Body

Paris, France - 31 Aug 2019: A low-cost text-messaging programme improves blood sugar control in patients with diabetes and coronary heart disease. That's the finding of the CHAT-DM randomised trial reported today at ESC Congress 2019 together with the World Congress of Cardiology (1) and published in Circulation: Cardiovascular Quality and Outcomes.(2)

Study author Dr Xiqian Huo of the Fuwai Hospital, Beijing, China said: "The effect in this study was not only statistically significant but also has the potential to be clinically relevant by reducing risk of diabetic complications and death."

"Capitalising on the exponential growth in mobile phone usage over the past decade, a simple text-messaging programme could increase the reach of diabetes self-management support," she added. "It may provide a means to better address the burgeoning healthcare demand-capacity imbalance."

CHAT-DM enrolled 502 patients from 34 clinics in China. In addition to usual care, patients were randomly assigned to the text messaging intervention or a control group for six months. The intervention group received six messages per week, at random times of day, from an automated system set up by the researchers. Topics included diabetes and coronary heart disease, glucose monitoring and control, blood pressure control, medication adherence, physical activity, and lifestyle recommendations on diet, foot care and emotional management. The control group received two thank you text messages per month.

At six months, blood glycated haemoglobin (3) (HbA1c) was significantly lower in the intervention group compared to control group (6.7% versus 7.2%). On average, HbA1c fell by 0.2% in the intervention group and rose by 0.1% in the control group - a difference of 0.3% between groups.

To reduce the complications of diabetes, the target HbA1c is less than 7%. Significantly more participants in the intervention group achieved the target (69.3%) compared to the control group (52.6%). The change in fasting blood glucose was larger in the intervention, compared to control, group (-0.5 versus 0.1 mmol/L, respectively).

Systolic blood pressure, low-density lipoprotein (LDL) cholesterol, body mass index, and self-reported physical activity did not differ between groups. The intervention was acceptable to participants, most of whom (97%) found the text messages useful, readable, and an appropriate method of contact.

While the study did not measure which text messages were most effective, Dr Huo said: "Lifestyle advice such as strict dietary control may have contributed to glycaemic improvements, together with reminders to monitor blood glucose regularly. The messages were designed to provide information and motivation, and help patients set goals and manage stress."

She added that the text messages were culturally sensitive - for example using traditional Chinese sayings and catchy rhyming. "Chinese people tend to prefer direct and structured counselling instructions rather than indirect and insight-oriented approaches, so motivational messages were practical, with real-life examples instead of abstract theories. Social and family-oriented goals were used more often than individual achievement to help improve health behaviours, consistent with cultural norms in China," added Dr Huo.

Dr Huo noted that sending text messages to patients in the intervention group with low baseline HbA1c was safe and did not result in further reduction in blood sugar levels or hypoglycaemia.

She concluded: "This study has important public health implications since patients with coronary heart disease and diabetes are at high risk for diabetes-related complications and death; achieving glycaemic control is a central pillar of high-quality care. Further investigation is needed, but this non-pharmacological intervention could serve as a powerful tool to transform worldwide delivery of health services and improve health across diverse populations."

Examples of text messages sent to the intervention group:

Diabetes is not terrible and there are many things you can do to prevent problems from diabetes, such as monitoring blood glucose, watching your diet, keeping fit, and taking pills regularly.

Afraid of testing blood glucose because it hurts? Try to test on the sides of your fingertips or rotate your fingers, which can help to minimise pain.

Taking diabetes medications or injecting insulin regularly can help control your blood glucose level. Forgetting to take your medication? Try to set a repeating alarm on your cell phone to remind you to take medication or insulin injection.

Try brisk walking - a convenient, safe and cost-effective way of exercising! It's good for your heart and will help control blood glucose.

Examples of text messages sent to the control group:

Thank you for participating in our study!

We appreciate your participation in this study. Please let us know when you change the phone number.

Paris, France - 31 Aug 2019: The European Society of Cardiology (ESC) Guidelines on diabetes, pre-diabetes and cardiovascular diseases are published online today in European Heart Journal,(1) and on the ESC website.(2) They were developed in collaboration with the European Association for the Study of Diabetes (EASD).

Professor Francesco Cosentino, ESC Chairperson of the guidelines Task Force and professor of cardiology at the Karolinska Institute and Karolinska University Hospital in Stockholm, Sweden said: "The emphasis of these guidelines is to provide state of the art information on how to prevent and manage the effects of diabetes on the heart and vasculature, with a focus on new data that has emerged since the 2013 document."

Professor Peter J. Grant, EASD Chairperson of the guidelines Task Force and professor of medicine at the University of Leeds, UK said: "Recent trials have shown the cardiovascular safety and efficacy of SGLT2 inhibitors and GLP-1 receptor agonists for type 2 diabetes. We provide clear recommendations here."

The global prevalence of diabetes continues to increase. It is predicted that more than 600 million individuals will develop type 2 diabetes worldwide by 2045, with around the same number developing pre-diabetes. Estimates state that diabetes affects 10% of populations in previously underdeveloped countries such as China and India, which are now adopting western lifestyles, and 60 million Europeans, of which half are undiagnosed.

"These figures pose serious questions to developing economies, where the very individuals who support economic growth are those most likely to develop type 2 diabetes and to die of premature cardiovascular disease," states the document.

Healthy behaviours are the mainstay of preventing cardiovascular disease. Lifestyle changes are now advised to avoid or delay the conversion of pre-diabetes states, such as impaired glucose tolerance, to diabetes. Physical activity, for example, delays conversion, improves glycaemic control and reduces cardiovascular complications.

The document states that moderate alcohol intake should not be promoted as a means to protect against cardiovascular disease. "There has been a long-standing view that moderate alcohol intake has beneficial effects on the prevalence of cardiovascular disease," said Prof Grant. "Two high-profile analyses have reported this is not the case and that alcohol consumption does not appear to be beneficial. On the basis of these new findings we changed our recommendations."

Self-monitoring of blood glucose and blood pressure is advocated for patients with diabetes to achieve better control. Data has emerged to implicate glucose variability in the causes of heart disease in diabetes. In addition, glucose variation at night is particularly linked with hypoglycaemia and deterioration in quality of life.

"This indicates that it is no longer appropriate to depend on occasional glucose measures to manage control, particularly in type 1 diabetes," said Prof Cosentino. "At the same time, flash technology has been developed which uses a small sensor worn on the skin to continuously monitor glucose levels. Similar arguments pertain to home blood pressure monitoring."

Statins are not recommended in diabetic women of childbearing potential and should be used with caution in young people. "We have no experience of the effects of 50 or 60 years of statin use in an individual and we do not advocate non-essential drugs in pregnancy when the potential adverse effects on the unborn child are unknown," explained Prof Grant.

Clinical trials on the cardiovascular safety of medications for type 2 diabetes have led to a paradigm shift in glucose-lowering treatment. Two groups of diabetes drugs - GLP-1 receptor agonists and gliflozins - showed cardiovascular safety and benefit in patients with diabetes who either already had heart disease and/or had multiple risk factors.

"Our main recommendation in the light of these findings is that GLP-1 receptor agonists and gliflozins should be used as first line treatment in type 2 diabetes patients with established cardiovascular disease or at high risk of cardiovascular disease," said Prof Cosentino.

Drugs that prevent blood clots - non-vitamin K antagonist oral anticoagulants, specifically rivaroxaban - have been reported to benefit peripheral vascular disease and should be considered in combination with aspirin for patients with diabetes who have poor circulation in the legs.

PCSK9 inhibitors are advised for patients with diabetes at very high risk of cardiovascular disease who do not achieve low-density lipoprotein (LDL) cholesterol goals despite treatment with statins. In these patients, a more ambitious LDL cholesterol target of below 1.4 mmol/L is recommended.

Lifestyle advice for patients with diabetes and pre-diabetes

Quit smoking.

Reduce calorie intake to lower excessive body weight.

Adopt a Mediterranean diet supplemented with olive oil and/or nuts to lower the risk of cardiovascular events.

Avoid alcohol.

Do moderate-to-vigorous physical activity (a combination of aerobic and resistance exercise) at least 150 minutes per week to prevent/control diabetes - unless contraindicated, such as in patients with severe comorbidities or limited life expectancy.

Paris, France - 31 Aug 2019: The detrimental impact of pollution and noise on patients with chronic coronary syndromes is highlighted for the first time in European Society of Cardiology (ESC) Guidelines published online today in European Heart Journal,(1) and on the ESC website.(2)

Professor Juhani Knuuti, Chairperson of the guidelines Task Force and director of the Turku PET Centre, Finland said: "Air pollution and environmental noise increase the risk of heart attack and stroke, so policies and regulations are needed to minimise both. Patients with chronic coronary syndromes should avoid areas with heavy traffic congestion and may consider wearing a respirator face mask. Air purifiers with high efficiency particulate air filters can be used to reduce indoor pollution."

The document covers chronic coronary syndromes and is a continuation of the previous stable coronary artery disease (CAD) guidelines. "This reflects the fact that CAD can be acute (covered in separate guidelines) or chronic and both are dynamic conditions," said Professor William Wijns, Chairperson of the guidelines Task Force and professor in interventional cardiology at the Lambe Institute for Translational Medicine, Galway, Ireland. "Therapy is lifelong and aimed at preventing progression of the disease and cardiac events such as heart attacks."

Lifestyle is given stronger emphasis than in the previous document, since unhealthy behaviours will have contributed to the development of a chronic coronary syndrome and changes can prevent it worsening.

Patients should stop smoking, avoid passive smoking, eat a diet high in vegetables, fruit, and whole grains, and limit saturated fat and alcohol. A healthy body weight is advised, plus 30 to 60 minutes of moderate physical activity most days. Sexual activity is low risk for patients with no symptoms (e.g. chest pain). An annual flu vaccination is promoted, particularly for elderly patients, to prevent heart attacks and premature death.

Patients with CAD have a twofold higher risk of mood and anxiety disorders compared to those without. Stress, depression, and anxiety are linked to worse outcomes and make it difficult to improve lifestyle and adhere to medications. Counselling is encouraged for those with depression, anxiety, or stress.

Cognitive behavioural therapy can also help patients achieve a healthy lifestyle - for example supporting patients to set realistic goals, self-monitor, harness support from friends and family, and plan how to implement changes and deal with difficult situations. In addition, some patients - for example after an acute event or the morbidly obese - should be referred to exercise-based cardiac rehabilitation and receive assistance from a multidisciplinary team including cardiologists, GPs, dietitians, physiotherapists, psychologists, and pharmacists.

Patients with chronic coronary syndromes require medication to alleviate symptoms and prevent acute events such as heart attack and cardiac death. Statins are recommended in all patients and antithrombotic drugs in high-risk patients, while other drugs such as angiotensin-converting enzyme (ACE) inhibitors are for specific groups.

"Patients need to take medications as prescribed even if they have no symptoms," said Prof Knuuti. "Promoting behaviour change and medication adherence should be part of each appointment with GPs or specialists including nurses and cardiologists."

Revascularisation to open blocked arteries is an important therapy for some patients, such as those at high risk of poor outcomes and those whose symptoms are not controlled through lifestyle and drugs.

Diagnosis of chronic coronary syndromes has evolved significantly since the last document. The six most frequently encountered clinical scenarios are outlined:

Those with suspected CAD and stable chest pain (angina) or shortness of breath.

Patients without symptoms or with stable symptoms less than one year after an acute coronary syndrome or with recent revascularisation.

Patients with and without symptoms more than one year after initial diagnosis or revascularisation.

Patients with new onset of heart failure or left ventricular dysfunction and suspected CAD.

Those with chest pain (angina) and suspected vasospastic or microvascular disease.

Asymptomatic patients in whom CAD is detected at screening
.

Prof Wijns said: "Each of these scenarios requires different diagnostic and therapeutic approaches. But in general, treatment of a chronic coronary syndrome demands long-lasting healthy habits, medication adherence, and interventions in selected patients."

Paris, France - 31 Aug 2019: Microorganisms in the body may contribute to destabilisation of coronary plaques and subsequent heart attack, according to late breaking research presented today at ESC Congress 2019 together with the World Congress of Cardiology.(1)

The study found that unlike gut bacteria, the bacteria in coronary plaques were pro-inflammatory. In addition, patients with acute coronary syndrome (heart attack) had different bacteria in their guts compared to patients with stable angina.

Diet, smoking, pollution, age, and medications have a major impact on cell physiology, the immune system, and metabolism. Previous research indicates that these effects are mediated by microorganisms in the intestinal tract. This study investigated the contribution of the microbiota to the instability of coronary plaques.

The study enrolled 30 patients with acute coronary syndrome and ten patients with stable angina. The researchers isolated gut bacteria from faeces samples. Coronary plaque bacteria were extracted from angioplasty balloons.

Comparison of microbiota in faeces and coronary plaques revealed a different composition in the two sites. While faecal bacteria had a heterogeneous composition, and a pronounced presence of Bacteroidetes and Firmicutes, coronary plaques primarily contained microbes with pro-inflammatory phenotypes belonging to Proteobacteria and Actinobacteria.

First author Eugenia Pisano, of the Catholic University of the Sacred Heart, Rome, Italy said: "This suggests a selective retention of pro-inflammatory bacteria in atherosclerotic plaques, which could provoke an inflammatory response and plaque rupture."

The analyses also revealed differences in gut microbiota between the two groups of patients. Those with acute coronary syndrome had more Firmicutes, Fusobacteria and Actinobacteria, while Bacteroidetes and Proteobacteria were more abundant in those with stable angina.

Ms Pisano said: "We found a different make-up of the gut microbiome in acute and stable patients. The varying chemicals emitted by these bacteria might affect plaque destabilisation and consequent heart attack. Studies are needed to examine whether these metabolites do influence plaque instability."

She noted that to date, research has not convincingly shown that infections and the ensuing inflammation are directly involved in the process of plaque instability and heart attack onset. As an example, antibiotics against Chlamydia Pneumoniae failed to reduce the risk of cardiac events.

But she said: "While this is a small study, the results are important because they regenerate the notion that, at least in a subset of patients, infectious triggers might play a direct role in plaque destabilisation. Further research will tell us if antibiotics can prevent cardiovascular events in certain patients."

Ms Pisano concluded: "Microbiota in the gut and coronary plaque could have a pathogenetic function in the process of plaque destabilisation and might become a potential therapeutic target."

Memphis, Tenn. - Transplantation of kidneys from Hepatitis C-infected donors to uninfected recipients is safe and can be successfully implemented as a standard of care, according to an observational study by physicians at the University of Tennessee Health Science Center and the James D. Eason Transplant Institute at Methodist University Hospital.

The practice, which has been tested in two smaller clinical trials, could greatly expand the number of kidneys available for transplantation and reduce wait times for donors, said Miklos Z. Molnar, MD, PhD, FEBTM, FERA, FASN, associate professor of Medicine at UTHSC, transplant nephrologist at the James D. Eason Transplant Institute, and director of the Transplant Nephrology Fellowship program at UTHSC. Dr. Molnar is the principal author of the study published by the American Journal of Transplantation.

In current practice, Hepatitis C-infected kidneys are transplanted only to patients already infected with the disease, Dr. Molnar said. The number of these available kidneys greatly exceeds the infected population. As a result, up to 1,000 Hepatitis C-infected kidneys or more are discarded annually.

"Our thought was using these kidneys, which are usually pretty good, other than the Hepatitis C," he said.

The Memphis team began its study in March 2018. To date, more than 80 uninfected recipients have received Hepatitis C-infected kidneys. The paper cites 53 patients, since the remainder are too soon after transplant to evaluate fully.

All patients consented to the surgery in three separate steps, after being made aware that by receiving an infected kidney, they would be infected with Hepatitis C. All were successfully transplanted, and after receiving 12 weeks of antiviral therapy, show no signs of Hepatitis C and are considered cured. "We did not lose any patients, but there were some unexpected complications," Dr. Molnar said. High volume of BK virus, common after transplantation and generally treatable, was evidenced in a number of the recipients.

While this factor will demand further research, Dr. Molnar said the study results are positive for patients in need of transplant. "These people would not get this offering (a transplant) without these kidneys," he said. "If you're willing to accept these kidneys, the waiting time can go down by two years."

The five-year survival rate on dialysis is 50 percent, Dr. Molnar said. "We are losing 10 percent of the patients every year on dialysis."

Dr. Molnar said the study indicates that transplantation of Hepatitis C-infected kidneys to Hepatitis C-negative recipients has potential to become the standard of care in the United States. "Otherwise, the patients would be on dialysis and die," he said. "These patients have good kidney graft function. The transplantation of Hep C-infected kidney to non-Hep C-infected recipients can be done and should be done."

Director of the Transplant Institute James Eason, MD, said, "This is a landmark paper outlining a novel approach to using kidneys, that would otherwise be discarded, to save more lives."

Bottom Line: Physicians at primary care appointments were more likely to prescribe opioids for pain later in the day and as appointments ran more behind schedule, although the absolute difference in the prescribing rate across the day was modest in this analysis of electronic health records. The observational study included 678,319 primary care appointments for patients with a new painful condition who hadn't received an opioid prescription within the past year. The likelihood that an appointment resulted in an opioid prescription increased from 4% in the first three appointments of the day to 5.3% later on at the 19th to 21st appointments; and from 4.4% for appointments running less than 10 minutes late to 5.2% for appointments at least 60 minutes late. Similar patterns weren't observed for prescriptions for nonsteroidal anti-inflammatory drugs and referrals to physical therapy. Limitations of the study include other unobserved reasons patients may be prescribed opioids.

(doi:10.1001/jamanetworkopen.2019.10373)

Editor's Note: The study includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

For women of average weight in Western countries, five years of menopausal hormone therapy (MHT), starting at age 50 years, would increase breast cancer incidence from age 50 to 69 years by about one additional case in every 50 users of oestrogen plus daily progestogen MHT, one in every 70 users of oestrogen plus intermittent progestogen MHT, and one in every 200 users of oestrogen-only MHT.

After ceasing MHT, some excess risk persists for more than 10 years - the size of this risk depended on the duration of previous use. If a woman had used MHT for less than a year, however, there was little excess risk thereafter.

An international collaboration, using data from more than 100,000 women with breast cancer from 58 epidemiological studies worldwide, has found that using MHT is associated with an increased risk of breast cancer, and that some increased risk persists for more than a decade after use stops.

The findings, published in The Lancet, suggest that all types of MHT, except topical vaginal oestrogens, are associated with increased risks of breast cancer, and that the risks are greater for users of oestrogen-progestagen hormone therapy than for oestrogen-only hormone therapy. For oestrogen-progestagen therapy, the risks were greater if the progestagen was included daily rather than intermittently (eg, for 10-14 days per month).

Women tend to begin MHT at around the time of the menopause, when ovarian function ceases, causing oestrogen levels to fall substantially, progesterone levels to fall to near zero, and some women to experience serious hot flushes and discomfort that can be alleviated by MHT. Although regulatory bodies in Europe and the USA recommend MHT be used for the shortest time that is needed, some clinical guidelines recommended less restrictive prescribing.

In Western countries, MHT use increased rapidly during the 1990s, halved abruptly in the early 2000s, then stabilised during the 2010s. Currently, there are about 12 million users in Western countries - about six million in North America and six million in Europe (including one million in the UK). [1] Although some are short-term users, about five years of use is now common, whereas about 10 years of use used to be common.

A previous meta-analysis of the worldwide evidence found that current and recent users of MHT were at an increased risk of breast cancer, but insufficient information was available about the effects of different types of MHT or about long-term risks after MHT use had ceased.

Co-author Professor Valerie Beral from the University of Oxford, UK, says: "Our new findings indicate that some increased risk persists even after stopping use of menopausal hormone therapy. Previous estimates of risks associated with use of menopausal hormone therapy are approximately doubled by the inclusion of the persistent risk after use of the hormones ceases." [2]

In the new study, the authors brought together and re-analysed centrally all the eligible prospective studies from 1992-2018 that had recorded MHT use and then monitored breast cancer incidence, with 108,647 women subsequently developing breast cancer at an average age of 65 years [3]. They looked at the type of MHT last used, duration of use, and time since last use in these women.

Among women who developed breast cancer in the prospective studies, half had used MHT, the average age at menopause was 50 years and the average age at starting MHT was also 50 years. The average duration of use of MHT use was 10 years in current users and seven years in past users.

For women of average weight in Western countries who have never used MHT, the average risk of developing breast cancer over the 20 years from ages 50 to 69 inclusive is about 6.3 per 100 women (ie, about 63 in every 1,000 women who never use MHT develop breast cancer during the 20 years from ages 50 to 69).

The authors estimate that for women with five years use of the three main types of MHT, starting at age 50, the 20-year breast cancer risks from ages 50 to 69 inclusive would increase from 6.3 per 100 in never-users to:

8.3 per 100 in users of oestrogen plus daily progestagen (ie, 83 in every 1,000 users would develop breast cancer) - an absolute increase of 2 per 100 users (one in every 50 users);

7.7 per 100 in users of oestrogen plus intermittent progestagen (ie, 77 in every 1,000) - an absolute increase of 1.4 per 100 users (one in every 70 users);

6.8 per 100 in users of oestrogen-only (ie, 68 in every 1,000 users) - an absolute increase of 0.5 per 100 users (one in every 200 users).

Increases in breast cancer risk would be about twice as great for women who use MHT for 10 years rather than 5 years (see Figure 7).

The increases in the 20-year risk include the increased risks both during the five years when MHT is being used and during the 15 years after use had stopped. The excess risks during and after MHT use depended on how long MHT had been used for (see Figures 2 and 7 - for MHT taken for five years, about half of the excess risk would be during the five years of current use, and the other half would be during the following 15 years after a woman stopped taking MHT). There was little excess risk after using any form of MHT for less than a year.

Co-author Professor Gillian Reeves from the University of Oxford, UK, says: "Use of menopausal hormone therapy for 10 years results in about twice the excess breast cancer risk associated with 5 years of use. But, there appears to be little risk from use of menopausal hormone therapy for less than one year, or from topical use of vaginal oestrogens that are applied locally as creams or pessaries and are not intended to reach the bloodstream." [2]

Overall, MHT use was much more strongly associated with oestrogen-receptor-positive (ER+) breast cancer than with other types of breast cancer (as hormonal factors mainly affect ER+ breast cancer). The increased risk of developing ER+ breast cancer accounted for most of the excess breast cancer risk associated with MHT (see Figure 5).

As menopause usually occurs in women's 40s and 50s, almost all the evidence was for women who had had their menopause and started MHT in this age range. The proportional increases in risk were similar for women starting MHT at ages 40-44, 45-49, 50-54 and 55-59. The risks appeared, however, to be somewhat attenuated among the few who had started using MHT after age 60 years (see Figure 3). The risks were also attenuated by adiposity (particularly for oestrogen-only MHT, which had little effect in obese women: figures 6-7).

The findings were robust to variations in the analytical methodology used. Nor did they differ by family history of breast cancer, or by any characteristics of the women (other than obesity).

The authors note that a limitation of the currently available epidemiological evidence is that there is still not enough information on women who had used MHT for long periods and had stopped more than 15 years ago. In addition, they did not collect information on breast cancer mortality, although evidence is cited that the results for breast cancer mortality would parallel the results for incidence [4].

Writing in a linked Comment, Dr Joanne Kotsopoulos, Women's College Hospital, Canada, notes that it is important to estimate accurately the increased risks of breast cancer from MHT. She says: "Clinicians must heed the message of this study but also to take a rational and comprehensive approach to the management of menopausal symptoms, with careful consideration of the risks and benefits of initiating MHT for each woman. This might be dependent on severity of the symptoms, contraindications for MHT [...], and BMI, and could take into account patient preference."

A new method for permanently marking cells infected with chikungunya virus could reveal how the virus continues to cause joint pain for months to years after the initial infection, according to a study published August 29 in the open-access journal PLOS Pathogens by Deborah Lenschow of Washington University School of Medicine in St. Louis, and colleagues. According to the authors, uncovering the mechanisms for long-term disease could aid in the development of treatments and preventative measures for this incapacitating, virally induced chronic arthritis.

Chikungunya virus is spread by mosquitoes and causes severe joint and muscle pain. Approximately 30 to 60 percent of people infected with the virus continue to experience joint pain for months to years after the initial infection. However, the cause of this persistent joint pain is unclear, as replicating virus cannot be detected during the chronic phase. To address this question, Lenschow and colleagues developed a reporter system to permanently mark cells infected by chikungunya virus.

Using this system, they show in mice that marked cells surviving chikungunya virus infection are a mixture of muscle and skin cells that are present for at least 112 days after initial virus inoculation. Treatment of mice with an antibody that blocks chikungunya virus infection reduces the number of marked cells in the muscle and skin. Moreover, surviving marked cells contain most of the persistent chikungunya virus RNA. Taken together, the findings provide further evidence for musculoskeletal cells as targets of chikungunya virus infection in the acute and chronic stages of disease. According to the authors, this reporter system represents a useful tool for identifying and isolating cells that harbor chronic viral RNA in order to study the mechanisms underlying chronic disease.

"Persistent CHIKV RNA can be detected in human and animal models but no one has been able to identify where the RNA resides due to insensitive techniques," adds Lenschow. "Using our reporter system we have demonstrated that cells can survive CHIKV infection, and these cells harbor most of the persistent RNA. Since many believe that this persistent RNA contributes to chronic arthritis, this system will be a useful tool to study the mechanisms underlying chronic disease."

BOSTON- Opioid-related deaths continue to take the lives of thousands in the U.S. each year, with non-fatal opioid overdoses as a significant risk factor for a subsequent fatal overdose. Post-overdose interventions are emerging in affected communities, using what support systems are available to assist in the program design.

Survivors often do not seek treatment or overdose risk reduction services immediately after an overdose for many reasons, including shame and stigma, and lack of referrals to substance use treatment.

In a scoping review article published in Preventive Medicine, Sarah M. Bagley, MD, MSc, medical director of the CATALYST (Center for Addiction Treatment for Adolescents/Young adults who use Substances) Clinic and addiction specialist at Boston Medical Center's Grayken Center for Addiction, provides an overview about the emerging prevalence of post-overdose intervention programs in the U.S. and the variety of methods that communities and states are using based on availability of resources and support.

For the review, researchers examined articles published between 1999 and January 2019 that specifically described a specific post-overdose program. A total of 27 unique programs were identified for qualitative synthesis, which were organized into five categories based on timing, setting, and collaborations - emergency department-based, emergency department and home-based, home and/or overdose venue-based, mobile/not site-specific outreach, and diversion programs.
Some of the key takeaways from the review are:

Nine post-overdose programs operated directly out of the emergency department

18 programs provided post-overdose support in additional ways:

Three were operated both in the ED and home setting

Four were through mobile means or non-site specific

One was through law enforcement diversion, offering quick connections into treatment

10 were based in the community where follow-up occurred in the homes or venues where the overdose took place

Individuals were either approached while still in the ED for a non-fatal overdose or within one week of discharge; follow-up usually occurred between two and seven days

Many programs rely on collaboration between fire departments, law enforcement, emergency medical services, and public health departments to generate lists for those requiring follow-up post-overdose

Follow-ups typically involved a police/fire/sheriff's officer and health clinician or harm reduction specialist, including support and referrals for friends and family

Many programs were peer-based - found to be effective in other chronic illness programs due to greater comfort and more credibility based on a shared experience

"We are at a time when post-overdose programs are imperative to supporting people who are struggling with opioid use disorder," said Bagley, who is also an assistant professor of medicine and pediatrics at Boston University School of Medicine. "It is important to engage individuals in care after they have survived an overdose so that we can provide the services and support necessary to reduce the risk of future overdose and prevent opioid-related fatalities in the U.S."

As more peer-based programs are implemented, further research should follow the role of collective responsibility with overdose risk reduction and treatment engagement. In addition, rigorous evaluation of existing and emerging programs is needed assess effectiveness of programs to reduce overdose and engage survivors in harm reduction and substance use disorder treatment.

By mapping out more than 100,000 immune cells in patients with Crohn's disease, Mount Sinai researchers have discovered a signature of cells that are involved in a type of the disease that does not respond to treatment, according to a study published in Cell in August. The discovery opens the door to identifying biomarkers and tailoring therapeutic options for patients.

The study analyzed biopsy samples of inflamed and uninflamed Crohn's disease lesions on small intestine tissue as soon as it was removed from patients. Researchers used single-cell RNA sequencing and CyTOF technology to look into the intestinal lesions in real time on a single- cellular level, identifying the immune cells and circulating blood cells and their interaction in and around the lesion, and mapping a landscape of thousands of cells in the lesion.

The analysis found a signature of precise cell types, never previously identified, that correlates with a patient's resistance to the standard therapy for Crohn's disease, an anti-inflammatory drug called a TNF inhibitor. A TNF inhibitor is the major agent given to patients with moderate to severe Crohn's disease, but about 40 percent of patients who take the inhibitor end up either not responding to it or having their Crohn's worsen.

"Single-cell profiling could transform drug discovery," said co-corresponding author Miriam Merad, MD, PhD, Director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, Mount Sinai Professor in Cancer Immunology, Co-Director of the Cancer Immunology program at The Tisch Cancer Institute and Director of the Mount Sinai Human Immune Monitoring Center. "It's really going to give us much more clarity into inflammatory bowel disease and why patients are resisting and what else we could be targeting."

Having a signature to identify patients who will fail on the inhibitor is helpful to avoid surgery and complications. Based on this study's results, researchers have already developed a clinical trial that will test whether it's possible to find the signature in a blood test when a patient is diagnosed with inflammatory bowel disease. If so, doctors could avoid using a TNF inhibitor and instead use other biologics that will work for that patient.

"We designed this study in a way that defines inflammation with unprecedented precision using immunology and computational biology to get a better understanding of this disease," said co- corresponding author Judy H. Cho, MD, Senior Associate Dean for Precision Medicine, Director of The Charles Bronfman Institute for Personalized Medicine, Ward-Coleman Professor of Translational Genetics, and Professor of Medicine, and Genetics and Genomic Sciences, at the Icahn School of Medicine. "These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers for treatment response and tailored therapeutic opportunities."

This study looked at four groups of patients and used single-cell analysis of one group to identify the signature. The researchers then overlaid the data from the single-cell analysis onto multiple, large datasets consisting of the other three groups of patients whose tissues had been analyzed and whose outcomes with the TNF inhibitor were known. Using an algorithm and computational biology, the researchers corroborated the signature identified from the single-cell sequence results in the multiple, independent groups with known treatment outcomes.

"Our study shows that approaches that combine high-resolution single-cell mapping of inflammatory lesions in small numbers of patients with bulk RNA sequencing on large cohorts with extensive clinical characterization leads to generalizable insights, highlighting the potential to broadly transform understanding of human multifactorial immune-mediated inflammatory diseases," said co-corresponding author Ephraim Kenigsberg, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn Institute for Data Science and Genomic Technology. First author Jerome C. Martin, PharmD, PhD, postdoctoral fellow in the Precision Immunology Institute in the Icahn School of Medicine at Mount Sinai, also played a major role in this research.

The new type of drugs for type 2 diabetes, the so-called SGLT2 inhibitors, are associated with a reduced risk of heart failure and death as well as of major cardiovascular events, a major Scandinavian registry study led from Karolinska Institutet reports in The BMJ.

Cardiovascular disease is a serious complication of type 2 diabetes. The new SGLT2 inhibitors, which are now a commonly used drug group, reduce blood glucose. Clinical studies have also shown that SGLT2 inhibitors can reduce the risk of cardiovascular events in patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk.

However, it is unclear whether these findings also mean that there are positive cardiovascular effects from SGLT2 inhibitors in a broader patient group. This has now been investigated in a study published in The BMJ.

The study was a collaboration between researchers at Karolinska Institutet in Sweden, Statens Serum Institut in Denmark, the NTNU in Norway and the Swedish National Diabetes Register. The researchers used several national registries containing data on drug use, diseases, cause of death and other data from close to 21,000 patients with type 2 diabetes who began treatment with SGLT2 inhibitors between April 2013 and December 2016.

This information was then compared with an equally sized matched population who began treatment with a different diabetes drug, a DPP4 inhibitor. The primary outcomes in the study were major cardiovascular events (defined as myocardial infarction, stroke or cardiovascular death) and hospital admission for heart failure. An important secondary outcome was any-cause death.

In the primary analysis, the patients were monitored throughout the follow-up period, regardless of whether they had completed their treatment. The researchers found that the use of SGLT2 inhibitors was associated with a reduced risk of heart failure but not with major cardiovascular events. The risk of heart failure was 34 per cent lower in the SGLT2-inhibitor group than in the DPP4-inhibitor group. The use of SGLT2 inhibitors was also linked to a 20 per cent lower risk of death.

In an additional analysis the researchers studied the risks only when the patients took the drug and found a reduced risk of both heart failure and major cardiovascular events.

"Our study suggests that there is cardiovascular benefit from SGLT2 inhibitors for a broader patient group in routine clinical care," says principal investigator Björn Pasternak, associate professor at Karolinska Institutet's Department of Medicine in Solna. "This is an important result that we believe may be of interest to patients as well as drug authorities and doctors."

The results are applicable primarily to dapaglifozin, which was the predominant SGLT2 inhibitor used in Scandinavia during the study period.

The study is an observational study, which means that causality cannot be established.

PHILADELPHIA - Blocking a kinase known as CDK7 sets off a chain reaction that results in the death of prostate cancer cells that have spread and are resistant to standard therapies, according to a new study from researchers in the Abramson Cancer Center at the University of Pennsylvania. The team identified the role of CDK7 as the on/off switch that controls Med-1, a process that works in partnership with the androgen receptor to drive prostate cancer growth. Researchers show turning the switch off eventually leads to the death of cancer cells in mice. Cancer Discovery published the findings today.

Androgen deprivation therapy is a standard approach to treating prostate cancer, but over the course of treatment, a majority of patients will eventually become resistant to the therapy, allowing the cancer to grow and spread. This is referred to as metastatic castration-resistant prostate cancer (CRPC). There are two drugs approved by the U.S. Food and Drug Administration for these cases, but patients see little or no long-term survival benefit from these therapies.

Since the androgen receptor (AR) continues to be the main the driver of cancer growth in CRPC, taking away its function is still critical. Given the disease's resistance to therapies that try to take on AR directly, a new approach is needed. While these cancers do not have additional mutations or other genetic overexpression, the Penn team was still able to identify a new target thanks to what researchers called "AR's co-pilot."

"We know that AR does not work alone; that it needs Med-1 as its partner," said the study's senior author Irfan A. Asangani, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania. "Our study found a way to turn off Med-1, leaving AR without its co-pilot which means the cancer cannot grow and the cells eventually die."

Using an inhibitor to turn off CDK7 led to the death of CRPC cells in both the lab setting and in animal models. Researchers also saw very limited off-target effects of this approach, since healthy cells have redundancies in place to deal with the loss of Med-1, meaning only the cancer cells end up dying off.

"Our theory is that these cancer cells are addicted to Med-1 and AR but other cells are not, so we're essentially cutting them off from their addiction," Asangani said.

CDK7 inhibitors are already being tested in phase I clinical trials for other cancers - including leukemia, lung cancer, glioblastoma, and breast cancer - but Asangani said this study shows the rationale for testing them in CRPC.

Reyaz ur Rasool, Ramakrishnan Natesan, and Qu Deng are co-first authors on the study. Other Penn authors include Shweta Aras, Priti Lal, Samuel Sander Effron, Erick Mitchell-Velasquez, Jessica M. Posimo, Lauren E. Schwartz, Daniel J. Lee, and Donita C. Brady.

Researchers at the Stanford University School of Medicine have found that inflammation in the lungs of rats, triggered by something as simple as the flu, may wake up a silent genetic defect that causes sudden onset cases of pulmonary hypertension, a deadly form of high blood pressure in the lungs.

"It's a kind of one-two punch," said Amy Tian, PhD, senior research scientist in pulmonary and critical care. "Basically, the first hit is the mutation, and the second hit is inflammation in the arteries of the lungs. You can be healthy and carrying this mutation, and all of the sudden you get a bacterial or viral infection, and it leads to this terrible disease. "

Tian is the lead author of the study, which will be published Aug. 29 in Circulation. Mark Nicolls, MD, professor and chief of pulmonary and critical care medicine, is the senior author of the study.

"This is important research for understanding how 'second hits' can render ordinarily silent genetic mutations deadly," Nicolls said. "It also further advances the scientific understanding of the role of inflammation in pulmonary hypertension."

Currently there is no known cause for pulmonary hypertension, a debilitating disease that causes difficulty breathing, fatigue and chest pain. It can leave patients too weakened to perform simple daily activities, such as climbing a flight of stairs. About 200,000 people a year are hospitalized with the disease in the United States, according to the Pulmonary Hypertension Association of America. The only available cure for severe forms of the disease is lung transplantation, but it has only a 30 percent survival rate.

Weakening the heart

Pulmonary hypertension occurs when the arteries that transport blood from the heart to the lungs mysteriously thicken and become increasingly clogged, thereby weakening the heart, which has to pump extra hard to get blood to flow through the body. After diagnosis, most patients face a prognosis of just a few years of life before they die of heart failure. Some patients are born with the disease, but often it strikes in later life.

Treatment is limited to vasodilators, drugs that cause the smooth muscle cells of the diseased blood vessels in the lungs to relax, permitting more blood to flow through. These drugs help to extend survival and relieve some symptoms, but they are not a cure. Thus, scientists have been searching for other therapies.

Past research has shown that the majority of patients with the inherited form of pulmonary hypertension, which is also the most lethal, carry a mutation in the gene BMPR2. Whether the mutation plays a role in causing the disease has been unclear. Surprisingly, 80 percent of people with the mutation don't get the disease and remain perfectly healthy, Nicolls said.

Based on previous research into inflammation in the lungs, the Stanford researchers hypothesized that an inflammation-producing pathway may provide the second "hit" that triggers the mutation to cause the disease in certain patients. To test the theory, the researchers developed a rat model with a mutation in the BMPR2 gene. They followed the rats for a year, and found that the animals remained healthy. Yet when the rats were injected with a virus carrying the 5LO enzyme that triggered temporary lung inflammation, they developed pulmonary hypertension.

"At first, the rats with this mutation were healthy, running around the cage," Tian said. "Then we squirted the virus into their lungs, which stimulated the production of inflammation in the vessels of the lung, and they got really sick."

The lung inflammation caused by the virus usually lasts only a few weeks and, in humans, can also be caused by environmental triggers, such as a severe flu or bacterial infection or even hiking to high altitudes. However, in the genetically susceptible rats, the virus led to permanent inflammation, damaging the lung vessels and causing a lethal form of pulmonary hypertension.

"Asthma, a bad flu, temporary types of lung injury from bacterial or virus infections -- all can be 5LO-mediated," Tian said. "This type of inflammation normally has a pretty short life span. But in these rats, even after the injected virus died, the damage to the endothelial cells in the lining of the blood vessels continued. The cells become the bad player, and they continued to proliferate the inflammation."

These results indicate that limiting potential environmental causes of lung inflammation in patients with a genetic risk for pulmonary hypertension may help prevent the development of the disease, the study said.

Researchers have come one step closer to understanding how our immune system responds to acute dengue fever, a disease that has affected hundreds of thousands of people in Southeast Asia this summer alone. In a study published today in Nature Communications, researchers at Karolinska Institutet and Duke-NUS Medical School show that so-called natural killer cells were especially active shortly after an infection. The discovery could hopefully contribute to the development of new vaccines and improve care of patients with acute infections.

Dengue virus is common in tropical and sub-tropical regions of the world and is transmitted via mosquitoes to humans in whom the infection can cause severe hemorrhagic fever. In the summer of 2019, several countries in Southeast Asia have suffered severe outbreaks of the disease. Sweden annually reports 150-200 cases of dengue fever, typically in tourists returning from endemic countries such as Thailand.

Currently, effective vaccines and methods to treat dengue fever are lacking. To increase our understanding of the course of the disease and thereby find new treatment options, researchers have studied which immune cells are activated by the infection and how these migrate to the part of the body that has been infected.

The study followed 32 patients with acute dengue fever in Singapore. Their blood and skin sample analyses showed that a type of immune cell called natural killer (NK) cells were especially activated in the blood shortly after the infection. This activation had completely disappeared after about two months.

The cells were activated by cytokines, small molecules that spread in the bloodstream and are produced by other cells in the immune system. The natural killer cells had surface receptors, indicating they can leave the blood and migrate to the infected area of the skin.

"By studying immune cells and soluble molecules directly present in the skin of acutely infected patients we could gain unique insight into the very first steps of the immune response," says Niklas Björkström, physician and researcher at the Department of Medicine at Karolinska Institutet in Huddinge, Sweden, who led the study.

The findings provide important new knowledge about how people's immune system functions in acute viral infections. In the future, researchers hope this knowledge may be used for vaccine development as well as to improve care, diagnostics and treatment of patients with acute infections.

MINNEAPOLIS - Can a person with multiple sclerosis (MS) get regular vaccines? According to a new guideline, the answer is yes. The guideline, developed by the American Academy of Neurology (AAN), recommends that people with MS receive recommended vaccinations, including yearly flu shots. The guideline is published in the August 28, 2019, online issue of Neurology®, the medical journal of the AAN, and is endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America. The guideline updates the 2002 AAN guideline on immunization and multiple sclerosis.

Multiple sclerosis is an autoimmune disease that can affect a person's brain, optic nerves and spinal cord. People with MS often experience muscle weakness and have trouble with balance and coordination.

"We reviewed all of the available evidence and for people with MS, preventing infections through vaccine use is a key part of medical care," said guideline lead author Mauricio F. Farez, MD, MPH, of the FLENI Institution in Buenos Aires, Argentina, and a member of the American Academy of Neurology. "People with MS should feel safe and comfortable getting their recommended vaccinations."

In addition, the guideline recommends that people with MS should make sure their doctor or care team knows what MS medications they are using before receiving vaccinations. There is some evidence that shows that certain vaccinations may not work as well with certain MS medications.

The guideline recommends that people experiencing an MS flare consult their doctor before receiving vaccinations. They may want to consider waiting until the flare has passed before receiving vaccinations.

"After reviewing all the available evidence, we found that there is not enough information to say whether or not vaccinations trigger or worsen MS flares," said Farez. "Still, experts in MS urge their patients to hold off on scheduling their vaccinations if they are having an MS flare simply to avoid the potential for any complications."

Finally, the guideline states that some vaccines might not work well enough to prevent infection for some people with MS who take certain MS medications. However, it is recommended that people still work with their care team to maintain their regular recommended vaccinations, including the flu shot.