Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

Real-Time Compound Imaging Ultrasound of Hidradenitis Suppurativa

BACKGROUND Hidradenitis suppurativa (HS) is a difficult disease to treat. Surgery may be curative, but just like cancer surgery, it must be complete to effect a cure. Preoperative imaging of hidradenitis lesions is therefore of interest.
OBJECTIVE The objective was to study the ultrasound characteristics of hidradenitis and compare these to the clinical findings.
MATERIALS AND METHODS Real-time compound imaging ultrasound systems were used (Philips HDI 5000 and iU22) to visualize HS lesions in seven patients and regional controls images from eight healthy volunteers.
RESULTS Hidradenitis-related features were identified: various fluid collections, increased dermal thickness (mean±SD, 3.3±1.0 mm vs. 1.4±0.3 mm for controls) and lower echogenicity of the skin. In comparison with clinical examination, we were able to identify both subclinical lesions and subclinical extension of lesions into clinically normal looking paralesional skin. Hair follicles appeared distended.
CONCLUSION A number of HS features can be identified by ultrasound. These features include both actual lesions and possible predisposing factors such as skin thickness and hair follicle morphology. Ultrasonography can identify the true extent of lesions in HS, which may be of use in the preoperative planning.     

Complete duplication of urinary bladder and urethra: prenatal sonographic features.

Prenatal sonographic features of the rare anomaly of complete duplication of the urinary bladder and urethra are described in this case report. A coronal scan of the fetal pelvis at 29 weeks of gestation revealed two pyriform cystic structures. The umbilical arteries coursed around both of them. They emptied independently of each other. Postnatally the newborn had two vulvae, two anal openings, two bladders and two uteri.     

Endoscopic pH monitoring for patients with suspected or refractory gastroesophageal reflux disease.

BACKGROUND: Wireless pH studies can offer prolonged pH monitoring, which may potentially facilitate the diagnosis and management of patients with gastroesophageal reflux disease (GERD). The aim of the present study was to evaluate the detection rate of abnormal esophageal acid exposure using prolonged pH monitoring in patients with suspected or refractory GERD symptoms. METHODS: Patients undergoing prolonged ambulatory pH studies for the evaluation of GERD-related symptoms were assessed. Patients with a known diagnosis of GERD were tested on medical therapy, while patients with suspected GERD were tested off therapy. The wireless pH capsules were placed during upper endoscopy 6 cm above the squamocolumnar junction. RESULTS: One hundred ninety-one patients underwent a total of 198 pH studies. Fifty ambulatory pH studies (25%) were excluded from the analysis: 27 patients (14%) had insufficient data capture (less than 18 h on at least one day of monitoring), 15 patients had premature capsule release (7%), seven were repeat studies (3.5%) and one had intolerable pain requiring capsule removal (0.5%). There were 115 patients undergoing pH studies who were off medication, and 33 patients were on therapy. For the two groups of patients, results were as follows: 32 (28%) and 22 (67%) patients with normal studies on both days; 58 (50%) and five (15%) patients with abnormal studies on both days; 18 (16%) and three (9%) patients with abnormal studies on day 1 only; and seven (6%) and three (9%) patients with abnormal studies on day 2 only, respectively. CONCLUSIONS: Prolonged 48 h pH monitoring can detect more abnormal esophageal acid exposure but is associated with a significant rate of incomplete studies.