Design of experiment in drug development: optimal allocations in multi-arm clinical trials and design space for multi-step processes

In this thesis, we deal with the design of experiments in the drug development process, focusing on the design of clinical trials for treatment comparisons (Part I) and the design of preclinical laboratory experiments for proteins development and manufacturing (Part II). In Part I we propose a multi-purpose design methodology for sequential clinical trials. We derived optimal allocations of patients to treatments for testing the efficacy of several experimental groups by also taking into account ethical considerations. We first consider exponential responses for survival trials and we then present a unified framework for heteroscedastic experimental groups that encompasses the general ANOVA set-up. The very good performance of the suggested optimal allocations, in terms of both inferential and ethical characteristics, are illustrated analytically and through several numerical examples, also performing comparisons with other designs proposed in the literature. Part II concerns the planning of experiments for processes composed of multiple steps in the context of preclinical drug development and manufacturing. Following the Quality by Design paradigm, the objective of the multi-step design strategy is the definition of the manufacturing design space of the whole process and, as we consider the interactions among the subsequent steps, our proposal ensures the quality and the safety of the final product, by enabling more flexibility and process robustness in the manufacturing.

Big data analytics for proactive and predictive maintenance in electric car battery packs

The idea behind the project is to develop a methodology for analyzing and developing techniques for the diagnosis and the prediction of the state of charge and health of lithium-ion batteries for automotive applications. For lithium-ion batteries, residual functionality is measured in terms of state of health; however, this value cannot be directly associated with a measurable value, so it must be estimated. The development of the algorithms is based on the identification of the causes of battery degradation, in order to model and predict the trend. Therefore, models have been developed that are able to predict the electrical, thermal and aging behavior. In addition to the model, it was necessary to develop algorithms capable of monitoring the state of the battery, online and offline. This was possible with the use of algorithms based on Kalman filters, which allow the estimation of the system status in real time. Through machine learning algorithms, which allow offline analysis of battery deterioration using a statistical approach, it is possible to analyze information from the entire fleet of vehicles. Both systems work in synergy in order to achieve the best performance. Validation was performed with laboratory tests on different batteries and under different conditions. The development of the model allowed to reduce the time of the experimental tests. Some specific phenomena were tested in the laboratory, and the other cases were artificially generated.

PCM-based battery thermal management systems, energy saving materials and LCA strategy for automotive

This PhD work arises from the necessity to give a contribution to the energy saving field, regarding automotive applications. The aim was to produce a multidisciplinary work to show how much important is to consider different aspects of an electric car realization: from innovative materials to cutting-edge battery thermal management systems (BTMSs), also dealing with the life cycle assessment (LCA) of the battery packs (BPs). Regarding the materials, it has been chosen to focus on carbon fiber composites as their use allows realizing light products with great mechanical properties. Processes and methods to produce carbon fiber goods have been analysed with a special attention on the university solar car Emilia 4. The work proceeds dealing with the common BTMSs on the market (air-cooled, cooling plates, heat pipes) and then it deepens some of the most innovative systems such as the PCM-based BTMSs after a previous experimental campaign to characterize the PCMs. After that, a complex experimental campaign regarding the PCM-based BTMSs has been carried on, considering both uninsulated and insulated systems. About the first category the tested systems have been pure PCM-based and copper-foam-loaded-PCM-based BTMSs; the insulated tested systems have been pure PCM-based and copper-foam-loaded-PCM-based BTMSs and both of these systems equipped with a liquid cooling circuit. The choice of lighter building materials and the optimization of the BTMS are strategies which helps in reducing the energy consumption, considering both the energy required by the car to move and the BP state of health (SOH). Focusing on this last factor, a clear explanation regarding the importance of taking care about the SOH is given by the analysis of a BP production energy consumption. This is why a final dissertation about the life cycle assessment (LCA) of a BP unit has been presented in this thesis.

High performance battery chargers for full electric and hybrid cars

This Doctoral Thesis aims to study and develop advanced and high-efficient battery chargers for full electric and plug-in electric cars. The document is strictly industry-oriented and relies on automotive standards and regulations. In the first part a general overview about wireless power transfer battery chargers (WPTBCs) and a deep investigation about international standards are carried out. Then, due to the highly increasing attention given to WPTBCs by the automotive industry and considering the need of minimizing weight, size and number of components this work focuses on those architectures that realize a single stage for on-board power conversion avoiding the implementation of the DC/DC converter upstream the battery. Based on the results of the state-of-the-art, the following sections focus on two stages of the architecture: the resonant tank and the primary DC/AC inverter. To reach the maximum transfer efficiency while minimizing weight and size of the vehicle assembly a coordinated system level design procedure for resonant tank along with an innovative control algorithm for the DC/AC primary inverter is proposed. The presented solutions are generalized and adapted for the best trade-off topologies of compensation networks: Series-Series and Series-Parallel. To assess the effectiveness of the above-mentioned objectives, validation and testing are performed through a simulation environment, while experimental test benches are carried out by the collaboration of Delft University of Technology (TU Delft).

Hemorrhagic Shock Secondary To Button Battery Ingestion.

Button battery ingestion is a frequent pediatric complaint. The serious complications resulting from accidental ingestion have increased significantly over the last two decades due to easy access to gadgets and electronic toys. Over recent years, the increasing use of lithium batteries of diameter 20 mm has brought new challenges, because these are more detrimental to the mucosa, compared with other types, with high morbidity and mortality. The clinical complaints, which are often nonspecific, may lead to delayed diagnosis, thereby increasing the risk of severe complications. A five-year-old boy who had been complaining of abdominal pain for ten days, was brought to the emergency service with a clinical condition of hematemesis that started two hours earlier. On admission, he presented pallor, tachycardia and hypotension. A plain abdominal x-ray produced an image suggestive of a button battery. Digestive endoscopy showed a deep ulcerated lesion in the esophagus without active bleeding. After this procedure, the patient presented profuse hematemesis and severe hypotension, followed by cardiorespiratory arrest, which was reversed. He then underwent emergency exploratory laparotomy and presented a new episode of cardiorespiratory arrest, which he did not survive. The battery was removed through rectal exploration. This case describes a fatal evolution of button battery ingestion with late diagnosis and severe associated injury of the digestive mucosa. A high level of clinical suspicion is essential for preventing this evolution. Preventive strategies are required, as well as health education, with warnings to parents, caregivers and healthcare professionals.

The Effect Of Soy Dietary Supplement And Low Dose Of Hormone Therapy On Main Cardiovascular Health Biomarkers: A Randomized Controlled Trial.

To assess the effects of a soy dietary supplement on the main biomarkers of cardiovascular health in postmenopausal women compared with the effects of low-dose hormone therapy (HT) and placebo. Double-blind, randomized and controlled intention-to-treat trial. Sixty healthy postmenopausal women, aged 40-60 years, 4.1 years mean time since menopause were recruited and randomly assigned to 3 groups: a soy dietary supplement group (isoflavone 90mg), a low-dose HT group (estradiol 1 mg plus noretisterone 0.5 mg) and a placebo group. Lipid profile, glucose level, body mass index, blood pressure and abdominal/hip ratio were evaluated in all the participants at baseline and after 16 weeks. Statistical analyses were performed using the χ2 test, Fisher's exact test, Kruskal-Wallis non-parametric test, analysis of variance (ANOVA), paired Student's t-test and Wilcoxon test. After a 16-week intervention period, total cholesterol decreased 11.3% and LDL-cholesterol decreased 18.6% in the HT group, but both did not change in the soy dietary supplement and placebo groups. Values for triglycerides, HDL-cholesterol, glucose level, body mass index, blood pressure and abdominal/hip ratio did not change over time in any of the three groups. The use of dietary soy supplement did not show any significant favorable effect on cardiovascular health biomarkers compared with HT. The trial is registered at the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos - ReBEC), number RBR-76mm75.

Post Hoc Analysis Of The Patricia Randomized Trial Of The Efficacy Of Human Papillomavirus Type 16 (hpv-16)/hpv-18 As04-adjuvanted Vaccine Against Incident And Persistent Infection With Nonvaccine Oncogenic Hpv Types Using An Alternative Multiplex Type-specific Pcr Assay For Hpv Dna.

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.).

Obstacle Crossing With Dual Tasking Is A Danger For Individuals With Alzheimer's Disease And For Healthy Older People.

The aim of this study was to analyze the effects of dual tasking on obstacle crossing during walking by individuals with Alzheimer's disease (AD) and by healthy older people. Thirty four elderly individuals (16 healthy subjects and 18 individuals with AD) were recruited to participate in this study. Three AD individuals and one control participant were excluded due to exclusion criteria. The participants were instructed to walk barefoot at their own speed along an 8 m long pathway. Each participant performed five trials for each condition (unobstructed walking, unobstructed walking with dual tasking, and obstacle crossing during walking with dual tasking). The trials were completely randomized for each participant. The mid-pathway stride was measured in the unobstructed walking trials and the stride that occurred during the obstacle avoidance was measured in the trials that involved obstacle crossing. The behavior of the healthy elderly subjects and individuals with AD was similar for obstacle crossing during walking with dual tasking. Both groups used the posture first strategy to prioritize stability and showed decreased attention to executive tasking while walking. Additionally, AD had a strong influence on the modifications that are made by the elderly while walking under different walking conditions.

Clinical trials in Brazilian journals of ophthalmology: where we are

PURPOSE: To compare clinical trials published in Brazilian journals of ophthalmology and in foreign journals of ophthalmology with respect to the number of citations and the quality of reporting [by applying the Consolidated Standards for Reporting Trials (CONSORT) statement writing standards]. METHODS: The sample of this systematic review comprised the two Brazilian journals of ophthalmology indexed at Science Citation Index Expanded and six of the foreign journals of ophthalmology with highest Impact Factor® according ISI. All clinical trials (CTs) published from January 2009 to December 2010 at the Brazilians journals and a 1:1 randomized sample of the foreign journals were included. The primary outcome was the number of citations through the end of 2011. Subgroup analysis included language. The secondary outcome included likelihood of citation (cited at least once versus no citation), and presence or absence of CONSORT statement indicators. RESULTS: The citation counts were statistically significantly higher (P<0.001) in the Foreign Group (10.50) compared with the Brazilian Group (0.45). The likelihood citation was statistically significantly higher (P<0.001) in the Foreign Group (20/20 - 100%) compared with the Brazilian Group (8/20 - 40%). The subgroup analysis of the language influence in Brazilian articles showed that the citation counts were statistically significantly higher in the papers published in English (P<0.04). Of 37 possible CONSORT items, the mean for the Foreign Group was 20.55 and for the Brazilian Group was 13.65 (P<0.003). CONCLUSION: The number of citations and the quality of reporting of clinical trials in Brazilian journals of ophthalmology still are low when compared with the foreign journals of ophthalmology with highest Impact Factor®.

Análise do desempenho em testes de triathlon com diferentes intensidades durante a etapa natação = : Analysis of triathlon trials performance using different intensities during swimming phase

Universidade Estadual de Campinas . Faculdade de Educação Física

Hand and ultrasonic instrumentation for orthograde root canal treatment of permanent teeth

Root canal treatment is a frequently performed dental procedure and is carried out on teeth in which irreversible pulpitis has led to necrosis of the dental pulp. Removal of the necrotic tissue remnants and cleaning and shaping of the root canal are important phases of root canal treatment. Treatment options include the use of hand and rotary instruments and methods using ultrasonic or sonic equipment. OBJECTIVES: The objectives of this systematic review of randomized controlled trials were to determine the relative clinical effectiveness of hand instrumentation versus ultrasonic instrumentation alone or in conjunction with hand instrumentation for orthograde root canal treatment of permanent teeth. MATERIAL AND METHODS: The search strategy retrieved 226 references from the Cochrane Oral Health Group Trials Register (7), the Cochrane Central Register of Controlled Trials (CENTRAL) (12), MEDLINE (192), EMBASE (8) and LILACS (7). No language restriction was applied. The last electronic search was conducted on December 13th, 2007. Screening of eligible studies was conducted in duplicate and independently. RESULTS: Results were to be expressed as fixed-effect or random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confdence intervals. Heterogeneity was to be investigated including both clinical and methodological factors. No eligible randomized controlled trials were identifed. CONCLUSIONS: This review illustrates the current lack of published or ongoing randomized controlled trials and the unavailability of high-level evidence based on clinically relevant outcomes referring to the effectiveness of ultrasonic instrumentation used alone or as an adjunct to hand instrumentation for orthograde root canal treatment. In the absence of reliable research-based evidence, clinicians should base their decisions on clinical experience, individual circumstances and in conjunction with patients' preferences where appropriate. Future randomized controlled trials might focus more closely on evaluating the effectiveness of combinations of these interventions with an emphasis on not only clinically relevant, but also patient-centered outcomes.

Influence of separate and mixed experimental designs on reaction times to two simple visual stimuli

Testing contexts have been shown to critically influence experimental results in psychophysical studies. One of these contexts that show important modulation of the behavioral effects of different stimulatory conditions is the separate (blocked) or mixed presentation of these stimulatory conditions. The study presents evidence that the apparent discriminabilities of two target stimuli can change according to which of these two testing contexts is used. A cross inside a ring and a vertical line inside a ring were presented as go stimuli in a go/no-go reaction time task. In one experiment, each of these stimuli was presented to a different group of volunteers and in another experiment they were presented to the same group of volunteers, randomly mixed in the blocks of trials. Similar reaction times were obtained for the two stimuli in the first experiment, and different reaction times (faster for the cross) in the second experiment. The latter result indicates that the two stimuli have different discriminabilities from the no-go stimulus; the cross having greater discriminability. This difference is however masked, presumably by the adoption of specific compensatory attentional sets, in a separate testing context.

Density and survival rate of Culex quinquefasciatus at Parque Ecológico do Tietê, São Paulo, Brazil

Parity rate, gonotrophic cycle length, and density of a Culex quinquefasciatus female population was estimated at the Parque Ecológico do Tietê (PET), São Paulo, Brazil. Adult Cx. quinquefasciatus females were collected from vegetation along the edges of a polluted drainage canal with the use of a battery-powered backpack aspirator from September to November 2005 and from February to April 2006. We examined 255 Cx. quinquefasciatus ovaries to establish the parity rate of 0.22 and determined the gonotrophic cycle length under laboratory conditions to be 3 and 4 days. From these data, we calculated the Cx. quinquefasciatus survival rate to be 0.60 and 0.68 per day. Density of the Cx. quinquefasciatus female (5.71 females per m2) was estimated based on a population size of 28,810 individuals divided by the sampled area of 5,040 m2. Results of all experiments indicate medium survivorship and high density of the Cx. quinquefasciatus female population. This species is epidemiologically relevant in the PET area and should be a target of the vector control program of São Paulo municipality

Efficacy of sweet solutions for analgesia in infants between 1 and 12 months of age: a systematic review

Objective To compare the efficacy of oral sweet solutions to water or no treatment in infants aged 1-12 months during immunisation. Methods Randomised controlled trials (RCTs) were retrieved through internet searches or manual searches of reference lists. Search terms included newborn, infant, pain, sucrose and alternative names for sweet solutions. Summary estimates with 95% CIs were calculated and included relative risk (RR), risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, and weighted mean differences (WMD) for continuous outcomes. Where pooling of results was not possible, a narrative summary of study results is presented. Results Of the 695 studies identified, 14 RCTs with 1674 injections met the inclusion criteria. Sucrose or glucose, compared to water or no treatment decreased crying during or following immunisation in 13 of the 14 studies. Infants receiving 30% glucose (three trials, 243 infants) had a decreased RR in crying incidence following immunisation (typical RR 0.80, 95% CI 0.69 to 0.93; RD -0.17, 95% CI -0.29 to -0.05; NNTB 6, 95% CI 3 to 20). With sucrose or glucose, there was a 10% WMD reduction in proportion of crying time (95% CI - 18 to - 2) and a 12 s reduction in crying duration (95% CI - 23 to -0.7 s). An optimal dose of sucrose or glucose could not be ascertained due to the varied volumes and concentrations used. Conclusion Infants aged 1-12 months administered sucrose or glucose before immunisation had moderately reduced incidence and duration of crying. Healthcare professionals should consider using sucrose or glucose before and during immunisation.

The International LAM Registry: A Component of an Innovative Web-Based Clinician, Researcher, and Patient-Driven Rare Disease Research Platform

Background: A relative friability to capture a sufficiently large patient population in any one geographic location has traditionally limited research into rare diseases. Methods and Results: Clinicians interested in the rare disease lymphangioleiomyomatosis (LAM) have worked with the LAM Treatment Alliance, the MIT Media Lab, and Clozure Associates to cooperate in the design of a state-of-the-art data coordination platform that can be used for clinical trials and other research focused on the global LAM patient population. This platform is a component of a set of web-based resources, including a patient self-report data portal, aimed at accelerating research in rare diseases in a rigorous fashion. Conclusions: Collaboration between clinicians, researchers, advocacy groups, and patients can create essential community resource infrastructure to accelerate rare disease research. The International LAM Registry is an example of such an effort.