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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."

A large number of changes, distant from the site or sites of inflammation and involving many organ systems, may accompany inflammation. In 1930 interest was focused on these changes by the discovery of C-reactive protein (so named because it reacted with the pneumococcal C-polysaccharide) in the plasma of patients during the acute phase of pneumococcal pneumonia.1 Accordingly, these systemic changes have since been referred to as the acute-phase response,2 even though they accompany both acute and chronic inflammatory disorders. New acute-phase phenomena continue to be recognized, and the mechanisms mediating them are becoming better understood. This review summarizes much of . . .

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.)

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.

<h3>Objective.</h3> —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. <h3>Design.</h3> —Prospective cohort study. <h3>Setting.</h3> —Five US teaching hospitals between 1989 and 1994. <h3>Subjects.</h3> —A total of 5735 critically ill adult patients receiving care in an ICU for 1 of 9 prespecified disease categories. <h3>Main Outcome Measures.</h3> —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. <h3>Results.</h3> —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. <h3>Conclusion.</h3> —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.

BACKGROUND: One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation. METHODS: We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. RESULTS: By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P=0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. CONCLUSIONS: Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT ClinicalTrials.gov number, NCT00256152.).

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.

BACKGROUND AND PURPOSE: The goal of the present study was to prospectively determine how frequently early growth of intracerebral hemorrhage occurs and whether this early growth is related to early neurological deterioration. METHODS: We performed a prospective observational study of patients with intracerebral hemorrhage within 3 hours of onset. Patients had a neurological evaluation and CT scan performed at baseline, 1 hour after baseline, and 20 hours after baseline. RESULTS: Substantial growth in the volume of parenchymal hemorrhage occurred in 26% of the 103 study patients between the baseline and 1-hour CT scans. An additional 12% of patients had substantial growth between the 1- and 20-hour CT scans. Hemorrhage growth between the baseline and 1-hour CT scans was significantly associated with clinical deterioration, as measured by the change between the baseline and 1-hour Glasgow Coma Scale and National Institutes of Health Stroke Scale scores. No baseline clinical or CT prediction of hemorrhage growth was identified. CONCLUSIONS: Substantial early hemorrhage growth in patients with intracerebral hemorrhage is common and is associated with neurological deterioration. Randomized treatment trials are needed to determine whether this early natural history of ongoing bleeding and frequent neurological deterioration can be improved.

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: Limb salvage for severe trauma has replaced amputation as the primary treatment in many trauma centers. However, long-term outcomes after limb reconstruction or amputation have not been fully evaluated. METHODS: We performed a multicenter, prospective, observational study to determine the functional outcomes of 569 patients with severe leg injuries resulting in reconstruction or amputation. The principal outcome measure was the Sickness Impact Profile, a multidimensional measure of self-reported health status (scores range from 0 to 100; scores for the general population average 2 to 3, and scores greater than 10 represent severe disability). Secondary outcomes included limb status and the presence or absence of major complications resulting in rehospitalization. RESULTS: At two years, there was no significant difference in scores for the Sickness Impact Profile between the amputation and reconstruction groups (12.6 vs. 11.8, P=0.53). After adjustment for the characteristics of the patients and their injuries, patients who underwent amputation had functional outcomes that were similar to those of patients who underwent reconstruction. Predictors of a poorer score for the Sickness Impact Profile included rehospitalization for a major complication, a low educational level, nonwhite race, poverty, lack of private health insurance, poor social-support network, low self-efficacy (the patient's confidence in being able to resume life activities), smoking, and involvement in disability-compensation litigation. Patients who underwent reconstruction were more likely to be rehospitalized than those who underwent amputation (47.6 percent vs. 33.9 percent, P=0.002). Similar proportions of patients who underwent amputation and patients who underwent reconstruction had returned to work by two years (53.0 percent and 49.4 percent, respectively). CONCLUSIONS: Patients with limbs at high risk for amputation can be advised that reconstruction typically results in two-year outcomes equivalent to those of amputation.

OBJECTIVE: The authors determined the risk factors of mortality in patients with necrotizing soft-tissue infections (NSTIs) and examined the incidence and mortality from NSTI secondary to Streptococcus pyogenes. METHODS: All patients with NSTIs who were treated between January 1989 and June 1994 were analyzed for presentation, etiology, factors important in pathogenesis and treatment, and mortality. RESULTS: Sixty-five patients were identified with NSTIs secondary to postoperative wound complications (18), trauma (15), cutaneous disease (15), idiopathic causes (10), perirectal abscesses (3), strangulated hernias (2), and subcutaneous injections (2). Necrotizing soft-tissue infections were polymicrobial in 45 patients (69%). S. pyogenes was isolated in only 17% of the NSTIs, but accounted for 53% of monomicrobial infections. Eight of ten idiopathic infections were caused by a single bacterium (p = 0.0005), whereas 82% of postoperative infections were polymicrobial. An average of 3.3 operative debridements per patient and amputation in 12 patients were necessary to control infection. The overall mortality was 29%; mortality from S. pyogenes infection was only 18%. The average time from admission to operation was 90 hours in nonsurvivors versus 25 hours in survivors (p = 0.0002). Other risk factors previously associated with the development of NSTIs did not affect mortality. CONCLUSIONS: Early debridement of NSTI was associated with a significant decrease in mortality. S. pyogenes infection was the most common cause of monomicrobial NSTI, but was not associated with an increased mortality.

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

CONTEXT: Pediatric hypertension is increasing in prevalence with the pediatric obesity epidemic. Diagnosis of hypertension in children is complicated because normal and abnormal blood pressure values vary with age, sex, and height and are therefore difficult to remember. OBJECTIVES: To determine the frequency of undiagnosed hypertension and prehypertension and to identify patient factors associated with this underdiagnosis. DESIGN, SETTING, AND PARTICIPANTS: A cohort study of 14,187 children and adolescents aged 3 to 18 years who were observed at least 3 times for well-child care between June 1999 and September 2006 in the outpatient clinics in a large academic urban medical system in northeast Ohio. For children and adolescents who met criteria for hypertension or prehypertension at 3 or more well-child care visits, the proportion with a hypertension-related International Classification of Diseases, Ninth Revision code in the diagnoses list, problem list, or past medical history list of any visit was determined. MAIN OUTCOME MEASURES: Proportion of children and adolescents with 3 or more elevated age-adjusted and height-adjusted blood pressure measurements at well-child care visits and with a diagnosis of hypertension or prehypertension documented in the electronic medical record. Multivariate logistic regression identified patient factors associated with a correct diagnosis. RESULTS: Of 507 children and adolescents (3.6%) who had hypertension, 131 (26%) had a diagnosis of hypertension or elevated blood pressure documented in the electronic medical record. Patient factors that increased the adjusted odds of a correct diagnosis were a 1-year increase in age over age 3 (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.03-1.16), number of elevated blood pressure readings beyond 3 (OR, 1.77; 95% CI, 1.21-2.57), increase of 1% in height-for-age percentile (OR, 1.02; 95% CI, 1.01-1.03), having an obesity-related diagnosis (OR, 2.61; 95% CI, 1.49-4.55), and number of blood pressure readings in the stage 2 hypertension range (OR, 1.68; 95% CI, 1.29-2.19). Of 485 children and adolescents (3.4%) who had prehypertension, 55 (11%) had an appropriate diagnosis documented in the electronic medical record. Patient factors that increased the adjusted odds of being diagnosed with prehypertension included a 1-year increase in age over age 3 (OR, 1.21; 95% CI, 1.09-1.34) and number of elevated blood pressure readings beyond 3 (OR, 3.07; 95% CI, 2.20-4.28). CONCLUSIONS: Hypertension and prehypertension were frequently undiagnosed in this pediatric population. Patient age, height, obesity-related diagnoses, and magnitude and frequency of abnormal blood pressure readings all increased the odds of diagnosis.

The incidence of gestational diabetes mellitus (GDM) has doubled over the last 6–8 years and is paralleling the obesity epidemic. GDM carries longterm implications for the subsequent development of type 2 diabetes in the mother and increased risk for obesity and glucose intolerance in the offspring. Insulin resistance exists before pregnancy in women with a history of GDM but worsens during gestation. Insulin secretion is inadequate to compensate for the insulin resistance, leading to hyperglycemia that is detected by routine glucose screening in pregnancy. Thus, chronic insulin resistance is a central component of the pathophysiology of GDM. Human pregnancy is characterized by a series of metabolic changes that promote adipose tissue accretion in early gestation, followed by insulin resistance and facilitated lipolysis in late pregnancy. In early pregnancy, insulin secretion increases, while insulin sensitivity is unchanged, decreased, or may even increase (1,2). However, in late gestation, maternal adipose tissue depots decline, while postprandial free fatty acid (FFA) levels increase and insulin-mediated glucose disposal worsens by 40–60 % compared with prepregnancy (2).

BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS: The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

RATIONALE: ICU-acquired paresis (ICUAP) is common in survivors of critical illness. There is significant associated morbidity, including prolonged time on the ventilator and longer hospital stay. However, it is unclear whether ICUAP is independently associated with mortality, as sicker patients are more prone and existing studies have not adjusted for this. OBJECTIVES: To test the hypothesis that ICUAP is independently associated with increased mortality. Secondarily, to determine if handgrip dynamometry is a concise measure of global strength and is independently associated with mortality. METHODS: A prospective multicenter cohort study was conducted in intensive care units (ICU) of five academic medical centers. Adults requiring at least 5 days of mechanical ventilation without evidence of preexisting neuromuscular disease were followed until awakening and were then examined for strength. MEASUREMENTS AND MAIN RESULTS: We measured global strength and handgrip dynamometry. The primary outcome was in-hospital mortality and secondary outcomes were hospital and ICU-free days, ICU readmission, and recurrent respiratory failure. Subjects with ICUAP (average MRC score of < 4) had longer hospital stays and required mechanical ventilation longer. Handgrip strength was lower in subjects with ICUAP and had good test performance for diagnosing ICUAP. After adjustment for severity of illness, ICUAP was independently associated with hospital mortality (odds ratio [OR], 7.8; 95% confidence interval [CI], 2.4-25.3; P = 0.001). Separately, handgrip strength was independently associated with hospital mortality (OR, 4.5; 95% CI, 1.5-13.6; P = 0.007). CONCLUSIONS: ICUAP is independently associated with increased hospital mortality. Handgrip strength is also independently associated with poor hospital outcome and may serve as a simple test to identify ICUAP. Clinical trial registered with www.clinicaltrials.gov (NCT00106665).

Touch perception on the fingers and hand is essential for fine motor control, contributes to our sense of self, allows for effective communication, and aids in our fundamental perception of the world. Despite increasingly sophisticated mechatronics, prosthetic devices still do not directly convey sensation back to their wearers. We show that implanted peripheral nerve interfaces in two human subjects with upper limb amputation provided stable, natural touch sensation in their hands for more than 1 year. Electrical stimulation using implanted peripheral nerve cuff electrodes that did not penetrate the nerve produced touch perceptions at many locations on the phantom hand with repeatable, stable responses in the two subjects for 16 and 24 months. Patterned stimulation intensity produced a sensation that the subjects described as natural and without "tingling," or paresthesia. Different patterns produced different types of sensory perception at the same location on the phantom hand. The two subjects reported tactile perceptions they described as natural tapping, constant pressure, light moving touch, and vibration. Changing average stimulation intensity controlled the size of the percept area; changing stimulation frequency controlled sensation strength. Artificial touch sensation improved the subjects' ability to control grasping strength of the prosthesis and enabled them to better manipulate delicate objects. Thus, electrical stimulation through peripheral nerve electrodes produced long-term sensory restoration after limb loss.

OBJECTIVES: This study examined the relationship of functional health literacy to self-reported health and use of health services. METHODS: Patients presenting to two large, urban public hospitals in Atlanta, Ga, and Torrance, Calif, were administered a health literacy test about their overall health and use of health care services during the 3 months preceding their visit. RESULTS: Patients with inadequate functional health literacy were more likely than patients with adequate literacy to report their health as poor. Number of years of school completed was less strongly associated with self-reported health. Literacy was not related to regular source of care or physician visits, but patients in Atlanta with inadequate literacy were more likely than patients with adequate literacy to report a hospitalization in the previous year. CONCLUSIONS: Low literacy is strongly associated with self-reported poor health and is more closely associated with self-reported health than number of years of school completed.

IMPORTANCE: Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. OBJECTIVE: To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. DESIGN, SETTING, AND PARTICIPANTS: Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. MAIN OUTCOMES AND MEASURES: Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. RESULTS: In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. CONCLUSIONS AND RELEVANCE: Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

BACKGROUND: Colonization and infection with vancomycin-resistant enterococci have been associated with exposure to antibiotics that are active against anaerobes. In mice that have intestinal colonization with vancomycin-resistant enterococci, these agents promote high-density colonization, whereas antibiotics with minimal antianaerobic activity do not. METHODS: We conducted a seven-month prospective study of 51 patients who were colonized with vancomycin-resistant enterococci, as evidenced by the presence of the bacteria in stool. We examined the density of vancomycin-resistant enterococci in stool during and after therapy with antibiotic regimens and compared the effect on this density of antianaerobic agents and agents with minimal antianaerobic activity. In a subgroup of 10 patients, cultures of environmental specimens (e.g., from bedding and clothing) were obtained. RESULTS: During treatment with 40 of 42 antianaerobic-antibiotic regimens (95 percent), high-density colonization with vancomycin-resistant enterococci was maintained (mean [+/-SD] number of organisms, 7.8+/-1.5 log per gram of stool). The density of colonization decreased after these regimens were discontinued. Among patients who had not received antianaerobic antibiotics for at least one week, 10 of 13 patients who began such regimens had an increase in the number of organisms of more than 1.0 log per gram (mean increase, 2.2 log per gram), whereas among 10 patients who began regimens of antibiotics with minimal antianaerobic activity, there was a mean decrease in the number of enterococci of 0.6 log per gram (P=0.006 for the difference between groups). When the density of vancomycin-resistant enterococci in stool was at least 4 log per gram, 10 of 12 sets of cultures of environmental specimens had at least one positive sample, as compared with 1 of 9 sets from patients with a mean number of organisms in stool of less than 4 log per gram (P=0.002). CONCLUSIONS: For patients with vancomycin-resistant enterococci in stool, treatment with antianaerobic antibiotics promotes high-density colonization. Limiting the use of such agents in these patients may help decrease the spread of vancomycin-resistant enterococci.