Body

From the vibrations of the rear-view mirror just as your car reaches precisely 70 miles per hour to a building that collapses when, in an earthquake, it begins to vibrate at a specific frequency, there is untapped energy that could be harnessed for propulsion.

In recent research, Andres J.Goza, found relationships between frequencies and the passive dynamics at play when vehicles move in air or water toward a better understanding of how to use these forces to enhance performance.

According to Goza, assistant professor in the Department of Aerospace Engineering at the University of Illinois at Urbana-Champaign, his work is an effort to seek new bio-inspired propulsion strategies.

"Fish swim very efficiently and birds can fly very efficiently, so how can we use those observations to inform real paradigm shifts in the locomotion strategies that we engineer," he said. "For example, the wing of a bird and the tail of a fish are flexible and when these animals fly or swim, the air and water around them induce passive motion.

"Another example is when air blows past a flag, making it flap, it affects the air motion around it," Goza said. "If we can understand this fluid-structure interaction or fluid-structure coupling at a very basic level, could we use it to design aircraft and submarines with a very different kind of locomotion?"

Goza said the speed of the air or water flow around the vehicle and the density of the materials they are made from play a role, both in the resonance and in the passively induced motion.

"Scientists have understood, outside of this fluid-structure interaction context, that there's a profound response when you excite a structure or system at its resonant frequency," Goza said. "But what role do these passive dynamics play, and can we tune the structural properties so that the resonant frequency of your system is somehow meaningfully tied to the flow--that is, to the motion that you're prescribing?"

One sticking point in this research was that the standard definition of resonant frequency assumed that the structure was in a vacuum. "But it's not; it's in fluid and the fluid affects what that resonance frequency is," Goza said.

Consequently, step one was to define a notion of resonance that incorporates the effect of the fluid.

"One of the big contributions of this research was unambiguously defining this resonant frequency, and then confirming that over a wide range of different parameters we actually see performance benefits near this resonant frequency," he said. "Namely, if the structure flaps or moves at a certain frequency within this flow, it leads to an improvement in thrust."

Goza said the larger heave amplitude computations are more reflective of fish swimming. The results indicated that at these larger amplitudes, both resonant and non-resonant mechanisms played a role. "Resonance is defined in terms of super small undulations, but we understand that fish are actually swimming at large amplitudes," Goza said. "We bridged the gap between defining what resonance means in this small amplitude setting when there's a fluid present, but also embracing the fact that fish undergo much larger emotions. We established connections to results in the small amplitude case, finding that performance benefits persist near resonance even at large amplitudes that are actually relevant to biological propulsion."

Depending on the regime, Goza said, the peak thrust is near this resonant frequency associated with small amplitude. "The key is, as you move to these large amplitudes, resonance continues to play a predominant role. We found that the small linear amplitude notion of resonance was appropriate for predicting and understanding these peaks and thrust in the majority of cases.

"If this passive motion can be useful in locomotion, it can reduce the amount of energy put into the system," Goza said. "We can harness these passive dynamics and let them do the propulsion for us."

Goza said one of the next phases of this research will be to look at modern active materials that can be tuned to have the right resonant frequency to induce passive dynamics with the desired output.

DALLAS – April 29, 2020 – Strategies that treat households in the broad vicinity of a recent malaria case with anti-malarial drugs, insecticides, or both could significantly reduce malaria in low-transmission settings, a challenge with approaches currently in use, a study led by UT Southwestern scientists suggests. The findings, published in the April 25, 2020, The Lancet, could bring efforts to eradicate malaria worldwide closer to fruition.

Malaria, a mosquito-borne disease that annually infects more than 200 million people and kills nearly 400,000, used to exist in almost every inhabited location on Earth. However, explains Michelle S. Hsiang, M.D., a Horchow Family Scholar in Pediatrics at UT Southwestern Medical Center, tremendous strides have been made in efforts to eliminate malaria in countries and worldwide, which accelerated in the early 2000s with the aid of more intensive efforts and new tools such as drugs and insecticide-treated bed nets.

Although many countries are very close to completely eradicating malaria, it continues to linger at low levels in some locations, emerging as outbreaks with the rainy season every year. The strategies that have been successful at decreasing malaria in high-transmission settings don’t work as well in these low-transmission ones, says Hsiang, assistant professor of pediatrics.

“These countries are left with the challenge of, do we keep doing business as usual, or do we do something different to interrupt transmission and potentially eliminate this disease?” she says. “That requires a different and more aggressive approach.”

Some countries have approached this challenge using a strategy called reactive case detection (RACD), in which people in the immediate vicinity of a positive case are also screened and treated with anti-malarial drugs. However, says Hsiang, because the sensitivity of malaria tests is low, this strategy hasn’t proved effective. On the opposite end of the spectrum, the World Health Organization recommends mass drug administration (MDA), treating all individuals in an endemic area with anti-malarial medications. But this strategy is expensive and can be difficult for large populations to accept.

Seeking a compromise between these two approaches, Hsiang and her colleagues from University of Namibia; University of California, San Francisco; London School of Hygiene and Tropical Medicine; and Wits University tested strategies in which those in close vicinity to a positive malaria case – 500 meters from the positive household – received anti-malarial efforts: either medication (a strategy known as reactive focal mass drug administration, or rfMDA), insecticide spraying (a strategy known as reactive focal vector control, or RAVC), or both. The administered drug was artemether-lumefantrine, a drug with a long history of safe use. The insecticide was a new organophosphate known as pirimiphos-methyl, which can be effective for up to a year when sprayed on the walls and ceilings of affected homes.

The researchers chose the Zambezi Region of Namibia in Africa, a low malarial transmission setting, to study these interventions from Jan. 1 to Dec. 31, 2017. They randomized 56 areas within this region to receive either RACD, rfMDA, RAVC, or a combination of rfMDA and RAVC. As soon as anyone in these areas tested positive, a mobile response team was dispatched to these locations to administer the assigned intervention. By the end of the study, 1,150 of these index cases triggered 342 interventions that covered 8,948 individuals. The researchers then followed the malarial caseload in these areas over the next few weeks and months.

Their results showed that rfMDA and RAVC cut the rate of new cases by 50 percent in each area where they had been administered compared with areas that received RACD. When the researchers administered rfMDA and RAVC in combination, the effect was additive, decreasing new cases by 75 percent.

Residents in each area found these interventions acceptable, Hsiang says, with few refusing to participate. In addition, the interventions appeared safe, causing no serious adverse events. Together, Hsiang says, these findings suggest that rfMDA and RAVC, separately or together, could offer hope to significantly reduce or potentially eliminate malaria in low-transmission settings and facilitate worldwide eradication.

“A child dies from malaria every two minutes, mostly in poor countries,” Hsiang says. “We have the tools to get rid of this disease for good. We just need to learn how to wield them effectively.”

The ability to detect smells predicts recovery and long-term survival in patients who have suffered severe brain injury, a new study has found. A simple, inexpensive 'sniff test' could help doctors to accurately diagnose and determine treatment plans for patients with disorders of consciousness.

Published today in the journal Nature, the study involved brain injured patients showing very minimal or no signs of awareness of the external world. It found that 100% of patients who reacted to the sniff test went on to regain consciousness, and over 91% of these patients were still alive three and a half years after injury.

"The accuracy of the sniff test is remarkable - I hope it will help in the treatment of severely brain injured patients around the world," said Anat Arzi, a researcher in the University of Cambridge's Department of Psychology and the Weizmann Institute of Science Israel, who led the research, together with Professor Noam Sobel from the Weizmann Institute of Science Israel and Dr Yaron Sacher from the Loewenstein Rehabilitation Hospital Israel.

It is often difficult for doctors to determine a patient's state of consciousness after a severe brain injury. Errors in diagnosis are made in up to 40% of cases. A patient that is minimally conscious differs from one in a vegetative state, and their future outcomes differ. An accurate diagnosis is critical because it informs treatment strategies such as pain management, and can underlie end-of-life decisions.

Our sense of smell is a very basic mechanism and relies on structures deep within the brain. The brain automatically changes the way we sniff in response to different smells - for example, when presented with an unpleasant smell we automatically take shorter, shallower breaths. In healthy humans the sniff-response happens in both waking and sleeping states of consciousness.

Research was conducted on 43 severely brain-injured patients. The experimenter first explained to each patient that different smells would be presented to them in jars, and the breathing through their nose would be monitored using a small tube called a nasal cannula. There was no indication that the patients heard or understood.

Next, a jar containing either a pleasant smell of shampoo, an unpleasant smell of rotten fish, or no smell at all was presented to each patient for five seconds. Each jar was presented ten times in a random order, and a measurement was made of the volume of air sniffed by the patient.

The researchers found that minimally conscious patients inhaled significantly less in response to smells, but did not discriminate between nice and nasty smells. These patients also modified their nasal airflow in response to the jar with no smell. This implies awareness of the jar or a learned anticipation of a smell. Vegetative state patients varied - some did not change their breathing in response to either of the smells, but others did.

A follow-up investigation three and a half years later found that over 91% of the patients who had a sniff response shortly after injury were still alive, but 63% of those who had showed no response had died.

By measuring the sniff-response in severely brain injured patients, the researchers could measure the functioning of deep-seated brain structures. Across the patient group they found that sniff-responses differed consistently between those in a vegetative state and those in a minimally conscious state - providing further evidence for an accurate diagnostic.

"We found that if patients in a vegetative state had a sniff response, they later transitioned to at least a minimally conscious state. In some cases, this was the only sign that their brain was going to recover - and we saw it days, weeks and even months before any other signs," said Arzi.

In a vegetative state the patient may open their eyes, wake up and fall asleep regularly and have basic reflexes, but they don't show any meaningful responses or signs of awareness. A minimally conscious state differs because the patient may have periods where they can show signs of awareness or respond to commands.

"When the sniff response is functioning normally it shows that the patient might still have some level of consciousness even when all other signs are absent," said Dr Tristan Bekinschtein in the University of Cambridge's Department of Psychology, who was involved in the study. "This new and simple method to assess the likelihood of recovery should be immediately incorporated in the diagnostic tools for patients with disorders of consciousness."

A one-hour exercise designed to increase feelings of social belonging administered during the first year of college appears to significantly improve the lives and careers of black students up to eleven years later, psychologists report. The authors say their findings suggest that targeted and timely psychological intervention can be an important tool to interrupt generational sociocultural disadvantages. Their paper follows up on a 2011 study published in Science, which hypothesized that minority students or first-generation college students arrive at college feeling as if they don't belong, and may interpret common social and academic setbacks as confirmation of this feeling. Black students who completed a short exercise, which presented such setbacks as common and temporary, later reported higher GPAs, better mental health and wellbeing, and even fewer doctor visits. Now, Shannon Brady and colleagues reconnected with the students from the original trial and found that those who had completed the exercise continue to report greater career satisfaction, physical health, community involvement, and psychological wellbeing. Students who completed the exercise were more likely to find good mentors, who in turn were important factors in the students' success. The authors write that the social belonging intervention will likely only work in environments where care and resources are available to the students, as opposed to schools that are actively hostile to the students or those without sufficient resources. Their findings indicate that improving students' feelings of belonging can be an important strategy to reduce inequality in school and in the workplace.

Berkeley -- Childhood vaccination may be a powerful tool in the fight against antimicrobial resistance in low- and middle-income countries, finds a new analysis led by researchers University of California, Berkeley.

Around the world, overuse of antibiotics is driving the proliferation of bacterial "superbugs" that have evolved to survive antimicrobial exposure, making humans more vulnerable to diseases like sepsis, tuberculosis, malaria and pneumonia. Countries classified as low- and middle- income currently bear the brunt of the human and economic impacts of antimicrobial resistance.

The new study found that immunization with two common vaccines -- the pneumococcal conjugate and rotavirus vaccines -- significantly reduces the rates of acute respiratory infections and diarrhea among small children in these settings. And, with fewer children getting sick or severely sick, fewer are receiving antibiotic treatment.

"Right now, almost all countries have developed or are in the process of developing national action plans to address the crisis that antibiotic resistance poses to their health systems, but there is very little evidence addressing which interventions are effective," said Joseph Lewnard, an assistant professor of epidemiology at UC Berkeley, and lead author of the paper. "By providing hard numbers on the substantial impact that has been achieved with just these two vaccines alone, our work demonstrates that vaccines should be among the interventions that are strongly prioritized."

The study, which is the first to examine the connection between vaccination and antibiotic use in low- and middle-income settings, appears online April 29 in the journal Nature.

Pneumococcal conjugate vaccines protect against the bacterium Streptococcus pneumoniae (pneumococcus), which can cause respiratory and ear infections, sepsis and meningitis, while rotavirus vaccines protect against diarrheal infections caused by rotavirus. Though rotavirus infection itself is not treatable by antibiotics, diarrhea caused by rotavirus is hard to distinguish from diarrhea caused by bacterial infection. Many children with rotavirus diarrhea, therefore, receive antibiotic treatment, even it is not needed.

Using data from health and demographic studies of 78 low- and middle-income countries, the researchers found that pneumococcal and rotavirus vaccines prevent an estimated 19.7% of antibiotic-treated acute respiratory infections and 11.4% of antibiotic-treated episodes of diarrhea in children under five years old.

By combining data on the effectiveness of the two vaccines with current vaccination rates, the team projected that the inoculations are now preventing 23.8 million and 13.6 million episodes of antibiotic-treated acute respiratory infections and diarrhea each year, respectively, among children under the age of five in these settings around the world.

If universal vaccination was achieved, an additional 40 million cases of antibiotic-treated illness could be prevented each year, they predicted.

These numbers are likely underestimates, Lewnard said.

"We're not accounting for the fact that there are indirect reductions in disease associated with declining transmission of the pathogens themselves, and that there might be additional benefits in other age groups as well," Lewnard said. "Moreover, we are looking at a narrow spectrum of all pneumococcal diseases, which, further, include ear infections and sinusitis cases that often receive antibiotic treatment."

At this point, there isn't enough data on the effectiveness of other efforts to combat antibiotic resistance, such as improving hygiene and sanitation or reducing agricultural use of antibiotics, to know how they compare to vaccination, Lewnard said.

While the two vaccines are commonly administered to children under 2 years old in high-income countries, children in low- and middle-income countries do not always receive them because of their relatively high cost and families' lower access to health care.

Charities like GAVI, the Vaccine Alliance are working aggressively to expand access to vaccinations, especially in low-income settings. Lewnard said he hopes this study motivates countries that are not eligible for this type of aid, such as middle-income countries and low-income countries transitioning to middle-income status, to provide this support for their children.

"Effects on antibiotic use and antimicrobial resistance have not been included in economic assessments of the value of these vaccine programs," Lewnard said. "As low- and middle-income countries make decisions around maintaining or introducing these vaccination programs, it's very important to have evidence that demonstrates the impact these vaccines are having domestically."

By studying blood vessel tissue from 674 patients, a research team has discovered how insulin contributes to the dysfunction of blood vessels in atherosclerosis, one of the most common chronic health conditions worldwide. Their research explains why insulin treatment fails to treat vessel damage in patients with diabetes and highlights a promising alternative therapy to correct insulin signaling and protect blood vessels. Insulin is a fundamental hormone in the body, as it regulates processes ranging from blood sugar control to chemical reactions in the cardiovascular system. Patients with type 2 diabetes often develop other chronic conditions such as heart disease and atherosclerosis, and research suggests that abnormal insulin signaling may be to blame. However, lowering blood sugar with insulin-like compounds has failed to reduce cardiovascular risk in diabetic patients. To understand why, Ioannis Akoumianakis and colleagues examined blood vessels from 674 patients with atherosclerosis who underwent coronary artery bypass surgery. They discovered that the patients' blood vessels were resistant to insulin - which normally controls the tone of blood vessels - and showed elevated levels of stress from harmful oxygen molecules. Instead, high levels of insulin correlated with more dysfunction in cells that line the insides of blood vessels. Treating the vessels with an experimental inhibitor of the enzyme DPP4 reduced oxidative stress and restored normal insulin activity, and chronic treatment with a DPP4 inhibitor reversed the damaging vascular effects of insulin in patients and in mice fed a high-fat diet. The authors conclude that future trials should explore the possibility of combining insulin treatment with DPP4 inhibitors to mitigate vessel damage in patients with atherosclerosis.

A new COVID-19 transmission model, based on contact survey data from nearly 1200 people in the cities of Wuhan and Shanghai, China, suggests that strict social distancing measures implemented there were sufficient to curtail the transmission of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. The results show that the average resident's daily interpersonal contacts dropped 7- to 9-fold, from 14 and 20 people per day in Wuhan and Shanghai, respectively, to about two contacts per day in both locations by early February, after social distancing measures were put in place. The survey data further show that between 78% and 94% of these contacts occurred at home, between fellow household members, during the social distancing period. Juanjuan Zhang and colleagues used the contact survey data, along with contact tracing data collected in the nearby province of Hunan, to build a mathematical model of SARS-CoV-2 transmission dynamics. Their model results suggest that social distancing measures - and the resulting decrease in daily interpersonal contacts - led transmission rates to drop below epidemic levels in Wuhan and Shanghai, the researchers say. The model also estimated that, in China, children under the age of 15 are about 40% as susceptible to infection with SARS-CoV-2 as elderly people over the age of 64. The model results further suggest that, while school closures helped to stem the rate of disease transmission in China - reducing the overall number of cases and the burden on the healthcare system there - such closures would not have been enough to quell the outbreak. For that, Zhang et al. conclude, it proved necessary to restrict residents' human contact to others residing within their own household.

Whether or not you are a smoker could condition how the coronavirus affects you. At least that is what numerous researchers are saying, insisting that tobacco use is to blame for the weakened cardiovascular systems which are at greatest risk from COVID-19. Among these researchers are Javier C. Vázquez, from the Bordeaux Neurocampus, and Diego Redolar, from the Universitat Oberta de Catalunya (UOC), who confirm that the data indicates that "tobacco use is one of the reasons that more men die from the virus than women in Spain". Over 30% of those who have died from the disease suffered from some form of cardiovascular disease - the leading cause of death in Spain (28% in 2018) - and approximately 10% of cardiovascular disease is attributed to smoking. COVID-19 is an infectious disease provoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As explained repeatedly in the news on the virus, it is transmitted mainly person to person via small respiratory droplets through sneezing or coughing, and the most common symptoms are fever, cough and difficulty breathing. Regarding its impact on the population in Spain, over 90% of deaths have occurred in people over 60 and over 45% had some pre-existing condition.

Men versus women

Although the number of COVID-19 infections among men and women is fairly similar in Spain, the mortality rate after 5 April stood at 8% for men and 4% for women. This is what the analysis by Redolar, associate dean for research at the UOC's Faculty of Health Sciences and researcher with the Cognitive NeuroLab research group, and Vázquez, researcher in the University of Bordeaux's Neuroscience Department, has shown. In Redolar's opinion, "it is evidence that gender plays a role in patterns such as the prevalence of tobacco use", since according to data for 2017, in Spain over 25% of men smoke while only 18% of women do.

The biological effects of tobacco use

The researchers, who have published an article on this topic in the scientific journal Tobacco Induced Diseases, state that it is important that biological data be taken into account. For instance, smoking tobacco can upregulate the angiotensin-converting enzyme 2 (ACE2), which, among other things, lowers blood pressure. Some coronaviruses use this enzyme as a cellular entry receptor. SARS-CoV-2 is one such virus, joining itself to ACE2 receptors in the lower respiratory tract of infected individuals to again access to the lungs. The researchers confirm that "existing data suggests that patients with COPD, or chronic obstructive pulmonary disease, or who smoke have a higher risk of becoming more seriously ill from COVID-19, since it increases ACE2 expression in weaker airways, which this type of patient has". These conclusions have already been confirmed in lab mice.

More data and measures against tobacco use

Given tobacco's apparent interaction with the coronavirus, the two researchers are alarmed at the lack of data that would allow us to better study how smoking and the pandemic are related. The researchers point out that in Spain there is currently no data on smoking in patients with COVID-19 and that this is something to be remedied by registering and sharing data on the issue.

They also state that we should launch campaigns to reduce tobacco use adapted to the current context and adopt interventions that have proven effective in curbing the habit, like increased taxes on tobacco, prohibiting its sale during the pandemic or improving programmes to help people quit smoking.

Researchers demand data on tobacco use among those infected and advise that its sale should be prohibited during the pandemic

Cardiovascular diseases aggravated by smoking are present in over 30% of coronavirus mortalities

Whether or not you are a smoker could condition how the coronavirus affects you. At least that is what numerous researchers are saying, insisting that tobacco use is to blame for the weakened cardiovascular systems which are at greatest risk from COVID-19. Among these researchers are Javier C. Vázquez, from the Bordeaux Neurocampus, and Diego Redolar, from the Universitat Oberta de Catalunya (UOC), who confirm that the data indicates that "tobacco use is one of the reasons that more men die from the virus than women in Spain". Over 30% of those who have died from the disease suffered from some form of cardiovascular disease - the leading cause of death in Spain (28% in 2018) - and approximately 10% of cardiovascular disease is attributed to smoking.

COVID-19 is an infectious disease provoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As explained repeatedly in the news on the virus, it is transmitted mainly person to person via small respiratory droplets through sneezing or coughing, and the most common symptoms are fever, cough and difficulty breathing. Regarding its impact on the population in Spain, over 90% of deaths have occurred in people over 60 and over 45% had some pre-existing condition.

Philadelphia, April 29, 2020—Patients with untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma now have a new treatment option—a combination of the targeted agent ibrutinib with the immunologic agent rituximab. The U.S. Food and Drug Administration (FDA) has approved the combination based on data from E1912, a phase 3 trial developed and led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN). The E1912 study showed that the ibrutinib-rituximab combination not only provided better leukemia control, it also prolonged life and had fewer side effects when compared with the standard chemotherapy/immunotherapy of fludarabine, cyclophosphamide, and rituximab (FCR). The E1912 trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health. The importance of these findings is reinforced by the breadth of participation of academic and community institutions that together completed this innovative study.

CLL is one of the most common types of leukemia in adults. It typically occurs during or after middle age and rarely occurs in individuals under the age of 40. Ibrutinib (Imbruvica®, Pharmacyclics, an AbbVie company/Janssen) is a Bruton’s tyrosine kinase (BTK) inhibitor that interferes with the survival of lymphocytic leukemia cells. Rituximab (Rituxan, Roche/Genentech, and generics) enhances the ability of the body’s immune system to destroy the cells. The FDA had previously approved ibrutinib as monotherapy, in combination with obinutuzumab, or in combination with bendamustine and rituximab (BR) for patients with CLL.

In addition to ECOG-ACRIN, the E1912 trial represents a collaboration with the Alliance for Clinical Trials in Oncology, NRG Oncology, and SWOG cooperative groups in the NCI’s National Clinical Trials Network. These groups participated in the design and conduct of the trial and supported the enrollment and treatment of the 529 patients.

The trial met its primary endpoint of an improvement in progression-free survival (the length of time patients live before their disease worsens). The combination also improved overall survival, the trial’s secondary endpoint. In general, patients in the ibrutinib-rituximab arm were less likely to experience serious side effects than those in the standard treatment arm.

The New England Journal of Medicine published final results in August 2019. Those results reported a two-thirds reduction in the risk of disease progression and less toxicity from therapy with ibrutinib plus rituximab compared to standard FCR.

Dr. Shanafelt presented results from an extended follow-up analysis of patients in E1912 at the ASH annual meeting in December 2019. The analysis provided new safety and efficacy information on the patients in E1912 who completed six months of combined ibrutinib plus rituximab therapy and continued to receive ibrutinib alone for as long as it remained effective. The analysis, based on a median follow-up of 48 months, reported that 73% of patients in the ibrutinib plus rituximab treatment arm remained on ibrutinib. At the time of that report, the median time on treatment was 43 months (range of 0.2 to 61 months). The median time to progression or death after discontinuing ibrutinib was 23 months. Superior progression-free survival benefits were sustained for the ibrutinib plus rituximab arm compared to the FCR treatment arm (hazard ratio [HR]=0.39; 95 percent CI, 0.26-0.57; p<0.0001). Overall survival also continued to favor the ibrutinib plus rituximab arm (HR=0.34, 95 percent CI, 0.15-0.80; p=0.010).

The only pretreatment characteristic that predicted discontinuation of ibrutinib for a reason other than progression was the number and severity of health problems other than CLL.

E1912 clinicaltrials.gov record: NCT02048813

Study stopped early by data safety monitoring board because of difficulty recruiting patients after COVID-19 outbreak in Wuhan, China brought under control, so the true effectiveness of antiviral drug remdesivir remains unclear.

Treatment with remdesivir did not speed recovery or reduce deaths from COVID-19 compared with placebo in hospitalised patients in the trial.

While not statistically significant, pre-specified secondary outcomes found that time to clinical improvement and duration of invasive mechanical ventilation were shorter in people treated with remdesiver within 10 days of showing symptoms, compared to standard care.

The authors say that future studies of remdesivir are needed to better understand its potential effectiveness.

Treatment with the antiviral drug remdesivir does not speed recovery from COVID-19 compared with placebo in hospitalised patients who are critically ill, according to the first randomised trial of its kind involving 237 adults (aged 18 and older) from ten hospitals in Wuhan, China, published in The Lancet.

Although their study is the first randomised controlled trial (considered the gold standard for evaluating the effectiveness of interventions) of remdesivir, the authors caution that interpretation of their findings is limited because the study was stopped early after they were unable to recruit enough patients due to the steep decline in cases in China [1]. They conclude that more evidence from ongoing clinical trials is needed to better understand whether remdesivir can provide meaningful clinical benefit.

In the absence of any known treatment for COVID-19, remdesivir is one of a handful of experimental drugs undergoing clinical trials worldwide. It has only been available to patients with COVID-19 on compassionate grounds (the use of unapproved drugs when no other treatment is available). In the trial, all patients received standard care including lopinavir-ritonavir, interferons, and corticosteroids.

"Unfortunately, our trial found that while safe and adequately tolerated, remdesivir did not provide significant benefits over placebo", says Professor Bin Cao from China-Japan Friendship Hospital and Capital Medical University in China, who led the research. "This is not the outcome we hoped for, but we are mindful that we were only able to enrol 237 of the target 453 patients because the COVID-19 outbreak was brought under control in Wuhan. What's more, restrictions on bed availability resulted in most patients being enrolled later in the disease course, so we were unable to adequately assess whether earlier treatment with remdesivir might have provided clinical benefit." [2]

He continues: "Future studies need to determine whether earlier treatment with remdesivir, higher doses, or combination with other antivirals or SARS-CoV-2 neutralising antibodies, might be more effective in those with severe illness." [2]

Remdesivir was originally developed to treat Ebola, and is designed to interfere with the way a virus reproduces, thereby stopping it from multiplying inside the body. It has been shown to successfully block SARS-CoV-2 from replicating in vitro, and had activity against other coronavirus infections like severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 in animal studies. Case studies have also reported benefit in some severely ill patients with COVID-19, but until now, there have been no clinical trials of remdesivir, so its efficacy against COVID-19 in patients is unknown.

In this study, 237 adults hospitalised with severe laboratory-confirmed SARS-CoV-2 infection were enrolled between February 6 and March 12, 2020. To be eligible, patients had to enter the study within 12 days of symptom onset, have pneumonia confirmed by chest imaging, and oxygen saturation of 94% or lower. Participants were randomly assigned to either daily infusions of remdesivir (158 patients; 200mg on day 1 followed by 100mg on days 2-10) or a placebo infusions (79 patients) for 10 days. One patient in the placebo group withdrew before receiving treatment.

Trained investigators measured time to clinical improvement over 28 days using a six-point scale of clinical status ranging from hospital discharge (score=1) to death (score=6). Clinical improvement was defined as at least a two point improvement compared to a patient's admission status.

No statistically significant difference in time to clinical improvement was noted between the groups (average time to clinical improvement 21 days for remdesivir group vs 23 days placebo group). In a secondary outcome (a planned outcome measure in a trial that is not as important as the primary outcome measure, but is still of interest in evaluating the effect of an intervention [3]), although not statistically significant, in patients treated within 10 days of illness onset, those receiving remdesivir appeared to recover faster than those given placebo (average time to clinical improvement 18 days vs 23 days).

Death within 28 days of randomisation was similar between the groups, with 14% (22/158) patients dying in the remdesivir group compared with 13% (10/78) in the placebo group. However, in secondary outcomes, patients treated with remdesivir within 10 days of illness onset had a lower, but not statistically significant, difference in mortality, with 11% (8/71) patients dying compared with 15% (7/47) receiving placebo.

Similarly, in secondary outcomes, the duration of invasive mechanical ventilation, although not significantly different between the groups, was shorter in remdesivir recipients than placebo recipients (average 7 days vs 15.5 days). No significant differences were noted between the groups in duration of oxygen support, length of hospital stay, or time to discharge or death (table 3).

Furthermore, treatment with remdesivir did not result in significant reductions in viral load (how much SARS-CoV-2 is present in an infected person's body) or detection of the virus in the upper or lower respiratory tract compared with placebo (figure 3).

There was no difference in adverse events between the groups (65%; 102/155 remdesivir patients included in the safety analysis vs 64%; 50/78 placebo), and the overall proportion of serious adverse events was lower in patients given remdesivir than placebo (18%; 28/155 vs 26%; 20/78). However, more patients in the remdesivir group discontinued treatment because of adverse events including gastrointestinal symptoms (eg, nausea, vomiting) and cardiopulmonary failure (18 remdesivir group; 12% vs 4 placebo; 5%).

"Participants in our trial were less ill, and treated earlier in their disease course, compared with a recent observational study of patients with COVID-19, who received remdesivir on compassionate grounds [4]. Yet, remdesivir did not provide greater benefits in our study population as expected", says co-author Professor Ronghui Du from Wuhan Lung Hospital, China. "Ongoing clinical trials of remdesivir, will provide important additional information about whether and under what circumstances it may provide benefit." [2]

The authors note several limitations of the study, including that stopping early gives insufficient power to detect differences in clinical outcomes, and it did not account for the possible emergence of reduced susceptibility to remdesivir (which would contribute to a reduction of remdesivir effectiveness), because of a lack of data at the time. Finally, they point out that the frequent use of corticosteroids in patients in this study might have aided viral production, as observed in SARS and MERS.

Writing in a linked Comment, Professor John Norrie (who was not involved in the study) from the University of Edinburgh, UK, discusses the challenges, and importance, of conducting randomised trials in epidemics, and writes: "Promising signals from observational data must be rigorously confirmed or refuted in high-quality randomised trials--particularly given that for COVID-19 no proven safe and effective treatments yet exist...That is additionally challenging in a pandemic, and the temptation to lower the threshold of convincing evidence must be resisted, because adopting ineffective and potentially unsafe interventions risks only harm without worthwhile benefit, while making it even harder to undertake trials to find truly effective and safe interventions."

He continues: "The study was well designed--a double-blind, placebo-controlled, multicentre randomised trial--and well conducted, with high protocol adherence and no loss-to-follow up...An absence of statistical significance in an underpowered trial means that the findings are inconclusive. The particular challenges of delivering pandemic trials underline the importance of data sharing, allowing rapid curation of relevant datasets for individual patient data meta-analyses. With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like it will be our best way to obtain robust insights into what works, safely, and on whom. We eagerly await the ongoing trials."

In a special report published today in the journal Blood, an international working group of experts in myelodysplastic syndromes (MDS) proposes - for the first time - the recognition of a distinct subtype of MDS based on the presence of a nonheritable genetic mutation that causes the disease. The mutation is found in approximately one in every five patients with MDS.

"This study represents an important step forward in the ability to diagnose MDS on the basis of genetic features, and this is paving the way to obtain a diagnosis without the need to analyze bone marrow," said lead author Luca Malcovati, MD, of the University of Pavia Medical School in Italy. "Patients who carry this genetic variant may benefit from treatment with an approved drug, luspatercept. In addition, other potential new treatments that directly target this genetic mutation are in the early stages of development and may benefit patients in the future."

The mutation, known as SF3B1, is the most common genetic variant found in patients with MDS, Malcovati said. Patients with MDS who carry this genetic variant tend to have a less severe or aggressive form of the disease. Moreover, a recent clinical trial showed that a high proportion of patients with MDS who carried the SF3B1 mutation responded to treatment with luspatercept, which was approved by the U.S. Food and Drug Administration in November 2019 to treat anemia in patients with a rare blood disorder.

A major strength of this proposal, Malcovati said, is that it has been developed and is supported by an international working group of experts who represent all of the major institutions worldwide that diagnose and treat MDS.

Selecting the best treatment for MDS - a group of disorders that commonly occur when the bone marrow fails to produce enough healthy blood cells - depends on identifying the patient's specific subtype of the disease. This is often difficult to do, however, since the diagnosis generally relies on looking at bone marrow through a microscope to identify abnormalities. With the change that the expert group is proposing, patients with MDS who carry the SF3B1 mutation will be able to get a definitive classification by means of a simple test.

A common feature of SF3B1-mutated MDS is red blood cells in the bone marrow that, under a microscope, can be seen to have a ring of iron surrounding the nucleus. These abnormal cells are known as ring sideroblasts. They develop as a result of the mutation's interference with the blood cells' use of iron, Malcovati explained. This interference impairs the cells' capacity to produce hemoglobin, the protein responsible for transporting oxygen to the body's organs and tissues. This chain of events results in anemia (a shortage of both red blood cells and hemoglobin), which is a primary symptom in patients with SF3B1-mutated MDS.

In this study, Malcovati and his colleagues analyzed the results of several previous studies that they say support the hypothesis that SF3B1-mutated MDS is a distinct subtype of the disease. They also examined records from a large international database of patients with MDS, in which 795 patients carried the SF3B1 mutation and 2,684 did not. The researchers concluded that SF3B1-mutated MDS has three main distinctive features: ineffective production of red blood cells, a relatively good prognosis, and a likelihood that patients' anemia will improve when treated with the drug luspatercept, which promotes the growth and development of red blood cells.

In an earlier phase III trial, published in the New England Journal of Medicine in January, luspatercept reduced anemia severity in patients with MDS with ring sideroblasts who had not responded to, or could not tolerate, treatment with drugs that stimulated the production of red blood cells. Of the patients treated with luspatercept, 93% carried the SF3B1 mutation.

Malcovati and his team also identified a number of other genetic variants that may occur in MDS in addition to the SF3B1 mutation. The presence of these additional mutations may signify more aggressive forms of the disease, said Malcovati. MDS with these additional genetic features would be excluded from the proposed new subtype of SF3B1-mutated disease, he said.

A University of Washington researcher calculates that 14.4 million workers face exposure to infection once a week and 26.7 million at least once a month in the workplace, pointing to an important population needing protection as the novel coronavirus disease, COVID-19, continues to break out across the U.S.

Marissa Baker, an assistant professor in the UW School of Public Health, based her calculations on research she published in 2018 in the American Journal of Industrial Medicine. In that paper, Baker and co-authors calculated that about 8% of workers in Federal Region X -- comprised of Alaska, Washington, Oregon and Idaho -- work in jobs where exposure to infection or disease occurs at least once a week at work. Those risks include flu-like illnesses, MRSA and other respiratory illnesses, like COVID-19, as well as wound infections.

Using federal employment data, and the same analysis method, Baker and her co-authors determined:

10% (14,425,070) of U.S. workers are employed in occupations where exposure to disease or infection happens at least weekly, based on employee and employer self-report.

18.4% (26,669,810) of U.S. workers are employed in occupations where exposure to disease or infection happens at least monthly, based on employee and employer self-report.

The new paper on worker exposures was published on PLOS ONE on April 28.

"While healthcare occupations represent the bulk of workers exposed to infection and disease, other occupations that frequently interface with the public and provide essential services are also at increased risk of exposure. Those include police officers, firefighters, childcare workers, and personal care aides," said Baker, who is also program director of UW's Industrial Hygiene/Exposure Science program, Department of Environmental & Occupational Health Sciences. "This underscores the importance of all types of occupations developing workplace response plans for infectious disease."

While those response plans must include how to keep workers safe from exposure at work, Baker added, they must also ensure workers don't have to show up sick, potentially spreading disease within and outside the workplace.

Some workers who are in higher paying and more secure jobs, often salaried, can work from home or afford more time away from work, but many don't have these same options, such as workers who participate in the gig economy or are independent contractors and are typically not considered employees. These workers don't benefit from employee protective policies, such as sick leave, putting them at increased risk of having to work when they or a loved one is sick, despite public health guidance.

Even if a worker does have paid sick leave, and knows how to access it, a variety of other real and perceived pressures -- such as an economy that rewards people who are working hard at all times, or pressure to perform work that no one else can perform, encourages workers to come to work sick, a phenomena researchers term "presenteeism."

"Our findings serve as an important reminder that the workplace should be a focus for public health intervention, especially during disease outbreaks such as COVID-19," Baker said, adding that researchers produced the new work to help shed light on this fact, and to respond to questions about their 2018 paper and its application to the current, nationwide outbreak. Estimating the burden of U.S. workers exposed to infection or disease is a key factor in containing risk of COVID-19 infection.

"The public health implications from our study," Baker said, "are that workplaces need to make sure that they are not only protecting their workers at work, but also coming up with contingency plans to make sure that sick workers are not coming to work, and that can be accomplished through training workers to fill in for each other, providing additional paid sick leave during this time and similar measures."

New physiotherapy guidelines are targeting COVID-19 patient recovery for respiratory management, exercise and mobilisation in acute hospital wards and Intensive Care Units.

The new guidelines published in Australian Journal of Physiotherapy aim to prevent complications of the respiratory system and muscle deconditioning, speed up recovery from mechanical ventilation, and improve long-term physical function and recovery.

It also provides physiotherapists with workforce planning and preparation in a pandemic, PPE (personal protective equipment) requirements and how to safely deliver treatments, how to determine who physiotherapists should treat, and how to protect health care workers and resources.

Physiotherapists are an essential professional group who will be required to limit the severity of ICU-acquired weakness in patients and provide longer term rehabilitation and interventions to survivors of COVID-19 to allow them to function upon returning home and regain their life roles, the researchers say.

The clinical practice guidelines were developed by a group of international experts in cardiorespiratory physiotherapy. The authors have extensive clinical experience in ICUs and on the wards, as well as academic physiotherapists who have experience in a range of research methods including clinical practice guidelines.

The physiotherapy guidelines were prepared with reference to existing medical guidelines, relevant literature and a process to determine consensus agreement within the expert group.

The guide has been endorsed by professional associations across the world, is being translated into several languages and is already having a large international impact on physiotherapy practice and workforce issues in response to the COVID-19 pandemic.

Flinders University Caring Futures Institute researcher Dr Claire Baldwin, a co-author of the clinical practice guide, says there is an urgent need globally for clinical guidance for acute care physiotherapists.

"For physiotherapists, these guidelines are just as much about who not to treat (where treatment benefits may be minimal, but health care worker risks are high), just as it is about where there is an indication for physiotherapy," she says.

"Patients with pre-existing health conditions who contract COVID-19 and those who require treatment in an ICU will especially need our help."

Dr Baldwin says key points of difference in these guidelines compared to medical guidelines relate to the specific respiratory care that physiotherapists can provide.

"The common presentation of COVID-19 does not appear to be characterised by a cough with phlegm. However, some people may develop phlegm that they are unable to clear from their lungs, or, have added challenges because they have difficulty with coughing up phlegm even under normal circumstances. This is where respiratory physiotherapy treatments may be needed."

"Because cough generates aerosols, it is important that respiratory physiotherapy techniques are recognised as an aerosol generating exposure and physiotherapists can be protected with the correct PPE," she says.

"Physiotherapy input to the prevention and treatment of ICU acquired weakness is vitally important, but COVID-19 brings unique challenges and some adaptations to the way that care is delivered."

Dr Baldwin drew on experience in ICU physiotherapy, mechanical ventilation, respiratory management, physical function, outcome measurement and long-term outcomes after critical illness, all of which are relevant to hospitalised COVID-19 cases.

Her research is usually centred on helping hospital patients with illness including respiratory issues to "get moving"

The research, published in The Lancet Infectious Diseases is the fruit of joint project between investigators from around the world to conduct the largest individual patient data meta-analysis to date under The WorldWide Antimalarial Resistance NetworkWWARNumbrella. The study found that artemether-lumefantrine (AL) (*1) and other artemisinin-based combination therapies (ACTs) (*2) were significantly more effective than quinine, the current recommended treatment. Authors urgently call for further investigation into dose optimisation for pregnant women to ensure the highest possible treatment success. A joint research group consisting of WWARN, A joint research group consisting of WWARN,The Nuffield Department of Medicine, University of Oxford and The Institute of Medical Science, The University of Tokyo announced on the 29th (GMT).

An estimated 125 million pregnant women are at risk of malaria every year

Pregnant women are particularly susceptible to malaria, with the infection adversely affecting both mother and fetus. An estimated 60% of pregnant women in the world live in malaria endemic regions, with 125 million pregnant women at risk every year. Despite this, expectant mothers have been hugely understudied in antimalarial clinical trials.

Typically, this group was excluded from clinical trials due to concerns over drug safety on the fetus, however the last two decades have seen increasing evidence that commonly used malaria treatments are in fact safe. Despite this, there are no agreed guidelines to assess antimalarial drug efficacy during pregnancy.

At present, quinine with clindamycin is the recommended drug to treat women during their first trimester of pregnancy. However, clindamycin is not widely available in malaria-endemic areas and quinine monotherapy is commonly used throughout all trimesters.

In this study, WWARN conducted an individual patient data meta-analysis of existing data from 4,968 pregnant women from 19 studies across 10 countries - representing 92% of patients in the available literature. Pooling and standardising the data from many regions and time-periods into a single dataset for analyses increases the statistical power needed to address key knowledge gaps, particularly when the existing data is sparse. Researchers assessed the efficacy and tolerability of quinine-based treatments and ACTs, including AL, the most commonly used ACT.

"Pregnant women no longer have to put up with quinine"

Authors found that the efficacy and tolerability of ACTs was better than that for quinine. AL had the best tolerability, but the lowest efficacy in comparison to other ACTs. Authors suggest the lower efficacy may be because dosing of AL is too low and recommend further investigation into dose optimisation.

The lead author of the study, Dr Makoto Saito, Assistant Professor at The Institute of Medical Science, The University of Tokyo(IMSUT) says: "As the safety of ACTs have been shown previously, the most efficacious drug with fewer side effects should be used to minimise the adverse impact of malaria on mother and fetus. Although the current dosing of ACT for pregnant women may not be optimal, pregnant women no longer have to put up with quinine."

"We found that women in their first pregnancy or with higher malaria parasite burden were at a higher risk of treatment failure and should be carefully monitored"

Regardless of transmission intensity, over 95% of women treated with all ACTs except AL were free of recurrence

In high malaria transmission areas, there was recurrence of falciparum malaria in 58.0% of women within 28 days of quinine treatment, while there was 13.8% recurrence after AL treatment. In low transmission areas, both treatments were more efficacious but 33.6% of women treated with quinine had recurrence within 28 days. Regardless of transmission intensity, over 95% of women treated with all other ACTs were free of recurrence.

Presence of gametocytes(*3), the sexual form of malaria parasites, were more frequent after quinine treatment compared with ACTs, this favours the use ACTs as they will be reducing the overall transmission of malaria parasites. Quinine was associated with lower tolerability due to higher risks of side effects such as abdominal pain, nausea and vomiting. This could be further exacerbated by morning sickness in the first trimester, the time during which quinine is recommended. As pregnant women infected with malaria generally have less symptoms than non-pregnant women, they are less likely to tolerate adverse drug events.

Authors caution that updated variable local patterns of resistant to antimalarial treatments should be considered when applying these findings to specific settings, and also both efficacy and tolerability of ACTs need to be re-assessed if a new dosing regimen is proposed for pregnant women.

Prof Philippe Guérin, Director of WWARN and senior author on the study says: "The findings of this study as well as evidence of safety shown in previous research provides compelling evidence that quinine provides lower efficacy and tolerability than ACTs. Further research into drug dosing to ensure optimum treatment effectiveness for both mother and fetus is paramount."

WASHINGTON, April 28, 2020 -- Many months since the first COVID-19 outbreak in Wuhan, China, countries continue to explore solutions that are effective at managing the spread of the virus and culturally feasible to implement. Chaos theory analysis has provided insight on how well infection prevention strategies can be adopted by multiple countries.

Researchers in Brazil analyzed the growth of confirmed infected COVID-19 cases across four continents to better characterize the spread of the virus and examine which strategies are effective in reducing its spread.

Their results, published in Chaos, from AIP Publishing, found the virus commonly grows along a power law curve, in which the social, economic and geographical features of a particular area affect the exponent to which the infection spreads rather than affecting traits of the infection itself.

"We decided to use our expertise to perform extensive numerical analysis using the real-time series of the cumulative confirmed cases of COVID-19 in order to search for answers about the spreading of this pathogen," said author Cesar Manchein.

The study draws on data current through March 27 from Brazil, China, France, Germany, Italy, Japan, South Korea, Spain and the United States.

The group's approach draws from a technique called numerical modeling, which leverages computing power to solve a set of differential equations in drawing comparisons between groups.

The high correlation in power law curves between each of the countries has allowed the group to single out generic effective strategies. Softer quarantine measures, they write, are inefficient at flattening curves compared to stricter isolation guidelines.

"Our results essentially show that an efficient strategy to avoid the increase of the number of infected individuals by coronavirus combines two actions: Keep to a high level of social distance and implement a significant number of tests to identify and isolate asymptomatic individuals," said author Rafael M. da Silva.

They mention that the combination of the two actions, stay-at-home measures and more aggressive disease testing, are essentially the strategies used in South Korea.

The researchers plan on continuing to apply real-world data to further improve their model. Da Silva said the group hopes to use their models to test distinct strategies that could avoid the use of long quarantines.

"Physics and chaos theory researchers can have a fundamental role in the battle against the coronavirus," said author Cesar Manchein. "From the theoretical point of view, researchers can use their knowledge and experience to study the time and territorial evolution of the disease."