Preclinical Serological Signatures are Associated With Complicated Crohn's Disease Phenotype at Diagnosis.

BACKGROUND: At diagnosis, up to one-third of patients with Crohn's disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature. METHODS: Prediagnosis serum was obtained from 201 patients with CD and 201 healthy controls. Samples were evaluated with a comprehensive panel of 1129 proteomic markers (SomaLogic) and antimicrobial antibodies. CD diagnosis and complications were defined by the International Classification of Diseases-Ninth Revision and Current Procedural Terminology codes. Cox regression models were utilized to assess the association between markers and the subsequent risk of being diagnosed with complicated CD. In addition, biological pathway and network analyses were performed. RESULTS: Forty-seven CD subjects (24%) had a B2 (n = 36) or B3 (n = 9) phenotype or CD-related surgery (n = 2) at diagnosis. Subjects presenting with complicated CD at diagnosis had higher levels of antimicrobial antibodies six years before diagnosis as compared with those diagnosed with noncomplicated CD. Twenty-two protein biomarkers (reflecting inflammatory, fibrosis, and tissue protection markers) were found to be associated with complicated CD. Pathway analysis of the altered protein biomarkers identified higher activation of the innate immune system and complement or coagulation cascades up to six years before diagnosis in complicated CD. CONCLUSIONS: Proteins and antimicrobial antibodies associated with dysregulated innate immunity, excessive adaptive response to microbial antigens, and fibrosis precede and predict a complicated phenotype at the time of diagnosis in CD patients.

A candidate-gene association study of topiramate-induced weight loss in obese patients with and without type 2 diabetes mellitus.

OBJECTIVE: Clinical response to topiramate can vary greatly in obese patients. Identifying genetic variants associated with treatment response could help gain insight into the mechanism of action of topiramate. Little is known about the relationship between genetic variability and topiramate treatment response. We performed a large-scale candidate-gene study to identify genetic risk factors predictive of topiramate-induced weight loss. METHODS: We collected DNA samples from patients who had previously participated in clinical trials to assess the efficacy of topiramate for the treatment of obesity. A custom chip containing single nucleotide polymorphisms from ∼ 480 candidate genes was utilized to genotype a discovery cohort of 445 obese patients from a clinical study. Variants predictive of topiramate-induced weight loss were identified and further tested in an independent replication cohort of drug-naive, obese patients with type 2 diabetes (N=139). RESULTS: We identified a haplotype in INSR that may contribute to differential topiramate-induced weight loss. Carriers and noncarriers of an INSR haplotype lost 9.1 and 7.0% of body weight, respectively (P = 6.5 × 10(-6), P adj = 0.001). This finding was replicated, with carriers and noncarriers losing 9.5 and 7.3% of body weight, respectively (P Bonf=0.02), in the independent replication cohort. We also identified an SNP in HNF1A that may be associated with topiramate response and an SNP in GRIA3 that may be associated with nonpharmacologic treatment response. CONCLUSION: According to our preliminary findings, genetic variation in the INSR and HNF1A genes may differentially affect weight loss in obese individuals treated with topiramate and genes related to insulin action are implicated in modulating topiramate response. However, these findings need to be further replicated in additional larger samples.

Maintenance Golimumab Treatment in Pediatric UC Patients With Moderately to Severely Active UC: PURSUIT PEDS PK Long-Term Study Results.

Background: Long-term safety, pharmacokinetics, and efficacy of open-label golimumab therapy in children with moderate-severe ulcerative colitis were evaluated. Methods: Week-6 golimumab responders (Mayo score decrease of ≥30% and ≥3 points from baseline, rectal bleeding subscore of 0/1 or ≥1 decrease from baseline) entered the long-term extension at week 14 and received maintenance therapy (subcutaneous, q4w). Patients ≥45 kg could receive at-home treatments at week 18. Pharmacokinetic, safety, and efficacy results were summarized through week 126 (2 years). Results: Among 35 enrolled children, 21 (60%) responded at week 6 and 20 entered the long-term extension (median age of 14.5 years and median weight of 46.1 kg). Eleven of 20 patients (55%) completed 2 years of treatment. No anaphylactic or serum sickness-like reactions, opportunistic infections, malignancies, tuberculosis, or deaths occurred. The safety profile of golimumab from weeks 14 through 126 and that observed through week 14 was generally consistent. Median trough golimumab concentrations in evaluable patients were consistent from weeks 14 (1.39, interquartile range 0.67-3.60) through 102 (1.18, 0.78-2.16), but higher at week 110 (4.10, 1.30-4.81). The incidence of antigolimumab antibodies increased from 10% (2/20) at week 30 to 25.0% (5/20) at week 126; 1 patient had neutralizing antibodies. At week 110, 50% (10/20) of patients were in remission (ie, Pediatric Ulcerative Colitis Activity Index <10). Among all enrolled patients, 28.6% (10/35) achieved remission at week 110. Conclusions: Among children with ulcerative colitis who initially responded to golimumab induction and received q4w maintenance treatment in the long-term extension, 50% showed continued clinical benefit through 2 years. No new safety signals were observed.

Pharmacodynamic profiling of ceftobiprole for treatment of complicated skin and skin structure infections.

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for >or=30 and >or=50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a >or=30 or >or=50% T>MIC and a clinical cure (P = 0.003 and P = 0.007, respectively; Pearson's chi(2) test). The fractional TAR was greater than 90% at a MIC of MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of >or=30 or >or=50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.

Population Pharmacokinetics and Exposure-Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis.

Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to compare the PK and E-R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6-17 years) in the PURSUIT-PEDS-PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2-17 years) in the GO-KIDS study, were included in the population PK analysis. E-R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score-based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1-compartment model with first-order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model-estimated terminal half-life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT-PEDS-PK may be needed for children ≤45 kg to achieve exposures comparable to adults. Comparable E-R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E-R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population.

A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections.

BACKGROUND: A randomized, double-blind, multicenter trial involving patients with a broad range of complicated skin and skin-structure infections due to either gram-positive or gram-negative bacteria was conducted to compare ceftobiprole monotherapy with treatment with vancomycin plus ceftazidime. METHODS: Patients were randomized 2:1 to receive ceftobiprole or to receive vancomycin plus ceftazidime. Outcomes were determined at a test-of-cure visit (7-14 days after completion of therapy) and were analyzed for all patients with complicated skin and skin-structure infections, as well as for subgroups, on the basis of major types of infections and severity of disease. RESULTS: Among the clinically evaluable and the intent-to-treat populations, clinical cure rates at the test-of-cure visit were similar in the ceftobiprole and comparator treatment arms (clinical cure rate, 90.5% [439 of 485 patients] and 90.2% [220 of 244 patients] in the clinically evaluable population, respectively; 81.9% [448 of 547 patients] and 80.8% [227 of 281 patients] in the intent-to-treat population, respectively). Clinical cure rates in ceftobiprole-treated patients ranged from 86.2% (125 of 145 patients) among those with diabetes who had foot infections to 93.0% (80 of 86 patients) among those with cellulitis. Among patients treated with ceftobiprole, clinical cure rates were similar among patients from whom gram-negative bacteria were isolated (87.9% [109 of 124 patients]) and among patients from whom gram-positive bacteria were isolated (91.8% [292 of 318 patients]) and were not statistically different from the clinical cure rates among comparator-treated patients (89.7% [61 of 68 patients] and 90.3% [149 of 165 patients], respectively). Rates of adverse events and serious adverse events in the 2 treatment groups were similar. CONCLUSIONS: Ceftobiprole monotherapy is as effective as vancomycin plus ceftazidime for treating patients with a broad range of complicated skin and skin-structure infections and infections due to gram-positive and gram-negative bacteria.

Chronic abdominal pain and depressive symptoms: analysis of the national longitudinal study of adolescent health.

BACKGROUND & AIMS: Abdominal pain is common in adolescence. The aim of this study was to determine the prevalence of depressive symptoms in a large cohort of patients with frequent abdominal pain. METHODS: A prospective, cross-sectional, nationally representative sample of children aged 13 to 18 years (mean age, 16.2 +/- 1.7 y; 49% male) completed in-home interviews and separate in-school questionnaires for the National Longitudinal Study in Adolescent Health (the Add Health Study). Depressed mood was assessed with the Center for Epidemiologic Studies Depression Scale. Subjective measures of abdominal pain were reported by 20,745 adolescents from wave 1 of the Add Health Study. Frequency of abdominal pain over the previous 1 year was rated as rare (0-1 episode/wk), moderate (2-3 episodes/wk), or daily (>or=4 episodes/wk). RESULTS: Daily pain is reported in 3.2% of adolescents, with an additional 14% reporting pain as moderate in frequency. Sixteen percent of all adolescents are at risk for developing depression. The risk for depression goes from 16% to 45% (P < .001) when the pain is daily. Compared with rare pain, children with daily pain were more likely to miss school 10 or more times per year (46% vs 19%, P < .001), cry (12.1% vs 1%, P < .001), feel sad (25.2% vs 5.3%, P < .001), and lonely (25.2% vs 6.4%, P < .001). Children with daily pain were likely to consider life a failure versus those with no pain (10.2% vs 3.3%, P < .001). CONCLUSIONS: Adolescents with frequent abdominal pain are at increased risk for depressive symptoms, social isolation, and missing school.

Social marginalization of overweight children.

BACKGROUND: Overweight is the most common health problem that faces children and adolescents. Although the correlation among overweight, low self-esteem, and depression is well known, social isolation among overweight children and adolescents has not been studied. OBJECTIVE: To investigate social networks of overweight and normal-weight adolescents in a large, nationally representative sample. DESIGN: Cross-sectional, nationally representative cohort study. Population A total of 90 118 adolescents aged 13 to 18 years who were enrolled in the National Longitudinal Study of Adolescent Health, of which a 1:5 subsample was selected for detailed in-home assessment, including height and weight measurements (n = 17 557). Overweight was defined according to body mass index (>95th percentile for age and sex). MAIN OUTCOME MEASURES: This analysis focuses on the number of friendship nominations each adolescent received from other adolescents. The number of friendship nominations and other social network measures were calculated using statistical software. RESULTS: Overweight adolescents were more likely to be socially isolated and to be peripheral to social networks than were normal-weight adolescents. Although overweight adolescents listed similar numbers of friends as normal-weight adolescents, overweight adolescents received significantly fewer friendship nominations from others than were received by normal-weight adolescents (mean [SE] number of friendship nominations, 3.39 [0.08] vs 4.79 [0.04]; P<.001). Overweight adolescents were also more likely to receive no friendship nominations than were normal-weight adolescents (odds ratio, 1.71; 95% confidence interval, 1.39-2.20). Decreased television viewing (P<.001), increased levels of sports participation (P<.001), and increased participation in school clubs (P<.001) were associated with significantly more friendship nominations and higher network centrality scores among both overweight and normal-weight adolescents. CONCLUSIONS: Many overweight adolescents are socially marginalized. Such isolation may aggravate the social and emotional consequences of overweight in this age group.

Childhood obesity.

The pediatrician's approach to overweight was best summarized by Bruch 25 years ago: The pediatrician plays an important role in the prevention of obesity. From birth on, feeding a child always involves a dual task--namely, offering food in appropriate amounts and gearing it to the child's expression of his needs. Only in this way can he develop discriminating awareness and become active in establishing self-regulation.... If a child is fed when he is hungry, played with when he needs attention, and encouraged to be active when he is restless, he is not likely to grow up inhibited and passive or overstuffed and helpless, unable to control his eating because every discomfort is misinterpreted as a need to eat.

A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation.

Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrials.gov identifier: NCT00326287].

Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria.

Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, -4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, -8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.

Bariatric surgery for severely overweight adolescents: concerns and recommendations.

As the prevalence of obesity and obesity-related disease among adolescents in the United States continues to increase, physicians are increasingly faced with the dilemma of determining the best treatment strategies for affected patients. This report offers an approach for the evaluation of adolescent patients' candidacy for bariatric surgery. In addition to anthropometric measurements and comorbidity assessments, a number of unique factors must be critically assessed among overweight youths. In an effort to reduce the risk of adverse medical and psychosocial outcomes and increase compliance and follow-up monitoring after bariatric surgery, principles of adolescent growth and development, the decisional capacity of the patient, family structure, and barriers to adherence must be considered. Consideration for bariatric surgery is generally warranted only when adolescents have experienced failure of 6 months of organized weight loss attempts and have met certain anthropometric, medical, and psychologic criteria. Adolescent candidates for bariatric surgery should be very severely obese (defined by the World Health Organization as a body mass index of > or =40), have attained a majority of skeletal maturity (generally > or =13 years of age for girls and > or =15 years of age for boys), and have comorbidities related to obesity that might be remedied with durable weight loss. Potential candidates for bariatric surgery should be referred to centers with multidisciplinary weight management teams that have expertise in meeting the unique needs of overweight adolescents. Surgery should be performed in institutions that are equipped to meet the tertiary care needs of severely obese patients and to collect long-term data on the clinical outcomes of these patients.