TB Tolerance Exposed

One of the reasons tuberculosis (TB) continues to be a substantial public health problem is because the bacteria that cause TB, Mycobacterium tuberculosis, develop drug tolerance quickly. This requires patients to follow a 6-month-long drug regimen to ensure bacterial eradication, to which many patients fail to adhere. In order to identify new drug targets that may lead to shorter therapeutic regimens, Adams et al. dissected the development of drug tolerance in a zebrafish model of TB. Zebrafish infection with Mycobacterium marinum followed a similar disease course as human infection, which included the rapid development of drug tolerance. Multidrug-tolerant bacteria were present in macrophages just days after infection and were expanded and disseminated by granulomas. Bacteria acquired tolerance by replicating in macrophages, in both fish and mammalian cells. Upon infection, macrophages increased expression of bacterial efflux pumps, which can pump drugs out. Use of pump inhibitors demonstrated that these complexes mediated drug tolerance. Together, these studies suggest that adding efflux pump inhibitors to the standard TB therapies may be an effective way to reduce the course of treatment.

source: Cell

Virologic and Histologic Features of Chronic Hepatitis B Virus-Infected Asymptomatic Patients With Persistently Normal ALT

There is a paucity of data on hepatitis B virus (HBV) DNA levels and histologic lesions in patients with chronic HBV (CHBV) infection and persistently normal alanine aminotransferase (ALT) levels (PNALT). We studied the ALT, HBV DNA levels, and spectrum of histologic lesions in such patients. Methods: One thousand three hundred eighty-seven incidentally detected asymptomatic hepatitis B surface antigen (HBsAg)-positive patients with ≥1-year follow-up and either PNALT (n = 189; hepatitis B e antigen [HBeAg⁺], 73; HBeAg⁻, 116) or persistently or intermittently elevated ALT (PIEALT; n = 1198; HBeAg⁺, 530; HBeAg⁻, 668) were included. Results: In the PIEALT and PNALT patients, baseline DNA ≥5-log copies/mL was seen in 73.8% and 60.3% in HBeAg⁺ (P = .018) and 76% and 35.3% in HBeAg⁻ (P < .001) patients and histologic fibrosis stage ≥2 in 65.5% and 40.2% in HBeAg⁺ (P < .001) and 63.9% and 13.8% in HBeAg⁻ (P < .001) patients, respectively. Approximately 21% of HBeAg⁻ patients with PNALT and HBV DNA <5-log copies/mL had histologically active liver disease (histologic activity index ≥3 and/or fibrosis stage ≥2). Conclusions: A fair proportion of patients with CHBV infection with PNALT have HBV DNA ≥5-log copies/mL and significant histologic fibrosis. Use of ALT and HBV DNA levels without resorting to liver biopsy to define “inactive carrier state” in HBeAg⁻ PNALT patients may miss histologically significant disease in a proportion of patients.

source: gastroenterology

Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation.

Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning.
OBJECTIVES: To evaluate the diagnostic accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer.
DATA SOURCES: A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK. REVIEW
METHODS: One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second.
RESULTS: Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (<= 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients.
LIMITATIONS: No included studies directly compared PET and MRI.
CONCLUSIONS: Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility.

source: health technology assessment

Vaccines for prophylaxis of viral infections in patients with hematological malignancies.

Viral infections cause significant morbidity and mortality in patients with hematological malignancies. It remains uncertain whether viral vaccinations in these patients are supported by good evidence.
OBJECTIVES: We aimed to determine the effectiveness and safety of viral vaccines in patients with hematological malignancies.
SEARCH STRATEGY: We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL (June 2010), reference lists of relevant papers, abstracts from scientific meetings and contacted vaccine manufacturers.
SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating viral vaccines in patients with hematological malignancies were included.
DATA COLLECTION AND ANALYSIS: Relative risk (RR) was used for binary data and mean difference (MD) for continuous data. Primary outcome was incidence of infection. Secondary outcomes were mortality, incidence of complications and severe viral infection, hospitalization, immune response and adverse effects. Fixed-effect model was used in meta-analyses.
MAIN RESULTS: Eight RCTs were included, with 305 patients in the intervention groups and 288 in the control groups. They evaluated heat-inactivated varicella zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials) and inactivated poliovirus vaccine (IPV) (one trial). Seven trials had high and one trial had moderate risk of bias.VZV vaccine might reduce herpes zoster compared to no vaccine (RR 0.54, 95% CI 0.3 to 1.0, P=0.05), but not statistically significant. Vaccination also demonstrated efficacy in immune response but frequently caused local adverse effects. One trial reported severity score of zoster, which favored vaccination (MD 2.6, 95% CI 0.94 to 4.26, P=0.002).Two RCTs compared inactivated influenza vaccine with no vaccine and reported lower risk of lower respiratory infections (RR 0.39, 95% CI 0.19 to 0.78, P=0.008) and hospitalization (RR 0.17, 95% CI 0.09 to 0.31, P<0.00001) in vaccine recipients. However, vaccine recipients more frequently experienced irritability and local adverse effects. There was no significant difference in seroconversion between one and two doses of influenza vaccine (one trial), or between recombinant and standard influenza vaccine (one trial), or influenza vaccine given with or without re-induction chemotherapy (one trial).The IPV trial comparing vaccination starting at 6 versus 18 months after stem cell transplant (SCT) found no significant difference in seroconversion.
AUTHORS’ CONCLUSIONS: Inactivated VZV vaccine might reduce zoster severity in adult SCT recipients. Inactivated influenza vaccine might reduce respiratory infections and hospitalization in adults with multiple myeloma or children with leukemia or lymphoma. However, the quality of evidence is low. Local adverse effects occur frequently. Further high-quality RCTs are needed.

source: cochrane database

Dynamic spectral imaging colposcopy: higher sensitivity for detection of premalignant cervical lesions.

OBJECTIVE: to validate the dynamic spectral imaging (DSI) colposcope`s colour-coded map in discriminating high- from low-grade cervical lesions and non-neoplastic tissue.
DESIGN: prospective, comparative, multicentre clinical trial.
SETTING: the colposcopy clinics of three Dutch hospitals. POPULATION: women of 18 years or over with an intact cervix, referred for colposcopy.
METHODS: during a 3-minute image acquisition phase, the DSI colposcope was used as a regular video colposcope: the colposcopist located and graded potential lesions based on conventional colposcopic criteria. Subsequently, a colour-coded map was calculated and displayed, representing localisation and severity of the cervical lesion. Biopsies were collected from all atypical sites, as identified by digital mapping and/or conventional colposcopy. Furthermore, one additional biopsy was taken.
MAIN OUTCOME MEASURES: histologically confirmed high-grade cervical disease (CIN2+).
RESULTS: in total 275 women were included in the study: 183 women were analysed in the `according-to-protocol` (ATP) cohort and 239 women in the `intention-to-treat` (ITT) cohort. In the ATP cohort, the sensitivity of DSI colposcopy to identify women with high-grade (CIN2+) lesions was 79% (95% CI 70-88) and the sensitivity of conventional colposcopy was 55% (95% CI 44-65) (P = 0.0006, asymptotic McNemar test). When the DSI colour-coded map was combined with conventional colposcopy, the sensitivity was 88% (95% CI 82-95).
CONCLUSIONS: DSI colposcopy has a significantly higher sensitivity to detect cervical lesions than conventional colposcopy. If the colour-coded map is combined with conventional colposcopic examination, the sensitivity increases further.

source:BJOG

Prevention of pain on injection of propofol: systematic review and meta-analysis.

To systematically determine the most efficacious approach for preventing pain on injection of propofol.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: PubMed, Embase, Cochrane Library, http://www.clinicaltrials.gov, and hand searching from the reference lists of identified papers.
STUDY SELECTION: Randomised controlled trials comparing drug and non-drug interventions with placebo or another intervention to alleviate pain on injection of propofol in adults.
RESULTS: Data were analysed from 177 randomised controlled trials totalling 25 260 adults. The overall risk of pain from propofol injection alone was about 60%. Using an antecubital vein instead of a hand vein was the most effective single intervention (relative risk 0.14, 95% confidence interval 0.07 to 0.30). Pretreatment using lidocaine (lignocaine) in conjunction with venous occlusion was similarly effective (0.29, 0.22 to 0.38). Other effective interventions were a lidocaine-propofol admixture (0.40, 0.33 to 0.48); pretreatment with lidocaine (0.47, 0.40 to 0.56), opioids (0.49, 0.41 to 0.59), ketamine (0.52, 0.46 to 0.57), or non-steroidal anti-inflammatory drugs (0.67, 0.49 to 0.91); and propofol emulsions containing medium and long chain triglycerides (0.75, 0.67 to 0.84). Statistical testing of indirect comparisons showed that use of the antecubital vein and pretreatment using lidocaine along with venous occlusion to be more efficacious than the other interventions.
CONCLUSIONS: The two most efficacious interventions to reduce pain on injection of propofol were use of the antecubital vein, or pretreatment using lidocaine in conjunction with venous occlusion when the hand vein was chosen. Under the assumption of independent efficacy a third practical alternative could be pretreatment of the hand vein with lidocaine or ketamine and use of a propofol emulsion containing medium and long chain triglycerides. Although not the most effective intervention on its own, a small dose of opioids before induction halved the risk of pain from the injection and thus can generally be recommended unless contraindicated.

source: BMJ

New Alzheimer’s Genes Found

Gigantic Scientific Effort Discovers Clues to Treatment, Diagnosis of Alzheimer’s Disease

 

A massive scientific effort has found five new gene variants linked to Alzheimer’s disease.

The undertaking involved analyzing the genomes of nearly 40,000 people with and without Alzheimer’s. The mammoth task was undertaken by two separate research consortiums in the U.S. and in Europe, which collaborated to confirm each other’s results.

The finding may lead to earlier detection of Alzheimer’s disease as well as to new treatments, says William Theis, PhD, chief scientific officer for the Alzheimer’s Association.

“We will see more and more of these kinds of genes. And the more we have, the more we will be able to define a person’s risk of Alzheimer’s disease and the more possibilities we will have for therapeutic interventions,” Theis tells WebMD.

Before the new discovery, four genes had been definitively linked to Alzheimer’s. Three of them affect only the risk of relatively rare forms of Alzheimer’s. The fourth is APOE, until now the only gene known to affect risk of the common, late-onset form of Alzheimer’s.

All five of the newly discovered genes affect this more common form of the disease. None is as powerful as APOE. Roughly 27% of Alzheimer’s disease can be attributed to the five new gene variants, calculates Julie Williams, PhD, of the U.K.’s Cardiff University. Some 60% of Alzheimer’s disease can be attributed to the five new genes plus APOE, she says.

“But you will never have the perfect treatments to take out all the disease-causing effects of these genes,” Williams tells WebMD. “The point is that now there is the possibility to take out a considerable amount of disease if we take these results forward, understand the Alzheimer’s disease process, and make interventions, including lifestyle changes.”

Williams led a consortium of European researchers that identified two of the new Alzheimer’s genes. Her group also confirmed that three gene variants identified by a U.S. research consortium were indeed linked to Alzheimer’s.

Theis notes that Alzheimer’s is a very complex disease, and that eventually as many as 100 genes may be involved. Even so, the new findings represent a large chunk of Alzheimer’s risk.

“If you look at all the Alzheimer’s genes we now know, we have accounted for 20% of the causal risk of Alzheimer’s disease and 32% of the genetic risk,” Williams tells WebMD.

One of the leaders of the U.S. consortium is Margaret A. Pericak-Vance, PhD, director of the Institute for Human Genomics at the University of Miami Miller School of Medicine.

“This is an unprecedented story of collaboration. The world is coming together to say, ‘We are going to beat this thing,'” Pericak-Vance tells WebMD. “These are not ‘possible’ Alzheimer genes; they are definite and further confirmed by the European studies. These are robust findings we can take to the next level.”

Perhaps the greatest value of the gene studies is the clues they offer to the causes of Alzheimer’s. The new genes affect three important pathways:

• Endocytosis, the process by which large molecules — such as the amyloid precursor protein — get into brain cells.
• Inflammatory immune responses, which seem to go awry in Alzheimer’s disease.
• Lipid processing. The brain makes its own cholesterol. APOE — and now a new gene called ABCA7 — are involved in this process. Misprocessing of cholesterol could contribute to Alzheimer’s, Williams speculates.

“Each one of these metabolic pathways becomes a place to look at interventions that may lower the risk of Alzheimer’s disease or may even result in a treatment,” Theis says.

Both the U.S. and European research teams report their findings in the April 3 advance online issue of Nature Genetics.

source: webMD

Satellite images could aid long-term disaster recovery

Satellite image of Ban Nam Khem, Thailand, featured in one of the team’s case studies on a tsunami in 2004

Satellite images could be used to track and quantify long-term recovery efforts in regions stricken by natural disasters, say researchers who will be entering talks with potential users in Haiti, Pakistan and Thailand from April.

In the immediate aftermath of a natural catastrophe, such as the earthquake and tsunami that hit Japan earlier this month (11 March), the priority is searching for survivors and saving lives through providing food, shelter and basic sanitation.

But longer term recovery — including the rebuilding of infrastructure and amenities such as schools and hospitals — can take decades, depending on the extent and the location of the disaster.

Now, a group based at the University of Cambridge, United Kingdom, working with industrial partners Cambridge Architectural Research Ltd. and ImageCat Inc., says it has developed the first systematic approach to monitoring and evaluating this process. The method, which has been submitted to Disasters journal, involves tracking a region using high-resolution satellite images, which have become more abundant and affordable in recent years.

The researchers say that the required, one-metre resolution satellite images can be purchased for US$25 per square kilometre, and updated images can be acquired every 2–3 days.

“The last year — especially since the 2010 Haiti earthquake — has seen an increased interest in the use of high-resolution images as a damage assessment tool,” Daniel Brown, a member of the Cambridge team, told SciDev.Net.

A recovery monitoring system could improve coordination and decision-making, and warn if the reconstruction is not going according to plan, say the researchers.

“Analysing past recovery processes will also allow us to identify examples of good and bad practice and to provide ‘lessons learned’ to stakeholders that can hopefully be applied to future and ongoing responses,” Brown said.

Their approach is to integrate satellite data into 13 ‘performance indicators’ such as length of roads and distribution of housing. Data is then compared with on-the-ground reports collected from household surveys and interviews with recovery workers.

The method is based on two case studies, in Pakistan and Thailand, which are documented in the team’s report, ‘Disaster Recovery Indicators’, aimed at policymakers and released last year.

In April, the researchers will begin a one-year project in which they hope to work more closely with the authorities in Haiti, Pakistan and Thailand. “We hope the system will be ready to deploy by the end of the [one-year] project,” Brown told SciDev.Net.

They also hope to develop links with other nations and international organisations, and dispatch researchers to Japan.

Sarah Bailey, research officer at the UK-based Overseas Development Institute said: “Finding practical and systematic ways to link technology with reconstruction processes could play an important role in monitoring progress”.

But she warned that the complexity of how and why communities and governments recover from disasters is difficult to capture through such indicators alone.

Author: James Dacey

Source : sciVX

 

 

More science needed for tackling disasters, says report

Science and technology will be essential for anticipating and responding to disasters, according to a review of the humanitarian practices of one of the world’s leading national aid agencies, the UK Department for International Development (DFID).

Natural disasters are killing more people each year, with climate-related disasters alone predicted to affect 375 million a year by 2015. Finding new ways of tackling them is essential, according to the Humanitarian Emergency Response Review, launched yesterday (28 March).

“We are … caught in a race between the growing size of the humanitarian challenge and our ability to cope,” said Paddy Ashdown, a former British politician and chair of the team that produced the report.

“It is, bluntly, not a race we think we are currently winning. Merely improving on what we have done in the past — enhancing the status quo — will not be sufficient. We must devise new ways of meeting these new, larger challenges.”

The report tackles seven areas, including the anticipation of disasters, where science could be put to better use, said Ashdown.

“What is clear is that prediction, although far from perfect, is possible for some high-risk nations. But disaster managers do not make enough use of such science, and scientists do not routinely produce information for this audience.”

The report cited the example of the 2010 floods in Pakistan: “The rainfall … happened a month before the flood water caused its greatest devastation. The effects were predicted, but not acted on.”

It added that slow-onset disasters, such as famines, are regularly missed, despite the existence of tools such as the Famine Early Warning Systems Network, supported by the US aid agency USAID. Yet early intervention in such disasters costs a fraction of the bill arising from late intervention.

Elsewhere, there have been “significant advances” in understanding earthquake risk — for example in locating major fault lines and understanding the reasons for damage to buildings. But these anticipatory tools needed to be used more: “Science in this area has … significantly reduced fatalities and damage in many countries but research and investment is needed elsewhere to promote safe construction”.

In another section, the report also highlights the importance of innovation in finding new ways of responding to disasters, saying that many of the most important innovations of the past 30 years — such as using cash instead of goods in relief operations, and community feeding therapy — have arisen as a result of listening to, and being more accountable to, affected communities.

It claimed that there was scope for “transformative” developments in innovation by harnessing Southern capacities for innovation.

Technologies already in use that offer “considerable potential” include the use of mobile phones for cash transfers; the use of satellites in tracking storms and providing imagery for humanitarian operations; and crowd-sourcing as a way of soliciting information from those affected by a disaster.

In addition, emerging technologies that could play an important role are nanotechnology, which could transform medicine, water safety and foodstuffs, within the next five to ten years, and agent-based modelling, which could help understand the spread of epidemics or population movement.

author: Naomi Antony

source : sciVX