Declining Use of Corticosteroids for Crohn's Disease Has Implications for Study Recruitment: Results of a Pilot Randomized Controlled Trial.

BACKGROUND: Corticosteroids (CS) have been used extensively to induce remission in Crohn's disease (CD); however, they are associated with severe side effects. We hypothesized that the administration of an exclusive enteral nutrition (EEN) formula to CS would lead to increased CD remission rates and to decreased CS-related adverse events. We proposed to undertake a pilot study comparing EEN and CS therapy to CS alone to assess decrease symptoms and inflammatory markers over 6 weeks. AIM: The overall aim was to assess study feasibility based on recruitment rates and acceptability of treatment in arms involving EEN. METHODS: The pilot study intended to recruit 100 adult patients with active CD who had been prescribed CS to induce remission as part of their care. The patients were randomized to one of three arms: (i) standard-dose CS; (ii) standard-dose CS plus EEN (Modulen 1.5 kcal); or (iii) short-course CS plus EEN. RESULTS: A total of 2009 CD patients attending gastroenterology clinics were screened from October 2018 to November 2019. Prednisone was prescribed to only 6.8% (27/399) of patients with active CD attending outpatient clinics. Of the remaining 372 patients with active CD, 34.8% (139/399) started or escalated immunosuppressant or biologics, 49.6% (198/399) underwent further investigation and 8.8% (35/399) were offered an alternative treatment (e.g., antibiotics, surgery or investigational agents in clinical trials). Only three patients were enrolled in the study (recruitment rate 11%; 3/27), and the study was terminated for poor recruitment. CONCLUSION: The apparent decline in use of CS for treatment of CD has implications for CS use as an entry criterion for clinical trials.

Quantitative Characterization of the Exposure-Response Relationship for Cancer Immunotherapy: A Case Study of Nivolumab in Patients With Advanced Melanoma.

To inform the benefit-risk assessment of nivolumab in patients with advanced melanoma, analyses of efficacy and safety exposure-response (E-R) relationships were conducted with data from patients with advanced melanoma enrolled in two clinical studies (phase I and phase III) who received nivolumab 0.1-10.0 mg/kg every 2 weeks. E-R efficacy analyses were performed by relating the nivolumab time-averaged concentration after the first dose (Cavg1 ) to two endpoints: RECIST objective response (OR) and overall survival (OS). E-R safety analyses characterized the relationship between nivolumab Cavg1 and the hazard of all-causality adverse events leading to discontinuation or death (AE-DC/D). Nivolumab exposure represented by Cavg1 was not a significant predictor of OR, OS, or the hazard of AE-DC/D. E-R efficacy and safety relationships were relatively flat over the exposure range.

Model-Based Population Pharmacokinetic Analysis of Nivolumab in Patients With Solid Tumors.

Nivolumab is a fully human monoclonal antibody that inhibits programmed death-1 activation. The clinical pharmacology profile of nivolumab was analyzed by a population pharmacokinetics model that assessed covariate effects on nivolumab concentrations in 1,895 patients who received 0.3-10.0 mg/kg nivolumab in 11 clinical trials. Nivolumab pharmacokinetics is linear with a time-varying clearance. A full covariate model was developed to assess covariate effects on pharmacokinetic parameters. Nivolumab clearance and volume of distribution increase with body weight. The final model included the effects of baseline performance status (PS), baseline body weight, and baseline estimated glomerular filtration rate (eGFR), sex, and race on clearance, and effects of baseline body weight and sex on volume of distribution in the central compartment. Sex, PS, baseline eGFR, age, race, baseline lactate dehydrogenase, mild hepatic impairment, tumor type, tumor burden, and programmed death ligand-1 expression had a significant but not clinically relevant (<20%) effect on nivolumab clearance.

A randomised controlled trial comparing eusol and sugar as dressing agents in the treatment of traumatic wounds.

We conducted a randomized controlled trial comparing EUSOL (Edinburgh University Solution of Lime) and sugar as dressing agents in the treatment of traumatic wounds. Patients in both groups were matched for age and gender. We found EUSOL did better than sugar in terms of contraction of size of wound, presence of discharge, floor area covered with slough, formation of healthy granulation and early possibility of wound coverage.

Limitations to body length/serum creatinine ratio as an estimate of glomerular filtration in children.

The ability of the Schwartz formula (CSCH) to estimate glomerular filtration rate (GFR) accurately was investigated in children with renal disease. 125Iodine-iothalamate clearance (CIO) was used as the reference standard for measuring GFR. Data from 176 CIO studies performed on 133 children (aged between 1 and 18 years) were compared with the simultaneous estimation of GFR by CSCH. The overestimation of GFR by CSCH was inversely proportional to the level of renal function. When CIO was > 90 ml/min per 1.73 m2, CSCH overestimated GFR by only 0.1% +/- 3%, but when CIO was < or = 15 ml/min per 1.73 m2, CSCH overestimated GFR by 164% +/- 42%. When renal function is normal or mildly reduced (GFR > 50 ml/min per 1.73 m2), CSCH overestimated CIO by only 10.3 +/- 3.0%, compared with 90.3 +/- 14.5% when renal function was moderately to severely curtailed (GFR < or = 50 ml/min per 1.73 m2). We conclude that CSCH is valid in predicting GFR only in children with normal renal function and mild insufficiency.

Proximal tubule dysfunction in cystine-loaded tubules: effect of phosphate and metabolic substrates.

Intracellular cystine loading by use of cystine dimethyl ester (CDME) results in a generalized inhibition in proximal tubule transport due, in part, to a decrease in intracellular ATP. The present study examined the importance of phosphate and metabolic substrates in the proximal tubule dysfunction produced by cystine loading. Proximal tubule intracellular phosphorus was 1.8 +/- 0.1 in control tubules and 1.1 +/- 0.1 nmol/mg protein in proximal tubules incubated in vitro with CDME P < 0.001). Infusion of sodium phosphate in rabbits and subsequent incubation of proximal tubules with a high-phosphate medium attenuated the decrease in proximal tubule respiration and prevented the decrease in intracellular ATP with cystine loading. Tricarboxylic acid cycle intermediates have been shown to preserve oxidative metabolism in phosphate-depleted proximal tubules. In proximal tubules incubated with either 1 mM valerate or butyrate, there was a 42 and 34% reduction (both P < 0.05) in the rate of oxygen consumption with cystine loading. However, tubules incubated with 1 mM succinate or citrate had only a 13 and 14% P = NS) reduction in the rate of oxygen consumption, respectively. These data are consistent with a limitation of intracellular phosphate in the pathogenesis of the proximal tubule dysfunction with cystine loading.

Renal tubular acidosis and deafness: report of a large family.

The syndrome of distal renal tubular acidosis (dRTA) and sensorineural deafness has been reported in consanguineous families and is believed to be inherited in an autosomal recessive pattern. All affected patients also have nephrocalcinosis. We report here a family with 6 of 12 children affected with this syndrome. The parents are unaffected and are not blood related. This is the largest family described to date with distal renal tubular acidosis and sensorineural deafness.

Maturation of rabbit proximal convoluted tubule chloride permeability.

Chloride transport in the rabbit proximal convoluted tubule (PCT) has components of active, transcellular, and passive, paracellular transport. The preferential reabsorption of bicarbonate and organic solutes by the early proximal tubule leaves the luminal fluid with a higher chloride concentration than that in the peritubular capillaries. Previous studies have suggested that solute permeability of the paracellular pathway may be higher in the neonatal PCT and that the neonatal proximal tubule reabsorbs solutes by passive mechanisms to a greater extent than the adult segment. A higher chloride permeability would provide a mechanism for the greater rate of passive NaCl transport by the neonatal proximal tubule. The purpose of the present in vitro microperfusion study was to directly examine the chloride permeability of neonatal and adult PCT. Superficial and juxtamedullary, neonatal and adult PCT were perfused with a high chloride perfusate without organic solutes, simulating late proximal tubular fluid, at 20 degrees C, and bathed in a serum-like albumin solution. Chloride concentrations in the perfusate and the collected fluid were measured by electrometric titration. Neonatal juxtamedullary PCT chloride permeability (PCl) was significantly lower than adult juxtamedullary PCT PCl (0.15 +/- 0.25 x 10(-5) cm/s versus 5.23 +/- 0.57 x 10(-5) cm/s, p < 0.001). The PCl of neonatal superficial PCT was not different from that of adult superficial PCT (0.81 +/- 0.48 x 10(-5) cm/s versus 0.05 +/- 0.62 x 10(-5) cm/s). Thus, there is a maturational increase in juxtamedullary PCT PCl, whereas superficial PCT PCl remains very low. The passive diffusion of chloride in neonatal PCT is extremely low and is not a mechanism to explain a higher rate of passive NaCl transport in this segment.

125Iodine-iothalamate clearance in children. A simple method to measure glomerular filtration.

Glomerular filtration rate (GFR) is the most widely used test to evaluate renal function. Several clearance markers have been used to measure GFR in adults. In children, however, a simple and reliable method to measure GFR is not available. Renal 125iodine (I)-iothalamate clearance, after a single subcutaneous injection, is a simple and accurate test to measure GFR in adults. The validity of unlabelled iothalamate, as a marker for measurement of GFR in children, was reported recently. Unfortunately, the unlabelled iothalamate assay is arduous. We report our experience with a single subcutaneous injection of 125I-iothalamate to measure GFR in normal children and those with renal disease. A weight-adjusted dosing regimen was adopted. This regimen resulted in sufficient above-background radioactivity in both blood and urine for reproducible measurement of GFR. Intra-test variability for GFR was not affected by the degree of renal insufficiency. The test was well tolerated with only 2 patients developing mild headache during the procedure. Our study showed that renal clearance of 125I-iothalamate is reproducible, simple, and practical in healthy children and those with mild and advanced renal disease.

Behavior problems in nephrotic syndrome.

OBJECTIVES: To evaluate the adaptive competences and behavioral problems in children with nephrotic syndrome, and whether their mothers also showed features of psychosocial stress. DESIGN: Prospective case-control study. SETTING: Pediatric Out-Patient Department. SUBJECTS: Seventy consecutive patients of nephrotic syndrome, between the ages of 4 to 14 years, and their mothers constituted cases. The control group, matched for age, sex and socioeconomic status comprised of 46 children and their mothers. The mother's description of the child's behavior, on the Child Behavior Checklist (CBCL), was obtained to assess behavioral problems and social competences. The level of anxiety in the mother was assessed using the PGI Health Questionnaire N2. RESULTS: Children with nephrotic syndrome showed features of depressed, hyperactive or aggressive behavior. Somatic complaints, social withdrawal and poor school performance were also observed. These problems did not interfere with compliance to treatment and only 7 patients required psychological interventions. Boys with nephrotic syndrome had more hyperactive and aggressive behavior as compared to girls. The scores on the CBCL were well correlated with the anxiety scores of the mother. CONCLUSIONS: These observations suggest the presence of minor behavior problems in a significant proportion of children with nephrotic syndrome. The severity of these problems may be related to the attitude of the mother towards the child's illness.

Antibiotic associated colitis.

It is a prospective study based on 100 consecutive cases of diarrhea following antibiotic therapy admitted to the pediatric services of J.N. Medical College, A.M.U., Aligarh between January to December 1987. They had C. penicillin (50), chloramphenicol (34), ampicillin (34), gentamicin (34), cephalosporin (4) and cotrimoxazole (4) for 3 days to 3 weeks prior to the onset of diarrhea. Apart from routine and special investigations, naked eye and microscopic examination of stool, its culture for pathogens including Cl. difficile were carried out in all cases. Presence of Cl. difficile cytotoxin was demonstrated by observing the cytopathic. Effect on veru cell culture, 18 grew Cl. difficile (14 cyto toxin positive). Frequency of fever, vomiting, abdominal distension, dehydration and duration of diarrhea was not different (p > 0.05) in the two groups. Purge rate and presence of mucus and blood in Cl. difficile positive patients was significantly higher (p < 0.05). Eight Cl. difficile positive (7 cytotoxin+ve) were subjected to endoscopy. Three of them showed P.M. colitis and 2 non specific colitis. Chloromycetin, gentamicin and penicillin were the main culprits responsible for AAC. None of the patients given ampicillin alone suffered from AAC. The mortality was 5%.

Errors in medication in a pediatric ward.

Iatrogenic errors in medication were studied in a busy pediatric ward. The study was based on voluntary reporting of errors noticed by the doctors and nurses in the ward. The error rate was 6.4%. Prescription errors accounted for 37.7% of the errors and 2 of these were potentially fatal. Dispensing errors and missed dosages were other frequent errors. Overcrowding in pediatric wards is an obstacle to optimum patient care. Adequate number of nurses and support of pharmacists is essential for safe and optimum drug therapy.

Circulating immune complexes in tuberculosis--an indicator of activity.

Circulating immune complexes (CIC) were assayed in 100 cases of tuberculosis and 30 age matched control children. The estimation was done by PEG assay before the commencement of antitubercular therapy. CIC were present in only 3.3% of the control children as compared to 68% of children with tuberculosis. The presence of CIC was observed to vary with the type of tuberculosis. The percentage positivity was highest (100%) in children with miliary tuberculosis. Subsequent estimation of CIC done after one and three months of antitubercular therapy showed a marked decrease in the percentage of positive cases (6.1 and zero percent respectively).

Prognostic value of 'C' reactive protein in tuberculosis.

'C' reactive protein (CRP) levels were determined in 100 cases of tuberculosis and 30 age and sex matched children. Serial estimations, one and 3 to 6 months after initiation of therapy was done in 81 and 41 of these patients, respectively. Mean initial levels of CRP in tuberculosis group was 18.52 micrograms/ml while in the control group it was 2.77 micrograms/ml (p less than 0.001). The elevated CRP levels fell significantly to 5.93 micrograms/ml after one month of treatment (p less than 0.001) and by 3 to 6 months of treatment had fallen to normal values. The fall in CRP levels correlated with clinical response. It is concluded that CRP can serve as a sensitive indicator of activity of the disease and the return to normal values of initially elevated CRP levels may indicate a good therapeutic response.