New screening methodology for selection of polymeric materials for transdermal drug delivery devices

As medical advances extend the human lifespan, the level of chronic illnesses will increase and thus straining the needs of the health care system that, as a result, governments will need to balance expenses without upsetting national budgets. Therefore, the selection of a precise and affordable drug delivery technology is seen as the most practical solution for governments, health care professionals, and consumers. Transdermal drug delivery patches (TDDP) are one of the best economical technologies that are favored by pharmaceutical companies and physicians alike because it offers fewer complications when compared to other delivery technologies. TDDP provides increased efficiency, safety and convenience for the patient. The TDDP segment within the US and Global drug delivery markets were valued at $5.6 and$12.7 billion respectively in 2009. TDDP is forecasted to reach $31.5 billion in 2015. The present TDDP technology involves the fabrication of a patch that consists of a drug embedded in a polymeric matrix. The diffusion coefficient is determined from the slope of the cumulative drug release versus time. It is a trial and error method that is time and labor consuming. With all the advantages that TDDPs can offer, the methodology used to achieve the so-called optimum design has resulted in several incidents where the safety and design have been put to question in recent times (e.g. Fentanyl). A more logical screening methodology is needed. This work shows the use of a modified Duda Zielinsky equation (DZE). Experimental release curves from commercial are evaluated. The experimental and theoretical Diffusion Coefficient values are found to be within the limits specified in the patent literature. One interesting finding is that the accuracy of the DZE is closer to experimental values when the type of Molecular Shape and Radius are used. This work shows that the modified DZE could be used as an excellent screening tool to determine the optimal polymeric matrices that will yield the desired Diffusion Coefficient and thus effectively decreasing the amount of time and labor when developing TDDPs

Anti epidermal growth factor receptor therapy in small bowel adenocarcinoma

Rationale:Small bowel adenocarcinoma (SBA) is an uncommon gastrointestinal cancer, thus limited data about treatment for advanced disease are available. The lack of specific guidelines has justified the use of therapeutic protocols usually applied in advanced colorectal cancer. Few and preliminary data have suggested possible clinical benefit from the use of target therapy such as bevacizumab and cetuximab.Patient concerns:We present the case of a young woman who was admitted to the emergency department for acute abdominal pain, nausea, and vomiting related to a jejunal stenosis.Diagnoses:An enteroscopy with jejunal biopsy showed poorly differentiated cancerous cells suggestive for primary intestinal cancer. There were no signs of metastatic disease at radiological evaluation. A jejunal resection was subsequently carried out and the diagnosis of mucinous adenocarcinoma of the jejunum was confirmed.Interventions:The computed tomography scan performed 1 month after surgery showed metastatic disease. Therefore, the patient received combined protocols of chemotherapy and either bevacizumab or the anti-epidermal growth factor receptor (EGFR) panitumumab.Outcomes:A partial response (PR) was achieved with Folfox plus panitumumab and a maintenance therapy with panitumumab is being conducted with a mild toxicity and a progression free survival of 19 months since the beginning of panitumumab.Lessons:This is, to the best of our knowledge, the first report in the literature of a patient with SBA who has benefitted from panitumumab with an overall survival of 83 months

Optimal seismic retrofitting of existing RC frames through soft-computing approaches

2016 - 2017Ph.D. Thesis proposes a Soft-Computing approach capable of supporting the engineer judgement in the selection and design of the cheapest solution for seismic retrofitting of existing RC framed structure. Chapter 1 points out the need for strengthening the existing buildings as one of the main way of decreasing economic and life losses as direct consequences of earthquake disasters. Moreover, it proposes a wide, but not-exhaustive, list of the most frequently observed deficiencies contributing to the vulnerability of concrete buildings. Chapter 2 collects the state of practice on seismic analysis methods for the assessment the safety of the existing buildings within the framework of a performancebased design. The most common approaches for modeling the material plasticity in the frame non-linear analysis are also reviewed. Chapter 3 presents a wide state of practice on the retrofitting strategies, intended as preventive measures aimed at mitigating the effect of a future earthquake by a) decreasing the seismic hazard demands; b) improving the dynamic characteristics supplied to the existing building. The chapter presents also a list of retrofitting systems, intended as technical interventions commonly classified into local intervention (also known “member-level” techniques) and global intervention (also called “structure-level” techniques) that might be used in synergistic combination to achieve the adopted strategy. In particular, the available approaches and the common criteria, respectively for selecting an optimum retrofit strategy and an optimal system are discussed. Chapter 4 highlights the usefulness of the Soft-Computing methods as efficient tools for providing “objective” answer in reasonable time for complex situation governed by approximation and imprecision. In particular, Chapter 4 collects the applications found in the scientific literature for Fuzzy Logic, Artificial Neural Network and Evolutionary Computing in the fields of structural and earthquake engineering with a taxonomic classification of the problems in modeling, simulation and optimization. Chapter 5 “translates” the search for the cheapest retrofitting system into a constrained optimization problem. To this end, the chapter includes a formulation of a novel procedure that assembles a numerical model for seismic assessment of framed structures within a Soft-Computing-driven optimization algorithm capable to minimize the objective function defined as the total initial cost of intervention. The main components required to assemble the procedure are described in the chapter: the optimization algorithm (Genetic Algorithm); the simulation framework (OpenSees); and the software environment (Matlab). Chapter 6 describes step-by-step the flow-chart of the proposed procedure and it focuses on the main implementation aspects and working details, ranging from a clever initialization of the population of candidate solutions up to a proposal of tuning procedure for the genetic parameters. Chapter 7 discusses numerical examples, where the Soft-Computing procedure is applied to the model of multi-storey RC frames obtained through simulated design. A total of fifteen “scenarios” are studied in order to assess its “robustness” to changes in input data. Finally, Chapter 8, on the base of the outcomes observed, summarizes the capabilities of the proposed procedure, yet highlighting its “limitations” at the current state of development. Some possible modifications are discussed to enhance its efficiency and completeness. [edited by author]XVI n.s

The role of stereotactic body radiation therapy in oligometastatic colorectal cancer

Rationale: Regorafenib is the new standard third-line therapy in metastatic colorectal cancer (mCRC). However, the reported 1-year overall survival rate does not exceed 25%. Patient concerns: A 55-year-old man affected by mCRC, treated with regorafenib combined with stereotactic body radiotherapy (SBRT), showing a durable response. Interventions: After 6 months of regorafenib, a PET/CT scan revealed a focal uptake in a solid lung nodule which was treated with SBRT, whereas continuing regorafenib administration. Fourteen months later, the patient had further progression in a parasternal lymph node, but treatment with regorafenib was continued. The regorafenib-associated side effects, such us the hand-foot syndrome, were favorable managed by reducing the dose from 160 to 120 mg/day. Outcomes: Patient-reported outcome was characterized by a progression-free survival of approximately 3 years. Lessons: in presence of oligometastatic progression, a local SBRT while retaining the same systemic therapy may be a better multidisciplinary approach. Moreover, disease progression is no longer an absolute contraindication for continuing the regorafenib treatment

Value iteration convergence of ε-monotone schemes for stationary Hamilton-Jacobi equations

International audienceWe present an abstract convergence result for the xed point approximation of stationary Hamilton{Jacobi equations. The basic assumptions on the discrete operator are invariance with respect to the addition of constants, "-monotonicity and consistency. The result can be applied to various high-order approximation schemes which are illustrated in the paper. Several applications to Hamilton{Jacobi equations and numerical tests are presented

Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin

BACKGROUND: Pneumonia is complicated by high rate of mortality and cardiovascular events (CVEs). The potential benefit of aspirin, which lowers platelet aggregation by inhibition of thromboxane A2 production, is still unclear. The aim of the study was to assess the impact of aspirin on mortality in patients with pneumonia. METHODS AND RESULTS: Consecutive patients admitted to the University-Hospital Policlinico Umberto I (Rome, Italy) with community-onset pneumonia were recruited and prospectively followed up until discharge or death. The primary end point was the occurrence of death up to 30 days after admission; the secondary end point was the intrahospital incidence of nonfatal myocardial infarction and ischemic stroke. One thousand and five patients (age, 74.7±15.1 years) were included in the study: 390 were receiving aspirin (100 mg/day) at the time of hospitalization, whereas 615 patients were aspirin free. During the follow-up, 16.2% of patients died; among these, 19 (4.9%) were aspirin users and 144 (23.4%; P<0.001) were aspirin nonusers. Overall, nonfatal CVEs occurred in 7% of patients, 8.3% in nonaspirin users, and 4.9% in aspirin users (odds ratio, 1.77; 95% confidence interval, 1.03 to 3.04; P=0.040). The Cox regression analysis showed that pneumonia severity index (PSI), severe sepsis, pleural effusion, and PaO(2)/FiO(2) ratio <300 negatively influenced survival, whereas aspirin therapy was associated with improved survival. Compared to patients receiving aspirin, the propensity score adjusted analysis confirmed that patients not taking aspirin had a hazard ratio of 2.07 (1.08 to 3.98; P=0.029) for total mortality. CONCLUSIONS: This study shows that chronic aspirin use is associated with lower mortality rate within 30 days after hospital admission in a large cohort of patients with pneumonia

Hospitalization for pneumonia is associated with decreased 1-year survival in patients with type 2 diabetes results from a prospective cohort study

Diabetes mellitus is a frequent comorbid conditions among patients with pneumonia living in the community. The aim of our study is to evaluate the impact of hospitalization for pneumonia on early (30 day) and late mortality (1 year) in patients with type 2 diabetes mellitus. Prospective comparative cohort study of 203 patients with type 2 diabetes hospitalized for pneumonia versus 206 patients with diabetes hospitalized for other noninfectious causes from January 2012 to December 2013 at Policlinico Umberto I (Rome). Enrolled patients were followed up to discharge and up to 1 year after initial hospital admission or death. Overall, 203 patients with type 2 diabetes admitted to hospital for pneumonia were compared to 206 patients with type 2 diabetes admitted for other causes (39.3% decompensated diabetes, 21.4% cerebrovascular diseases, 9.2% renal failure, 8.3% acute myocardial infarction, and 21.8% other causes). Compared to control patients, those admitted for pneumonia showed a higher 30-day (10.8% vs 1%, P&lt;0.001) and 1-year mortality rate (30.3% vs 16.8%, P&lt;0.001). Compared to survivors, nonsurvivor patients with pneumonia had a higher incidence of moderate to severe chronic kidney disease, hemodialysis, and malnutrition were more likely to present with a mental status deterioration, and had a higher number of cardiovascular events during the follow-up period. Cox regression analysis found age, Charlson comorbidity index, pH&lt;7.35 at admission, hemodialysis, and hospitalization for pneumonia as variables independently associated with mortality. Hospitalization for pneumonia is associated with decreased 1-year survival in patients with type 2 diabetes, and appears to be a major determinant of long-term outcome in these patients

West Nile Virus: Characteristics of an African Virus Adapting to the Third Millennium World

The emergence and spread of West Nile Virus (WNV) from North through South America during the last decade, and the recent outbreaks of disease in both humans and horses in Europe suggest that the epidemiology of this infection is evolving. WNV is now considered among the emerging threats for both human and veterinary public health in areas like Europe where it was previously regarded to as an exotic agent. Further knowledge has built up from studies investigating the characteristics of the virus and its genome evolution capacity, the adaptation to new avian host species, the changes in vector competence and biology, and the host-pathogen interactions, including the immune response. Also, the new needs for preparedness to future major outbursts of disease have stimulated research on virus detection and characterization, filling the gaps in both specialized diagnostic technology and the need for field rapid assays. This review will present an overview of WNV virology, remarking the impact of virus diversity and evolution on theoretical and practical aspects involved in both risk definition, detection and control of infection

Choline [amino acid] ionic liquid/water mixtures: A triple effect for the degradation of an organophosphorus pesticide

A series of ionic liquids (ILs) composed by choline (Ch) as a cation and different amino acids (AA) as anions and their respective aqueous mixtures were prepared using different [Ch][AA] contents in a range of 0.4-46 mol % IL. These solvents were used for the first time to achieve an eco-friendlier Paraoxon degradation. The results show that [Ch][AA]/water mixtures are an effective reaction medium to degrade Paraoxon, even when the IL content in the mixture is low (0.4 mol % IL) and without the need of an extra nucleophile. Both the kinetics and the degradation pathways of pesticides depend on the nature of the AA on [Ch][AA] and the amount of an IL present in the mixture. We have demonstrated that in those mixtures with a low amount of [Ch][AA], the hydrolysis reaction is the main pathway for Paraoxon degradation, showing a catalytic effect of the IL. However, as the percentage of [Ch][AA] increases in the mixture, the nucleophilic attack of [Ch][AA] is evident. Finally, the aim of this study was to provide evidence of a promising and biocompatible methodology to degrade a toxic compound (Paraoxon) using a minimal quantity of an IL designed totally from natural resources.Fil: Pavez, Paulina. Universidad Católica de Chile; ChileFil: Figueroa, Roberto. Universidad Católica de Chile; ChileFil: Medina, Mayte. Universidad Católica de Chile; ChileFil: Millán, Daniela Andrea. Universidad Bernardo O’Higgins. Centro Integrativo de Biología y Química Aplicada; ChileFil: Falcone, Ruben Dario. Universidad Nacional de Río Cuarto. Instituto para el Desarrollo Agroindustrial y de la Salud. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto para el Desarrollo Agroindustrial y de la Salud; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Química; ArgentinaFil: Tapia, Ricardo. Universidad Católica de Chile; Chil