Evaluation of the limitations and methods to improve rapid phage-based detection of viable Mycobacterium avium subsp. paratuberculosis in the blood of experimentally infected cattle

Background Disseminated infection and bacteraemia is an underreported and under-researched aspect of Johne’s disease. This is mainly due to the time it takes for Mycobacterium avium subsp. paratuberculosis (MAP) to grow and lack of sensitivity of culture. Viable MAP cells can be detected in the blood of cattle suffering from Johne’s disease within 48 h using peptide-mediated magnetic separation (PMMS) followed by bacteriophage amplification. The aim of this study was to demonstrate the first detection of MAP in the blood of experimentally exposed cattle using the PMMS-bacteriophage assay and to compare these results with the immune response of the animal based on serum ELISA and shedding of MAP by faecal culture. Results Using the PMMS-phage assay, seven out of the 19 (37 %) MAP-exposed animals that were tested were positive for viable MAP cells although very low numbers of MAP were detected. Two of these animals were positive by faecal culture and one was positive by serum ELISA. There was no correlation between PMMS-phage assay results and the faecal and serum ELISA results. None of the control animals (10) were positive for MAP using any of the four detection methods. Investigations carried out into the efficiency of the assay; found that the PMMS step was the limiting factor reducing the sensitivity of the phage assay. A modified method using the phage assay directly on isolated peripheral blood mononuclear cells (without PMMS) was found to be superior to the PMMS isolation step. Conclusions This proof of concept study has shown that viable MAP cells are present in the blood of MAP-exposed cattle prior to the onset of clinical signs. Although only one time point was tested, the ability to detect viable MAP in the blood of subclinically infected animals by the rapid phage-based method has the potential to increase the understanding of the pathogenesis of Johne’s disease progression by warranting further research on the presence of MAP in blood

The societal benefits of reducing six behavioural risk factors: an economic modelling study from Australia

BackgroundA large proportion of disease burden is attributed to behavioural risk factors. However, funding for public health programs in Australia remains limited. Government and non-government organisations are interested in the productivity effects on society from reducing chronic diseases. We aimed to estimate the potential health status and economic benefits to society following a feasible reduction in the prevalence of six behavioural risk factors: tobacco smoking; inadequate fruit and vegetable consumption; high risk alcohol consumption; high body mass index; physical inactivity; and intimate partner violence.MethodsSimulation models were developed for the 2008 Australian population. A realistic reduction in current risk factor prevalence using best available evidence with expert consensus was determined. Avoidable disease, deaths, Disability Adjusted Life Years (DALYs) and health sector costs were estimated. Productivity gains included workforce (friction cost method), household production and leisure time. Multivariable uncertainty analyses and correction for the joint effects of risk factors on health status were undertaken. Consistent methods and data sources were used.ResultsOver the lifetime of the 2008 Australian adult population, total opportunity cost savings of AUD2,334 million (95% Uncertainty Interval AUD1,395 to AUD3,347; 64% in the health sector) were found if feasible reductions in the risk factors were achieved. There would be 95,000 fewer DALYs (a reduction of about 3.6% in total DALYs for Australia); 161,000 less new cases of disease; 6,000 fewer deaths; a reduction of 5 million days in workforce absenteeism; and 529,000 increased days of leisure time.ConclusionsReductions in common behavioural risk factors may provide substantial benefits to society. For example, the total potential annual cost savings in the health sector represent approximately 2% of total annual health expenditure in Australia. Our findings contribute important new knowledge about productivity effects, including the potential for increased household and leisure activities, associated with chronic disease prevention. The selection of targets for risk factor prevalence reduction is an important policy decision and a useful approach for future analyses. Similar approaches could be applied in other countries if the data are available.<br /

Optimal cut-off criteria for duplex ultrasound for the diagnosis of restenosis in stented carotid arteries: Review and protocol for a diagnostic study

Background: Carotid angioplasty with stenting is a relatively new, increasingly used, less-invasive treatment for the treatment of symptomatic carotid artery stenosis. It is being evaluated in ongoing and nearly finished randomized trials. An important factor in the evaluation of stents is the occurrence of in-stent restenosis. An un-stented carotid artery is likely to have a more elastic vessel wall than a stented one, even if stenosis is present. Therefore, duplex ultrasound cut-off criteria for the degrees of an in-stent stenosis, based on blood velocity parameters, are probably different from the established cut-offs used for un-stented arteries. Routine criteria can not be applied to stented arteries but new criteria need to be established for this particular purpose. Methods/Design: Current literature was systematically reviewed. From the selected studies, the following data were extracted: publication year, population size, whether the study was prospective, which reference test was used, and if there was an indication for selection bias and for verification bias in particular. Previous studies often were retrospective, or the reference test (DSA or CTA) was carried out only when a patient was suspected of having restenosis at DUS, which may result in verification bias. Results: In general, the cut-off values are higher than those reported for unstented arteries. Previous studies often were retrospective, or the reference test (DSA or CTA) was carried out only when a patient was suspected of having restenosis at DUS, which may result in verification bias. Discussion: To address the deficiencies of the existing studies, we propose a prospective cohort study nested within the International Carotid Stenting Study (ICSS), an international multi-centre trial in which over 1,700 patients have been randomised between stenting and CEA. In this cohort we will enrol a minimum of 300 patients treated with a stent. All patients undergo regular DUS examination at the yearly follow-up visit according to the ICSS protocol. To avoid verification bias, an additional computed tomography angiography (CTA) will be performed as a reference test in all consecutive patients, regardless of the degree of stenosis on the initial DUS test

Sildenafil (Viagra) for male erectile dysfunction: a meta-analysis of clinical trial reports

BACKGROUND: Evaluation of company clinical trial reports could provide information for meta-analysis at the commercial introduction of a new technology. METHODS: Clinical trial reports of sildenafil for erectile dysfunction from September 1997 were used for meta-analysis of randomised trials (at least four weeks duration) and using fixed or dose optimisation regimens. The main outcome sought was an erection, sufficiently rigid for penetration, followed by successful intercourse, and conducted at home. RESULTS: Ten randomised controlled trials fulfilled the inclusion criteria (2123 men given sildenafil and 1131 placebo). NNT or NNH were calculated for important efficacy, adverse event and discontinuation outcomes. Dose optimisation led to at least 60% of attempts at sexual intercourse being successful in 49% of men, compared with 11% with placebo; the NNT was 2.7 (95% confidence interval 2.3 to 3.3). For global improvement in erections the NNT was 1.7 (1.6 to 1.9). Treatment-related adverse events occurred in 30% of men on dose optimised sildenafil compared with 11% on placebo; the NNH was 5.4 (4.3 to 7.3). All cause discontinuations were less frequent with sildenafil (10%) than with placebo (20%). Sildenafil dose optimisation gave efficacy equivalent to the highest fixed doses, and adverse events equivalent to the lowest fixed doses. CONCLUSION: This review of clinical trial reports available at the time of licensing agreed with later reviews that had many more trials and patients. Making reports submitted for marketing approval available publicly would provide better information when it was most needed, and would improve evidence-based introduction of new technologies

The effects of walking speed on minimum toe clearance and on the temporal relationship between minimum clearance and peak swing-foot velocity in unilateral trans-tibial amputees

yesBackground: Minimum toe clearance is a critical gait event because it coincides with peak forward velocity of the swing foot, and thus, there is an increased risk of tripping and falling. Trans-tibial amputees have increased risk of tripping compared to able-bodied individuals. Assessment of toe clearance during gait is thus clinically relevant. In able-bodied gait, minimum toe clearance increases with faster walking speeds, and it is widely reported that there is synchronicity between when peak swing-foot velocity and minimum toe clearance occur. There are no such studies involving lower-limb amputees. Objectives: To determine the effects of walking speed on minimum toe clearance and on the temporal relationship between clearance and peak swing-foot velocity in unilateral trans-tibial amputees. Study design: Cross-sectional. Methods: A total of 10 trans-tibial participants walked at slow, customary and fast speeds. Minimum toe clearance and the timings of minimum toe clearance and peak swing-foot velocity were determined and compared between intact and prosthetic sides. Results: Minimum toe clearance was reduced on the prosthetic side and, unlike on the intact side, did not increase with walking speed increase. Peak swing-foot velocity consistently occurred (~0.014 s) after point of minimum toe clearance on both limbs across all walking speeds, but there was no significant difference in the toe–ground clearance between the two events. Conclusion: The absence of speed related increases in minimum toe clearance on the prosthetic side suggests that speed related modulation of toe clearance for an intact limb typically occurs at the swing-limb ankle. The temporal consistency between peak foot velocity and minimum toe clearance on each limb suggests that swing-phase inter-segmental coordination is unaffected by trans-tibial amputation. Clinical relevance The lack of increase in minimum toe clearance on the prosthetic side at higher walking speeds may potentially increase risk of tripping. Findings indicate that determining the instant of peak swing-foot velocity will also consistently identify when/where minimum toe clearance occurs

Does tiotropium lower exacerbation and hospitalization frequency in COPD patients: results of a meta-analysis

<p>Abstract</p> <p>Background</p> <p>International guidelines recommend long-acting bronchodilators in patients who remain symptomatic despite adequate treatment with short-acting bronchodilators. The purpose of this study is to estimate the effect of tiotropium, a long-acting anticholinergic inhalant, on exacerbation and hospitalisation frequency.</p> <p>Methods</p> <p>Electronic databases (Medline, Embase, INAHTA, CRD databases, and the Cochrane Library) were searched for randomised controlled trials, comparing tiotropium to placebo, or other bronchodilators. Outcomes were the exacerbation frequency and hospitalisation frequency. Data were pooled using the generic inverse variance method for continuous outcomes.</p> <p>Results</p> <p>Nine studies reported comparisons with placebo (n = 8), ipratropium (short-acting anticholinergic inhalant, n = 1), and salmeterol (long-acting β₂-agonist inhalant, n = 1). Only two studies reported adequate concealment of allocation. Tiotropium reduces the number of exacerbations per patient year by 0.31 (95% CI 0.46- 0.17) compared to placebo, and by 0.23 (95% CI 0.31- 0.15) compared to ipratropium. A significant difference in exacerbation frequency between tiotropium and salmeterol was found (-0.16; 95% CI -0.29 - -0.03) based on approximations of the results of one study.</p> <p>The number of hospitalisations is reduced by 0.04 (95% CI 0.08- 0.01) per patient year compared to placebo and by 0.06 (95% CI -0.09 - -0.03) per patient year compared to ipratropium.</p> <p>Conclusions</p> <p>Statistically significant but clinically small effects were found for tiotropium compared to placebo and ipratropium. The comparison with salmeterol is significant for exacerbation frequency but not for hospitalisation frequency. Publication bias may be present.</p

Alcohol and marijuana use while driving-an unexpected crash risk in Pakistani commercial drivers: a cross-sectional survey

Background:A significant proportion of road traffic crashes are attributable to alcohol and marijuana use while driving globally. Sale and use of both substances is illegal in Pakistan and is not considered a threat for road traffic injuries. However literature hints that this may not be the case. We did this study to assess usage of alcohol and marijuana in Pakistani commercial drivers.Methods:A sample of 857 commercial bus and truck drivers was interviewed in October 2008 at the largest commercial vehicle station in Rawalpindi and Islamabad, Pakistan. Time location cluster sampling was used to select the subjects and a structured questionnaire was used to assess the basic demographic profile, substance abuse habits of the drivers while on the road, and reasons for usage of illicit substances while driving were recorded. Self reported information was collected after obtaining informed consent. Chi square and fisher exact tests were used to assess differences between groups and logistic regression was used to identify significant associations between driver characteristics and alcohol and marijuana use.Results:Almost 10% of truck drivers use alcohol while driving on Pakistani roads. Marijuana use is almost 30% in some groups. Statistically different patterns of usage are seen between population subgroups based on age, ethnicity, education, and marital status. Regression analysis shows association of alcohol and marijuana use with road rage and error behaviours, and also with an increased risk of being involved in road crashes. The reported reasons for using alcohol or marijuana show a general lack of awareness of the hazardous nature of this practice among the commercial driver population.Conclusion:Alcohol and marijuana use is highly prevalent in Pakistani commercial drivers. The issue needs to be recognized by concerned authorities and methods such as random breath tests and sobriety check points need to be employed for proper law enforcement

Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: Risks of breast/ovarian cancer quoted should reflect the cancer burden in the family

<p>Abstract</p> <p>Background</p> <p>The identification of a <it>BRCA1 </it>or <it>BRCA2 </it>mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation.</p> <p>Methods</p> <p>We reviewed 385 unrelated families (223 with <it>BRCA1 </it>and 162 with <it>BRCA2 </it>mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers – 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort.</p> <p>Results</p> <p>Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7–71.3%) and 79.5% (95%CI 75.5–83.5%) respectively for <it>BRCA1 </it>and 75% (95%CI 71.7–78.3%) and 88% (95%CI 85.3–91.7%) for <it>BRCA2</it>. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65–71%) and 65% (95%CI 75–84%) for <it>BRCA1 </it>and 30% (95%CI 25.5–34.5%) and 37% (95%CI 31.5–42.5%) for <it>BRCA2</it>. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005).</p> <p>Conclusion</p> <p>In high-risk families, selected in a genetics service setting, women who test positive for the familial <it>BRCA1/BRCA2 </it>mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.</p

Road traffic crash circumstances and consequences among young unlicensed drivers: A Swedish cohort study on socioeconomic disparities

<p>Abstract</p> <p>Background</p> <p>Young car drivers run a higher risk of road traffic crash and injury not only because of their lack of experience but also because of their young age and their greater propensity for adopting unsafe driving practices. Also, low family socioeconomic position increases the risk of crash and of severe crash in particular. Whether this holds true for young unlicensed drivers as well is not known. Increasing attention is being drawn to the prevalence and practice of unlicensed driving among young people as an important contributor to road traffic fatalities.</p> <p>Methods</p> <p>This is a population-based cohort study linking Swedish national register data for a cohort of 1 616 621 individuals born between 1977 and 1991. Crash circumstances for first-time road traffic crash (RTC) were compared considering licensed and unlicensed drivers. The socioeconomic distribution of injury was assessed considering household socioeconomic position, social welfare benefits, and level of urbanicity of the living area. The main outcome measure is relative risk of RTC.</p> <p>Results</p> <p>RTCs involving unlicensed drivers were over-represented among male drivers, suspected impaired drivers, severe injuries, crashes occurring in higher speed limit areas, and in fair road conditions. Unlicensed drivers from families in a lower socioeconomic position showed increased relative risks for RTC in the range of 1.75 to 3.25. Those living in rural areas had an increased relative risk for a severe RTC of 3.29 (95% CI 2.47 - 4.39) compared to those living in metropolitan areas.</p> <p>Conclusions</p> <p>At the time of the crash, young unlicensed drivers display more risky driving practices than their licensed counterparts. Just as licensed drivers, unlicensed young people from low socioeconomic positions are over-represented in the most severe injury crashes. Whether the mechanisms lying behind those similarities compare between these groups remains to be determined.</p

Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis

A previous systematic review reported that topical NSAIDs were effective in relieving pain in chronic conditions like osteoarthritis and tendinitis. More trials, a better understanding of trial quality and bias, and a reclassification of certain drugs necessitate a new review. Studies were identified by searching electronic databases, and writing to manufacturers. We identified randomised, double blind trials comparing topical NSAID with either placebo or another active treatment, in adults with chronic pain. The primary outcome was a reduction in pain of approximately 50% at two weeks, and secondary outcomes were local and systemic adverse events and adverse event-related withdrawals. Relative benefit and number-needed-to-treat (NNT), and relative harm and number-needed-to-harm (NNH) were calculated, and the effects of trial quality, validity and size, outcome reported, and condition treated, were examined by sensitivity analyses. Twelve new trials were added to 13 trials from a previous review. Fourteen double blind placebo-controlled trials had information from almost 1,500 patients. Topical NSAID was significantly better than placebo with relative benefit 1.9 (95% confidence interval 1.7 to 2.2), NNT 4.6 (95% confidence interval 3.8 to 5.9). Results were not affected by trial quality, validity or size, outcome reported, or condition treated. Three trials with 764 patients comparing a topical with an oral NSAID found no difference in efficacy. Local adverse events (6%), systemic adverse events (3%), or the numbers withdrawing due to an adverse event were the same for topical NSAID and placebo. Topical NSAIDs were effective and safe in treating chronic musculoskeletal conditions for two weeks. Larger and longer trials are necessary to fully elucidate the place of topical NSAIDs in clinical practice