Weakly Consistent Regularisation Methods for Ill-Posed Problems

This Chapter takes its origin in the lecture notes for a 9 h course at the Institut Henri Poincaré in September 2016. The course was divided in three parts. In the first part, which is not included herein, the aim was to first recall some basic aspects of stabilised finite element methods for convection-diffusion problems. We focus entirely on the second and third parts which were dedicated to ill-posed problems and their approximation using stabilised finite element methods. First we introduce the concept of conditional stability. Then we consider the elliptic Cauchy-problem and a data assimilation problem in a unified setting and show how stabilised finite element methods may be used to derive error estimates that are consistent with the stability properties of the problem and the approximation properties of the finite element space. Finally, we extend the result to a data assimilation problem subject to the heat equation

Analysis of discontinuous Galerkin methods using mesh-dependent norms and applications to problems with rough data

We prove the inf-sup stability of a discontinuous Galerkin scheme for second order elliptic operators in (unbalanced) mesh-dependent norms for quasi-uniform meshes for all spatial dimensions. This results in a priori error bounds in these norms. As an application we examine some problems with rough source term where the solution can not be characterised as a weak solution and show quasi-optimal error control

Patients' Costs and Cost-Effectiveness of Tuberculosis Treatment in DOTS and Non-DOTS Facilities in Rio de Janeiro, Brazil

Costs of tuberculosis diagnosis and treatment may represent a significant burden for the poor and for the health system in resource-poor countries.The aim of this study was to analyze patients' costs of tuberculosis care and to estimate the incremental cost-effectiveness ratio (ICER) of the directly observed treatment (DOT) strategy per completed treatment in Rio de Janeiro, Brazil.We interviewed 218 adult patients with bacteriologically confirmed pulmonary tuberculosis. Information on direct (out-of-pocket expenses) and indirect (hours lost) costs, loss in income and costs with extra help were gathered through a questionnaire. Healthcare system additional costs due to supervision of pill-intake were calculated considering staff salaries. Effectiveness was measured by treatment completion rate. The ICER of DOT compared to self-administered therapy (SAT) was calculated.DOT increased costs during the treatment phase, while SAT increased costs in the pre-diagnostic phase, for both the patient and the health system. Treatment completion rates were 71% in SAT facilities and 79% in DOT facilities. Costs per completed treatment were US$194 for patients and U$ 189 for the health system in SAT facilities, compared to US$336 and US$ 726 in DOT facilities. The ICER was US$ 6,616 per completed DOT treatment compared to SAT.Costs incurred by TB patients are high in Rio de Janeiro, especially for those under DOT. The DOT strategy doubles patients' costs and increases by fourfold the health system costs per completed treatment. The additional costs for DOT may be one of the contributing factors to the completion rates below the targeted 85% recommended by WHO

Conjunctival Reconstruction with Progenitor Cell-Derived Autologous Epidermal Sheets in Rhesus Monkey

Severe ocular surface diseases are some of the most challenging problems that the clinician faces today. Conventional management is generally unsatisfactory, and the long-term ocular consequences of these conditions are devastating. It is significantly important to find a substitute for conjunctival epithelial cells. This study was to explore the possibility of progenitor cell-derived epidermal sheets on denuded amniotic membrane to reconstruct ocular surface of conjunctiva damaged monkeys. We isolated epidermal progenitor cells of rhesus monkeys by type IV collagen adhesion, and then expanded progenitor cell-derived epidermal sheets on denuded amniotic membrane ex vivo. At 3 weeks after the conjunctiva injury, the damaged ocular surface of four monkeys was surgically reconstructed by transplanting the autologous cultivated epidermal progenitor cells. At 2 weeks after surgery, transplants were removed and examined with Hematoxylin-eosin staining, Periodic acid Schiff staining, immunofluorescent staining, scanning and transmission electron microscopy. Histological examination of transplanted sheets revealed that the cell sheets were healthy alive, adhered well to the denuded amniotic membrane, and had several layers of epithelial cells. Electron microscopy showed that the epithelial cells were very similar in appearance to those of normal conjunctival epithelium, even without goblet cell detected. Epithelial cells of transplants had numerous desmosomal junctions and were attached to the amniotic membrane with hemidesmosomes. Immunohistochemistry confirmed the presence of the conjunctival specific markers, mucin 4 and keratin 4, in the transplanted epidermal progenitor cells. In conclusion, our present study successfully reconstructed conjunctiva with autologous transplantation of progenitor cell-derived epidermal sheets on denuded AM in conjunctival damaged monkeys, which is the first step toward assessing the use of autologous transplantation of progenitor cells of nonocular surface origin. Epidermal progenitor cells could be provided as a new substitute for conjunctival epithelial cells to overcome the problems of autologous conjunctiva shortage

Initiating antiretrovirals during tuberculosis treatment: a drug safety review

Introduction: Integrating HIV and tuberculosis (TB) treatment can reduce mortality substantially. Practical barriers to treatment integration still exist and include safety concerns related to concomitant drug use because of drug interactions and additive toxicities. Altered therapeutic concentrations may influence the chances of treatment success or toxicity. Areas covered: The available data on drug-drug interactions between the rifamycin class of anti-mycobacterials and the non-nucleoside reverse transcriptase inhibitor and the protease inhibitor classes of antiretrovirals are discussed with recommendations for integrated use. Additive drug toxicities, the impact of immune reconstitution inflammatory syndrome (IRIS) and the latest data on survival benefits of integrating treatment are elucidated. Expert opinion: Deferring treatment of HIV to avoid drug interactions with TB treatment or the occurrence of IRIS is not necessary. In the integrated management of TB-HIV co-infection, rational drug combinations aimed at reducing toxicities while effecting TB cure and suppressing HIV viral load are possible

Can sleep and resting behaviours be used as indicators of welfare in shelter dogs (Canis lupusfamiliaris)?

Previous research on humans and animals suggests that the analysis of sleep patterns may reliably inform us about welfare status, but little research of this kind has been carried out for non-human animals in an applied context. This study explored the use of sleep and resting behaviour as indicators of welfare by describing the activity patterns of dogs (Canis lupus familiaris) housed in rescue shelters, and comparing their sleep patterns to other behavioural and cognitive measures of welfare. Sleep and activity patterns were observed over five non-consecutive days in a population of 15 dogs. Subsequently, the characteristics of sleep and resting behaviour were described and the impact of activity on patterns of sleep and resting behaviour analysed. Shelter dogs slept for 2.8% of the day, 14.3% less than previously reported and experienced less sleep fragmentation at night (32 sleep bouts). There were no statistically significant relationships between behaviours exhibited during the day and sleep behaviour. A higher proportion of daytime resting behaviour was significantly associated with a positive judgement bias, less repetitive behaviour and increased time spent coded as ‘relaxed’ across days by shelter staff. These results suggest that, in the context of a busy shelter environment, the ability to rest more during the day could be a sign of improved welfare. Considering the non-linear relationship between sleep and welfare in humans, the relationship between sleep and behavioural indicators of welfare, including judgement bias, in shelter dogs may be more complex than this study could detect

The effect of exposure to synthetic pheromone lures on male Zygaena filipendulae mating behaviour: implications for monitoring species of conservation interest

Pheromone based monitoring of insects of conservation value has the potential to revolutionise the way in which surveys are carried out. However, due to their effective use in pest management, concerns have been raised about potential negative effects of pheromone exposure on populations of rare insects. The effect of exposure to synthetic pheromone lures on male mating behaviour was examined in laboratory and field conditions using the six spot burnet moth Zygaena filipendulae (Linnaeus, 1758). For the laboratory experiment larvae were collected and cultured separately under controlled conditions. Virgin males were exposed to a synthetic pheromone lure for 24 h; then tested for responsiveness immediately after this exposure, 1 and 24 h later. Control males were tested three times: initially, 1 h later and 24 h later. The time taken for males to detect females, shown by exposure of their anal claspers, and the time taken for males to locate females were recorded. No significant difference was found between the time taken for control and exposed males to detect or locate females, and no significant difference between the proportions of males that successfully located females in exposed and control groups was found. In the field experiment the time males spent in the presence of contained females, both with and without a pheromone lure present, was recorded. Males spent more time in the presence of the females when the pheromone lure was present. Both experiments indicate male Z. filipendulae mating behaviour is not adversely affected by exposure to synthetic pheromone lures

Pharmacodynamic evaluation of commonly prescribed oral antibiotics against respiratory bacterial pathogens

<p>Abstract</p> <p>Background</p> <p>Upper and lower respiratory tract infections (RTIs) account for a substantial portion of outpatient antibiotic utilization. However, the pharmacodynamic activity of commonly used oral antibiotic regimens has not been studied against clinically relevant pathogens. The objective of this study was to assess the probability of achieving the requisite pharmacodynamic exposure for oral antibacterial regimens commonly prescribed for RTIs in adults against bacterial isolates frequently involved in these processes (<it>S. pneumoniae</it>, <it>H. influenzae</it>, and <it>M. catharralis</it>).</p> <p>Methods</p> <p>Using a 5000-subject Monte Carlo simulation, the cumulative fractions of response (CFR), (i.e., probabilities of achieving requisite pharmacodynamic targets) for the most commonly prescribed oral antibiotic regimens, as determined by a structured survey of medical prescription patterns, were assessed against local respiratory bacterial isolates from adults in São Paulo collected during the same time period. Minimal inhibitory concentration (MIC) of 230 isolates of <it>Streptococcus pneumoniae </it>(103), <it>Haemophilus influenzae </it>(98), and <it>Moraxella catharralis </it>(29) from a previous local surveillance were used.</p> <p>Results</p> <p>The most commonly prescribed antibiotic regimens were azithromycin 500 mg QD, amoxicillin 500 mg TID, and levofloxacin 500 mg QD, accounting for 58% of the prescriptions. Varied doses of these agents, plus gatifloxacin, amoxicillin-clavulanate, moxifloxacin, and cefaclor made up the remaining regimens. Utilizing aggressive pharmacodynamic exposure targets, the only regimens to achieve greater than 90% CFR against all three pathogens were amoxicillin/amoxicillin-clavulanate 500 mg TID (> 91%), gatifloxacin 400 mg QD (100%), and moxifloxacin 400 mg QD (100%). Considering <it>S. pneumoniae </it>isolates alone, azithromycin 1000 mg QD also achieved greater than 90% CFR (91.3%).</p> <p>Conclusions</p> <p>The only regimens to achieve high CFR against all three pathogen populations in both scenarios were gatifloxacin 400 mg QD, moxifloxacin 400 mg QD, and amoxicillin-clavulanate 500 mg TID. These data suggest the need for reconsideration of empiric antibiotic regimen selection among adult patients with RTIs in the São Paulo area. Additionally, this type of study could be used to optimize prescribing patterns in specific regions in light of emerging resistance.</p

Transcendental-Phenomenological Proof and Descriptive Metaphysics

Following P.F. Strawson's reading of Kant, the majority of the literature on transcendental arguments seeks to divorce such arguments from their original Kantian context. This thesis is concerned with Mark Sacks's recent defence of transcendental arguments, which takes a different approach. A critique is given of Sacks's work and extensions and modifications of his approach are recommended. It is proposed that certain difficulties encountered by Kant's transcendentally-ideal approach can be overcome with Hegelian solutions

Staphylococcal protein Ecb impairs complement receptor-1 mediated recognition of opsonized bacteria

Staphyloccus aureus is a major human pathogen leading frequently to sepsis and soft tissue infections with abscesses. Multiple virulence factors including several immune modulating molecules contribute to its survival in the host. When S. aureus invades the human body, one of the first line defenses is the complement system, which opsonizes the bacteria with C3b and attract neutrophils by release of chemotactic peptides. Neutrophils express Complement receptor-1 [CR1, CD35) that interacts with the C3b-opsonized particles and thereby plays an important role in pathogen recognition by phagocytic cells. In this study we observed that a fraction of S. aureus culture supernatant prevented binding of C3b to neutrophils. This fraction consisted of S. aureus leukocidins and Efb. The C-terminus of Efb is known to bind C3b and shares significant sequence homology to the extracellular complement binding protein [Ecb). Here we show that S. aureus Ecb displays various mechanisms to block bacterial recognition by neutrophils. The presence of Ecb blocked direct interaction between soluble CR1 and C3b and reduced the cofactor activity of CR1 in proteolytic inactivation of C3b. Furthermore, Ecb could dose-dependently prevent recognition of C3b by cell-bound CR1 that lead to impaired phagocytosis of NHS-opsonized S. aureus. Phagocytosis was furthermore reduced in the presence of soluble CR1 [sCR1). These data indicate that the staphylococcal protein Ecb prevents recognition of C3b opsonized bacteria by neutrophil CR1 leading to impaired killing by phagocytosis and thereby contribute to immune evasion of S. aureus.Peer reviewe