Body

CLEVELAND, Ohio (February 21, 2018)--The Women's Health Initiative found that hormone therapy (HT) use was associated with a reduction in vertebral fracture risk. A new study shows these same benefits may also guard against a woman's risk of developing hyperkyphosis, an exaggerated curvature of the spine that creates a forward stooped posture. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

It is well documented that the significant declines in estrogen experienced during the menopause transition contribute to accelerated bone loss. Hormone therapy reverses bone loss and helps prevent fractures. During the first 3 years of HT use, bone density has been shown to increase steadily and then is maintained during continued use. Given that hyperkyphosis is also associated with bone loss and vertebral fractures, the authors of the article "Patterns of menopausal hormone therapy use and hyperkyphosis in older women" hypothesized that HT may also be effective in helping prevent exaggerated spine curvature, sometimes called dowager's hump.

The study on which the article is based involved more than 9,700 women aged 65 years and older who were evaluated over a 15-year period. Women who reported continuous or remote past HT use had less pronounced kyphosis by the time they were in their mid-80s than never-users, supporting the argument for HT as a possible early postmenopause treatment for women concerned about their posture and fracture risk. Beyond its adverse aesthetic effects, hyperkyphosis is associated with poor physical function, an increased risk of falls and fractures, and earlier mortality.

"Women who reported early use of HT were less likely to develop age-related kyphosis, and the protective benefits continued even after stopping HT," says Dr. JoAnn Pinkerton, NAMS executive director. "This supports a benefit of prescribing HT close to menopause."

New research published in The Journal of Physiology sheds light on the effects of high blood pressure by considering the way the body responds to a lack of oxygen.

When a healthy person has a deficiency of oxygen in the blood (a state called 'hypoxia') caused by reduced oxygen pressure in the air (e.g. at high altitude) or when their upper airway is blocked during sleep (sleep apnoea) their body compensates by increasing blood flow to vital organs and tissues such as the brain and muscles in order to maintain oxygen supply to them. This is important to protect these organs and tissues.

To understand how high blood pressure impacts these compensatory responses to hypoxia, the study conducted by researches from the Fluminense Federal University, Brazil and The University of Copenhagen, Denmark, involved measuring the blood flow to the brain and the leg muscles whilst middle-aged men with normal and high blood pressure inhaled air with a low oxygen concentration for 5 minutes.

This research then showed that this increased blood supply response to hypoxia does not occur for middle-aged men with high blood pressure, and therefore when they are deprived of oxygen, oxygen delivery to parts of the brain and the leg skeletal muscles is limited. According to the study, this compromised response may be caused by the high blood pressure-induced impairment in the function of the blood vessels as well as increases in neural signals from the hypoxic brain to the circulation, increasing resistance to blood supply.

Importantly, this study only offers insights into the disturbances caused by high blood pressure during a short-term exposure (5 minutes) to low oxygen concentrations in a controlled environment (i.e. carbon dioxide concentration was kept constant and blood pressure to hypoxia did not change). Looking into these responses during a longer exposure to hypoxia in daily life situations such as high altitude exposure or sleep apnoea is also necessary to confirm these findings.

Dr Igor A Fernandes, the lead investigator of the project, also highlights the importance to understand the mechanisms that maintain brain and skeletal muscle oxygen supply of healthy individuals in hypoxic conditions and how high blood pressure affects them:

"We are interested in determining how high blood pressure impacts the mechanisms by which hypoxia increases brain and skeletal muscle blood supply and oxygen delivery. This will enable us to investigate how to prevent their deterioration or restore their adequate functioning."

Identifying frailty in surgical patients, especially those without apparent disability, will help predict risk of adverse events and repeat hospitalizations, according to research in CMAJ (Canadian Medical Association Journal).

Few studies have looked at the risk of further health care use associated with frailty in older surgical patients.

Researchers looked at data on 308 older patients with a median age of 75 years (45% were women) who underwent abdominal surgery at two hospitals in Alberta. Almost three-quarters of them had been living at home independently. Based on the Canadian Study of Health and Aging Clinical Frailty Scale, 23% of patients were classified as "well," 55% "vulnerable," and 22% as "frail." One-third of patients were readmitted or died within 6 months. Both vulnerable and frail patients were at higher risk of readmission or death within 30 days and 6 months, independent of other clinical and surgical factors. By 6 months, the degree of frailty predicted increasing risk of readmission or death, with frail patients at greatest risk.

"Identifying frailty in surgical patients will help to predict which patients are at high risk of adverse outcomes, thus improving patient and family discussions and targeting patients for enhanced postoperative care," writes Dr. Rachel Khadaroo, University of Alberta, Edmonton, Alberta, with coauthors. "Moreover, the results of this study suggest that poor postoperative prognosis is not limited to the most severely frail patients, but that vulnerable patients without evident disability are also at higher risk of readmission or death after discharge."

In a related commentary, Dr. Olga Theou, Dalhousie University, Halifax, Nova Scotia, writes, "frailty can also be considered a useful outcome measure. It is a measure of overall health state and, arguably, a better predictor of adverse health outcomes than other individual health measures, although it is a dynamic process. Future research should focus on whether modifying clinical treatment plans can modify level of frailty or enable patients to recover to their level of frailty before surgery and admission to hospital."

Performing a comprehensive geriatric assessment may be a way to improve outcomes.

Philadelphia, Feb. 20, 2018 - Blacks have a higher incidence of stroke and stroke-associated disability than whites. However, few studies have evaluated racial differences in stroke before a diagnosis of atrial fibrillation (AF). A new report published in HeartRhythm examined stroke risk in the short term prior to a diagnosis of AF. Investigators determined that, although blacks have a lower risk of developing AF, blacks with AF have a significantly higher risk of stroke during this period compared with whites with AF.

Investigators assessed racial differences in ischemic and hemorrhagic strokes using data on more than 3,500 patients from the Penn Atrial Fibrillation Free (PAFF) study with incident AF and without any history of stroke. This enabled them to evaluate strokes that occurred in a short window of time prior to the clinical diagnosis of AF, as well as ischemic and hemorrhagic stroke risk after the diagnosis of AF. PAFF consists of nearly 57,000 patients from the University of Pennsylvania Health System who were free of AF or atrial flutter at the beginning of the study.

"Our study design was unique because we have a time point that represents the initial diagnosis of AF," explained senior author Rajat Deo, MD, MTR, Associate Professor of Medicine, Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. "A better understanding of the burden of AF before and after an ischemic stroke is important. Anticoagulation with newer agents such as novel oral anticoagulant (NOAC) medications could help mitigate the risk of a first stoke and recurrent events."

The study showed that nearly half of the ischemic strokes in this population (254/538) occurred within six months before the diagnosis of AF. In many cases stroke was the presenting symptom of AF. Analysis demonstrated that blacks with a new diagnosis of AF were 62 percent more likely to have had an ischemic stroke prior to AF diagnosis than whites who developed AF. In strokes that occurred after the diagnosis of AF, blacks had 67 percent higher and independent risk of developing an ischemic stroke compared with whites with AF.

"The clinical implications of these findings indicate that a more rigorous effort to identify individuals from the community with AF, for example by using mobile and wearable technologies, may result in a reduction in overall stroke burden. Further, any effort to enhance AF management across diverse populations is a critical area of public health importance. A widespread screening effort to diagnose subclinical AF may help to reduce the racial disparities observed in the incidence of stroke," commented Dr Deo.

In an accompanying editorial, Sumeet S. Chugh, MD, FHRS, from the Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, observed that an earlier study into reasons for geographic and racial differences in stroke reported a significantly lower awareness of AF and anticoagulation in blacks. The same study also showed that self-reported AF is a strong predictor of stroke that can be used interchangeably or in combination with electrocardiogram-detected AF in stroke risk prediction models.

"Dr. Deo and colleagues are to be congratulated for successfully bringing together the electronic data repositories of several hospitals to study their PAFF cohort," stated Dr. Chugh. "Their findings provide a strong impetus for implementing community-based efforts that address racial disparities in AF and stroke. Given what we already know, it is time to act on these disparities, while continuing to investigate other factors such as differential access to preventive healthcare and compliance with prescribed medications"

OAK BROOK, Ill. - An MRI breast imaging technique that requires no contrast agent, combined with sophisticated data analysis, could reduce the number of unnecessary breast biopsies, according to a new study appearing online in the journal Radiology.

Breast MRI currently is used to screen women at high risk of breast cancer and as a diagnostic adjunct to mammography. The examination relies on gadolinium-based contrast agents that need to be injected intravenously.

Researchers recently studied an alternative approach that eliminates the need for contrast agents in some cases by using diffusion-weighted imaging (DWI) measurements derived from MRI. The technique, known as diffusion kurtosis imaging, provides a picture of breast tissue on a microstructural level.

"Diffusion kurtosis imaging has been introduced in DWI to provide important information on tissue structures at a microscopic level," said study lead author Sebastian Bickelhaupt, M.D., from the German Cancer Research Center in Heidelberg, Germany. "Since malignant lesions disrupt the tissue structures at this level, diffusion kurtosis might serve as a relevant marker of changes."

Dr. Bickelhaupt, co-lead author Paul Jaeger, M.Sc., and colleagues evaluated a retrospective analysis of data collected from 222 women at two independent study sites. The women had suspicious findings on mammography that were classified under the Breast Imaging Reporting and Data System (BI-RADS) as BI-RADS 4 and 5 breast lesions. A BI-RADS 4 lesion is considered a suspicious abnormality, while a 5 is considered highly suspicious of malignancy. The women underwent DWI followed by biopsy.

For the analysis, a software algorithm was developed for lesion characterization, and imaging features were extracted using a kurtosis-based radiomics model. Radiomics is a rapidly growing field that enables the extraction of a large amount of quantifiable data from images.

In an independent test set of 127 women, the radiomics analysis reduced false-positive findings by 70 percent, while detecting 60 of 61 malignant lesions, or 98 percent.

"The model might help to lower the number of BI-RADS 4 lesions suspected of being cancer on the basis of screening mammography while retaining a high sensitivity similar to the sensitivity reported for biopsies themselves," Jaeger said.

Should the results hold in larger trials, the model has potential advantages in the clinic beyond its ability to reduce unnecessary biopsies in women with BI-RADS 4 lesions. The software algorithm makes the assessment reader-independent, ensuring that its accuracy is maintained across different imaging facilities.

The new approach is not intended to replace current contrast-enhanced breast MRI protocols in general, Dr. Bickelhaupt emphasized, but to expand the spectrum of options available for answering specific clinical questions.

"This might also improve the efficiency of reporting," he said.

New research on why the influenza vaccine was only modestly effective in recent years shows that immune history with the flu influences a person's response to the vaccine.

Low effectiveness of the flu vaccine is often blamed on problems with how the vaccine is designed and produced. Sometimes the flu strains chosen for the vaccine are a poor match for those that end up circulating in the public, especially in years when the H3N2 strain predominates. The majority of flu vaccines given around the world are also grown in eggs, which can cause the virus to mutate and differ from circulating strains, and thus become less protective.

In 2012-13, the H3N2 component of the flu vaccine was effective in just 39 percent of people. That season, public health officials believed that adaptations in egg-grown vaccines were the problem. But in a new study published this week in the journal Clinical Infectious Diseases, researchers from the University of Chicago, Harvard University and others show that poor immune responses, not egg adaptions, may explain the low effectiveness of the vaccine that year.

"Egg adaptations have variable effects," said Sarah Cobey, PhD, assistant professor of ecology and evolution at UChicago and lead author of the study. "Sometimes they matter and sometimes they don't, but what seems to make the most difference is immune history."

What's at play seems to be a phenomenon known as "original antigenic sin." Flu vaccines are designed to get the immune system to produce antibodies that recognize the specific strains of the virus someone may encounter in a given year. These antibodies target unique sites on the virus, and latch onto them to disable it. Once the immune system already has antibodies to target a given site on the virus, it preferentially reactivates the same immune cells the next time it encounters the virus.

This is efficient for the immune system, but the problem is that the virus changes ever so slightly from year to year. The site the antibodies recognize could still be there, but it may no longer be the crucial one to neutralize the virus. Antibodies produced from our first encounters with the flu, either from vaccines or infection, tend to take precedence over ones generated by later inoculations. So even when the vaccine is a good match for a given year, if someone has a history with the flu, the immune response to a new vaccine could be less protective.

This story may be complicated by an additional factor, which is that the vaccine could be inducing a weak immune response in many who receive it.

"We see that both vaccinated and unvaccinated people were infected with similar flu viruses and that the vaccine didn't elicit a strong immune response from most people in our study," said Yonatan Grad, MD, PhD, assistant professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health and co-author of the study.

Researchers often test the relationship between different flu strains, or how well infection or vaccination to one strain protects you from infection with another, in lab animals like ferrets. In 2012-13, ferrets immunized with the egg-adapted strain had an antibody response that reacted poorly with that season's circulating H3N2 strains. Thus, officials believed egg adaptations were the culprit that year.

But when Cobey, Grad and their colleagues analyzed blood samples from people who got vaccinated that year, they saw no differences in antibody responses to the vaccine or circulating strains. It seems that their immune systems didn't bother to recognize the differences from the egg mutations because they already recognized so many other sites on the vaccine strain.

"Imagine influenza viruses are like different makes and models of cars," said Grad. "The ferrets, which hadn't seen influenza before, learned to tell the difference between closely related strains-like telling the difference between a Honda Civic and a Toyota Camry. But people didn't distinguish between them and instead just saw cars."

That's not to say egg adaptations don't always matter. In a separate study from 2017, Cobey and a team led by researchers from the University of Pennsylvania found that egg adaptations did cause mismatches in the most common vaccine given in 2016-17, another rough season dominated by H3N2.

Egg adaptations may be a factor during this year's record-breaking flu season as well. H3N2 is again the predominant strain making people sick, and the most common vaccine is the same one from last year with its potentially problematic egg adaptations.

There is an alternative, however. New vaccines grown without eggs, either in insect cells or dog kidney cells, are much less prone to developing mutations that can make them less protective against the flu. Until now they have been more expensive, but the researchers hope continuing research will help shift the focus to these more effective vaccines.

"There hasn't been enough consumer and medical demand to shift to more effective vaccines," Cobey said. "Until recently, there also hadn't been as much research on the complexity and variation in the immune response to influenza."

"We need to do more basic research on how to induce responses to the right sites on the virus, and this will require us to understand original antigenic sin better," she said. "We also need to understand why the vaccine appears to be bad at eliciting responses in some people some of the time. Is there really no response, or are we just not looking in the right places?"

Clocking up just a few minutes at a time of any level of physical activity, including of light intensity, is linked to a lower risk of death in older men, suggests research published online in the British Journal of Sports Medicine.

Providing the recommended 150 minute weekly tally of moderate to physical activity is reached, total volume, rather than activity in 10 minute bouts, as current guidelines suggest, might be key, the findings indicate.

This lower level of intensity is also likely to be a better fit for older men, most of whose daily physical activity is of light intensity, say the researchers.

Current exercise guidelines recommend accumulating at least 150 minutes a week of moderate to vigorous physical activity in bouts lasting 10 or more minutes. But such a pattern is not always easy for older adults to achieve, say the researchers.

To find out if other patterns of activity might still contribute to lowering the risk of death, the researchers drew on data from the British Regional Heart Study.

This involved 7735 participants from 24 British towns, who were aged between 40 and 59 when the study stated in 1978-80.

In 2010-12, the 3137 survivors were invited for a check-up, which included a physical examination, and questions about their lifestyle, sleeping patterns, and whether they had ever been diagnosed with heart disease.

They were also asked to wear an accelerometer--a portable gadget that continuously tracks the volume and intensity of physical activity--during waking hours for 7 days. Their health was then tracked until death or June 2016, whichever came first.

In all, 1566 (50%) men agreed to wear the device, but after excluding those with pre-existing heart disease and those who hadn't worn their accelerometer enough during the 7 days, the final analysis was based on 1181 men, whose average age was 78.

During the monitoring period, which averaged around 5 years, 194 of the men died.

The accelerometer findings indicated that total volume of physical activity, from light intensity upwards, was associated with a lower risk of death from any cause.

Each additional 30 minutes a day of light intensity activity, such as gentle gardening or taking the dog for a walk, for example, was associated with a 17 percent reduction in the risk of death. This association persisted even after taking account of potentially influential lifestyle factors, such as sedentary time.

Whilst the equivalent reduction in the risk of death was around 33 percent for each additional 30 minutes of moderate to vigorous intensity physical activity a day, the benefits of light intensity activity were large enough to mean that this too might prolong life.

And there was no evidence to suggest that clocking up moderate to vigorous activity in bouts of 10 minutes or more was better than accumulating it in shorter bouts. Sporadic bouts of activity were associated with a 41 percent lower risk of death; bouts lasting 10 or more minutes were associated with a 42 percent lower risk.

Sporadic bouts seemed easier to achieve as two thirds (66%) of the men achieved their weekly total of moderate to vigorous physical activity in this way while only 16% managed to do so in bouts of 10 or more minutes.

Finally, there was no evidence to suggest that breaking up sitting time was associated with a lower risk of death.

This is an observational study so no firm conclusions can be drawn about cause and effect. And those who wore the accelerometer tended to be younger and have healthier lifestyles than those who didn't, so this might have skewed the results, say the researchers. Nor is it clear if the findings would be equally applicable to younger age groups or older women.

Nevertheless, the results could be used to refine current physical activity guidelines and make them more achievable for older adults, suggest the researchers.

Future guidance might emphasise that all physical activity, however modest, is worthwhile for extending the lifespan--something that is particularly important to recognise, given how physical activity levels tail off rapidly as people age, they point out.

"[The ] results suggest that all activities, however modest, are beneficial. The finding that [low intensity physical activity] is associated with lower risk of mortality is especially important among older men, as most of their daily physical activity is of light intensity," write the researchers.

"Furthermore, the pattern of accumulation of physical activity did not appear to alter the associations with mortality, suggesting that it would be beneficial to encourage older men to be active irrespective of bouts," they add.

Results from Innovative Phase 2 Tuberculosis Vaccine Trial Offer Potential for New BCG Revaccination Strategies, Hope For Subunit Vaccines

Study is the First "Prevention of Infection" Trial Conducted for Tuberculosis, the World's Leading Infectious Disease Killer

Results to Be Presented at the 5th Global Forum on TB Vaccines

NEW DELHI (February 19, 2018) --Aeras, a nonprofit organization dedicated to developing vaccines against tuberculosis (TB), today announced results from an innovative clinical trial that provides encouraging new evidence that TB vaccines could prevent sustained infections in high-risk adolescents. In a prevention-of-infection Phase 2 trial conducted in South Africa, revaccination with the Bacille Calmette-Guerin (BCG) vaccine significantly reduced sustained TB infections in adolescents. An experimental vaccine candidate, H4:IC31, also reduced sustained infections, although not at statistically significant levels. However, the trend observed for H4:IC31 is the first time a subunit vaccine has shown any indication of ability to protect against TB infection or disease in humans.

TB infections that developed during the study were determined using a QuantiFERON®-TB Gold in Tube (QFT-GIT) test, a commercially available blood test that helps diagnose TB infections. In the trial, individuals who tested negative for QFT-GIT were considered to not have a TB infection. The trial measured the rate by which individuals converted to QFT-GIT positive, implying evidence of TB infection. Those individuals who tested QFT-GIT positive consecutively over 6 months were considered to have a sustained infection.

The results will be presented at the 5th Global Forum on TB Vaccines in New Delhi, India.

According to the World Health Organization (WHO), about one-third of the world's population has what is called a latent TB infection, which means people have been infected by TB bacteria but are not (yet) ill with the disease and cannot transmit the disease. People infected with TB bacteria have a lifetime risk of falling ill with TB of 10 percent. People ill with TB can infect 10-15 other people through close contact over the course of a year. Without proper treatment, 45% of HIV-negative people with TB on average and nearly all HIV-positive people with TB will die.

Mark Hatherill, MD, Director of the South African Tuberculosis Vaccine Initiative (SATVI) at the University of Cape Town, and the study's principal investigator, said: "We are pleased to have performed the first-known randomized, placebo-controlled prevention-of-infection trial for TB and to have demonstrated that vaccination has the potential to reduce the rate of sustained TB infection in a high-transmission setting. While neither vaccine proved to be statistically significant in preventing an initial TB infection, we are extremely encouraged by the signals observed for both vaccines in preventing sustained TB infections. We believe the results from this novel trial design will provide significant scientific benefit to the field in understanding TB infection, and based on this positive signal, we look forward to testing the potential of such vaccines to prevent TB disease among uninfected adolescents in a larger, more traditional prevention-of-disease clinical trial."

The study evaluated H4:IC31 vaccination and BCG revaccination for safety, immunogenicity and the ability to prevent initial and sustained TB infections among healthy adolescents in the Western Cape Province of South Africa. H4:IC31 is an investigative subunit vaccine candidate being developed jointly by Aeras and Sanofi Pasteur, the vaccines business of Sanofi (EURONEXT: SAN) (NYSE: SNY), and the Statens Serum Institut. BCG is the only licensed tuberculosis vaccine available globally. The clinical trial was conducted at SATVI and at the Emavundleni Research Centre (part of the Desmond Tutu HIV Centre). It was funded by Sanofi Pasteur, the United Kingdom’s Department for International Development, The Bill & Melinda Gates Foundation and Aeras. The study was approved by the Medicines Control Council of South Africa and the relevant local independent ethics committees.

Linda-Gail Bekker, MD, PhD, a lead investigator for the trial, the Chief Operating Officer at the Desmond Tutu HIV Foundation and President of the International AIDS Society, said: "We would like to thank all the study participants and their families for participating in this novel clinical trial. We believe the results are important and warrant further investigation into other subunit vaccines and a reevaluation of BCG revaccination as a potential strategy to prevent TB in high-incidence countries. An effective TB vaccine remains an urgent global goal."

Jacqui Shea, PhD, CEO of Aeras, stated: "New TB vaccines are essential to end this deadly epidemic, especially with the rise of drug-resistant strains. In this innovative study, we not only observed important results for BCG, we also saw the first early efficacy signal against infection to be shown by a subunit TB vaccine candidate (H4:IC31). Further, we established that the novel prevention-of-infection trial design has the potential to provide evidence of a biological signal earlier and at lower cost than traditionally designed TB vaccine prevention of disease efficacy studies. The data collected will inform the next series of clinical studies as well as enable the search for correlates of protection against sustained infection. Later this year, Aeras and its partners look forward to announcing primary results from a Phase 2b prevention of disease trial with M72/AS01E, another subunit vaccine candidate, and to commencing two Phase 2 clinical trials with an additional, promising subunit vaccine candidate."

Study Design and Results for H4:IC31 Vaccination and BCG Revaccination

The study involved 990 HIV-negative, healthy adolescents (12 to 17 years of age) who had been vaccinated as infants with BCG. All participants were randomized evenly into three study arms: placebo, H4:IC31, or BCG revaccination. All participants were screened to ensure they were not infected with Mycobacterium tuberculosis (Mtb) prior to vaccination in the study. At the outset of this innovative proof-of-concept study, statistical significance was set at one-sided p

The data showed that both vaccines appeared to be safe and produced an immune response in the adolescents studied. No vaccine-related serious adverse events were reported in the study, and the most common vaccine-related adverse event was injection site swelling in BCG revaccinated participants, typical for BCG vaccination.

For the primary efficacy endpoint, 134 participants tested positive for an initial Mtb infection as measured by QFT-GIT conversion from negative to positive (placebo=49; BCG=41; H4:IC31=44). When compared to placebo, neither vaccine achieved statistical significance in preventing an initial QFT-GIT conversion. Observed vaccine efficacy was 20.1% (p=0.15) for BCG revaccination and 9.4% (p=0.32) for H4:IC31.

For the secondary efficacy endpoint, 82 participants exhibited a sustained QFT-GIT conversion lasting at least 6 months following initial conversion (placebo=36; BCG=21; H4:IC31=25). These participants were evaluated to see if they would revert to negative as measured by the QFT-GIT test. In the BCG revaccination arm, the vaccine efficacy for preventing a sustained infection was 45.4% (p=0.013) and in the H4:IC31 arm the vaccine efficacy was 30.5% (p=0.08).

1. Hydroxychloroquine no more effective than placebo for relieving osteoarthritis hand pain

These findings do not support off-label use of hydroxychloroquine in patients with hand osteoarthritis

Abstract: http://annals.org/aim/article/doi/10.7326/M17-1430

Editorial: http://annals.org/aim/article/doi/10.7326/M18-0035

URLs go live when the embargo lifts

Hydroxychloroquine is no more effective than placebo for relieving moderate to severe hand pain and radiographic osteoarthritis. The findings of a randomized trial are published in Annals of Internal Medicine.

Symptomatic hand osteoarthritis affects up to 31 percent of adults over the age of 70 and up to 15 percent of those over the age of 60. The pain can be debilitating and few therapies are effective. As such physicians seek alternatives to improve quality of life for patient suffering from hand osteoarthritis. Hydroxychloroquine has been used as an off-label treatment, but data on its efficacy is sparse.

Researchers from the Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR Leeds Biomedical Research Centre randomly assigned 248 participants with symptomatic and radiographic hand osteoarthritis to either hydroxychloroquine (200 to 400 mg) or placebo for 12 months with ongoing usual care. The goal was to determine the effectiveness of hydroxychloroquine versus placebo as an analgesic treatment. At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group. The authors concluded that hydroxychloroquine was no more effective than placebo for pain relief. According to the researchers, these findings do not support the current practice of off-label use of hydroxychloroquine in patients with hand osteoarthritis. The researchers also noted that a lot of hand pain may be caused by tendon problems, rather than arthritis, which hydroxychloroquine would not have helped.

Note: For an embargoed PDF, please contact Angela Collom. To interview the lead author, Sarah R. Kingsbury, PhD, please contact David Lewis at D.Lewis@leeds.ac.uk.

2. New guidelines offer recommendations for diagnosis and treatment of CKD-MBD

Abstract: http://annals.org/aim/article/doi/10.7326/M17-2640

URLs go live when the embargo lifts

The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update provides revisions to 15 recommendations for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). A synopsis of the guidelines is published in Annals of Internal Medicine.

CKD is defined as abnormalities in kidney structure or function that are present for more than 3 months and have health implications. As kidney function decreases, marked changes in bone mineral metabolism occur, resulting in increased risk for fractures, cardiovascular disease, and overall mortality.

To assist clinicians in caring for patients with CKD-MBD, the 2017 guideline update provides recommendations for diagnosis of bone abnormalities in CKD-MBD, treatment of CKD-MBD by decreasing serum phosphate levels and maintaining serum calcium levels, treatment of parathyroid hormone abnormalities in CKD-MBD, treatment of bone abnormalities using antiresorptive agents and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease. The target audience for the synopsis includes nephrologists, primary care physicians, and other health professionals caring for adults with CKD or those receiving dialysis.

Media contacts: For an embargoed PDF, please contact Angela Collom. To interview the lead author, Mary B. Leonard, MD, MSCE, please contact Ruthann Richter at richter1@stanford.edu.

3. Complex government-mandated hospital performance measure not supported by evidence

Abstract: http://annals.org/aim/article/doi/10.7326/M17-2947

Editorial: http://annals.org/aim/article/doi/10.7326/M18-0290

URLs go live when the embargo lifts

Evidence supporting the use of a complex government-mandated hospital performance measure does not hold up to scientific rigor. Findings from a systematic evidence review are published in Annals of Internal Medicine.

The Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) is a hospital performance measure introduced by the Centers for Medicare & Medicaid Services (CMS). It requires clinicians perform up to 7 interventions, and as many as 141 tasks and 3 hours to document for a single patient. Hospitals will be forced to fully adopt this complex performance measure or jeopardize reimbursement and accreditation. CMS uses published criteria to grade the evidence supporting its performance measures. To be considered high- or moderate-level evidence, studies must be free of confounders and have low risk of bias.

Researchers from the National Institutes of Health searched databases for all available scientific evidence and examined whether moderate- or high-level evidence shows that SEP-1 or five of its hemodynamic interventions improve survival in adults with sepsis. They found 20 published studies addressing this question. These were mostly observational studies (n=15) subject to selection bias and not randomized controlled trials. Only one single-center, observational study reported lower in-hospital mortality after implementation of the SEP-1 bundle. Sixteen studies, again mostly observational (n=14), reported increased survival with serial lactate measurements or 30-mL/kg fluid infusions, which are part of the mandate. None of these 17 studies were free of confounders or at low risk of bias. No studies showed that other investigated hemodynamic interventions improved survival.

According to the researchers, these findings suggest that CMS should examine its performance measure approval process to determine how it adopted interventions lacking evidence meeting the agency's own criteria and how it can improve this process in the future.

Media contacts: For an embargoed PDF, please contact Angela Collom. To interview the corresponding author, Peter Q. Eichacker, MD, please email Dr. Eichacker directly at peichacker@mail.cc.nih.gov or call 301-402-2914.

4. Treatment-free remission of chronic myeloid leukemia is possible following second-line nilotinib

Abstract: http://annals.org/aim/article/doi/10.7326/M17-1094

URLs go live when the embargo lifts

Treatment-free remission seems to be achievable in patients with chronic myeloid leukemia (CML) who have achieved sustained deep molecular response (DMR) after discontinuation of second-line nilotinib therapy. Results from a Phase 2, open-label study are published in Annals of Internal Medicine.

Tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, and bosutinib, have dramatically improved outcomes for patients with CML. Treatment-free remission, or stopping TKI therapy without loss of response, is an emerging treatment goal for patients with CML in chronic phase. Potential benefits of treatment-free remission include relief of treatment side effects, reduced risk for long-term TKI toxicity, and the ability to plan a family. In the STIM1 (Stop Imatinib 1) trial, 38 percent of patients with sustained DMR while receiving long-term imatinib treatment had molecular recurrence-free survival at 5 years. These results confirm the feasibility of treatment-free remission after sustained DMR in patients receiving TKI.

Researchers from South Australian Health and Medical Research Institute studied 163 patients who had achieved sustained DMR after switching from imatinib to nilotinib to determine if they could maintain remission without TKI. They found that most of those patients maintained treatment-free remission for 48 weeks or longer. In addition, for those who do not achieve sustained DMR with imatinib, switching to nilotinib may enable more patients to become eligible for treatment-free remission.

Media contacts: For an embargoed PDF or author contact information, please contact Angela Collom.

TORONTO, Feb. 19, 2018--A new study published today found that a newly discovered gene helps grow blood vessels when it senses inadequate blood flow to tissues.

The research, published online in the prestigious Proceedings of the National Academy of Sciences, was led by Dr. Philip Marsden, a clinician scientist in the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, and Dr. Jeffrey Man, a researcher in his lab.

Dr. Marsden and his team set out to better understand how blood vessels regulate the delivery of blood and nutrients to tissues and organs, and how to improve healing after injury caused by inadequate blood flow.

The findings are important because they could help scientists better understand cardiovascular diseases such as heart disease and strokes, which result from inadequate blood flow. The information could also lead to advances in efforts to grow replacement organs or to block blood vessels in tumours.

Dr. Marsden's lab studies endothelial cells, the cells that line the inside of blood vessels. For this study they looked at a newly described group of genes called long non-coding RNAs, or lncRNAs. RNA, or ribonucleic acid, is found in all cells and it has traditionally been thought that its main job was to carry instructions from genes in DNA to make proteins. But lncRNAs have other roles, including determining the eventual function that individual cells will play in an organism. Studying lncRNAs gives researchers opportunities to find new markers and tests to help make diagnoses for patients.

Dr. Man said this study was the first to identify which lncRNAs are more enriched with endothelial cells compared to other cell types. They plan to make the list public for other researchers to use.

They then discovered that one of those lncRNAs, called STEEL (for spliced-transcript endothelial-enriched lncRNA) was the one that sensed inadequate blood flow in microscopic blood vessels.

"What is really interesting is that STEEL helps our body respond to inadequate blood flow by growing more blood vessels," Dr. Man said.

"These results show that our bodies are really finely tuned to perform, just as we need them to, and also demonstrate that disruptions to this fine balance can cause problems. This data can be used to improve our understanding of blood vessel diseases and help us find ways to improve healing and recovery after injury."

This study also made some findings that could be helpful for researchers studying lncRNAs in general, Dr. Marsden said. This study is one of the early studies to assess on a large scale which and how many proteins can associate with an individual lncRNA.

LA JOLLA, CA--Asthma is a chronic inflammatory disease driven by the interplay of genetics, environmental factors and a diverse cast of immune cells. In their latest study, researchers at La Jolla Institute for Allergy and Immunology (LJI) identified a subset of T cells, whose frequency serves as early childhood immune signature that predicts the risk of developing asthma later on.

"We found what I would consider very strong biomarkers for those children who are most likely to develop asthma as they get older," says senior author Mitchell Kronenberg, Ph.D, president and chief scientific officer of La Jolla Institute. "Children who, at the age of one, had a higher frequency of so called MAIT cells appear to be less likely to develop asthma by the age of seven."

Consistent with the "hygiene hypothesis," which holds that increased microbial exposure in the first years of life is protective for asthma, the team's findings also indicate that the presence of house dust components that stimulate the innate immune system decreases asthma risk. "We are not advocating for dirt and we don't know enough about the microbiome to know which aspects are beneficial," says Kronenberg, "but as we learn more it is feasible that one day the protective components could even be taken in pill form."

The study, published in this week's online edition of the Journal of Immunology, was part of the larger Urban Environment and Childhood Asthma (URECA) study funded by the National Institutes of Health. Initiated in 2005, the study follows 560 families from four disadvantaged urban areas who are at high risk for asthma to uncover potential risk factors that contribute to increased asthma rate in children growing up in impoverished neighborhoods.

Postdoctoral researcher and co-first author Shilpi Chandra, Ph.D., and her colleagues were particularly interested in MAIT cells (short for mucosal-associated invariant T cells) and their brethren, invariant natural killer T (iNKT) cells. Both cell types are an integral part of the innate immune response, which reacts almost immediately to foreign invaders.

Unlike conventional T cells, which belong to the adaptive arm of the immune response and take a few days before they are fully trained on a single, specific protein fragment or peptide antigen, MAIT and iNKT cells recognize molecular components common to many microbes.

The team analyzed the frequency of different types of immune cells in blood collected from 110 one year-old study participants, the presence of immune-stimulatory components in the subjects' house dust and asked whether any of the factors correlated with an increased of asthma at age seven.

"We found certain immune signatures such as having more MAITs that are protective," says Chandra. "In humans MAIT cells are unique in that they are borne to make gamma interferon, which could help skew the immune system toward an asthma-protective Th1 immune response."

And while the absolute numbers of iNKT cells had no bearing on asthma risk, the iNKT cell antigenic content in house dust from subjects' houses did. "iNKT activity reflects a home environment with increased microbe exposure and therefore protection from asthma," says Shilpi.

New Rochelle, NY, February 15, 2018--China is helping to advance gene and cell therapy and genome editing research and clinical development by creating novel viral and nonviral vectors for gene delivery and innovative applications of CRISPR technology in a broad range of disease areas. An exciting and timely series of original research articles and commentaries documenting the progress, opportunities, and challenges in the Chinese research and biomedical communities is published in a groundbreaking new special issue of Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The articles are available free on the Human Gene Therapy website.

The Special Issue on Chinese Gene and Cell Therapy Research is led by Co-Guest Editors Yuquan Wei, MD, PhD, Professor and Director, National Key Laboratory of Biotherapy, West China Hospital, and Vice President of Sichuan University, Chengdu, and De-Pei Liu, MD, PhD, Professor and Former President of Beijing Union Medical College and Chinese Institute of Medical Research, Beijing, and features a comprehensive look at the latest gene therapy research and developments in China.

In the article entitled "Applications of Virus Vector-Mediated Gene Therapy in China," De-Pei Liu and coauthors from Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, highlight the contributions of Chinese researchers in modifying the main groups of viral vectors being used to develop gene therapies. The authors report on progress in China in the application of viral vector-based gene therapy in cancer and monogeneic, neurologic, cardiovascular, liver, and infectious diseases.

Xiawei Wei and coauthors from West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, present "Current Status of Nonviral Vectors for Gene Therapy in China." They describe the progress and challenges associated with efforts to optimize nonviral vectors using structural modifications and opportunities and hurdles related to clinical translation.

In the Clinical Review article "Consideration of Cellular Therapy Products in China," coauthors Chenyan Gao et al. from the China Food and Drug Administration (CFDA), Beijing, discuss the principles on which clinical review of cellular therapy, including CAR-T products in China are based. These include protection of the clinical trial population, pharmacodynamics, pharmacokinetics, dosing, safety, efficacy, and risk management.

Rare diseases research, diagnosis, and related development of new molecular treatments have been lacking in China and held back by inadequate definitions and best practices, orphan drug development, and biobanking to collect samples and genomic data. Shuyang Zhang and colleagues from Peking Union Medical College, National Rare Diseases Registry System of China, Digital China Health Technologies Co., and Rare Diseases Research Center, Chinese Academy of Medical Sciences, Beijing, describe the new opportunities to advance rare diseases medical research and healthcare in China in the article entitled "National Rare Diseases Registry System of China and Related Cohort Studies: Vision and Roadmap."

"This special issue, released coincident with the New Year in China, illustrates the tremendous scientific progress that has been made at certain leading institutions in China working in cell and gene therapy," says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA. "We hope that these particular focused commentaries can provide a roadmap for gene therapy scientists from other parts of the world to identify important achievements and opportunities for future collaboration."