Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac

Internet-Based Photoaging Within Australian Pharmacies to Promote Smoking Cessation: Randomized Controlled Trial

Background: Tobacco smoking leads to death or disability and a drain on national resources. The literature suggests that cigarette smoking continues to be a major modifiable risk factor for a variety of diseases and that smokers aged 18-30 years are relatively resistant to antismoking messages due to their widely held belief that they will not be lifelong smokers. Objective: To conduct a randomized controlled trial (RCT) of a computer-generated photoaging intervention to promote smoking cessation among young adult smokers within a community pharmacy setting. Methods: A trial was designed with 80% power based on the effect size observed in a published pilot study; 160 subjects were recruited (80 allocated to the control group and 80 to the intervention group) from 8 metropolitan community pharmacies located around Perth city center in Western Australia. All participants received standardized smoking cessation advice. The intervention group participants were also digitally photoaged by using the Internet-based APRIL Face Aging software so they could preview images of themselves as a lifelong smoker and as a nonsmoker. Due to the nature of the intervention, the participants and researcher could not be blinded to the study. The main outcome measure was quit attempts at 6-month follow-up, both self-reported and biochemically validated through testing for carbon monoxide (CO), and nicotine dependence assessed via the Fagerström scale.Results: At 6-month follow-up, 5 of 80 control group participants (6.3%) suggested they had quit smoking, but only 1 of 80 control group participants (1.3%) consented to, and was confirmed by, CO validation. In the intervention group, 22 of 80 participants (27.5%) reported quitting, with 11 of 80 participants (13.8%) confirmed by CO testing. This difference in biochemically confirmed quit attempts was statistically significant (χ21=9.0, P=.003). A repeated measures analysis suggested the average intervention group smoking dependence score had also significantly dropped compared to control participants (P<.001). These differences remained statistically significant after adjustment for small differences in gender distribution and nicotine dependence between the groups. The mean cost of implementing the intervention was estimated at AU $5.79 per participant. The incremental cost-effectiveness ratio was AU$46 per additional quitter. The mean cost that participants indicated they were willing to pay for the digital aging service was AU $20.25 (SD 15.32). Conclusions: Demonstrating the detrimental effects on facial physical appearance by using a computer-generated simulation may be both effective and cost-effective at persuading young adult smokers to quit

Study of Sexual Functioning Determinants in Breast Cancer Survivors

Our goal was to identify the treatment, personal, interpersonal, and hormonal (testosterone) factors in breast cancer survivors (BCSs) that determine sexual dysfunction. The treatment variables studied were type of surgery, chemotherapy, radiation, and tamoxifen. The personal, interpersonal, and physiologic factors were depression, body image, age, relationship distress, and testosterone levels. A sample of 55 female breast cancer survivors seen for routine follow-up appointments from July 2002 to September 2002 were recruited to complete the Female Sexual Functioning Index (FSFI), Hamilton Depression Inventory (HDI), Body Image Survey (BIS), Marital Satisfaction Inventory-Revised (MSI-R), a demographic questionnaire, and have a serum testosterone level drawn. The average time since diagnosis was 4.4 years (SD 3.4 years). No associations were found between the type of cancer treatment, hormonal levels, and sexual functioning. BCS sexual functioning was significantly poorer than published normal controls in all areas but desire. The BCSs’ level of relationship distress was the most significant variable affecting arousal, orgasm, lubrication, satisfaction, and sexual pain. Depression and having traditional role preferences were the most important determinants of lower sexual desire. BCSs on antidepressants had higher levels of arousal and orgasm dysfunction. Women who were older had significantly more concerns about vaginal lubrication and pain. Relationship concerns, depression, and age are important influences in the development of BCS sexual dysfunction. The relationship of testosterone and sexual dysfunction needs further study with larger samples and more accurate assay techniques.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72034/1/j.1075-122X.2005.00131.x.pd

Digital PCR methods improve detection sensitivity and measurement precision of low abundance mtDNA deletions

Mitochondrial DNA (mtDNA) mutations are a common cause of primary mitochondrial disorders, and have also been implicated in a broad collection of conditions, including aging, neurodegeneration, and cancer. Prevalent among these pathogenic variants are mtDNA deletions, which show a strong bias for the loss of sequence in the major arc between, but not including, the heavy and light strand origins of replication. Because individual mtDNA deletions can accumulate focally, occur with multiple mixed breakpoints, and in the presence of normal mtDNA sequences, methods that detect broad-spectrum mutations with enhanced sensitivity and limited costs have both research and clinical applications. In this study, we evaluated semi-quantitative and digital PCR-based methods of mtDNA deletion detection using double-stranded reference templates or biological samples. Our aim was to describe key experimental assay parameters that will enable the analysis of low levels or small differences in mtDNA deletion load during disease progression, with limited false-positive detection. We determined that the digital PCR method significantly improved mtDNA deletion detection sensitivity through absolute quantitation, improved precision and reduced assay standard error

Ageing of enteric neurons: oxidative stress, neurotrophic factors and antioxidant enzymes

Background: Ageing is associated with gastrointestinal dysfunction, which can have a major impact on quality of life of the elderly. A number of changes in the innervation of the gut during ageing have been reported, including neuronal loss and degenerative changes. Evidence indicates that reactive oxygen species (ROS) are elevated in ageing enteric neurons, but that neurotrophic factors may reduce generation of neuronal ROS. Two such factors, glial cell line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) have also been found to protect enteric neurons against oxidative stress induced cell death of enteric ganglion cells in vitro. We have investigated the possible roles of neurotrophic factors further, by examining their expression in the gut during ageing, and by analysing their effects on antioxidant enzyme production in cultures of enteric ganglion cells. Results: Analysis of the expression of GDNF and its receptors c-Ret and GFR α − 1 in rat gut by RT-PCR showed that expression continues throughout life and into ageing, in both ad libitum(AL) and calorically-restricted (CR) animals. Levels of expression of GDNF and GFR α − 1 were elevated in 24 month AL animals compared to 24 month CR animals, and to 24 CR and 6 month control animals respectively. The related factor Neurturin and its receptor GFR α − 2 were also expressed throughout life, the levels of the GFR – α-2(b) isoform were reduced in 24 m AL animals. Immunolabelling showed that c-Ret and GFR α − 1 proteins were expressed by myenteric neurons in ageing animals. GDNF, but not NT-3, was found to increase expression of Cu/Zn superoxide dismutase and catalase by cultured enteric ganglion cells. Conclusions: The neurotrophic factors GDNF and neurturin and their receptors continue to be expressed in the ageing gut. Changes in the levels of expression of GDNF , GFR α-1 and GFR α-2(b) isoform occurred in 24 m AL animals. GDNF, but not NT-3, increased the levels of antioxidant enzymes in cultured enteric ganglion cells, indicating a possible mechanism for the reported protective effect of GDNF against menadione-induced neuronal apoptosis in the ageing gut. Together these data suggest that GDNF family members may play a protective role in the gut throughout life, and support the suggestion that dysregulation of neurotrophic factor support could contribute to neuronal ageing in the gut

The effect of feedback to general practitioners on quality of care for people with type 2 diabetes. A systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>There have been numerous efforts to improve and assure the quality of treatment and follow-up of people with Type 2 diabetes (PT2D) in general practice. Facilitated by the increasing usability and validity of guidelines, indicators and databases, feedback on diabetes care is a promising tool in this aspect. Our goal was to assess the effect of feedback to general practitioners (GPs) on the quality of care for PT2D based on the available literature.</p> <p>Methods</p> <p>Systematic review searches were conducted using October 2008 updates of Medline (Pubmed), Cochrane library and Embase databases. Additional searches in reference lists and related articles were conducted. Papers were included if published in English, performed as randomized controlled trials, studying diabetes, having general practice as setting and using feedback to GPs on diabetes care. The papers were assessed according to predefined criteria.</p> <p>Results</p> <p>Ten studies complied with the inclusion criteria. Feedback improved the care for PT2D, particularly process outcomes such as foot exams, eye exams and Hba1c measurements. Clinical outcomes like lowering of blood pressure, Hba1c and cholesterol levels were seen in few studies. Many process and outcome measures did not improve, while none deteriorated. Meta analysis was unfeasible due to heterogeneity of the studies included. Two studies used electronic feedback.</p> <p>Conclusion</p> <p>Based on this review, feedback seems a promising tool for quality improvement in diabetes care, but more research is needed, especially of electronic feedback.</p

Generation of E-band metasurface-based vortex beam with reduced divergence angle

Vortex beams carrying orbital angular momentum (OAM) have attracted considerable attention for the development of high-capacity wireless communication systems due to their infinite sets of orthogonal modes. However, the practical applications of Laguerre-Gaussian type vortex beams are limited due to the fact that the divergence angle increases as the order of the OAM mode increases. In this work, we present metasurfaces that generate vortex beams carrying OAM modes with reduced divergence angles in the E-band frequency range. The metasurfaces were designed using eight different meta-atom phase elements, including a spiral phase distribution for OAM modes l=1 and 2, a phase gradient array to avoid interference with the source beam, and a lens pattern array to reduce the divergence angle. Through simulation and experimental measurement, it was confirmed that the divergence angle of the vortex beam generated by the metasurface with the lens pattern was reduced from 13 degrees to 9 degrees and 14 degrees to 11 degrees for OAM modes l=1 and 2, respectively, in comparison with the metasurface without the lens pattern. Our results provide new design methods for various applications based on OAM multiplexing especially in high frequency E-band range

Active, but not passive cigarette smoking was inversely associated with mammographic density

The opposing carcinogenic and antiestrogenic properties of tobacco smoke may explain why epidemiologic studies have not consistently reported positive associations for active smoking and breast cancer risk. A negative relation between mammographic density, a strong breast cancer risk factor, and active smoking would lend support for an antiestrogenic mechanism. We used multivariable linear regression to assess the associations of active smoking and secondhand smoke (SHS) exposure with mammographic density in 799 pre- and early perimenopausal women in the Study of Women’s Health Across the Nation (SWAN). We observed that current active smoking was associated with 7.2% lower mammographic density, compared to never active smoking and no SHS exposure (p = 0.02). Starting to smoke before 18 years of age and having smoked ≥20 cigarettes/day were also associated with statistically significantly lower percent densities. Among nulliparous women having smoked ≥20 cigarettes/day was associated with 23.8% lower density, compared to having smoked ≤9 cigarettes/day (p &lt; 0.001). Our findings support the hypothesis that tobacco smoke exerts an antiestrogenic effect on breast tissue, but counters the known increased risk of breast cancer with smoking prior to first full-term birth. Thus, our data suggest that the antiestrogenic but not the carcinogenic effects of smoking may be reflected by breast density

Two-Particle-Self-Consistent Approach for the Hubbard Model

Even at weak to intermediate coupling, the Hubbard model poses a formidable challenge. In two dimensions in particular, standard methods such as the Random Phase Approximation are no longer valid since they predict a finite temperature antiferromagnetic phase transition prohibited by the Mermin-Wagner theorem. The Two-Particle-Self-Consistent (TPSC) approach satisfies that theorem as well as particle conservation, the Pauli principle, the local moment and local charge sum rules. The self-energy formula does not assume a Migdal theorem. There is consistency between one- and two-particle quantities. Internal accuracy checks allow one to test the limits of validity of TPSC. Here I present a pedagogical review of TPSC along with a short summary of existing results and two case studies: a) the opening of a pseudogap in two dimensions when the correlation length is larger than the thermal de Broglie wavelength, and b) the conditions for the appearance of d-wave superconductivity in the two-dimensional Hubbard model.Comment: Chapter in "Theoretical methods for Strongly Correlated Systems", Edited by A. Avella and F. Mancini, Springer Verlag, (2011) 55 pages. Misprint in Eq.(23) corrected (thanks D. Bergeron

The deuteron: structure and form factors

A brief review of the history of the discovery of the deuteron in provided. The current status of both experiment and theory for the elastic electron scattering is then presented.Comment: 80 pages, 33 figures, submited to Advances in Nuclear Physic