Culture

A new study highlights the risks of pulmonary complications in patients with SARS-CoV-2 infection who undergo surgery, according to an observational study of 1,128 patients across 24 countries, published in The Lancet. The study was conducted between 1 January and 31 March 2020 and included data from hospitals mainly in Europe and America with ongoing SARS-CoV-2 infection outbreaks.

In the study, post-operative pulmonary complications (such as pneumonia, acute respiratory distress syndrome, and/or unexpected postoperative ventilation) occurred in half of patients with SARS-CoV-2 infection who underwent surgery (51.2%, 577/1,128 people). Among patients with SARS-CoV-2 infection who underwent surgery, 23.8% (268/1128) died within 30 days. Of those with pulmonary complications, over two-thirds (38%, 219/577 people) died within 30 days of their surgery.

The study also identified factors associated with worse outcomes. As well as being male or aged 70 years or older, patients with comorbidities and those undergoing cancer surgery, emergency or major surgery were among the most vulnerable.

Lead author Dr Aneel Bhangu from the University of Birmingham, UK, says: "Although the risks associated with COVID-19 need to be carefully balanced against the risks of delaying surgery for every individual patient, our study suggests that the thresholds for surgery should be raised, compared to normal practice. Medical teams should consider postponing non-critical procedures and promoting other treatment options, which may delay the need for surgery or sometimes avoid it altogether." [1]

Dr Ana Minaya-Bravo, Hospital Universitario del Henares and Universidad Francisco de Vitoria, Spain, says: "When hospitals resume routine surgery, it's likely it will take place in environments that remain exposed to SARS-CoV-2. Hospital-acquired infection will remain a challenge, but strategies are urgently required to minimise it, as well as to minimise the risk of pulmonary complications for infected patients whose surgery cannot be delayed. Future studies should assess the role that preoperative testing could play in deciding which patients are selected for surgery." [1]

Patients undergoing surgery are a vulnerable group at risk of SARS-CoV-2 exposure in hospital and may be particularly susceptible to subsequent pulmonary complications, due to the increased inflammation and immunosuppressive responses to surgery and mechanical ventilation. A number of guidelines have been published for managing surgical patients during the SARS-CoV-2 pandemic, but this is the first study to examine the impact of SARS-CoV-2 infection on pulmonary complications and death rates.

For the current study, researchers analysed outcomes from 1,128 patients across 235 hospitals in 24 countries. Most patients (74%, or 835/1,128) underwent emergency surgery, and 24.8% (280/1,128) had elective surgery, with data missing for 13 patients. The reasons to operate were benign disease (54.5%, or 615/1,128) [2], cancer (24.7%, or 278/1,128) and trauma (20.1%, or 227/1,128), with the reasons missing for eight patients.

The patients included in the study had tested positive for SARS-CoV-2 within seven days leading up to their operation, or 30 days following surgery. The researchers gathered data on 30-day post-surgery death rates and pulmonary complications.

Pulmonary complications occurred in 51.2% (577/1,128) of patients. Of those with pulmonary complications, 38.0% (219/577) died within 30 days of their operation, accounting for 81.7% (219/268) of all deaths in the study. Overall, 23.8% (268/1,128) of patients died within 30 days.

The authors say that these rates for mortality and pulmonary complications are higher than those associated with even the highest risk groups before the pandemic. However, they note that it was not feasible for participating hospitals, many of which were experiencing significant stress due to the pandemic, to collect data on all patients undergoing surgery, so comparisons were not made during the same period against patients not infected with SARS-CoV-2. Instead, the authors provide comparisons to pre-pandemic mortality rates and pulmonary complications, which should be interpreted with caution.

For example, a 2016 study across 58 countries reported 30-day mortality of 14.9% in a high-risk subgroup who underwent emergency, major surgery of the abdomen (midline laparotomy) [3], and a 2019 study across 211 hospitals from 28 European countries found a pulmonary complication rate of 8%. [4] The death rate of 38% approaches that of the sickest patients with community acquired COVID-19 who are admitted to intensive care. [5]

In the new study, a greater proportion of men died (28.4%, or 172/605) compared to women (18.2%, or 94/517). Of people aged 70 and over, 33.7% (188/558) died, which contrasts to 13.9% (79/567) of patients under 70-years-old. The subgroup with the highest mortality rate were men aged 70 and above. Those with severe comorbidities (ASA grades 3-5) were more likely to develop pulmonary complications than those with mild comorbidities (ASA grades 1-2) (59.4%, 407/685 patients with severe comorbidities vs 39.4%, 153/386 patients with mild comorbidities).

The type of surgery also had an impact on patients' prognosis. Death rates were higher after emergency surgery than after elective surgery (25.6%, or 214/835 versus 18.9%, or 53/280), and after cancer surgery (27.1%, or 68/251) than after surgery related to benign conditions and obstetrics (21.7%, or 133/613).

The authors note that although this is the first multi-country study that reaches across all surgical specialties, it has some limitations. The data were collected at the early stages of the pandemic, when routine testing was not available at all locations, therefore some patients (6%) were included on the basis of clinical diagnosis rather than a laboratory test confirming SARS-CoV-2. Future studies will need to investigate the role of pre-operative testing in patient selection for surgery, and the authors call for longer-term studies to collect data on a wider range of outcomes, to enable surgeons and patients to make evidence-based decisions about whether to go ahead with surgery.

The findings are based on data collected mostly in European and North American hospitals, but are also relevant to countries where large-scale outbreaks are yet to take place.

Writing in a linked Comment, Paul S. Myles, Alfred Hospital and Monash University, Melbourne, Australia (who was not involved in the study) notes some limitations of the study, including the lack of control group and that testing was not standardised, which may lead to uncertainty around COVID-19-attributed mortality and respiratory complications. He adds: "Nevertheless, these results are worrying because the rate of poor outcomes exceeded those seen in most types of major surgery. Severe COVID-19 is associated with a marked inflammatory and prothrombotic state. These pathological processes are exacerbated by surgery and immobilisation, leading to a perfect storm detrimental to good postoperative outcomes... The study highlights the need for clear perioperative guidelines for emergency and elective surgery during the pandemic. Further research is needed to define what threshold of community prevalence would threaten adequate supplies of PPE and hospital capacity as elective surgery recommences... Most patients in the study came from Italy, Spain, the UK, and the USA--these countries' health systems were all largely overwhelmed in the early stages of the COVID-19 pandemic. Staff training, PPE, intensive care unit (ICU) beds, and ventilators were often scarce or insufficient. Countries vary widely in terms of their capacity to respond to an outbreak of a novel infectious disease... Some elective (eg, cancer surgery or caesarean section) and most non-elective surgery must continue throughout any pandemic, and if the prevalence of COVID-19 is low and hospital resources are coping with demand for ward and ICU beds, more elective surgery can recommence. Globally, many governments and professional bodies are moving from a position of curtailment to reopening of elective surgery. This requires a low prevalence in the community and access to SARS-CoV-2 testing, and ensuring there are sufficient trained staff, hospital and ICU beds, PPE, and all other necessary medical supplies."

Patients undergoing surgery after contracting coronavirus are at greatly increased risk of postoperative death, a new global study published in The Lancet reveals. Researchers found that amongst SARS-CoV-2 infected patients who underwent surgery, mortality rates approach those of the sickest patients admitted to intensive care after contracting the virus in the community.

Researchers examined data for 1,128 patients from 235 hospitals. A total of 24 countries participated, predominantly in Europe, although hospitals in Africa, Asia, and North America also contributed.

Experts at the University of Birmingham-led NIHR Global Research Health Unit on Global Surgery have now published their findings that SARS-CoV-2 infected patients who undergo surgery experience substantially worse postoperative outcomes than would be expected for similar patients who do not have SARS-CoV-2 infection.

Overall 30-day mortality in the study was 23.8%. Mortality was disproportionately high across all subgroups, including elective surgery (18.9%), emergency surgery (25.6%), minor surgery such as appendicectomy or hernia repair (16.3%), and major surgery such as hip surgery or colon cancer surgery (26.9%).

The study identified that mortality rates were higher in men (28.4%) versus women (18.2%), and in patients aged 70 years or over (33.7%) versus those aged under 70 years (13.9%). In addition to age and sex, risk factors for postoperative death included having severe pre-existing medical problems, undergoing cancer surgery, undergoing major procedures, and undergoing emergency surgery.

Report co-author Aneel Bhangu, Senior Lecturer in Surgery at the University of Birmingham, commented: "We would normally expect mortality for patients having minor or elective surgery to be under 1%, but our study suggests that in SARS-CoV-2 patients these mortality rates are much higher in both minor surgery (16.3%) and elective surgery (18.9%). In fact, these mortality rates are greater than those reported for even the highest-risk patients before the pandemic; for example, the 2019 UK National Emergency Laparotomy Audit reported 30-day mortality of 16.9% in the highest-risk patients, and a previous study across 58 countries reported a 30-day mortality of 14.9% in patients undergoing high-risk emergency surgery."

"We recommend that thresholds for surgery during the SARS-CoV-2 pandemic should be raised compared to normal practice. For example, men aged 70 years and over undergoing emergency surgery are at particularly high risk of mortality, so these patients may benefit from their procedures being postponed."

Patients undergoing surgery are a vulnerable group at risk of SARS-CoV-2 exposure in hospital. They may be particularly susceptible to subsequent pulmonary complications, due to inflammatory and immunosuppressive responses to surgery and mechanical ventilation. The study found that overall in the 30 days following surgery 51% of patients developed a pneumonia, acute respiratory distress syndrome, or required unexpected ventilation. This may explain the high mortality, as most (81.7%) patients who died had experienced pulmonary complications.

Report co-author Dmitri Nepogodiev, Research Fellow at the University of Birmingham commented "Worldwide an estimated 28.4 million elective operations were cancelled due to disruption caused by COVID-19. Our data suggests that it was the right decision to postpone operations at a time when patients were at risk of being infected with SARS-CoV-2 in hospital. There's now an urgent need for investment by governments and health providers in to measures to ensure that as surgery restarts patient safety is prioritised. This includes provision of adequate personal protective equipment (PPE), establishment of pathways for rapid preoperative SARS-CoV-2 testing, and consideration of the role of dedicated 'cold' surgical centres."

What to do. You're a dog. Your owner is trapped in a box and is crying out for help. Are you aware of his despair? If so, can you set him free? And what’s more, do you really want to?

That's what Joshua Van Bourg and Clive Wynne wanted to know when they gave dogs the chance to rescue their owners.

Until recently, little research has been done on dogs' interest in rescuing humans, but that's what humans have come to expect from their canine companions -- a legend dating back to Lassie and updated by the popular Bolt.

"It's a pervasive legend," said Van Bourg, a graduate student in Arizona State University's Department of Psychology.

Simply observing dogs rescuing someone doesn't tell you much, Van Bourg said. "The difficult challenge is figuring out why they do it."

So, Van Bourg and Wynne, an ASU professor of psychology and director of the Canine Science Collaboratory at ASU, set up an experiment assessing 60 pet dogs' propensity to rescue their owners. None of the dogs had training in such an endeavor.

In the main test, each owner was confined to a large box equipped with a light-weight door, which the dog could move aside. The owners feigned distress by calling out "help," or "help me."

Beforehand, the researchers coached the owners so their cries for help sounded authentic. In addition, owners weren't allowed to call their dog's name, which would encourage the dog to act out of obedience, and not out of concern for her owner's welfare.

"About one-third of the dogs rescued their distressed owner, which doesn't sound too impressive on its own, but really is impressive when you take a closer look," Van Bourg said.

That's because two things are at stake here. One is the dogs' desire to help their owners, and the other is how well the dogs understood the nature of the help that was needed. Van Bourg and Wynne explored this factor in control tests -- tests that were lacking in previous studies.

In one control test, when the dog watched a researcher drop food into the box, only 19 of the 60 dogs opened the box to get the food. More dogs rescued their owners than retrieved food.

"The key here is that without controlling for each dog's understanding of how to open the box, the proportion of dogs who rescued their owners greatly underestimates the proportion of dogs who wanted to rescue their owners," Van Bourg said.

"The fact that two-thirds of the dogs didn't even open the box for food is a pretty strong indication that rescuing requires more than just motivation, there's something else involved, and that's the ability component," Van Bourg said. "If you look at only those 19 dogs that showed us they were able to open the door in the food test, 84% of them rescued their owners. So, most dogs want to rescue you, but they need to know how."

In another control test, Van Bourg and Wynne looked at what happened when the owner sat inside the box and calmly read aloud from a magazine. What they found was that four fewer dogs, 16 out of 60, opened the box in the reading test than in the distress test.

"A lot of the time it isn't necessarily about rescuing," Van Bourg said. "But that doesn't take anything away from how special dogs really are. Most dogs would run into a burning building just because they can't stand to be apart from their owners. How sweet is that? And if they know you're in distress, well, that just ups the ante."

The fact that dogs did open the box more often in the distress test than in the reading control test indicated that rescuing could not be explained solely by the dogs wanting to be near their owners.

The researchers also observed each dog's behavior during the three scenarios. They noted behaviors that can indicate stress, such as whining, walking, barking and yawning.

"During the distress test, the dogs were much more stressed," Van Bourg said. "When their owner was distressed, they barked more, and they whined more. In fact, there were eight dogs who whined, and they did so during the distress test. Only one other dog whined, and that was for food."

What's more, the second and third attempts to open the box during the distress test didn't make the dogs less stressed than they were during the first attempt. That was in contrast to the reading test, where dogs that have already been exposed to the scenario, were less stressed across repeated tests.

"They became acclimated," Van Bourg said. "Something about the owner's distress counteracts this acclimation. There's something about the owner calling for help that makes the dogs not get calmer with repeated exposure."

In essence, these individual behaviors are more evidence of "emotional contagion," the transmission of stress from the owner to the dog, explains Van Bourg, or what humans would call empathy.

"What's fascinating about this study," Wynne said, "is that it shows that dogs really care about their people. Even without training, many dogs will try and rescue people who appear to be in distress -- and when they fail, we can still see how upset they are. The results from the control tests indicate that dogs who fail to rescue their people are unable to understand what to do -- it's not that they don't care about their people.

"Next, we want to explore whether the dogs that rescue do so to get close to their people, or whether they would still open the box even if that did not give them the opportunity to come together with their humans," Wynne added.

Wearing face masks at home might help ward off COVID-19 spread among family members

79% effective at curbing transmission--but only before symptoms emerge

Wearing face masks at home might help ward off the spread of COVID-19 infection among family members living in the same household, but only before symptoms develop, suggests a study of Chinese families in Beijing, accepted for publication in BMJ Global Health.

This practice was 79% effective at curbing transmission before symptoms emerged in the first person infected, but it wasn't protective once symptoms had developed, the study shows.

The figures in China suggest that most of the person to person transmission of SARS-CoV-2, the coronavirus responsible for COVID-19 infection, has occurred in families. But it's not clear if the wearing of face masks might help curb household transmission rates, along with social distancing and disinfection.

The World Health Organization (WHO) and Public Health England haven't endorsed the wearing of face masks indoors or outdoors, on the grounds that there's little good quality evidence to warrant recommending this.

To explore whether face masks might make a difference, the researchers questioned 460 people from 124 families in Beijing, China, on their household hygiene and behaviours during the pandemic.

Each family had at least one laboratory confirmed case of COVID-19 infection between late February and late March 2020. Average family size was 4, but ranged from 2 to 9, and usually comprised three generations.

Family members were defined as those who had lived with the infected person for 4 days before and more than 24 hours after that person's symptoms first appeared.

The researchers wanted to know what factors might heighten or lessen the risk of subsequently catching the virus within the incubation period--14 days from the start of that person's symptoms.

During this time, secondary transmission--spread from the first infected person to other family members--occurred in 41 out of the 124 families. A total of 77 adults and children were infected in this way, giving an 'attack rate' of 23% or around 1 in 4.

Around a third of the study children caught the virus (36%; 13 out of 36) compared with more than two thirds of the adults (just over 69.5%; 64 out of 92).

Twelve of the children had mild symptoms; one had none. Most (83%) of the adults had mild symptoms; in around 1 in 10, symptoms were severe, and one person became critically ill.

Daily use of disinfectants, window opening, and keeping at least 1 metre apart were associated with a lower risk of passing on the virus, even in more crowded households.

But daily contact and the number of family members wearing a face mask after the start of symptoms in the first person to develop them were associated with a heightened risk.

Of all the behavioural and hygiene factors, four were significantly associated with secondary transmission of the virus.

Diarrhoea in the first person to become infected and close daily contact with them increased the risk of passing on the virus: diarrhoea was associated with a quadrupling in risk, while close daily contact, such as eating meals round a table or watching TV together, was associated with an 18-fold increased risk.

Frequent use of bleach or disinfectants for household cleaning and the wearing of a face mask at home before symptoms emerged, including by the first person to have them, were associated with a reduced risk of viral transmission.

A face mask worn before symptoms started was 79% effective, and disinfection 77% effective, at stopping the virus from being passed on.

The authors acknowledge some limitations to their study: telephone interviews are subject to recall and the strength of household disinfectants and bleach used wasn't recorded.

Nevertheless, they suggest the findings back universal face mask use, not just in public spaces, but also at home. And the findings may also be relevant for families living with someone in quarantine or in enforced social isolation, and for the families of health workers who may face an ongoing risk of infection, they say.

"This study confirms the highest risk of household transmission being prior to symptom onset, but that precautionary [non-pharmaceutical interventions], such as mask use, disinfection and social distancing in households can prevent COVID-19 transmission during the pandemic," independent of household size or crowding, they write.

"Household transmission is a major driver of epidemic growth," they point out, adding that their findings could be used to "inform precautionary guidelines for families to reduce intrafamilial transmission in areas where there is high community transmission or other risk factors for COVID-19."

[Ends]

Peer reviewed? Yes
Evidence type: Observational
Subjects: People

The first study of COVID-19 to specifically analyse the effect of the disease in hospitalised patients with diabetes has found that one in ten patients dies within 7 days of hospital admission, and one in five is intubated and mechanically ventilated by this point. The research is published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]), by Professor Bertrand Cariou and Professor Samy Hadjadj, diabetologists at l'institut du thorax, University Hospital Nantes, INSERM, CNRS, and University of Nantes, France, and colleagues.

The study shows that two thirds (65%) of COVID-19 patients with diabetes admitted to hospital are men, and the average age of all patients is 70 years. Worse blood sugar control did not seem to impact a patient's outcome, however the presence of diabetic complications and increasing age increase the risk of death, and increased BMI is associated with both increased risk of needing mechanical ventilation and with increased risk of death.

The CORONADO study analysed 1,317 patients admitted to 53 French hospitals (public and private) between 10 and 31 March 2020. The majority of hospitalised subjects had type 2 diabetes (89%) while only 3% had type 1 diabetes, with other types of diabetes in the remaining cases. In 3% of cases, diabetes was actually diagnosed during hospitalisation for COVID-19.

Microvascular complications (eye, kidney and nerves) were found in 47% of the subjects in the study, while macrovascular complications (arteries of the heart, brain, legs) were present in 41% of the patients analysed. Across all patients in this study, by day 7 one in five (20.3%) had been intubated and placed on a ventilator in intensive care, and one in 10 (10.3%) had died. A further 18% had been discharged home at this point.

The presence of microvascular or macrovascular complications each more than doubled the risk of death at day 7. Advanced age also substantially increased the risk of death, with the group of patients aged 75 years and more than 14 times more likely to die than younger patients aged under 55 years, while patients 65-74 years old were three times more likely to die than those under 55 years. The presence of the respiratory condition obstructive sleep apnoea almost tripled the risk of death at 7 days, as did the presence of dyspnoea symptoms (shortness of breath).

The study also confirmed that insulin, and indeed all treatments for modifying blood sugar, are not a risk factor for severe forms of COVID-19 and should be continued in patients with diabetes. Encouragingly, there were no deaths in patients under 65 years old with type 1 diabetes, but the authors highlight there were only 39 patients with type 1 diabetes in this study and other work is ongoing to establish the effect of COVID-19 in this specific population.

Increasing BMI raised the risk of reaching the combined primary outcome of the study (intubation/ventilation or death at day 7). Women were 25% less likely to reach the combined primary endpoint than men (a result that had borderline statistical significance). However, when looking at death only, men were not statistically more likely to die at day 7 than women.

The authors say: "The risk factors for severe form of COVID-19 are identical to those found in the general population: age and BMI."

They add: "Elderly populations with long-term diabetes with advanced diabetic complications and/or treated obstructive sleep apnoea were particularly at risk of early death, and might require specific management to avoid infection with the novel coronavirus. BMI also appears as an independent prognostic factor for COVID-19 severity in the population living with diabetes requiring hospital admission. The link between obesity and COVID-19 requires further study."

The authors plan to publish further work in the summer detailing outcomes of some 3000 patients with diabetes hospitalised with COVID-19, looking at their status 28 days after admission to hospital. The next study will also make more detailed comparisons of COVID-19 outcomes in patients with and without diabetes.

The combination of carfilzomib, lenalidomide, and dexamethasone (KRd) did not show superior efficacy in patients with newly diagnosed myeloma absent a high-risk disease prognosis, compared with the standard of care--bortezomib, lenalidomide, and dexamethasone (VRd). Data from a planned interim analysis for efficacy and toxicity for the ENDURANCE (E1A11) randomized phase three trial will be presented in the plenary session of the American Society of Clinical Oncology (ASCO) annual meeting to occur virtually from May 29-31 (Abstract LBA3). The data safety monitoring committee for the trial recommended the release of the interim data based on futility.

The ECOG-ACRIN Cancer Research Group designed and conducted the ENDURANCE trial with funding from the National Cancer Institute, part of the National Institutes of Health.

"There was no improvement in progression-free survival by replacing bortezomib with carfilzomib in the current standard initial treatment of patients with newly diagnosed standard- or intermediate-risk myeloma, even though we observed a higher very good partial response rate with the carfilzomib combination," said lead investigator Shaji K. Kumar, MD (Mayo Clinic). "We observed more severe cardiac, pulmonary, and renal toxicities with carfilzomib, while neuropathy was more common among those receiving bortezomib."

The combination of bortezomib, lenalidomide, and dexamethasone (VRd) is the current standard initial therapy in patients with newly diagnosed multiple myeloma. Carfilzomib (Kyprolis®, Amgen) is a next-generation proteasome inhibitor. It is used to treat patients with relapsed or refractory multiple myeloma who have received one to three previous treatments for multiple myeloma. Carfilzomib is FDA-approved for use in combination with dexamethasone or with lenalidomide plus dexamethasone.

In the ENDURANCE trial, patients with newly diagnosed multiple myeloma were randomized to receive VRd or KRd (1:1) for 36 weeks (induction) and stratified based on intent for transplant at disease progression. Upon completion of induction treatment, patients were randomized a second time to receive indefinite lenalidomide maintenance versus two years (1:1). Currently, following standard treatment, patients often receive lenalidomide as maintenance therapy until disease progression. However, the ideal duration of maintenance is presently unknown and will be addressed as part of this trial.

Among the key eligibility criteria for the ENDURANCE trial was no intent for immediate autologous stem cell transplantation (ASCT) or ineligible for ASCT. Patients with a high-risk disease prognosis as defined by genetics [t(14;16), t(14;20) or deletion 17p on FISH; high-risk GEP70 signature] or clinically (serum LDH >2xULN; plasma cell leukemia) were not enrolled.

The ENDURANCE study enrolled 1087 patients between December 2013 and February 2019 at 272 centers in the US. The median age was 65 years. As of the planned second interim analysis (data cut-off January 7, 2020), there were 298 progression-free survival (PFS) events (75% of 399 events at full information). Median PFS (95% CI) was 34.4 (30.1 to NE) months for VRd compared with 34.6 (28.8 to 37.8) months for KRd; the PFS treatment hazard ratio (HR=KRd/VRd) in a stratified analysis was 1.04 (95%CI, 0.83 to 1.31); P=0.742.

Grade 3 or higher treatment-related non-hematologic toxicity rates were 41% for VRd and 48% for KRd; P=0.024. Very good partial response rates were higher on the KRD arm (74% versus 65%); P=0.002. At 29 months of follow-up, the three-year OS probability (95% CI) is 0.84 (0.80 to 0.88) for VRd and 0.86 (0.82 to 0.89) for KRd.

Dr. Kumar continued: "The ENDURANCE study highlights the importance of using data from phase three trials to drive clinical practice. Although phase two trial data suggested a better outcome with KRd, compared to historical data with VRd, this has not borne out in the phase three ENDURANCE trial. It also raises concern for toxicities, which need to be carefully monitored for."

The following cooperative research groups in the NCI's National Clinical Trials Network all collaborated in the trial: Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, NRG Oncology, and SWOG.

"This trial represents another success for the National Clinical Trials Network. We found that a regimen that was very promising in small phase two studies was not better than the current standard, but in fact, was associated with more side effects. To me, it reemphasizes the importance of randomized controlled trials in oncology," said ECOG-ACRIN Myeloma Committee Chair S. Vincent Rajkumar, MD (Mayo Clinic).

Dr. Kumar concluded: "Based on this analysis, VRd should remain the standard of care for standard and intermediate-risk newly diagnosed multiple myeloma patients who are ineligible or will defer transplant, and it should be the backbone for adding newer therapies for those patients."

If physical distancing measures in Ontario are relaxed too much or too quickly, the province could see hospitals overwhelmed with COVID-19 patients as well as exponential growth in deaths, concludes new research involving a University of Guelph infectious disease modeller.

The findings, contained in a research letter published in Annals of Internal Medicine, suggest that if Ontarians increase their contacts to normal levels in the coming weeks, the virus will quickly spread and result in cases exceeding hospital ICU (intensive care unit) capacity.

Population medicine professor Amy Greer, Canada Research Chair in Population Disease Modelling, and University of Toronto researchers used a mathematical model for this study that they developed in early spring.

"At that point, there were not a lot of cases and we were looking ahead to what could happen. This paper goes back, uses the same model, but updates it by calibrating it with observed Ontario data as well as data on what we now know about the biology of the disease," Greer said.

After including confirmed patients occupying ICU beds in Ontario between March 19 and May 3 as well as COVID-19 deaths among hospitalized patients, they found that had Ontario not imposed strict physical distancing measures in mid-March, the province would have seen five times as many deaths.

Deaths among hospitalized patients without intervention were projected to have been 12.7 deaths per 100,000, compared with 2.5 deaths per 100,000 with physical distancing.

"When you fit the model that we had to the data we observed, it does demonstrate that physical distancing has been impactful. We averted a large number of cases and were able to protect limited health infrastructure such as ICU beds and ventilators," she said.

The team also looked at how long it would take to exceed ICU capacity under relaxed physical distancing measures with no compensating steps.

Assuming that physical distancing measures reduced contacts in Ontario by 70 per cent, hospitals would be overwhelmed in only 35 days with no distancing measures.

Even if current restrictions stay in place until mid-June fully dropping distancing measures would lead to an overwhelmed health-care system in only 41 days, the researchers found.

Increasing contacts to anything greater than 50 per cent of pre-pandemic levels would lead to a spike in hospitalizations and deaths in the coming months, assuming that no other measures are implemented to control the spread of the virus.

"The amount of contact that happens as we begin to relax is a major factor for determining how quickly ICU capacity is exceeded," Greer said.

She said the only way to relax physical distancing safely is to vastly increase COVID-19 testing and to trace contacts of infected patients to urge them to self-isolate.

"If we let up on physical distancing without concurrent increases in testing and tracing, there is a rapid return to exponential growth."

Leesburg, VA, May 28, 2020--An investigation published open-access in the American Journal of Roentgenology (AJR) revealed a high frequency of negative chest CT findings among pediatric patients with laboratory-confirmed coronavirus disease (COVID-19), while also suggesting that bilateral, lower lobe-predominant ground-glass opacities (GGOs) are common in the subset of patients with positive CT findings.

"To our knowledge," wrote first author Sharon Steinberger from the Icahn School of Medicine at Mount Sinai, "this case series is the largest series to date that describes the imaging findings of pediatric patients with COVID-19."

Reviewing the CT findings and clinical symptoms of 30 pediatric patients (aged 10 months to 18 years) who tested positive for COVID-19 via quantitative real-time reverse transcription-polymerase chain reaction (rRT-PCR) at six centers in China from January 23 to February 8, 2020, Steinberger and colleagues noted that two cardiothoracic radiologists and a cardiothoracic imaging fellow characterized and scored the extent of lung involvement.

"CT findings were often negative (77%)," Steinberger et al. concluded, adding that positive CT findings seen in children included GGOs with peripheral lung distribution, crazy paving pattern, as well as the halo and reverse halo signs.

Consistent with reported symptomatology in children, the authors of this AJR article also observed a correlation between increasing age and increasing severity of findings.

Further questioning the utility of CT in the diagnosis and management of COVID-19 in children, 11 of 30 patients (37%) underwent follow-up chest CT--with 10 of 11 examinations (91%) showing no change.

For most people who die of cancer, the spread of the initial tumor is to blame. "Metastasis is what kills most cancer patients," says Serge Fuchs, a professor in Penn's School of Veterinary Medicine. "Yet there are not many, if any, drugs that specifically target metastatic processes."

In a paper in the journal Nature Cancer, Fuchs teamed with researchers from around campus and elsewhere to overcome that lack, studying the molecular players that foster cancer's spread and identifying a strategy to stop it. Using an inhibitor of the enzyme known as p38α kinase (p38), they successfully reduced the spread of melanoma in a mouse model, significantly prolonging survival time.

"In my opinion, this kind of therapy could be used in conjunction with surgery to remove the primary tumor or perhaps other cancer treatments, such as chemotherapy," says Fuchs.

The study emerged from conversations and collaborations that have been ongoing for years among Penn groups, including those of Penn Vet's Ellen Puré and the Perelman School of Medicine's Constantinos Koumenis, Sandra Ryeom, and Ben Stanger, as well as the nearby Wistar Institute's Dmitry Gabrilovich. All focus on different aspects of cancer biology.

Many of these conversations revolved around what are known as tumor-derived factors (TDF): the various proteins, lipids, vesicles, genetic material, signaling molecules, and other compounds that tumors secrete and which, in some cases, travel around the body. Scientists believe many of these factors help "prepare the soil," as it is often described, for the growth of metastases, making areas in the normal tissues more hospitable to tumor cells that are likewise traveling the body and disseminating to these areas.

"We kept saying how the tumors and the factors are so different and their chemical nature is so different and their receptors are different and how they're perceived by different types of normal cells," Fuchs says. "But these areas in the lung that invite disseminated malignant cells and are conducive to their growth as metastases are, generally speaking, all alike."

Aiming to focus on what united metastases, the researchers initially looked for elements that distinguished melanoma tumor cells that tended to be more metastatic from a melanoma cell line that was less so. When they introduced TDF from the more aggressive disease into normal mice, these animals developed pre-metastatic niches: areas conducive to the development of cancer metastases. Animals that received TDF from a less aggressive form of melanoma hardly developed these niches.

They also paid attention to the p38, as it is known to be activated in response to certain factors secreted by cancer cells. They observed that its activation correlated with metastasis, becoming more highly activated by the TDF from the highly metastatic melanoma and less activated by the less metastatic melanoma.

To confirm that this enzyme was important in the metastatic process, the team tried two tactics: either eliminating the enzyme using genetic manipulation or blocking the effect of the kinase's activity using an inhibitor that stopped the pathway it activates.

"By doing either of these, we didn't get a pre-metastatic niche," says Fuchs.

To give their findings a clinical context, they looked at white blood cells from patients with melanoma. Those who did not have signs of metastasis had significantly lower p38 activation than those with a diagnosis of metastatic disease.

Next they examined the lungs of mice that were given the TDF from a metastatic cancer to learn more about what p38 was doing to cultivate the pre-metastatic niche. The team found that activation of p38 by TDF in lung fibroblasts, which are connective tissue cells, increased the fibroblasts' activity and stimulated production of fibroblast activating protein (FAP), a molecule which Puré has long focused on and which has been shown to influence tumor growth and metastasis. Production of FAP then helped to recruit immune cells called neutrophils, which further acted on the pre-metastatic niche areas within lung tissue to augment their ability to trap and stimulate the growth of metastatic cells.

Hoping to prevent the formation of this niche and, ideally, metastasis, Fuchs and colleagues treated mice with two different inhibitors of p38, while also surgically removing their primary tumors. Both treatments suppressed the spread of cancer to the lung and prolonged the animals' survival.

One of the therapies they tested, ralimetinib, is an experimental cancer drug with somewhat lackluster performance at treating primary tumors. But initial trials have shown it to be relatively safe, suggesting that it could be a specialized component of the cancer-fighting arsenal, tamping down the primary tumor's ability to spread.

PITTSBURGH-- Faced with a common peril, people delay making decisions that might save lives, fail to alert each other to danger and spread misinformation. Those may sound like behaviors associated with the current pandemic, but they actually surfaced in experiments on how social networks function in emergencies.

Hirokazu Shirado, an assistant professor in Carnegie Mellon University's Human-Computer Interaction Institute, said he had expected his experiments to show that social networks, such as neighbors, work groups and extended families, would improve decision-making by giving people actionable information.

"What we found is that social networks make things worse," said Shirado, who began the research while a member of the Human Nature Lab at Yale University. A paper on their work appeared this week in the Proceedings of the Royal Society A.

Gathering data about social networks in the midst of a crisis is difficult, so Shirado devised a game in which online participants had an economic stake in making a decision whether to evacuate in the face of danger. He recruited 2,480 subjects and organized them into 108 groups, comparing how networked groups and isolated individuals compared in their decision making.

Participants received $2 at the outset of the 75-second experiment. If nothing happened, they could keep the $2 at the end. But if there was an impending disaster, they could leave the game and retain $1. If they failed to evacuate and disaster struck, they lost everything. They also received 10 cents for every other player who made a correct decision on whether to leave the game.

The participants thus had every incentive to choose correctly and were encouraged to communicate with each other. One member of each social network group also received the correct information about impending danger.

Compared with the isolated individuals, the networked players consistently tended to resist evacuation, regardless of whether the danger was real or not. Communication didn't improve decision-making so much as it delayed it, Shirado said. The networked players also generated misinformation, even though nobody had an incentive to do so.

One of the problems, he said, is that players didn't realize that they often used different strategies. A player who accepts "no news is good news," for instance, might think that all is safe simply because he hasn't heard anything. He might then send "safe" signals to other members of the group even though danger lurked. In other cases, players might be unable to learn the truth because the players adjacent to them all had bad information.

Shirado has used the same game as an educational tool in his CMU classes, including one instance just before the onset of the COVID-19 pandemic. He recalled one student was skeptical, arguing that there was no reason why the players couldn't choose correctly. But about 70 percent of the students -- including the skeptic -- erred in their decisions.

"Inside the networks, people could not understand why this was happening," he added.

Social media -- one type of social network -- was not included in the study, but might actually improve performance, Shirado said. Though individuals tend to follow like-minded people on social media, it's also easy to connect with others who might fall outside normal social networks, providing a way around some of the barriers that form within networks.

Shirado said he hopes to find ways of improving the performance of social networks.

"We cannot live without social networks," he explained. "I'm interested in how social networks can provide a benefit to individuals."

He acknowledged that one of the shortcomings of his experiment is that it was too simple and involved people who were randomly assigned into networks. Future experiments will require players to play several times with the same network of individuals, so they might learn who to trust.

May 27, 2020, NEW YORK, NY - As chromosomes go, X and Y make an unlikely pair. The X is large and contains thousands of genes critical for life. The Y, by contrast, is little more than a nub. Its main purpose is to provide the instructions for initiating male development and making sperm. Yet these two very different chromosomes must work together if they are to meet and pair up properly during meiosis -- the special form of cell division that creates sperm and egg.

How this happens has remained mysterious for decades. But scientists at the Sloan Kettering Institute have now figured it out. The answer involves some very deliberate breaking and rejoining of DNA.

Breaking is a theme of meiosis. During this process, every chromosome we got from our mothers lines up with every chromosome we got from our fathers and the two swap segments. Before this swapping can occur, the DNA in the chromosomes must be deliberately broken. The regions that are swapped are "homologous" -- they're found in the same place along the chromosome and contain the same genes (although the particular DNA sequence of each gene may be slightly different).

Homologous recombination is vastly more challenging for males because most of the X chromosome has nothing to pair with. In fact, only a very tiny portion of the already tiny Y chromosome has any homology with the X. This region is called the pseudoautosomal region (PAR), and it's critical for making sure that X and Y find their way into different sperm cells.

Scientists have known for a long time that the PAR undergoes breaking and swapping of segments at a level that far outpaces what one would expect, given its size.

"On most chromosomes, DNA double-strand breaks typically occur once every 10 million base pairs," says Scott Keeney, a molecular biologist at SKI, who studies this phenomenon. "The PAR in mice is less than 1/10 that size but it still manages to undergo frequent double-strand breaks."

In a new study published May 27 in the journal Nature, Dr. Keeney and colleagues -- including molecular biologist Laurent Acquaviva and longtime collaborator Maria Jasin -- show how this happens.

What's in a Blob?

The key to proper pairing of X and Y, they discovered, is a repeated sequence of DNA in the PAR that attracts several double-strand break-related proteins to this region. These protein clusters -- which Dr. Acquaviva dubbed "blobs" -- change the architecture of the chromosome in this region in such a way that the PAR becomes, as the authors put it, "the hottest area of double-strand break formation in the male mouse genome."

Similar blobs had been seen in images from published studies. But Dr. Acquaviva -- a postdoctoral fellow in the Keeney lab, the lead researcher on the project, and a co-corresponding author on the paper -- was the first to define what's in these blobs and connect them to the hyper-accumulation of double-strand breaks in this region.

"At first glance, the blobs just look like a mess you might see in the microscope if the experiment didn't work," Dr. Acquaviva says. "But they turned out to be completely predictable in number, timing, and location, so it became clear that in reality they are very complex structures that the cell builds on purpose."

In fact, he says, these blobs were key to understanding how the PAR DNA is tethered as short loops to the linear axis that is the structural backbone of the chromosome.

Though the X chromosome also has this same repeated DNA sequence, the two X chromosomes in female meiosis typically do not recombine at this region. Why not? The SKI scientists show that it is because pairing between other regions of the X tends to happen first and directly opposes breakage at the PAR.

This strategy of recruiting more than one's expected share of DNA-breaking proteins may not be limited to the PAR region. In a paper published earlier this month, the Keeney lab showed that small chromosomes in budding yeast resort to a similar tactic.

Groundbreaking Partnership

These new discoveries, which were made in mice, are the latest fruit of a longstanding collaboration between the Keeney and Jasin labs at SKI. "Scott and I began collaborating back in 1997 when he joined SKI," she says. "This paper will be our 40th together. It's a tribute to the collaborative atmosphere of SKI." In fact, an accompanying editorial published along with the new paper was written by a former collaborative fellow, Francesca Cole, now a faculty member at MD Anderson Cancer Center.

Drs. Jasin and Keeney are both interested in homologous recombination, but they bring complementary expertise to their collaboration. Dr. Jasin is an expert in mammalian double-strand break repair and Dr. Keeney is a specialist in how yeast does meiosis.

Last month, the team's 39th paper was published in the journal Molecular Cell. In it, they provide the most detailed look yet into how double-strand breaks are repaired. "I am hoping it will change the textbook version of how DNA strands move around during meiotic recombination," Dr. Jasin says. "But many exciting questions still remain to be tackled." In other words, stay tuned for more 'breaking' news from this team of scientists.

As the novel coronavirus spread across the globe in early 2020, hospitals worldwide scaled back medical procedures, including life-saving heart surgery, to deal with the emerging threat of COVID-19. Now, as the SARS-CoV-2 virus becomes a chronic fact of life, hospitals must find ways to resume cardiac surgeries while protecting patients and health care workers as much as possible from SARS-CoV-2.

Dr. Marc Ruel, professor in the Departments of Surgery and Cellular and Molecular Medicine at uOttawa Faculty of Medicine, and M. Pitfield Chair & Head, Division of Cardiac Surgery at the University of Ottawa Heart Institute, is the senior author of two recent articles that examine how cardiac surgery centres have been impacted by the COVID-19 pandemic, and how they can resume operations in an environment characterized by a low-grade, long-term prevalence of SARS-CoV-2.

"Cardiac surgeons, who provide lifesaving procedures, must manage two threats at the same time: obviously the threat from COVID, and that of death or complications from untreated heart disease. As such, patients with the most pressing cardiac needs have to be triaged as objectively and as reliably as possible, using predictor tools such as the one developed at the University of Ottawa by my colleague Dr. Louise Sun, from the Department of Anesthesia and Pain Medicine," Dr. Ruel said. "Every day we strive to preserve capacity for a possible COVID surge, but at the same time we must optimally manage our many patients who need heart surgery, help ease their anxieties, and safely return them to enjoying a healthy life."

In the first article, "Response of Cardiac Surgery Units to COVID-19: An Internationally-Based Quantitative Survey," published in Circulation, Dr. Ruel and his co-authors found that 60 cardiac surgery centres in 19 countries had reduced their cardiac surgeries by an average of 50 to 75% in response to the pandemic.

"The widespread interruption in cardiac surgery described herein adds to the concerning observation that excess non-COVID-19 mortality may now surpass mortality directly related to COVID-19 infections," the article noted.

The second article, "Committee Recommendations for Resuming Cardiac Surgery Activity in the SARS-CoV-2 Era: Guidance from an International Cardiac Surgery Consortium" published in The Annals of Thoracic Surgery, contains 12 recommendations developed by a consortium of experts in 19 countries. The recommendations cover topics such as: prioritizing surgeries; dealing with cardiac patients who test positive for COVID-19; and patient discharge and follow-up protocols.

DURHAM, N.C. – Small-scale gold mining in the Peruvian Amazon poses a health hazard not only to miners but also to nearby communities. Contrary to common assumption that communities closest to mining bear the brunt of exposure, new evidence shows that the highest non-occupational mercury exposures occur in native communities hundreds of kilometers away from mining.

In communities where fish is an important part of the diet, children under 12 with the highest levels of mercury in their hair (exceeding the World Health Organization guideline) have been found to have intellectual deficits amounting to a loss of 4.68 IQ points. Even children with exposure below this guideline show effects amounting to a 0.8 IQ point drop for every 1 part per million increase in hair mercury. This effect is roughly four times larger than detected in an earlier study of prenatal mercury exposure in the Republic of Seychelles.

Both findings come from a series of studies conducted by Duke University scientists in and around the Amarakaeri Communal Reserve in the Madre De Dios region of Peru. They appear in a pair of papers published May 20 GeoHealth and May 28 in the Journal of Exposure Science and Environmental Epidemiology.

The studies show that common assumptions about mercury exposure should be reexamined, and that native people in the region are more vulnerable to harm, probably because of their greater reliance on river fish, but also perhaps because their healthcare and standard of living is not as high.

“We can’t just rely on assumptions or “common sense” in science,” said lead author Caren Weinhouse, an assistant professor at Oregon Health & Science University. Many studies have looked at communities closest to the mines on the assumption that they would have the greatest mercury exposures. “We assumed that people closest to mining would have the highest exposure, but we were wrong,” she said. “The lesson is that if we only focus on the people we assume are at risk, we might end up missing the big picture.”

Artisanal and small-scale gold miners in the Peruvian Amazon use liquid elemental mercury to extract gold from soils and sediments. The mercury binds to the gold to form an amalgam, which is then extracted by burning, creating gaseous mercury that enters the atmosphere. The rest of the mercury ends up dumped on the landscape, which is ravaged and eroded by the mining. Miners are also known to simply pour excess mercury directly into surface waters.

As the mercury travels and mixes with the environment, it becomes methylmercury, which is more readily taken up by animals and tends to ‘bio-accumulate’ or add up in tissues, and then “biomagnify” as bigger fish eat contaminated little fish. Although all native communities showed high exposure, their river locations shed light on the likely exposure source. In two sampled native villages that were on tributaries of the Madre de Dios River, mercury exposure was lower than in native people living on the main stem of the river where mining runoff is concentrated, leading the scientists to conclude that fish is the likely exposure source and mining is the likely culprit.

Mercury is a neurotoxic metal that can lead to muscle weakness and problems with coordination in high doses, and neurodevelopmental delay, hyperactivity and IQ deficits in lower doses.

To gather data on hair and blood concentrations of mercury, both near mining operations and farther away, the researchers visited 1,221 Peruvian households in 23 communities in 2015 and returned to resample 900 of those households the following year.

Some of the children in a subsample of the population had higher mercury levels and were on average lower in cognitive ability. A third of the children were found to have mercury levels higher than the World Health Organization’s exposure guidelines.

“We knew going in that mercury caused IQ deficits. What we didn’t know was whether the risk was the same in this setting as it is in prior studies, which were done in “healthy, wealthy” populations,” said Duke graduate student Aaron Reuben, who led the smaller pilot study on children. Reuben explained that children in Madre de Dios are already at high risk for IQ deficits, because they have poor nutrition and socioeconomic status.

An earlier, benchmark study of prenatal mercury exposure conducted in the Republic of Seychelles reported a loss of 0.18 IQ points for every 1 part per million increase in maternal hair mercury, an effect about four times lower than those in the Peru study. Hair mercury levels in both the Seychelles and Peru studies likely reflect fetal exposure, which allows comparisons of their results.

“This study suggests that mercury may affect brain development more at the same doses in higher risk populations,” said Reuben. He noted that the group didn’t account for the effects of possible prenatal exposure in the tested children.

The researchers also found initial evidence that the higher the mercury levels in a child’s blood, the lower their hemoglobin levels, corroborating an earlier study from this research team.

“Although mercury is not generally considered a risk factor for anemia, it might be in a population with other, pre-existing risk factors for the disease,” said William Pan, the Elizabeth Brooks Reid and Whitelaw Reid associate professor of environmental sciences and policy at Duke. “Given that anemia affects over 2 billion people and mercury is a global pollutant, this is a priority research area.” Another earlier study by the Duke team found that children with higher mercury exposures were less responsive to vaccines, especially if they were also malnourished.

“Taken together, the message is that we can’t assume that we know who is exposed unless we look, and we can’t assume that health risks will translate from developed countries,” Weinhouse said. “These studies show that highest exposures happen in vulnerable, native communities and that they might be at risk for even greater harm than healthy people with the same exposures.”

ITHACA, N.Y. - Bacteria have a cunning ability to survive in unfriendly environments.

For example, through a complicated series of interactions, they can identify - and then build resistance to - toxic chemicals and metals, such as silver and copper. Bacteria rely on a similar mechanism for defending against antibiotics.

In E. coli bacterium, the inner membrane sensor protein CusS mobilizes from a clustered form upon sensing copper ions in the environment. CusS recruits the transcription regulator protein CusR and then breaks down ATP to phosphorylate CusR, which then proceeds to activate gene expression to help the cell defend against the toxic copper ions.

Cornell researchers combined genetic engineering, single-molecule tracking and protein quantitation to get a closer look at this mechanism and understand how it functions. The knowledge could lead to the development of more effective antibacterial treatments.

The team's paper, "Metal-Induced Sensor Mobilization Turns on Affinity to Activate Regulator for Metal Detoxification in Live Bacteria," published May 28 in Proceedings of the National Academy of Sciences.

"We were really interested in the fundamental mechanism," said Peng Chen, the Peter J.W. Debye Professor of Chemistry in the College of Arts and Sciences and the paper's senior author. "The broader concept is that once we know the mechanism, then perhaps we can come up with better or alternative ways to compromise bacteria's ability in defending against toxic chemicals. That will hopefully contribute to designing new ways of taming bacterial drug resistance."

The bacteria's resistance is actually a tag-team operation, with two proteins working together inside the cell. One protein (CusS), in the inner membrane, senses the presence of the chemical or metal and sends a signal to a regulator protein (CusR) in the cytosol, or intercellular fluid. The regulator protein binds to DNA and activates a gene that generates transport proteins, which purge the toxin from the cell.

Typically, scientists analyze these functions by using biochemical assays that remove the protein from the cell. However, that process prevents the scientists from observing the proteins in their native environment, and certain details, such as the spatial arrangement between proteins, have remained murky.

For a deeper analysis, Chen's team used single-cell imaging, whereby they tagged individual proteins in living E. coli with a fluorescent signal and imaged the proteins one at a time, tracking their motions. The procedure yielded millions of images and, ultimately, a finely detailed, qualitative map of the proteins' movement.

The team was specifically interested in the activities of sensor proteins, which come in two varieties - those that cluster together and those that move around the inner membrane. The researchers found that when E. coli encounters copper, the free-floating, mobile variety of the sensor proteins increase in number while the clustered faction are reduced. The mobilized sensor proteins interact with the regulator protein and initiate a complex series of steps - from binding the copper to binding and breaking down the compound ATP, which eventually lead to gene expression - that will flush the metal from the cell.

"One of the unknowns among the steps is at what point the sensor protein forms a protein-protein complex with the regulator protein," Chen said. "We found that as soon as the sensor binds copper, it already causes its recruitment of this regulator protein. This occurs really, really early in this sequence of events."

The early recruitment provides a functional advantage by initiating the sequence and quickly speeding it along before the sequence has time to decay. Chen likens this strategy to a game of hot potato.

"If I hold a hot potato and want to give it to you, I don't want to hold the potato before calling you over," Chen said. "I want you to be right next to me, so I can immediately pass it to you. Otherwise, the hot potato becomes cold. Or it's too hot, so I have to throw it away. In chemical terms, basically that species would decay or transfer to something else."

ITHACA, N.Y. - A new study examines the symbiotic relationship between two types of bacteria and spittlebugs that helps the insect live on very low-nutrient food. The bacteria use a metabolic "trick" also employed by cancer cells to create the right conditions for converting the poor food into the necessary building blocks for survival.

The study, "Syntrophic Splitting of Central Carbon Metabolism in Host Cells Bearing Functionally Different Symbiotic Bacteria," published April 29 in the journal of the International Society for Microbial Ecology.

Spittlebugs get their name from the bubbly spit they create in plant branches. The clusters of spit keeps them from drying out and allow them to hide from predators. There they feed on xylem plant sap, a very low-value food; xylem transports water and minerals from the plant's roots to its leaves.

"No animal should be able to subsist on xylem alone - it's really just water and a few nutrients," said lead author Nana Ankrah, a postdoctoral researcher in the lab of Angela Douglas, the Daljit S. and Elaine Sarkaria Professor of Insect Physiology and Toxicology in the Department of Entomology in the College of Agriculture and Life Sciences.

The answers to how these bugs survive lie in two types of bacteria that live in separate spittlebug organs, called bacteriomes; one is red, the other orange. Other similar insects that feed on plant sap have just one bacterial partner to help produce high-quality amino acids, the building blocks of proteins.

"We wanted to understand if there were any advantages to having two bacterial symbionts on this very poor diet," Ankrah said.

The researchers collected local spittlebugs, removed their red and orange bacteriomes, incubated the bacteria separately in glucose, and ran metabolic experiments and computer model simulations.

They discovered that the red bacteriome uses a process known as aerobic glycolysis to process glucose, from which the bacteria synthesize seven essential amino acids. Two byproducts of this process, pyruvate and lactate, are assimilated by the orange bacteriome to create ATP molecules, which make energy for cells. The energy boost from ATP allows the bacteria in the orange bacteriome to produce three additional essential amino acids that require a great deal of energy to produce.

Having two bacterial partners instead of one works because they have this method for exchanging products from one bacterium to the other to increase the overall energy available to them, Ankrah said.

The researchers were surprised to find aerobic glycolysis occurring in these bacteria, as cancer cells employ the same process to survive, with a subset of cancer cells undergoing glycolysis and producing pyruvate and lactate, which another subset of cancer cells consumes to create energy.

"To our knowledge," Ankrah said, "our article is the first demonstration of aerobic glycolysis as a strategy to facilitate amino acid production in symbioses."

Future studies will investigate glycolysis in other insect and bacteria partnerships, he said.