the TCA cycle, it is equally important to remove them to avoid the accumulation of anions in the mitochondrial matrix. Cataplerosis describes reactions involved in the disposal of TCA cycle intermediates. There are several cataplerotic enzymes; these include PEPCK, aspartate aminotransferase, and glutamate dehydrogenase. Each of these reactions has as substrate a TCA cycle anion that is converted to a product that effectively removes intermediates from the cycle. In the liver and kidney, the role of PEPCK in cataplerosis is of special importance because it is a common route for the generation of PEP from oxalacetate to be used for gluconeogenesis. Alternatively, in muscle, PEP can be converted to pyruvate that can be decarboxylated to acetyl-CoA for subsequent oxidation to CO2 in the TCA cycle. The regulation of anaplerosis and cataplerosis depends upon the metabolic and physiologic state and the specific tissue/organ involved. For example, during starvation, cataplerosis via phosphoenolpyruvate to support gluconeogenesis may be regulatory in the liver, whereas in the kidney anaplerosis via uptake of glutamine may be regulatory. Anaplerotic and cataplerotic intermediates entering and exiting the TCA cycle are shown in Fig. 1. A detailed and elegant analysis of amino acid metabolism can be found in a review by Jungas et al. (3Jungas R.L. Halperin M.L. Brosnan J.T. Physiol. Rev. 1992; 72: 419-448Crossref PubMed Scopus (234) Google Scholar). The interplay between anaplerotic and cataplerotic reactions in humans was demonstrated by renal metabolism during total, prolonged starvation (4Owen O.E. Felig P. Morgan A.P. Wahren J. Cahill Jr., G.F. J. Clin. Invest. 1969; 48: 584-594Crossref PubMed Scopus (569) Google Scholar). Arteriovenous concentration differences of metabolites across the kidneys coupled with urinary nitrogen losses showed that the kidney extracted glutamine and produced urinary ammonium (5Van Slyke D.D. Phillips R.A. Hamilton P.B. Archibald R.M. Futcher P.H. Hiller A. J. Biol. Chem. 1943; 150: 481-482Abstract Full Text PDF Google Scholar). Concurrently, the kidney released glucose into the blood. It was initially recognized that renal ammoniagenesis was related to ketonuria during prolonged starvation when there is an increase in ketogenesis (6Sapir D.G. Owen O.E. Cheng J.T. Ginsberg R. Boden G. Walker W.G. J. Clin. Invest. 1972; 51: 2093-2102Crossref PubMed Scopus (26) Google Scholar). However, it was not generally appreciated that the entry (anaplerosis) and removal (cataplerosis) of intermediates into and out of the TCA cycle as related to renal ammoniagenesis and gluconeogenesis had to be balanced. This fundamental principle is poorly understood and is the foundation of this paper. During prolonged starvation glutamine is transported from muscle to the kidney where the amino and amide groups are used for ammonia formation. The ammonia released from the renal cells serves to titrate the acidity of the tubular urine created by the disassociation of organic acids, primarily β-hydroxybutyric and acetoacetic acids. For ammonia generation to continue, glutamine undergoes anaplerotic reactions to form α-ketoglutarate that enters the TCA cycle and is sequentially converted to malate that leaves the mitochondria. Malate is oxidized in the cytosol to oxalacetate that is subsequently converted to PEP and then to glucose. Thus, anaplerotic and cataplerotic reactions are essential and balanced during renal ammoniagenesis and gluconeogenesis. The heightened ketonuria that occurs with ketonemia is related to the need for the kidney to generate glucose during total starvation when renal gluconeogenesis accounts for about 50% of the net glucose synthesis (4Owen O.E. Felig P. Morgan A.P. Wahren J. Cahill Jr., G.F. J. Clin. Invest. 1969; 48: 584-594Crossref PubMed Scopus (569) Google Scholar, 7Owen O.E. Smalley K.J. D'Alessio D.A. Mozzoli M.A. Dawson E.K. Am. J. Clin. Nutr. 1998; 68: 12-34Crossref PubMed Scopus (90) Google Scholar). Thus, renal ammoniagenesis and gluconeogenesis are tightly interlocked and dependent upon balanced anaplerotic reactions to replenish the α-ketoglutarate in the TCA cycle and cataplerotic reactions to drain remnant 4-carbon metabolic intermediates from the cycle to synthesize glucose (7Owen O.E. Smalley K.J. D'Alessio D.A. Mozzoli M.A. Dawson E.K. Am. J. Clin. Nutr. 1998; 68: 12-34Crossref PubMed Scopus (90) Google Scholar). In addition, there is a metabolic bonus when the kidneys excrete urinary ammonium during starvation. The caloric value of protein is greater when amino acid nitrogen is lost in the urine as ammonium rather than urea because it requires four molecules of ATP to generate a molecule of urea via the urea cycle. In addition, energy is required for the synthesis of creatine and uric acid. Despite the relatively slow rate of turnover of skeletal muscle protein, it represents the largest reservoir of amino acids because of its large mass. Following an overnight fast, there is a net release of amino acids from skeletal muscle; however, the amino acids released do not reflect the amino acid composition of the skeletal muscle proteins (3Jungas R.L. Halperin M.L. Brosnan J.T. Physiol. Rev. 1992; 72: 419-448Crossref PubMed Scopus (234) Google Scholar, 8Felig P. Bergman M. Felig P. Baxter J.D. Frohman L.A. Endocrinology and Metabolism. 3rd Ed. McGraw-Hill, Inc., New York1995: 1107-1250Google Scholar). This suggests that there is local metabolism and interconversion of amino acids in the muscle. Specifically, alanine and glutamine represent a disproportionately larger fraction of amino acids released by the skeletal muscle when compared with the amino acid composition of skeletal muscle proteins. The relative proportion of these amino acids released by muscle also changes with the metabolic status, such as prolonged starvation or diabetes, or in response to administration of insulin or glucagon (3Jungas R.L. Halperin M.L. Brosnan J.T. Physiol. Rev. 1992; 72: 419-448Crossref PubMed Scopus (234) Google Scholar, 8Felig P. Bergman M. Felig P. Baxter J.D. Frohman L.A. Endocrinology and Metabolism. 3rd Ed. McGraw-Hill, Inc., New York1995: 1107-1250Google Scholar, 9Reeds P.J. Fjeld C.R. Jahoor F. J. Nutr. 1994; 124: 906-910Crossref PubMed Scopus (282) Google Scholar, 10Castillo C.E. Katz A. Spencer M.K. Yan Z. Nyomba B.L. Am. J. Physiol. 1991; 261: E598-E605PubMed Google Scholar, 11Gibala M.J. MacLean D.A. Graham T.E. Saltin B. Am. J. Physiol. 1998; 275: E235-E242PubMed Google Scholar). These data suggest that a local metabolism of amino acids occurs in the skeletal muscle that results in the de novo synthesis of certain non-essential amino acids, primarily alanine and glutamine. Arteriovenous concentration differences across skeleton muscles show net uptake and/or release of lactate, ammonia, alanine, glutamine, and glutamate at rest and during exercise (11Gibala M.J. MacLean D.A. Graham T.E. Saltin B. Am. J. Physiol. 1998; 275: E235-E242PubMed Google Scholar). In addition, during exercise there is an increase in the TCA cycle intermediates; however, the increase in concentration is not equal in all the TCA intermediates (Table II).Table IIIntramuscular concentrations of individual TCA cycle intermediates at rest and during exerciseRest5 min10 minCitrate0.362 ± 0.0470.658 ± 0.0772-ap ≤ 0.05versus rest.0.631 ± 0.0522-ap ≤ 0.05versus rest.Isocitrate0.085 ± 0.0130.194 ± 0.0222-ap ≤ 0.05versus rest.0.200 ± 0.0222-ap ≤ 0.05versus rest.α-Ketoglutarate0.050 ± 0.0040.036 ± 0.0052-ap ≤ 0.05versus rest.0.038 ± 0.0052-ap ≤ 0.05versus rest.Succinate0.368 ± 0.0760.567 ± 0.1150.609 ± 0.118Fumarate0.087 ± 0.0060.198 ± 0.0292-ap ≤ 0.05versus rest.0.195 ± 0.0322-ap ≤ 0.05versus rest.Malate0.365 ± 0.0371.163 ± 0.2032-ap ≤ 0.05versus rest.1.182 ± 0.1602-ap ≤ 0.05versus rest.Oxalacetate0.012 ± 0.0030.030 ± 0.0052-ap ≤ 0.05versus rest.0.027 ± 0.0062-ap ≤ 0.05versus rest.2-a p ≤ 0.05versus rest. Open table in a new tab During caloric restriction, amino acids also provide a source of energy. Amino acids yield part of their energy during oxidative deamination, but their carbon skeleton must undergo subsequent catabolism to be fully metabolized. Although most amino acids enter the TCA cycle as 4- or 5-carbon compounds, only acetyl-CoA produced from their catabolism can be fully oxidized in the cycle. Recent data from studies in humans have shown that only a small increase in the concentration of TCA intermediates (mostly 4-carbon) occurs during fasting or exercise, thus confirming the concept that only small changes in the amounts of these intermediates are required to adapt to the need for energy (12Sahlin K. Katz A. Broberg S. Am. J. Physiol. 1990; 259: C834-C841Crossref PubMed Google Scholar, 13Garber A.J. Karl I.E. Kipnis D.M. J. Biol. Chem. 1976; 251: 826-835Abstract Full Text PDF PubMed Google Scholar). The removal (cataplerosis) of TCA cycle anions generated from the entry of amino acids occurs via the action of PEPCK, glutamate dehydrogenase, or aspartate aminotransferase. Alanine and glutamine are synthesized from other amino acids and released into the circulation. Alanine is generated by the transamination of pyruvate via alanine aminotransferase. The possible sources of pyruvate are glucose and lactate, or PEP via PEPCK, using as a substrate the oxalacetate generated in the TCA cycle (cataplerosis) (13Garber A.J. Karl I.E. Kipnis D.M. J. Biol. Chem. 1976; 251: 826-835Abstract Full Text PDF PubMed Google Scholar). The carbon skeleton for the synthesis of glutamine can be generated from the TCA cycle intermediates formed by the catabolism of gluconeogenic amino acids such as aspartate and asparagine (14Chang T.W. Goldberg A.L. J. Biol. Chem. 1978; 253: 3685-3695Abstract Full Text PDF PubMed Google Scholar). These amino acids are capable of generating intermediates that can be converted by forward flow of the TCA cycle to the α-ketoglutarate required for glutamate synthesis. Transamination of α-ketoglutarate, using the branched-chain amino acids as the source of the amino groups, accounts for the synthesis of glutamate, which is then converted to glutamine by glutamine synthase using ammonia generated in muscle by the purine nucleotide cycle. In light of the concept of balanced anaplerosis and cataplerosis, branched-chain amino acid metabolism in muscle needs to be studied further. Another paradigm for the metabolic roles of anaplerosis and cataplerosis is the oxidation of glutamine to CO2 in the small intestine. In this case, the α-ketoglutarate formed from glutamine is converted to malate by the TCA cycle; the malate leaves the mitochondria and is oxidized in the cytosol to oxalacetate by NAD:malate dehydrogenase. The oxalacetate is decarboxylated to PEP by PEPCK, and the PEP is converted to pyruvate by pyruvate kinase. The pyruvate re-enters the mitochondria where it is decarboxylated to acetyl-CoA by the pyruvate dehydrogenase complex; the acetyl-CoA is then oxidized by the TCA cycle. Alternately, a fraction of the pyruvate may be transaminated to alanine in the cytosol (Fig.2). Recent research on the metabolism of glutamine in human adults and infants illustrates the critical role of anaplerosis and cataplerosis in amino acid metabolism in the gut. In normal healthy adults, almost 74% of the enterally administered glutamine was extracted by the splanchnic compartment during the first pass (15Matthews D.E. Marano M.A. Campbell R.G. Am. J. Physiol. 1993; 264: E848-E854PubMed Google Scholar), whereas 70–80% of enterally administered [13C]glutamine tracer was found in respiratory CO2 (16Haisch M. Fukagawa N.K. Matthews D.E. Am. J. Physiol. 2000; 278: E593-E602Crossref PubMed Google Scholar). Other data from studies of newborn infants also show that enterally administered glutamine is rapidly metabolized in the gut as an energy source for the enterocytes, resulting in increased urea production (17Devapatla S. Parimi P. O'Brien A. Gruca L. Kalhan S. Pediatr. Res. 2002; 51: 286AGoogle Scholar). The majority of the glutamine is metabolized by the small intestine and not the liver, because there is no observed dilution of parenterally administered [15N]glutamine. This suggests that the carbon skeleton of dietary glutamine is oxidized by the small intestine (not the liver) as a source of energy. The metabolism of glutamine by the small intestine illustrates the importance of both anaplerosis and cataplerosis in the metabolism of the 5-carbon intermediates formed from the catabolism of the carbon skeletons of amino acids. For the carbon skeleton of glutamine to be metabolized to CO2 in the TCA cycle, the α-ketoglutarate formed from glutamate (originally from the deamination of glutamine) must be converted to acetyl-CoA for full oxidation. As shown in Fig. 2, the removal of carbon from the TCA cycle involves the cataplerotic activity of PEPCK in the small intestine, which synthesizes PEP from the oxalacetate generated from the oxidation of α-ketoglutarate. The synthesis of triglyceride in adipose tissue during starvation is another example of cataplerosis linked to a biosynthetic pathway. There is a net breakdown of triglyceride in adipose tissue during fasting (lipolysis) that is stimulated by cAMP and inhibited by insulin. During starvation when the rates of lipolysis are highest, a major fraction (up to 30%) of the free fatty acids generated from triglyceride breakdown is re-esterified back to triglyceride in adipose tissue (18Elia M. Zed C. Neale G. Livesey G. Metabolism. 1987; 36: 251-255Abstract Full Text PDF PubMed Scopus (89) Google Scholar, 19Miyoshi H. Shulman G.I. Peters E.J. Wolfe M.H. Elahi D. Wolfe R.R. J. Clin. Invest. 1988; 81: 1545-1555Crossref PubMed Scopus (117) Google Scholar, 20Patel D. Kalhan S. Pediatr. Res. 1992; 31: 52-58Crossref PubMed Scopus (66) Google Scholar, 21Vaughan M. J. Biol. Chem. 1962; 237: 3354-3361Abstract Full Text PDF PubMed Google Scholar). This process requires a source of 3-glycerol phosphate, which is generally supplied by glucose via glycolysis. However, during prolonged starvation glucose utilization by adipose tissue is curtailed to spare glucose as a fuel for the brain and red blood cells. An alternative source of 3-glycerol phosphate is provided by glyceroneogenesis, an abbreviated version of gluconeogenesis, which provides the glyceride glycerol in triglyceride in adipose tissue (Fig.3) (22Ballard F.J. Hanson R.W. Leveille G.A. J. Biol. Chem. 1967; 242: 2746-2750Abstract Full Text PDF PubMed Google Scholar, 23Reshef L. Hanson R.W. Ballard F.J. J. Biol. Chem. 1970; 245: 5979-5984Abstract Full Text PDF PubMed Google Scholar). Rats fed a high protein, carbohydrate-free diet synthesize up to 80% of their glyceride glycerol in white adipose tissue by glyceroneogenesis (24Botion L.M. Brito M.N. Brito N.A. Brito S.R. Kettelhut Metabolism. 1998; Full Text PDF PubMed Scopus Google Scholar). is also an important pathway for the synthesis of triglyceride during It has been that of the fatty acids up by the liver during fasting is converted to triglyceride and released as (7Owen O.E. Smalley K.J. D'Alessio D.A. Mozzoli M.A. Dawson E.K. Am. J. Clin. Nutr. 1998; 68: 12-34Crossref PubMed Scopus (90) Google Scholar). is a major pathway for the synthesis of the 3-glycerol phosphate that is required to support triglyceride synthesis in the by et al. (24Botion L.M. Brito M.N. Brito N.A. Brito S.R. Kettelhut Metabolism. 1998; Full Text PDF PubMed Scopus Google Scholar) have that glyceroneogenesis in the of fed a high protein, carbohydrate-free diet 80% of the glyceride glycerol in In humans have for of the glyceride glycerol is derived from glyceroneogenesis and only from glycerol S. L. Hanson R.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The TCA cycle is balanced between the and of intermediates for metabolic The of the TCA cycle as a needs in light of its role in The cycle as a on a in which the flow of into the must be balanced by the flow out or the be with In this we have several metabolic in which the two anaplerosis and cataplerosis, to ensure the balance of carbon flow into and out of the TCA cycle. The of this fundamental is in its and in its It is as in

BACKGROUND: The perinatal and maternal consequences of induction of labor at 39 weeks among low-risk nulliparous women are uncertain. METHODS: In this multicenter trial, we randomly assigned low-risk nulliparous women who were at 38 weeks 0 days to 38 weeks 6 days of gestation to labor induction at 39 weeks 0 days to 39 weeks 4 days or to expectant management. The primary outcome was a composite of perinatal death or severe neonatal complications; the principal secondary outcome was cesarean delivery. RESULTS: A total of 3062 women were assigned to labor induction, and 3044 were assigned to expectant management. The primary outcome occurred in 4.3% of neonates in the induction group and in 5.4% in the expectant-management group (relative risk, 0.80; 95% confidence interval [CI], 0.64 to 1.00). The frequency of cesarean delivery was significantly lower in the induction group than in the expectant-management group (18.6% vs. 22.2%; relative risk, 0.84; 95% CI, 0.76 to 0.93). CONCLUSIONS: Induction of labor at 39 weeks in low-risk nulliparous women did not result in a significantly lower frequency of a composite adverse perinatal outcome, but it did result in a significantly lower frequency of cesarean delivery. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ARRIVE ClinicalTrials.gov number, NCT01990612 .).

Iron-chelating therapy with deferoxamine in patients with thalassemia major has dramatically altered the prognosis of this previously fatal disease. The successes achieved with deferoxamine, as well as the limitations of this treatment, have stimulated the design of alternative strategies of iron-chelating therapy, including orally active iron chelators. The development of the most promising of these, deferiprone, has progressed rapidly over the last 5 years; data from several trials have provided direct and supportive evidence for its short-term efficacy. At the same time, the toxicity of this agent mandates a careful evaluation of the balance between risk and benefit of deferiprone in patients with thalassemia, in most of whom long-term deferoxamine is safe and efficacious therapy.

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.

OBJECTIVES: This study analyzed whether inadequate functional health literacy is an independent risk factor for hospital admission. METHODS: We studied a prospective cohort of 3260 Medicare managed care enrollees. RESULTS: Of the participants, 29.5% were hospitalized. The crude relative risk (RR) of hospitalization was higher for individuals with inadequate literacy (n = 800; RR = 1.43; 95% confidence interval [CI] = 1.24, 1.65) and marginal literacy (n = 366; RR = 1.33; 95% CI = 1.09, 1.61) than for those with adequate literacy (n = 2094). In multivariate analysis, the adjusted relative risk of hospital admission was 1.29 (95% CI = 1.07, 1.55) for individuals with inadequate literacy and 1.21 (95% CI = 0.97, 1.50) for those with marginal literacy. CONCLUSIONS: Inadequate literacy was an independent risk factor for hospital admission among elderly managed care enrollees.

What causes physicians to change the way they practice? This question is especially important today because physicians' decisions influence not only the health of their patients but also the cost of their care. Thus, the ability to change physicians' practices could improve the quality of health care while controlling expenditures.Changes in practice are sometimes rapid and dramatic. For example, laparoscopic cholecystectomy has virtually replaced the traditional procedure in the past several years1. At other times physicians are reluctant to change their practices even when randomized trials demonstrate the effectiveness of a new treatment2. In this article we . . .