Concept development of a Mach 4 high-speed civil transport

A study was conducted to configure and analyze a 250 passenger, Mach 4 High Speed Civil Transport with a design range of 6500 n.mi. The design mission assumed an all-supersonic cruise segment and no community noise or sonic boom constraints. The study airplane was developed in order to examine the technology requirements for such a vehicle and to provide an unconstrained baseline from which to assess changes in technology levels, sonic boom limits, or community noise constraints in future studies. The propulsion, structure, and materials technologies utilized in the sizing of the study aircraft were assumed to represent a technology availability date of 2015. The study airplane was a derivative of a previously developed Mach 3 concept and utilized advanced afterburning turbojet engines and passive airframe thermal protection. Details of the configuration development, aerodynamic design, propulsion system, mass properties, and mission performance are presented. The study airplane was estimated to weigh approx. 866,000 lbs. Although an aircraft of this size is a marginally acceptable candidate to fit into the world airport infrastructure, it was concluded that the inclusion of community noise or sonic boom constraints would quickly cause the aircraft to grow beyond acceptable limits using the assumed technology levels

Preliminary performance of a vertical-attitude takeoff and landing, supersonic cruise aircraft concept having thrust vectoring integrated into the flight control system

A performance study was made of a vertical attitude takeoff and landing (VATOL), supersonic cruise aircraft concept having thrust vectoring integrated into the flight control system. Those characteristics considered were aerodynamics, weight, balance, and performance. Preliminary results indicate that high levels of supersonic aerodynamic performance can be achieved. Further, with the assumption of an advanced (1985 technology readiness) low bypass ratio turbofan engine and advanced structures, excellent mission performance capability is indicated

Observed Coupling of the Mesosphere Inversion Layer to the Thermal Tidal Structure

Rayleigh lidar observations of mesosphere temperature profiles obtained from 40 to ∼100 km from Logan, Utah (41.7, 111.8 W, altitude, 1.9 km) over 10 nights in late February, 1995, revealed an interesting development between 60 to 75 km of a winter mesosphere inversion layer with an amplitude of ∼20–30 K and a downward phase progression of ∼1 km/hr. The data also showed two altitude regions exhibiting significant cooling of 10–30 K in extent. These were located below and above the peak of the inversion layer, respectively, at altitudes of ∼50–55 km and ∼70–80 km. When these results were compared with the predictions of a global wave scale model (GSWM), the observed thermal mesosphere structure is similar to the computed composite tidal structure based upon the semi‐diurnal and diurnal tides with the exception that observed amplitudes of heating and cooling are ∼10x larger than predicted GSWM values. We suggest that these events over Utah are caused through a localized mechanism involving the coupling of gravity waves to the mesopause tidal structure

Infection with Mansonella perstans Nematodes in Buruli Ulcer Patients, Ghana.

During August 2010-December 2012, we conducted a study of patients in Ghana who had Buruli ulcer, caused by Mycobacterium ulcerans, and found that 23% were co-infected with Mansonella perstans nematodes; 13% of controls also had M. perstans infection. M. perstans co-infection should be considered in the diagnosis and treatment of Buruli ulcer

Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring.

BACKGROUND: Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), is unique among human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone, making this molecule an attractive candidate target for diagnosis and disease monitoring. Whether mycolactone diffuses from ulcerated lesions in clinically accessible samples and is modulated by antibiotic therapy remained to be established. METHODOLOGY/PRINCIPAL FINDING: Peripheral blood and ulcer exudates were sampled from patients at various stages of antibiotic therapy in Ghana and Ivory Coast. Total lipids were extracted from serum, white cell pellets and ulcer exudates with organic solvents. The presence of mycolactone in these extracts was then analyzed by a recently published, field-friendly method using thin layer chromatography and fluorescence detection. This approach did not allow us to detect mycolactone accurately, because of a high background due to co-extracted human lipids. We thus used a previously established approach based on high performance liquid chromatography coupled to mass spectrometry. By this means, we could identify structurally intact mycolactone in ulcer exudates and serum of patients, and evaluate the impact of antibiotic treatment on the concentration of mycolactone. CONCLUSIONS/SIGNIFICANCE: Our study provides the proof of concept that assays based on mycolactone detection in serum and ulcer exudates can form the basis of BU diagnostic tests. However, the identification of mycolactone required a technology that is not compatible with field conditions and point-of-care assays for mycolactone detection remain to be worked out. Notably, we found mycolactone in ulcer exudates harvested at the end of antibiotic therapy, suggesting that the toxin is eliminated by BU patients at a slow rate. Our results also indicated that mycolactone titres in the serum may reflect a positive response to antibiotics, a possibility that it will be interesting to examine further through longitudinal studies

Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli

Laboratory Confirmation of Buruli Ulcer Disease in Togo, 2007–2010

Buruli ulcer disease (BUD) is an emerging disease particularly affecting children under the age of 15 years. Due to scarring and contractures BUD may lead to severe functional disability. Introduction of antimycobacterial treatment necessitated the laboratory confirmation of BUD, and WHO recommends confirmation of at least 50% of patients with suspected BUD by polymerase chain reaction (PCR). In Togo, cases have been reported since the early 1990s. However, less than five percent were laboratory confirmed. Since 2007, the German Leprosy and Tuberculosis Relief Organization (DAHW) has supported the Togolese National Buruli Ulcer Control Program in the area of training, treatment and laboratory confirmation of BUD. In close collaboration of DAHW and the Department for Infectious Diseases and Tropical Medicine, University Hospital, Munich (DITM), diagnostic samples from Togolese patients with suspected BUD were subjected to PCR. Out of 202 suspected BUD cases 109 BUD patients (54%) were PCR confirmed over a period of three years. Whereas the PCR case confirmation rate initially was below 50%, intensified training measures for health staff in the field of clinical diagnosis and collection of diagnostic samples ultimately resulted in 69% PCR confirmed cases. Our findings confirm the prevalence of BUD in Maritime Region

Comparative Study of the Sensitivity of Different Diagnostic Methods for the Laboratory Diagnosis of Buruli Ulcer Disease

Background. Several diagnostic laboratory methods are available for case confirmation of Buruli ulcer disease. This study assessed the sensitivity of various diagnostic tests in relation to clinical presentation of the disease, type of diagnostic specimen, and treatment history. Methods. Swab samples, 3-mm punch biopsy tissue specimens, and surgically excised tissue specimens from 384 individuals with suspected Buruli ulcer disease were obtained at 9 different study sites in Ghana and were evaluated with dry reagent-based polymerase chain reaction (PCR), microscopic examination, culture, and histopathological analysis. The study subjects presented with nonulcerative and ulcerative lesions and were divided into 3 treatment groups: (1) previously untreated patients scheduled for antimycobacterial treatment, (2) patients treated with surgery alone, and (3) patients treated with surgery in combination with previous antimycobacterial treatment. Results. Of 384 suspected cases of Buruli ulcer disease, 268 were confirmed by at least 1 positive test result. The overall sensitivity of PCR (85%) was significantly higher than that of microscopic examination (57%) and culture (51%). After data were stratified by treatment group, type of lesion, and diagnostic specimen type, analysis revealed that PCR of 3-mm punch biopsy tissue specimens (obtained from previously untreated nonulcerative lesions) and of swab samples (obtained from previously untreated ulcers) had the highest diagnostic sensitivity (94% and 90%, respectively). Although duration of the disease did not significantly influence the sensitivity of any test, previous antimycobacterial treatment was significantly associated with decreased sensitivity of PCR and culture. Conclusions. Across all subgroups, PCR had the highest sensitivity. PCR assessment of 3-mm punch biopsy tissue specimens proved to be the best diagnostic tool for nonulcerative lesions, and PCR assessment of swab samples was the best diagnostic tool for ulcerative lesions. For monitoring of antimycobacterial treatment success within controlled trials, however, only culture is appropriat

Activity pacing: moving beyond taking breaks and slowing down

This brief communication responds to the paper by Jeong and Cho (Qual Life Res 26(4):903–911, 2017) that has described activity pacing in limited terms of adjusting activities through going at a slower rate and taking breaks. Activity pacing was reported as not involving goal setting, in comparison to other strategies for long-term conditions such as Acceptance and Commitment Therapy. This brief communication aims to challenge this limited perception of activity pacing in light of numerous studies that recognise pacing to be a more complex strategy. Pacing is considered to be a multifaceted coping strategy, including broad themes of not only adjusting activities, but also planning activities, having consistent activity levels, acceptance of current abilities and gradually increasing activities, and one that includes goal setting as a key facet. It is essential that pacing is both defined and measured as a multifaceted strategy in order to assess the outcomes of pacing, and for meaningful comparisons with other strategies regarding efficacy for the management of long-term conditions

Kinetics of mycolactone in human subcutaneous tissue during antibiotic therapy for Mycobacterium ulcerans disease.

BACKGROUND: Mycobacterium ulcerans (M. ulcerans) causes a devastating necrotising infection of skin tissue leading to progressive ulceration. M. ulcerans is the only human pathogen that secretes mycolactone, a polyketide molecule with potent cytotoxic and immunomodulatory properties. These unique features make mycolactone an attractive biomarker for M. ulcerans disease. We sought to measure the concentration of mycolactone within lesions of patients with Buruli ulcer before, during and after antibiotic treatment to evaluate its association with the clinical and bacteriological response to therapy. METHODS: Biopsies of M. ulcerans infected skin lesions were obtained from patients before, during and after antibiotic therapy. Lipids were extracted from the biopsies and concentration of mycolactone was assayed by mass spectrometry and a cytotoxicity assay and correlated with clinical and bacteriological response to therapy. RESULTS: Baseline concentration of mycolactone measured by mass spectrometry predicted time to complete healing of small nodules and ulcers. Even though intra-lesional concentrations of mycolactone declined with antibiotic treatment, the toxin was still present after antibiotic treatment for 6 weeks and also 4 weeks after the end of treatment for 8 weeks in a subgroup of patients with slowly healing lesions. Additionally viable bacilli were detected in a proportion of these slowly healing lesions during and after treatment. CONCLUSIONS: Our findings indicate that baseline intra-lesional mycolactone concentration and its kinetics with antibiotic therapy are important prognostic determinants of clinical and bacteriological response to antibiotic treatment for Mycobacterium ulcerans disease. Mycolactone may be a useful biomarker with potential utility in optimising antibiotic therapy