Editorial: Molecular Mechanisms of Pathogen-Driven Infectious and Neoplastic Diseases

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Incorporating scale dependence in disease burden estimates:the case of human African trypanosomiasis in Uganda

The WHO has established the disability-adjusted life year (DALY) as a metric for measuring the burden of human disease and injury globally. However, most DALY estimates have been calculated as national totals. We mapped spatial variation in the burden of human African trypanosomiasis (HAT) in Uganda for the years 2000-2009. This represents the first geographically delimited estimation of HAT disease burden at the sub-country scale.Disability-adjusted life-year (DALY) totals for HAT were estimated based on modelled age and mortality distributions, mapped using Geographic Information Systems (GIS) software, and summarised by parish and district. While the national total burden of HAT is low relative to other conditions, high-impact districts in Uganda had DALY rates comparable to the national burden rates for major infectious diseases. The calculated average national DALY rate for 2000-2009 was 486.3 DALYs/100 000 persons/year, whereas three districts afflicted by rhodesiense HAT in southeastern Uganda had burden rates above 5000 DALYs/100 000 persons/year, comparable to national GBD 2004 average burden rates for malaria and HIV/AIDS.These results provide updated and improved estimates of HAT burden across Uganda, taking into account sensitivity to under-reporting. Our results highlight the critical importance of spatial scale in disease burden analyses. National aggregations of disease burden have resulted in an implied bias against highly focal diseases for which geographically targeted interventions may be feasible and cost-effective. This has significant implications for the use of DALY estimates to prioritize disease interventions and inform cost-benefit analyses

Quantifying the burden of rhodesiense sleeping sickness in Urambo district, Tanzania

Sleeping sickness (human African trypanosomiasis - HAT) is a disease transmitted by tsetse flies and is always fatal if left untreated. The disease occurs in foci affecting poor communities with limited access to health service provision and as such the disease is often left undiagnosed, mistaken for more common afflictions. Even if diagnosed, sleeping sickness is costly to treat, both for health services and patients and their families in terms of costs of diagnosis, transport, hospital care, and the prolonged period of convalescence. Here we estimate the health burden of the acute form T. b. rhodesiense sleeping sickness in Urambo District, Tanzania in terms of Disability Adjusted Life Years (DALYs), the yardstick commonly used by policy makers to prioritize disease management practices, representing a year of healthy life lost to disease. In this single district, the burden of the disease over one year was estimated at 979 DALYs and the estimated monetary costs to health services for the 143 treated patients at US$11,841 and to the patients themselves at US$ 3,673 for direct medical costs and US$ 9,781 for indirect non-medical costs. Sleeping sickness thus places a considerable burden on the affected rural communities and health services

In vitro comparison of the effects of rough and polished stem surface finish on pressure generation in cemented hip arthroplasty

Background and purpose High pressures around implants can cause bone lysis and loosening. We investigated how pressures are generated around cemented femoral stems

In vitro influence of stem surface finish and mantle conformity on pressure generation in cemented hip arthroplasty

Background and purpose Under physiological loads, debonded cemented femoral stems have been shown to move within their cement mantle and generate a fluid pump that may facilitate peri-prosthetic osteolysis by pressurizing fluid and circulating wear debris. The long-term physiological loading of rough and polished tapered stems in vitro has shown differences in performance, with greater interface pressures generated by the rough stems. In this study we investigated the individual effects of stem surface finish, degree of mantle wear, and mode of loading on the stem pump mechanism

Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis

BACKGROUND: Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. RESULTS: Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. CONCLUSIONS: The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.)

Implementation of the CALM intervention for anxiety disorders: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Investigators recently tested the effectiveness of a collaborative-care intervention for anxiety disorders: Coordinated Anxiety Learning and Management(CALM) []) in 17 primary care clinics around the United States. Investigators also conducted a qualitative process evaluation. Key research questions were as follows: (1) What were the facilitators/barriers to implementing CALM? (2) What were the facilitators/barriers to sustaining CALM after the study was completed?</p> <p>Methods</p> <p>Key informant interviews were conducted with 47 clinic staff members (18 primary care providers, 13 nurses, 8 clinic administrators, and 8 clinic staff) and 14 study-trained anxiety clinical specialists (ACSs) who coordinated the collaborative care and provided cognitive behavioral therapy. The interviews were semistructured and conducted by phone. Data were content analyzed with line-by-line analyses leading to the development and refinement of themes.</p> <p>Results</p> <p>Similar themes emerged across stakeholders. Important facilitators to implementation included the perception of "low burden" to implement, provider satisfaction with the intervention, and frequent provider interaction with ACSs. Barriers to implementation included variable provider interest in mental health, high rates of part-time providers in clinics, and high social stressors of lower socioeconomic-status patients interfering with adherence. Key sustainability facilitators were if a clinic had already incorporated collaborative care for another disorder and presence of onsite mental health staff. The main barrier to sustainability was funding for the ACS.</p> <p>Conclusions</p> <p>The CALM intervention was relatively easy to incorporate during the effectiveness trial, and satisfaction was generally high. Numerous implementation and sustainability barriers could limit the reach and impact of widespread adoption. Findings should be interpreted with the knowledge that the ACSs in this study were provided and trained by the study. Future research should explore uptake of CALM and similar interventions without the aid of an effectiveness trial.</p

ArteFill® Permanent Injectable for Soft Tissue Augmentation: I. Mechanism of Action and Injection Techniques

After more than 25 years of research and development, in October 2006 ArteFill® became the first and only permanent injectable wrinkle filler to receive FDA approval. ArteFill is a third-generation polymeric microsphere-based filler, following its predecessor Artecoll®, which was marketed outside the United States between 1994 and 2006. ArteFill is approved for the correction of nasolabial folds and has been used in over 15,000 patients since its U.S. market introduction in February 2007. No serious side effects have been reported to date according to the FDA’s MAUDE reporting database. ArteFill consists of polymethylmethacrylate (PMMA) microspheres (20% by volume), 30–50 μm in diameter, suspended in 3.5% bovine collagen solution (80% by volume) and 0.3% lidocaine. The collagen carrier is absorbed within 1 month after injection and completely replaced by the patient’s own connective tissue within 3 months. Each cc of ArteFill contains approximately six million microspheres and histological studies have shown that long-term wrinkle correction consists of 80% of the patient’s own connective tissue and 20% microspheres. The standard injection technique is subdermal tunneling that delivers a strand of ArteFill at the dermal–subdermal junction. This strand beneath a wrinkle or fold acts like a support structure that protects against further wrinkling and allows the diminished thickness of the dermis to recover to its original thickness

An eclipsing substellar binary in a young triple system discovered by SPECULOOS

Mass, radius, and age are three of the most fundamental parameters for celestial objects, enabling studies of the evolution and internal physics of stars, brown dwarfs, and planets. Brown dwarfs are hydrogen-rich objects that are unable to sustain core fusion reactions but are supported from collapse by electron degeneracy pressure. As they age, brown dwarfs cool, reducing their radius and luminosity. Young exoplanets follow a similar behaviour. Brown dwarf evolutionary models are relied upon to infer the masses, radii and ages of these objects. Similar models are used to infer the mass and radius of directly imaged exoplanets. Unfortunately, only sparse empirical mass, radius and age measurements are currently available, and the models remain mostly unvalidated. Double-line eclipsing binaries provide the most direct route for the absolute determination of the masses and radii of stars. Here, we report the SPECULOOS discovery of 2M1510A, a nearby, eclipsing, double-line brown dwarf binary, with a widely-separated tertiary brown dwarf companion. We also find that the system is a member of the $45\pm5$ Myr-old moving group, Argus. The system's age matches those of currently known directly-imaged exoplanets. 2M1510A provides an opportunity to benchmark evolutionary models of brown dwarfs and young planets. We find that widely-used evolutionary models do reproduce the mass, radius and age of the binary components remarkably well, but overestimate the luminosity by up to 0.65 magnitudes, which could result in underestimated photometric masses for directly-imaged exoplanets and young field brown dwarfs by 20 to 35%

An affordable, quality-assured community-based system for high-resolution entomological surveillance of vector mosquitoes that reflects human malaria infection risk patterns.

ABSTRACT: BACKGROUND: More sensitive and scalable entomological surveillance tools are required to monitor low levels of transmission that are increasingly common across the tropics, particularly where vector control has been successful. A large-scale larviciding programme in urban Dar es Salaam, Tanzania is supported by a community-based (CB) system for trapping adult mosquito densities to monitor programme performance. Methodology An intensive and extensive CB system for routine, longitudinal, programmatic surveillance of malaria vectors and other mosquitoes using the Ifakara Tent Trap (ITT-C) was developed in Urban Dar es Salaam, Tanzania, and validated by comparison with quality assurance (QA) surveys using either ITT-C or human landing catches (HLC), as well as a cross-sectional survey of malaria parasite prevalence in the same housing compounds. RESULTS: Community-based ITT-C had much lower sensitivity per person-night of sampling than HLC (Relative Rate (RR) [95% Confidence Interval (CI)] = 0.079 [0.051, 0.121], P < 0.001 for Anopheles gambiae s.l. and 0.153 [0.137, 0.171], P < 0.001 for Culicines) but only moderately differed from QA surveys with the same trap (0.536 [0.406,0.617], P = 0.001 and 0.747 [0.677,0.824], P < 0.001, for An. gambiae or Culex respectively). Despite the poor sensitivity of the ITT per night of sampling, when CB-ITT was compared with QA-HLC, it proved at least comparably sensitive in absolute terms (171 versus 169 primary vectors caught) and cost-effective (153US$versus 187US$ per An. gambiae caught) because it allowed more spatially extensive and temporally intensive sampling (4284 versus 335 trap nights distributed over 615 versus 240 locations with a mean number of samples per year of 143 versus 141). Despite the very low vectors densities (Annual estimate of about 170 An gambiae s.l bites per person per year), CB-ITT was the only entomological predictor of parasite infection risk (Odds Ratio [95% CI] = 4.43[3.027,7. 454] per An. gambiae or Anopheles funestus caught per night, P =0.0373). Discussion and conclusion CB trapping approaches could be improved with more sensitive traps, but already offer a practical, safe and affordable system for routine programmatic mosquito surveillance and clusters could be distributed across entire countries by adapting the sample submission and quality assurance procedures accordingly