Integration of electronic and optical techniques in the design and fabrication of pressure sensors

Since the introduction of micro-electro-mechanical systems fabrication methods, piezoresistive pressure sensors have become the more popular pressure transducers. They dominate pressure sensor commercialization due to their high performance, stability and repeatability. However, increasing demand for harsh environment sensing devices has made sensors based on Fabry-Perot interferometry the more promising optical pressure sensors due to their high degree of sensitivity, small size, high temperature performance, versatility, and improved immunity to environmental noise and interference. The work presented in this dissertation comprises the design, fabrication, and testing of sensors that fuse these two pressure sensing technologies into one integrated unit. A key innovation is introduction of a silicon diaphragm with a center rigid body (or boss), denoted as an embossed diaphragm, that acts as the sensing element for both the electronic and optical parts of the sensor. Physical principles of piezoresistivity and Fabry-Perot interferometry were applied in designing an integrated sensor and in determining analytic models for the respective electronic and optical outputs. Several test pressure sensors were produced and their performance was evaluated by collecting response and noise data. Diaphragm deflection under applied pressure was detected electronically using the principle of piezoresistivity and optically using Fabry-Perot interferometry. The electronic part of the sensor contained four p-type silicon piezoresistors that were set into the diaphragm. They were connected in a Wheatstone bridge configuration for detecting strain-dependent changes in resistance induced by diaphragm deflection. In the optical part of the sensor, an optical cavity was formed between the embossed surface of the diaphragm and the end face of a single mode optical fiber. An infrared laser operating at 1.55 was used for optical excitation. Deflection of the diaphragm, which causes the length of the optical cavity to change, was detected by Fabry-Perot interference in the reflected light. Data collected on several sensors fabricated for this dissertation were shown to validate the theoretical models. In particular, the principle of operation of a Fabry-Perot interferometer as a mechanism for pressure sensing was demonstrated. The physical characteristics and behavior of the embossed diaphragm facilitated the integration of the electronic and optical approaches because the embossed diaphragm remained flat under diaphragm deflection. Consequently, it made the electronic sensor respond more linearly to applied pressure. Further, it eliminated a fundamental deficiency of previous applications of Fabry-Perot methods, which suffered from non-parallelism between the two cavity surfaces (diaphragm and fiber), owing to diaphragm curvature after pressure was applied. It also permitted the sensor to be less sensitive to lateral misalignment during the fabrication process and considerably reduced back pressure, which otherwise reduced the sensitivity of the sensor. As an integrated sensor, it offered two independent outputs in one sensor and therefore the capability for measurements of: (a) static and dynamic pressures simultaneously, and (b) two different physical quantities such as temperature and pressure

Angiogenesis in tissue engineering : Breathing life into constructed tissue substitutes

Long-term function of three-dimensional (3D) tissue constructs depends on adequate vascularization after implantation. Accordingly, research in tissue engineering has focused on the analysis of angiogenesis. For this purpose, 2 sophisticated in vivo models (the chorioallantoic membrane and the dorsal skinfold chamber) have recently been introduced in tissue engineering research, allowing a more detailed analysis of angiogenic dysfunction and engraftment failure. To achieve vascularization of tissue constructs, several approaches are currently under investigation. These include the modification of biomaterial properties of scaffolds and the stimulation of blood vessel development and maturation by different growth factors using slow-release devices through pre-encapsulated microspheres. Moreover, new microvascular networks in tissue substitutes can be engineered by using endothelial cells and stem cells or by creating arteriovenous shunt loops. Nonetheless, the currently used techniques are not sufficient to induce the rapid vascularization necessary for an adequate cellular oxygen supply. Thus, future directions of research should focus on the creation of microvascular networks within 3D tissue constructs in vitro before implantation or by co-stimulation of angiogenesis and parenchymal cell proliferation to engineer the vascularized tissue substitute in situ

Autotransplantation, Surgical Repositioning of Retained Canine, and Apical Filling of Two Incisors with Root Resorption

The purpose is to show the autotransplantation and surgical repositioning of a retained canine, and the apical filling of central and lateral resorbed incisors from a 12-year-old female patient, healthy and with clinical absence of left maxillary canine. Radiographically, the retained canine between the resorbed central and lateral incisors was observed. Root canal treatment of the canine was performed after 8 weeks; apical curettage and placement of bovine graft in inter-incisal zone was done after 4 months. During 6 months, orthodontic traction of the canine was carried out with no positive results, and 12 months after the autotransplantation, surgical repositioning was performed. Clinical-radiographic control at 30 days and 24 months showed absence of inflammation, restoration and integration of the tooth-supporting structures. Autotransplantation combined with surgical repositioning of the retained canine and the apical filling of two incisors achieved the harmonious, aesthetic, functional, dental and psychological preservation of the patient.Keywords: Autotransplantation; Endodontics; Endodontic Surgery; Root Resorption; Surgical Repositionin

Think globally, measure locally: The MIREN standardized protocol for monitoring plant species distributions along elevation gradients

Climate change and other global change drivers threaten plant diversity in mountains worldwide. A widely documented response to such environmental modifications is for plant species to change their elevational ranges. Range shifts are often idiosyncratic and difficult to generalize, partly due to variation in sampling methods. There is thus a need for a standardized monitoring strategy that can be applied across mountain regions to assess distribution changes and community turnover of native and non-native plant species over space and time. Here, we present a conceptually intuitive and standardized protocol developed by the Mountain Invasion Research Network (MIREN) to systematically quantify global patterns of native and non-native species distributions along elevation gradients and shifts arising from interactive effects of climate change and human disturbance. Usually repeated every five years, surveys consist of 20 sample sites located at equal elevation increments along three replicate roads per sampling region. At each site, three plots extend from the side of a mountain road into surrounding natural vegetation. The protocol has been successfully used in 18 regions worldwide from 2007 to present. Analyses of one point in time already generated some salient results, and revealed region-specific elevational patterns of native plant species richness, but a globally consistent elevational decline in non-native species richness. Non-native plants were also more abundant directly adjacent to road edges, suggesting that disturbed roadsides serve as a vector for invasions into mountains. From the upcoming analyses of time series, even more exciting results can be expected, especially about range shifts. Implementing the protocol in more mountain regions globally would help to generate a more complete picture of how global change alters species distributions. This would inform conservation policy in mountain ecosystems, where some conservation policies remain poorly implemented

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Markovian chemical in silico design (MARCH-INSIDE), a promising approach for computer-aided molecular design I: discovery of anticancer compounds

A simple stochastic approach, designed to model the movement of electrons throughout chemical bonds, is introduced. This model makes use of a Markov matrix to codify useful structural information in QSAR. The self-return probabilities of this matrix throughout time (SRpgrk) are then used as molecular descriptors. Firstly, a calculation of SRpgrk is made for a large series of anticancer and non-anticancer chemicals. Then, k-Means Cluster Analysis allows us to split the data series into clusters and ensure a representative design of training and predicting series. Next, we develop a classification function through Linear Discriminant Analysis (LDA). This QSAR discriminates between anticancer compounds and non-active compounds with a correct global classification of 90.5% in the training series. The model also correctly classified 86.07% of the compounds in the predicting series. This classification function is then used to perform a virtual screening of a combinatorial library of coumarins. In this connection, the biological assay of some furocoumarins, selected by virtual screening using the present model, gives good results. In particular, a tetracyclic derivative of 5-methoxypsoralen (5-MOP) has an IC50 against HL-60 tumoral line around 6 to 10 times lower than those for 8-MOP and 5-MOP (reference drugs), respectively. Finally, application of Iso-contribution Zone Analysis (IZA) provides structural interpretation of the biological activity predicted with this QSAR