Flow-Control Effectiveness of Convergent Surface Indentations on an Aerofoil at Low Reynolds Numbers

Passive flow control on aerofoils has largely been achieved through the use of protrusions such as vane-type vortex generators. Consequently, innovative flow-control concepts should be explored in an effort to improve current component performance. Therefore, experimental research has been performed at The University of Manchester to evaluate the flow-control effectiveness of a novel type of vortex generator made in the form of a surface indentation. The surface indentation has a trapezoidal planform. A spanwise array of indentations has been applied in a convergent orientation around the maximum-thickness location of the upper surface of a NACA-0015 aerofoil. The aerofoil has been tested in a twodimensional set-up in a low-speed wind tunnel at an angle of attack (AoA) of 3° and a chordbased blockage-corrected Reynolds number (Recorr) of ~2.70 x 105 . The baseline model has been found to suffer from a long laminar separation bubble (LSB) at low AoA. The application of the indentations at low AoA has considerably shortened the separation bubble. The indentations achieve this by shedding up-flow pairs of streamwise vortices. Despite the considerable reduction in bubble length, the increase in leading-edge suction due to the shorter bubble is limited by the removal of surface curvature and blockage (increase in surface pressure) caused locally by the convergent indentations. Furthermore, the up-flow region of the vortices, which locally weakens the pressure recovery around the trailing edge of the aerofoil by thickening the boundary layer, also contributes to this limitation. Due to the conflicting effects of the indentations, the changes in the pressure-lift and pressure-drag coefficients, i.e., cl,p and cd,p, respectively, are small. Nevertheless, the indentations have improved cl,p and cd,p beyond the uncertainty range, i.e., by ~1.3% and ~0.3%, respectively, at 3° AoA. The wake measurements show that turbulence intensity and Reynolds stresses have considerably increased in the indented case, thus implying that the indentations increase the viscous drag on the model. In summary, the convergent indentations are able to reduce the size of the LSB, but conversely, they are not highly effective in enhancing cl,p and cd,p at the tested Re

The Envelope Stress Response in Sedimentation-Resistant Escherichia Coli

Previous research discovered the existence of sedimentation-resistant mutants of E. coli. Genomic studies revealed that these mutants resisted sedimentation due to independent modifications to genes that influenced the Rcs signal transduction pathway, causing increased secretion of an exopolysaccharide capsule comprised primarily of colanic acid. The Rcs system is responsible for detecting envelope stressors; consequently, ampicillin and osmotic stress were used to perturb the cellular envelope and study the response of the mutants compared to wild-type cells. It was found that the overproduction of colanic acid in the mutants confers some resistance to envelope stress; however, the mutants still behaved similarly to wild-type cells. The doubling times of the strains grown in sodium chloride solutions were calculated. A wavelength scan from 400 nm to 800 nm was performed on strains grown in different salt concentrations to determine if there were significant differences in light scattering between the wild-type and mutant cells. Further analysis was performed that, along with the doubling time data, suggested that wild-type cells may have turned on genes for capsule production in response to being grown in high salt concentrations. Additional research could be conducted to test this hypothesis, perhaps through the quantification of colanic acid through a methyl pentose assay for wild-type cultures grown with high salt concentrations. The idea that wild-type cells could digest colanic acid as a carbon source when lacking resources was also investigated with different preparations of colanic acid. One preparation of colanic acid showed promising results, which could indicate that bacteria are able to digest their capsule in a novel method to produce energy when starved. Again, additional investigation should be conducted to confirm these results. Other future experiments could study the metabolome of these mutants to determine if they have increased quantities of alarmones related to biofilm formation

Stability Indicating LC-Method for Estimation of Paracetamol and Lornoxicam in Combined Dosage Form

A simple, specific and stability indicating reversed phase high performance liquid chromatographic method was developed for the simultaneous determination of paracetamol and lornoxicam in tablet dosage form. A Brownlee C-18, 5 μm column having 250×4.6 mm i.d. in isocratic mode, with mobile phase containing 0.05 M potassium dihydrogen phosphate:methanol (40:60, v/v) was used. The flow rate was 1.0 ml/min and effluents were monitored at 266 nm. The retention times of paracetamol and lornoxicam were 2.7 min and 5.1 min, respectively. The linearity for paracetamol and lornoxicam were in the range of 5–200 μg/ml and 0.08–20 μg/ml, respectively. Paracetamol and lornoxicam stock solutions were subjected to acid and alkali hydrolysis, chemical oxidation and dry heat degradation. The proposed method was validated and successfully applied to the estimation of paracetamol and lornoxicam in combined tablet dosage form

Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade

SummaryThe treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure

Increasing Drug Resistance in Extensively Drug-Resistant Tuberculosis, South Africa

We expanded second-line tuberculosis (TB) drug susceptibility testing for extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa. Of 19 patients with extensively drug-resistant TB identified during February 2008–April 2009, 13 (68%) had isolates resistant to all 8 drugs tested. This resistance leaves no effective treatment with available drugs in South Africa

Estimating the clinical effectiveness and value-based price range of erenumab for the prevention of migraine in patients with prior treatment failures: a US societal perspective

BACKGROUND: Frequent migraine with four or more headache days per month is a common, disabling neurovascular disease. From a US societal perspective, this analysis models the clinical efficacy and estimates the value-based price (VBP) for erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor. METHODS: A Markov health state transition model was developed to estimate the incremental costs, quality-adjusted life-years (QALYs), and value-based price range for erenumab in migraine prevention. The model comprises "on preventive treatment", "off preventive treatment", and "death" health states across a 10-year time horizon. The evaluation compared erenumab to no preventive treatment in episodic and chronic migraine patients that have failed at least one preventive therapy. Therapeutic benefits are based on estimated changes in monthly migraine days (MMD) from erenumab pivotal clinical trials and a network meta-analysis of migraine studies. Utilities were estimated using previously published mapping algorithms. A VBP analysis was performed to identify maximum erenumab annual prices at willingness-to-pay (WTP) thresholds of $100,000-$200,000 per QALY. Estimates of VBP under different scenarios such as choice of different comparators, assumptions around inclusion of placebo effect, and exclusion of work productivity losses were also generated. RESULTS: Erenumab resulted in incremental QALYs of 0.185 vs supportive care (SC) and estimated cost offsets due to reduced MMD of $8,482 over 10 years, with an average duration of treatment of 2.01 years. The estimated VBP at WTP thresholds of$100,000-$200,000 for erenumab compared to SC ranged from$14,238-$23,998. VBP estimates including the placebo effect and excluding work productivity ranged from$7,445-$13,809; increasing to$12,151-$18,589 with onabotulinumtoxinA as a comparator in chronic migraine. CONCLUSION: Erenumab is predicted to reduce migraine-related direct and indirect costs, and increase QALYs compared to SC

Predictors of Multidrug- and Extensively Drug-Resistant Tuberculosis in a High HIV Prevalence Community

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) have emerged in high-HIV-prevalence settings, which generally lack laboratory infrastructure for diagnosing TB drug resistance. Even where available, inherent delays with current drug-susceptibility testing (DST) methods result in clinical deterioration and ongoing transmission of MDR and XDR-TB. Identifying clinical predictors of drug resistance may aid in risk stratification for earlier treatment and infection control. METHODS: We performed a retrospective case-control study of patients with MDR (cases), XDR (cases) and drug-susceptible (controls) TB in a high-HIV-prevalence setting in South Africa to identify clinical and demographic risk factors for drug-resistant TB. Controls were selected in a 1:1:1 ratio and were not matched. We calculated odds ratios (OR) and performed multivariate logistic regression to identify independent predictors. RESULTS: We enrolled 116, 123 and 139 patients with drug-susceptible, MDR, and XDR-TB. More than 85% in all three patient groups were HIV-infected. In multivariate analysis, MDR and XDR-TB were each strongly associated with history of TB treatment failure (adjusted OR 51.7 [CI 6.6-403.7] and 51.5 [CI 6.4-414.0], respectively) and hospitalization more than 14 days (aOR 3.8 [CI 1.1-13.3] and 6.1 [CI 1.8-21.0], respectively). Prior default from TB treatment was not a risk factor for MDR or XDR-TB. HIV was a risk factor for XDR (aOR 8.2, CI 1.3-52.6), but not MDR-TB. Comparing XDR with MDR-TB patients, the only significant risk factor for XDR-TB was HIV infection (aOR 5.3, CI 1.0-27.6). DISCUSSION: In this high-HIV-prevalence and drug-resistant TB setting, a history of prolonged hospitalization and previous TB treatment failure were strong risk factors for both MDR and XDR-TB. Given high mortality observed among patients with HIV and drug-resistant TB co-infection, previously treated and hospitalized patients should be considered for empiric second-line TB therapy while awaiting confirmatory DST results in settings with a high-burden of MDR/XDR-TB

Culture Conversion Among HIV Co-Infected Multidrug-Resistant Tuberculosis Patients in Tugela Ferry, South Africa

Little is known about the time to sputum culture conversion in MDR-TB patients co-infected with HIV, although such patients have, historically, had poor outcomes. We describe culture conversion rates among MDR-TB patients with and without HIV-co-infection in a TB-endemic, high-HIV prevalent, resource-limited setting.Patients with culture-proven MDR-TB were treated with a standardized second-line regimen. Sputum cultures were taken monthly and conversion was defined as two negative cultures taken at least one month apart. Time-to-conversion was measured from the day of initiation of MDR-TB therapy. Subjects with HIV received antiretroviral therapy (ART) regardless of CD4 count.Among 45 MDR-TB patients, 36 (80%) were HIV-co-infected. Overall, 40 (89%) of the 45 patients culture-converted within the first six months and there was no difference in the proportion who converted based on HIV status. Median time-to-conversion was 62 days (IQR 48-111). Among the five patients who did not culture convert, three died, one was transferred to another facility, and one refused further treatment before completing 6 months of therapy. Thus, no patients remained persistently culture-positive at 6 months of therapy.With concurrent second-line TB and ART medications, MDR-TB/HIV co-infected patients can achieve culture conversion rates and times similar to those reported from HIV-negative patients worldwide. Future studies are needed to examine whether similar cure rates are achieved at the end of MDR-TB treatment and to determine the optimal use and timing of ART in the setting of MDR-TB treatment