Role of modeling and simulation in pediatric investigation plans

Ethical and practical constraints encourage the optimal use of resources in pediatric drug development. Modeling and simulation has emerged as a promising methodology acknowledged by industry, academia, and regulators. We previously proposed a paradigm in pediatric drug development, whereby modeling and simulation is used as a decision tool, for study optimization and/or as a data analysis tool. Three and a half years since the Paediatric Regulation came into force in 2007, the European Medicines Agency has gained substantial experience in the use of modeling and simulation in pediatric drug development. In this review, we present examples on how the proposed paradigm applies in real case scenarios of planned pharmaceutical developments. We also report the results of a pediatric database search to further 'validate' the paradigm. There were 47 of 210 positive pediatric investigation plan (PIP) opinions that made reference to modeling and simulation (data included all positive opinions issued up to January 2010). This reflects a major shift in regulatory thinking. The ratio of PIPs with modeling and simulation rose to two in five based on the summary reports. Population pharmacokinetic (POP-PK) and pharmacodynamics (POP-PD) and physiologically based pharmacokinetic models are widely used by industry and endorsed or even imposed by regulators as a way to circumvent some difficulties in developing medicinal products in children. The knowledge of the effects of age and size on PK is improving, and models are widely employed to make optimal use of this knowledge but less is known about the effects of size and maturation on PD, disease progression, and safety. Extrapolation of efficacy from different age groups is often used in pediatric medicinal development as another means to alleviate the burden of clinical trials in children, and this can be aided by modeling and simulation to supplement clinical data. The regulatory assessment is finally judged on clinical grounds such as feasibility, ethical issues, prioritization of studies, and unmet medical need. The regulators are eager to expand the use of modeling and simulation to elucidate safety issues, to evaluate the effects of disease (e.g., renal or hepatic dysfunction), and to qualify mechanistic models that could help shift the current medicinal development paradigm.     

Cerebral perfusion pressure, microdialysis biochemistry, and clinical outcome in patients with spontaneous intracerebral hematomas

Purpose

The aim of our study was to investigate the roles of cerebral perfusion pressure (CPP) and microdialysis marker values on the clinical outcome of patients with spontaneous intracerebral hematoma.

Materials and Methods

Twenty-seven patients (18 men; mean ± SD age, 54.17 ± 10.05 years; 9 women, mean ± SD age, 65.00 ± 4.24 years) with a GCS of 8 or less upon admission were included in this study. After a 6-month follow-up period, a linear regression model was applied to evaluate the outcomes using the Glasgow Outcome Scale (GOS).

Results

Of the 27 patients, 16 died within the first 6 months after discharge from the hospital. Six patients had a favorable prognosis after 6 months. In the patients who had a favorable outcome (GOS = 4 or GOS = 5), the CPP was above 75.46 mm Hg, and intracranial pressure was below 14.21 mm Hg. No patient with a favorable prognosis had a lactate-pyruvate (L/P) ratio greater than 37.40. An inverse linear relationship was found among the L/P ratio, the CPP, and patient outcome.

Conclusion

The L/P ratio and CPP were found to be related to patient outcome. In addition, a CPP greater than 75.46 mm Hg and an L/P ratio lower than 37.40 mm Hg were related to a favorable outcome.     

Prediction of 1‐year mortality and impact of bivalirudin therapy according to level of baseline risk: A patient‐level pooled analysis from three randomized trials

Objectives : We aimed to construct a predictive model for one‐year mortality in patients undergoing invasive coronary evaluation and to examine the impact of bivalirudin on survival according to the level of baseline risk. Background : Compared to heparin plus GP IIb/IIIa inhibitors (HEP/GPI), bivalirudin decreases bleeding complications in a range of clinical presentations. The impact of preprocedural risk assessment on survival and whether this is modified by bivalirudin, has not been investigated in detail. Methods : We examined patient‐level data from the REPLACE‐2, ACUITY, and HORIZONS‐AMI trials (n = 18,819) to construct a risk‐adjusted mortality model using baseline clinical variables. Results : One‐year mortality occurred in 287 patients (3.1%) assigned to bivalirudin and 336 patients (3.6%) assigned to HEP/GPI (HR 0.85; 95% CI, 0.73–1.00; P = 0.048). Using 11 highly significant predictors of mortality, we developed an integer‐risk score to classify patients into risk tertiles. High‐risk patients had a rate of 1‐year mortality over 9‐fold greater than low‐risk patients. Consequently, the absolute mortality reduction attributed to bivalirudin was more marked in high‐risk patients: 3.1% (?0.8% to 7.0%) in the overall cohort, 4.8% (0.5% to 9.2%) in the PCI cohort (P‐interaction versus intermediate and low risk categories, 0.09 and P = 0.02, respectively). Conclusions : In patients undergoing invasive coronary evaluation, 1‐year mortality can be predicted using baseline variables. Bivalirudin treatment (versus HEP/GPI) conferred a survival benefit. © 2015 Wiley Periodicals, Inc.     

Heparin or bivalirudin for non‐primary PCI: Beware of neat and simple answers…

• The debate regarding the choice of heparin or bivalirudin as the preferred anticoagulant in PCI is still ongoing
• Nonrandomized registry data are severely limited for comparative analyses and should therefore always be interpreted with caution
• Clinicians should resist simplistic data interpretations or populist cries relating to cost, but rather focus on valid benefit:risk analyses for their clinical decision making

     

Human cytomegalovirus (HCMV) UL44 and UL57 specific antibody responses in anti-HCMV-positive patients with systemic sclerosis

The role of human cytomegalovirus (HCMV) has been postulated as a trigger of systemic sclerosis (SSc). The aim of the study was to assess the prevalence of antibodies against HCMV UL44 and UL57 antigens not tested in the past. Sixty SSc patients, 40 multiple sclerosis and 17 normal controls (NCs), all anti-HCMV positive, were tested by immunoblotting. Reactivity to HCMV antigens, expressed as arbitrary units (AUs), was assessed for correlation with clinical and immunological parameters, including types of SSc-related autoantibodies. Anti-UL44 and anti-UL57 HCMV antibodies were present in 3/60 (5%) and 58/60 (96.7%) SSc patients, respectively (p < 0.001). Anti-UL57 antibodies were present in 35/40 (87.5%) MS patients and 16/17 (94.1%) NCs (SSc vs MS, MS vs NC, p = ns). Strong (50-75 AU) and very strong (75–100 AU) anti-UL57 immunoreactivity was found in 24 (41.4%) and 22 (37.9%) SSc patients, respectively (p = ns). Dilution experiments showed anti-UL57 antibody persistence in up to 1/5000. Overall, there was no difference in the frequency or the magnitude of anti-UL57 immunoreactivity between diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis patients (96.67 vs 96.67%; 65.45 ± 20.19 vs 64.31 ± 21.11 AU, p > 0.05) but strong anti-UL57 reactivity were more frequent in SSc compared to NCs (p = 0.007). Anti-UL57 reactivity was not inhibited by SSc-specific autoantigens. Anti-UL57 seropositivity did not correlate with demographic, clinical or immunological features of SSc. Anti-HCMV UL57 antibodies are universally present in anti-HCMV-positive patients with SSc, while those against UL44 are rarely seen. Because anti-UL57 lack disease specificity and are not involved in cross-reactive responses, their immunopathogenetic potential is to be questioned.     

Cesarean wound scar characteristics for the prediction of pelvic adhesions: a meta-analysis of observational studies

Objective: The pathophysiologic processes that result in wound healing are the same regardless of the tissue involved. The purpose of the present meta-analysis is to evaluate whether cesarean scar characteristics may predict the presence of pelvic adhesions.

Materials and methods: We conducted a systematic review searching the Medline (1966–2016), Scopus (2004–2016), ClinicalTrials.gov (2008–2016), Cochrane Central Register of Controlled Trials CENTRAL (1999–2016) and Google Scholar (2004–2016) databases together with reference lists from included studies. All prospective and retrospective observational cohort studies were included. Statistical meta-analysis was performed using the RevMan 5.1 software.

Results: Current evidence suggests that depressed scars are positively associated with intra-abdominal adhesions (ΟR 2.79, 95%CI 1.74–4.46). Elevated scars might also correlate with the presence of adhesions, however, this association did not reach statistical significance (OR 1.61, 95%CI 0.91–2.85, p?=?0.10). The same was reported in the case of scar pigmentation (REM, OR 1.68, 95%CI 0.86–3.26, p?=?0.13). Flat scars were predictive of the absence of adhesions (899 patients, REM, OR 0.33, 95%CI 0.23-0.54, p?Conclusion: According to our meta-analysis, abdominal wound characteristics following cesarean section can predict the presence of adhesions. However, given the small number of published studies, further research is needed to corroborate our findings.     

The Development of Geriatric Assessment and Intervention Guidelines for an Online Geriatric Assessment Tool: A Canadian Modified Delphi Panel Study

Background: There are no guidelines available for what assessment tools to use in a patient’s self-completed online geriatric assessment (GA) with management recommendations. Therefore, we used a modified Delphi approach with Canadian expert clinicians to develop a consensus online GA plus recommendations tool. Methods: The panel consisted of experts in geriatrics, oncology, nursing, and pharmacy. Experts were asked to rate the importance and feasibility of assessments and interventions to be included in an online GA for patients. The items included in the first round were based on guidelines for in-person GA and literature review. The first two rounds were conducted using an online survey. A virtual 2 h meeting was held to discuss the items where no consensus was reached and then voted on in the final round. Results: 34 experts were invited, and 32 agreed to participate. In round 1, there were 85 items; in round 2, 50 items; and in round 3, 25 items. The final tool consists of fall history, assistive device use, weight loss, medication review, need help taking medication, social supports, depressive symptoms, self-reported vision and hearing, and current smoking status and alcohol use. Conclusion: This first multidisciplinary consensus on online GA will benefit research and clinical care for older adults with cancer.