“By using hydrogen peroxide to defeat the immune system, you could say that the bacteria are fighting fire with fire. The body itself also produces hydrogen peroxide as a defence against the bacteria. Therefore, it was surprising to see that many types of bacteria actually use the same substance to overcome the body´s defences,” says Nelson Gekara, research leader.

Saskia Erttmann and Nelson Gekara mainly focused their studies on Streptococcus pneumoniae. This bacterium, often called pneumococcus, is the most common bacterium causing pneumonia but can also cause, among other illnesses, meningitis or severe sepsis. In addition, this bacterium can pave the way for other microbes to attack. This makes the bacterium one of the most deadly in the world. At the same time, many people have the bacterium in the upper respiratory tract as a part of the normal flora without falling ill or even knowing about it. It is therefore important to understand how pneumococci affect the body’s immune system.

The ultimate goal of any invading microbe is to reside peacefully within our bodies without evoking a strong inflammatory reaction that may result in the elimination of the microbe or cause us harm. The researchers have found that pneumococcus and other bacteria accomplish this by targeting a key component of the immune system — the inflammasomes. Inflammasomes are protein complexes, which upon recognizing foreign molecules, for example those found in microbes or damaged cells, initiate reactions to kill microbes and to clear diseased cells. The researchers found that bacteria such as pneumococci release large quantities of hydrogen peroxide, and that this causes inactivation of inflammasomes thereby weakening the immune system.

In mice models, the researchers observed that bacteria manipulated to produce less hydrogen peroxide were unable to inactivate inflammasomes and therefore elicited a faster inflammatory response that effectively cleared the bacteria from mouse lungs. The researchers also found that by inoculating the mice with a special enzyme, catalase, which breaks down hydrogen peroxide, one could increase the inflammation and inflammatory symptoms, leading to faster elimination of pneumococci from the lung.

“Inflammation often has negative connotations. However, for the body inflammation is an important process in the immune system’s defence against attacking microbes. Most microbes produce hydrogen peroxide to varying degrees. Our studies demonstrate that hydrogen peroxide is an inhibitor of an important component of the inflammatory machinery suggesting that the mechanism we have uncovered is a common strategy employed by many microbes to thrive within us,” says Saskia Erttmann, first author in the study and former member of Nelson Gekara’s research group.

“One of the best known substances with the ability to neutralize hydrogen peroxide and that could hence boost anti-bacterial immunity are vitamins such as Vitamin C found in fruits. Perhaps the old adage ‘an apple a day keeps the doctor away’ is not off the mark,” adds Nelson Gekara.

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People with new or poorly controlled hypertension given an integrated and comprehensive intervention by non-physician health workers along with personal supporters over a year had a reduction in cardiovascular risk of more than 40 per cent compared to usual care.

“There was a doubling in blood pressure control, with reductions in low-density lipoprotein (LDL) cholesterol, and improvements in medication adherence, physical activity, and diet,” said lead author Jon-David Schwalm of the Population Health Research Institute (PHRI) of McMaster University and Hamilton Health Sciences.

The study results are part of a presentation today in Paris, France at the European Society of Cardiology Congress with the World Congress of Cardiology and are also being published in The Lancet. The clinical trial, called Heart Outcomes Prevention and Evaluation 4 or HOPE 4, is led by PHRI.

Hypertension is the leading cause of cardiovascular disease worldwide, with the majority of the burden in low- and middle-income countries. Although there are clear benefits and recommendations for the use of antihypertensive medications and statins in patients with hypertension, control of blood pressure and use of statins in these countries is very low.

The study involved 1,371 people 50 or older from 30 communities in Colombia and Malaysia.

People in sixteen communities received usual care and those in 14 communities had an intervention that included the initiation and monitoring of treatments and controlling risk factors by non-physician health workers using computer tablet-based management algorithms and counselling; the provision of free antihypertensive and statin medicines recommended by non-physician health workers under supervision of physicians, and the involvement of a friend or family member to support adherence to medications and lifestyle advice.

“Previous studies with non-physician health workers led to modest effects on cardiovascular risk factors. We tested whether an intervention involving health workers, general practitioners and family, with provision of evidence-based medications, can safely and substantially reduce individual cardiovascular risk and found it successful,” said Schwalm, an associate professor of medicine at McMaster, a scientist at the PHRI and an interventional cardiologist at Hamilton Health Sciences.

Regarding how the intervention was done, computer tablets were used to collect study data, help the health workers make decisions when with the patients using simplified management algorithms to initiate and monitor antihypertensives and statins, and support counselling participants on health behaviours.

The friend or family supporter was encouraged to attend sessions with the health worker or physician, and they were present at three-quarters of the visits. In addition, the supporter’s role was to give ongoing help to improve adherence to medications and healthy behaviours between scheduled health worker visits.

The primary outcome was change in Framingham Risk Score, which is an estimate of the ten-year risk of cardiovascular disease. In those who received the intervention, their risk score dropped by 11.2 per cent as compared to 6.4 per cent in the control. This is approximately two fold.

There was an 11.45 mmHg greater reduction in systolic blood pressure, and a 0.41 mmol/L larger reduction in serum LDL cholesterol in the intervention, compared to the control group. Both of these findings are statistically significant and predict large reductions in future cardiovascular disease events. The proportion of patients with controlled hypertension was more than twice as great, 69 per cent in the intervention group compared to 31 per cent in the control group.

In particular, there were important improvements in physical activity and diet.

“All components of the intervention were essential to the benefits observed,” Schwalm said. “Our intervention is innovative in how, by taking a systems approach, it is more than the sum of its parts. It was developed after a detailed health system assessment and barrier analysis in each country, using a combination of quantitative and qualitative research, to identify local challenges and tailor the intervention to overcome these.”

Salim Yusuf, principal investigator of the study and PHRI executive director, added that the research results will have global impact.

“This strategy is pragmatic, effective, and scalable, and has the potential to substantially reduce cardiovascular disease globally, compared to current methods that are solely physician based,” he said.

“Adopting or adapting the HOPE 4 strategy in different countries to better control hypertension and reduce other risk factors could help achieve the United Nations’ target for a one-third reduction in premature cardiovascular mortality by 2030.”

While earlier studies have looked at how atmospheric and oceanic processes drive climate extremes, the Columbia Engineering team has focused on examining and modeling land-atmosphere processes, especially in setting up concurrent extremes that can be very destructive. Soil drought, represented by very low soil moisture, and atmospheric aridity, represented by very high vapor pressure deficit, a combination of high temperature and low atmospheric humidity, are the two main stressors that drive widespread vegetation mortality and reduced terrestrial carbon uptake. Concurrent soil drought and atmospheric aridity is a time period when soil moisture is extremely low and vapor pressure deficit is extremely high.

“Concurrent soil drought and atmospheric aridity have dramatic impacts on natural vegetation, agriculture, industry, and public health,” says Pierre Gentine, associate professor of earth and environmental engineering and affiliated with the Earth Institute. “Future intensification of concurrent soil drought and atmospheric aridity would be disastrous for ecosystems and greatly impact all aspects of our lives.”

The researchers combined reanalysis datasets and model experiments to identify the main land-atmosphere processes leading to concurrent soil drought and atmospheric aridity, and used climate models and statistical methods to assess how land-atmosphere processes would impact the frequency and intensity of concurrent soil drought and atmospheric aridity in future climate. The challenge they faced was how to isolate the impact of land-atmosphere feedbacks on concurrent drought and aridity. After trying many different methods, they worked with the GLACE-CMIP5 (Global Land Atmosphere Coupling Experiment — Coupled Model Intercomparison Project) scientists at ETH Zurich’s Institute for Atmospheric and Climate Science and used their model experiments.

Gentine’s group is the first to isolate this phenomenon and were surprised their work produced such dramatic findings.

“Most groups have been focused on assessing concurrent drought and heatwaves, but we are finding stronger coupling between drought and aridity than between drought and heatwaves,” says Sha Zhou, the study’s lead author and a postdoc working with Gentine. “Concurrent drought and aridity also have a stronger impact on the carbon cycle and so we felt this was a critical point to study.”

The team discovered that the feedback of soil drought on the atmosphere is largely responsible for increasing the frequency and intensity of atmospheric aridity. In addition, the soil moisture-precipitation feedback contributes to more frequent extreme low precipitation and soil moisture conditions in most regions. These feedback loops lead to a high probability of concurrent soil drought and extreme aridity. The CMIP5 simulations suggest that land-atmosphere feedbacks will further increase the frequency and intensity of concurrent drought and aridity in the 21st century, with potentially large human and ecological impacts.

The PNAS study highlights the importance of soil moisture variability in enabling a series of processes and feedback loops affecting the Earth’s near-surface climate.

Says Gentine, “It’s critical that we better quantify and evaluate the representation of these processes in our climate models. Accurate model representation of both soil moisture variability and the associated feedbacks is crucial if we are to provide reliable simulations of the frequency, duration, and intensity of compound drought and aridity events and of their changes in a warmer climate. Ultimately, this will help us mitigate future risks associated with these events.”

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“With prolonged dual-antiplatelet therapy, we need to be thoughtful in considering which patients are most suited to taking the regimen — that is, those at high ischemic risk and low bleeding risk,” said THEMIS co-chair Deepak L. Bhatt, MD, MPH, executive director of Interventional Cardiovascular Programs at the Brigham and professor of medicine at Harvard Medical School. “Our findings show that the greatest benefit occurred in those patients with diabetes and stable coronary artery disease with a history of prior stenting for whom ticagrelor, when added to aspirin, reduced important cardiovascular events, such as heart attacks, strokes and amputations.”

THEMIS co-chair Philippe Gabriel Steg, MD, Chief of Cardiology at Hôpital Bichat, Greater Paris University Hospitals — AP-HP, and professor at Université de Paris, stated, “The THEMIS population is a critically important one in which to understand the potential benefits of taking ticagrelor in addition to aspirin. As the number of people with diabetes continues to rise globally, we need to evaluate ways of improving long-term outcomes and preventing cardiovascular and ischemic events.”

In THEMIS, the largest trial of patients with diabetes to date, more than 19,000 patients with stable coronary artery disease and diabetes were randomized to receive either ticagrelor plus aspirin or a placebo plus aspirin. Patients were followed for an average of more than three years. During that time, 736 of 9,619 patients (7.7 percent) taking ticagrelor plus aspirin experienced cardiovascular death, myocardial infarction, or stroke versus 818 of 9,601 patients (8.5 percent) taking placebo plus aspirin — a 10 percent reduction.

As seen with other anti-platelet medications, ticagrelor increased the risk of major bleeding (206 patients versus 100 patients) and intracranial hemorrhage (70 patients versus 46 patients) compared with placebo. The difference in intracranial hemorrhages was driven by an increased number of traumatic bleeds, most of them subdural, and not by spontaneous or procedural bleeding.

Among participants with a history of previous PCI, the risk reductions outweighed the increased bleeding risks. Patients who had received PCI, which commonly uses devices known as stents to widen a coronary blood vessel and keep blood flowing, accounted for the majority (58 percent) of the total THEMIS population. Among these patients in THEMIS-PCI, 404 of 5,558 (7.3 percent) participants taking ticagrelor plus aspirin experienced cardiovascular death, myocardial infarction, or stroke, versus 480 of 5,596 (8.6 percent) participants taking placebo plus aspirin — a 15 percent reduction. Major bleeding occurred in 111 of 5,536 (2.0 percent) patients receiving ticagrelor and 62 of 5,564 (1.1 percent) patients receiving placebo. The risk for intracranial bleeding was similar between ticagrelor and placebo (33 patients versus 31 patients, respectively). Ticagrelor provided a very favorable balance of benefit versus risk — more than in patients without a history of PCI.

“Our results indicate that among those with diabetes and stable coronary artery disease, we should focus on ticagrelor for patients with a history of prior stenting. This is an easily identifiable, logical sub-group,” said Bhatt. “Studies currently support using long-term dual antiplatelet therapy for patients with acute coronary syndrome who are at high ischemic risk but low bleeding risk. Our work suggests that a much broader population of patients with stable coronary artery disease and diabetes stand to benefit substantially.”

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