Being like Mike — Fear, Trust, and the Tragic Death of Michael Davidson After all, violence against physicians, though common in countries such as China, is relatively rare in the United States. One study, for instance, found that between 2000 and 2011, about 154 “hospital-related” shootings occurred2; physicians were victims 3% of the time, and nurses 5%. One study, for instance, found that between 2000 and 2011, about 154 “hospital-related” shootings occurred2; physicians were victims 3% of the time, and nurses 5%. The violence that does occur is most common in emergency departments; in one survey of emergency physicians, 28% reported having been physically assaulted in the previous year.3 But though most physicians can name colleagues who’ve been targeted, data from the Bureau of Labor Statistics suggest that the incidence of homicides at general medical and surgical hospitals is similar to that in lawyers’ offices and lower than the rates in hotels, real estate offices, and government workers. If we overstate the problem of violence against physicians, we risk grasping for solutions that may cause more harm than good: Metal detectors? Armed physicians? The need to seek meaning in tragedy is fundamentally human, and yet the impulse to find reasons where there are none is as dangerous as it is therapeutic.That when something bad happens, we assume there’s a cause that can be remedied, that someone is accountable? We are trained to ask ourselves, Where did I err? How could I do better? We are told that some 98,000 patients die in the United States each year because of medical errors. To Err Is Human – building a safer health system Yet the analogy between airplanes and hospitals is seriously flawed: people don’t get on airplanes because they would otherwise die. This creates the notion of an impossible expectation: that no one should die. In our era of publicly reported outcomes, Davidson took on the highest-risk patients. In a clinical environment intent on increasing efficiency, he willingly gave patients his time. We have agreed to do all we can, while also recognizing when no more can be done. We will always strive to do better, but sometimes we will fail. Somehow, though, the public’s trust in our best intentions seems to have slipped away. How can we convince patients that we are all on the same side?
Most common to the health care setting is a situation in which the perpetrator has a legitimate relationship with the business and becomes violent while being served by the business (categorized as a type II assault).4,5 The highest number of such assaults in U.S. workplaces each year are directed against health care workers. Data from the Bureau of Labor Statistics show that health care workers are nearly four times as likely to require time away from work as a result of violence as they are because of other types of injury.
Furthermore, data from the federal Bureau of Labor Statistics may be grossly inaccurate,14,15 as shown by one study in which investigators found that the actual number of reportable injuries was as much as three times the number in the federal survey.
A systematic review of the literature workplace violence in the emergency department. Incidence of workplace violence in the emergency department has been well documented in numerous published studies. Emergency department workers are exposed to significant rates of physical and verbal abuse. Under-reporting ofworkplace violence in the emergency department is common and contributes to the difficulty in accurately tracking violence
How Much Work-Related Injury and Illness is Missed By the Current National Surveillance System << We calculated that the current national surveillance system did not include 61% and with capture-recapture analysis up to 68% of the work-related injuries and illnesses that occurred annually in Michigan. This was true for injuries alone, 60% and 67%, and illnesses alone 66% and 69%, respectively.
Although the mix of patients seen in EDs is not modifi- able, these factors, which set the stage for aggression, can be compounded by a lack of security on site. Few studies document the security practices in EDs. One Michigan study found that only about one-quarter of hospitals had security officers permanently assigned to the ED, with another 24% of EDs using general hospital security staff that made occasional rounds in the ED to protect ED staff. The toll of WPV may be higher for non-physician staff. One survey of 65 US EDs showed that nurses feel the least safe of all ED staff
Availability Cascades and risk regulations An availability cascade is a self-reinforcing process of collective belief formation by which an expressed perception triggers a chain reaction that gives the perception increasing plausibility through its rising availability in public discourse. The driving mechanism involves a combination of informational and reputational motives: Individuals endorse the perception partly by learning from the apparent beliefs of others and partly by distorting their public responses in the interest of maintaining social acceptance. Availability entrepreneurs-activists who manipulate the content of public discourse-strive to trigger availability cascades likely to advance their agendas. Their availability campaigns may yield social benefits, but sometimes they bring harm, which suggests a need for safeguards.
Availability cascades-social cascades, or simply cascades, through which expressed perceptions trigger chains of individual responses that make these perceptions appear increasingly plausible through their rising availability in public discourse. Availability cascades may be accompanied by counter-mechanisms that keep perceptions consistent with the relevant facts. Under certain circumstances, however, they generate persistent social availability errors-widespread mistaken beliefs grounded in interactions between the availability heuristic and the social mechanisms we describe.2 The resulting mass delusions may last indefinitely, and they may produce wasteful or even detrimental laws and policies.
Emergency department visits involving misuse or abuse of prescription opioids increased 153% between 2004 and 2011, and admissions to substance-abuse treatment programs linked to prescription opioids more than quadrupled between 2002 and 2012.
N-of-1 Policymaking — Tragedy, Trade-offs, and the Demise of Morcellation From a policy perspective, the FDA has a mandate to keep the public safe, but medical products are associated with two types of risk: that caused by using the products and that caused by preventing their use. “I am unable to find a single instance where a congressional committee investigated the failure of FDA to approve a new drug. But the times when hearings have been held to criticize our approval of new drugs have been so frequent that we aren’t able to count them. The tendency to focus on eliminating an immediate harm while failing to consider potentially greater harms caused by that reaction is heightened by the power of tragic stories.Major policy and behavioral shifts often arise from visible tragedies. Residents’ duty-hour limits, for instance, sprang from the death of Libby Zion, which was attributed to resident fatigue; the death of Jesse Gelsinger during a gene-therapy trial led to an abrupt cessation of such research, delaying potential therapeutic benefits by years.At the individual level, such “availability bias” helps explain why we might hesitate to use anticoagulation therapy in a patient at risk for thromboembolism if we’ve just cared for a similar patient who had a rare bleeding complication At a broader level, a tragedy that focuses attention on a potential harm may lead to reactive behaviors or policies that ultimately pose more danger than the original threat. After 9/11, for instance, there was a sharp uptick in deaths from car accidents: many Americans, afraid to fly, traveled by car instead, although the latter carries a far greater risk of death.Media coverage featured the faces of women dying of LMS, ravaged by chemotherapy, flanked in photos by their husbands and young children. Meanwhile, the benefits of morcellation are largely invisible and thus “unavailable.” Who sees the women who undergo a minimally invasive procedure, recover quickly, and avoid losing income? What does a pulmonary embolus, a wound infection, or a hemorrhage that didn’t happen look like? You can’t post pictures of these nonevents on social media. But no matter how effectively the FDA separates reason from emotion in making decisions, its actions may ultimately carry less weight than the public outrage that catalyzes them.How do you use data to clarify tough trade-offs when the most compelling narratives paint evidence-based reasoning itself as anathema? In regards to silicone implants: But it seemed plausible that this foreign, “unnatural” substance could be toxic. When Dow Corning, the largest implant manufacturer, was accused of withholding knowledge of an increased risk of autoimmune disease, the narrative trifecta was complete: greedy corporation, vulnerable women, and self anointed “experts” who broadcast the purported harms, condemning anyone willing to propagate those harms as immoral. None of the data collected in the 14 years between the moratorium and the FDA’s 2006 approval of the implants for augmentation purposes supported the allegation that they caused autoimmune disease. But scientific reality mattered little to the media, the plaintiffs’ attorneys, and the thousands of American women with implants, half of whom registered for the $4.25 billion class-action settlement with Dow Corning. The chain of events typified what Cass Sunstein and Timur Kuran call “an availability cascade,” a phenomenon whereby stories inform public perceptions and anyone challenging those perceptions is vilified.The influence of such anecdote-driven representations of risk is as much social as cognitive: while people proclaiming the intolerability of the purported risk become heroes, those questioning its existence or magnitude are branded as heartless, so many people with a more accurate understanding of risk remain silent. Availability cascades often depend on “availability entrepreneurs” who claim the moral high ground and exploit reporters eager to break stories of transgression. For instance, he argues that informed consent merely fosters an “illusion of autonomy,” which primarily protects physicians from lawsuits. He emphasizes the inadequacy of postmarketing surveillance, driven by underregulated efforts to collect data on rare harms. As our patient-safety focus intensifies and physicians’ behavior is publicly dissected, a story that goes viral has outsized power. Questioning narratives that portray the victimization of the innocent seems monstrous. s. Policy debates often degenerate, their crux shifting from “Do this solution’s benefits outweigh its risks?” to “Are you good or evil?” Whether benefits outweigh risks is a value judgment, but evaluating such trade-offs is our job. Taken to their logical conclusion, arguments against assuming small risks in pursuit of larger social benefit imply that we’re ethically obligated never to do anything. Maisonneuve _ Worth the Risk_ < story of morcellation.
Zero pain is not the goal <<< There is, quite simply, no “getting it right” when it comes to pain. It is both undertreated and overtreated. It is ubiquitous, subjective, and sometimes feigned. Its experience is influenced by culture and varies among individuals, and its diagnosis easily distorted by bias. No wonder, then, that clinicians are concerned about being evaluated on their effectiveness in relieving patients’ pain, and policy makers are concerned about overuse of opioids contributing to narcotics addiction. But pain is part of life and part of medicine, as are patients’ fears about what the painmeans, whether it will worsen, and whether it will ever end. Clearly, giving sufficient analgesia to eliminate all pain for all patients is a wrong target—but so is treating pain insufficiently. A simple and useful framework for thinking about health care in general and pain in particular can be drawn from Sinek’s famous 2009 TED talk, “How Great Leaders Inspire Action,”2 which has been viewed more than 25 million times. In it, Sinek explores how leaders and organizations “can inspire cooperation, trust, and change”—reasonable goals for health care leaders and for individual clinicians. Great health care should begin with clarity about its purpose—and the why for health care has always been the reduction of suffering. This suffering includes physical pain and functional impairment, as well as fear, uncertainty, and confusion. Suffering is, of course, inherent to medicine; the word patient comes from the Latin for “one who suffers.” But some of that suffering can be avoided, much of it can be reduced, and there is no ambivalence in health care about the goal of reducing suffering. The what of health care is more than difficult: it is complex. Multiple issues matter to patients, and clinicians must do their best to weigh values that are often in conflict. For example, when considering an invasive procedure, physicians must balance immediate risk against longer-term benefits. Zero cannot be considered an ideal surgical mortality rate, because surgeons who achieve it are probably overvaluing short-term risk over potential improvement in outcomes compared with their colleagues. Similarly, performance data for which there is no “ideal” target can help clinicians understand if they are juggling the competing values in medicine differently from their colleagues. For example, there is no “right” rate of radiology test utilization, but physicians who have high rates should consciously reflect if theymight be overusing these tests, and physicians with the lowest rates should wonder if they are underusing them. When 100% is not the goal, measures should not be used to classify physicians as “good” or “bad” or to rank them. However, these measures could be used by outlier clinicians to recognize when they might have an opportunity to learn something from their colleagues.Guidelines such as these do not tell clinicians what to do with individual patients, but they offer a frame of reference.Patients want good clinicians, they want coordination, they want good communication, and they want compassion. After these factors are considered, issues such as pain control and waiting time are not drivers of patients’ overall experience with their care and their likelihood of recommending hospitals and physicians.
While many people get a headache after drinking alcohol, migraineurs have more severe headaches induced by fewer drinks. Using a rat model of migraines, Michael Oshinsky of Thomas Jefferson University and colleagues show that the headache is caused by an alcohol metabolite, acetate, and that the pain can be blocked by caffeine.
Researchers long assumed that the alcohol metabolite acetaldehyde caused alcohol-induced headaches, because disulfiram, a drug that blocks the breakdown of acetaldehyde to acetate in the bloodstream, causes headaches after a few drinks. However, acetaldehyde is metabolized quickly enough that it never reaches headache-causing levels without disulfiram, leading Oshinsky to question this hypothesis.
After sensitizing a pain circuit in the rats’ brains, the researchers varied the concentrations of alcohol metabolites in the rats’ blood to test which gave them headache-like pain. Higher concentrations of acetaldehyde did not cause a headache, but increased acetate did. “They challenged what had been a common assumption and showed that it just didn’t make any sense,” said F1000 member Peggy Mason.
Acetate can cause pain through the accumulation of one of its metabolites, adenosine. When caffeine, an adenosine receptor antagonist, was administered after alcohol, pain was blocked—but only until the caffeine was broken down. Next up is to see if the same mechanism holds true in nonmigraine alcohol-induced headaches.
Researchers have long realized that consuming a fiber-rich diet can suppress appetite and reduce food intake in mice and humans alike, a phenomenon previously attributed to the release of gut hormones. Writing in Nature Communications today (April 29), Imperial College London’s Gary Frost and his colleagues showed that small amounts of the short-chain fatty acid acetate, released as a result of the fermentation of dietary fiber in the mouse gut , accumulates within certain neurons in the animal’s hypothalamus, a part of the brain that helps regulate hunger.
For the first time, the researchers have traced “a link between fermentation in the lower part of the gut—the colon—with activity in the brain,” said Patrice Cani, who co-leads the Metabolism and Nutrition Research Group at Université Catholique de Louvain in Belgium, and was not involved in the work. “The originality was to show that acetate can in fact circulate and reach the brain . . . and affect appetite.”
Frost’s team was among the many that had been focusing on gut hormones, such as peptide YY and glucagon-like peptide-1, finding that these could directly affect neurons within the hunger-regulating hypothalamus. But using manganese-enhanced MRI (MEMRI) the researchers found “unusual brain signaling” in appetite-suppressed mice fed a fiber-rich diet, Frost said. “You’d usually expect that the actual activation levels [of hypothalamic neurons] to fall if the animal’s appetite is suppressed, but they actually go up.”
Frost’s group and others had previously studied several short-chain fatty acids produced through fiber fermentation in the gut and implicated in brain-based appetite regulation. Fatty acids propionate or butyrate have been well-studied, for example, but acetate—the most abundant short-chain fatty acid produced in the colon—has been “neglected so far—at least in the context of appetite regulation,” said Cani.
To investigate the role of acetate in appetite suppression, Frost and his colleagues used 13Carbon labeling to image the fatty acid from the mouse gut within the brain, and found that around 5 percent of the acetate was preferentially taken up by the hypothalamus. (Most acetate is processed within the colon itself, or by the liver—through a well-studied process related to the metabolism of alcohol.) They also showed that colonic administration of acetate was associated with reduced appetite and food intake in mice.
“Gary [Frost’s team] already demonstrated the in-brain activity of neurons involved in food intake,” said Cani, referring to a 2007 PLOS ONE paper, “but he couldn’t at that time really link the molecules sending the signals from the gut.” Little did anyone realize that “acetate was one of those molecules,” he added.
Of course, the biggest question at this point is whether acetate has similar appetite-suppressing effects in humans. “Currently, in western society, we probably consume somewhere between 12 to 14 grams of dietary fiber per day,” said Frost. “Our work [in mice] suggests that to reliably see appetite-suppressive effects, you’d need around 30 to 35 grams—nearly three times what we normally eat.”
He added that his team is now also working to determine whether targeted delivery of acetate could be a viable therapeutic option for conditions like obesity down the line.
The opioid system in the gastrointestinal tract
Common pain relief medication may encourage cancer growth
November 18, 2009
Although morphine has been the gold-standard treatment for postoperative and chronic cancer pain for two centuries, a growing body of evidence is showing that opiate-based painkillers can stimulate the growth and spread of cancer cells. Two new studies advance that argument and demonstrate how shielding lung cancer cells from opiates reduces cell proliferation, invasion and migration in both cell-culture and mouse models.
The reports–to be presented November 18, 2009, at “Molecular Targets and Cancer Therapeutics,” a joint meeting in Boston of the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer–highlight the mu opiate receptor, where morphine works, as a potential therapeutic target.
“If confirmed clinically, this could change how we do surgical anesthesia for our cancer patients,” said Patrick A. Singleton, PhD, assistant professor of medicine at the University of Chicago Medical Center and principal author of both studies. “It also suggests potential new applications for this novel class of drugs which should be explored.”
The proposition that opiates influence cancer recurrence, prompted by several unrelated clinical and laboratory studies, has gradually gained support. It started with a 2002 palliative-care trial in which patients who received spinal rather than systemic pain relief survived longer. Soon after that, Singleton’s colleague, anesthesiologist Jonathan Moss, noticed that several cancer patients receiving a selective opiate blocker in a compassionate-use protocol lived longer than expected. Two recent retrospective studies found that breast and prostate cancer patients who received regional rather than general anesthesia had fewer recurrences. In February, 2009, the Anesthesia Patient Safety Foundation highlighted the issue.
Moss’s palliative-care patients were taking methylnaltrexone (MNTX), developed in the 1980s for opiate-induced constipation by the late University of Chicago pharmacologist Leon Goldberg. Goldberg modified an established drug that blocks morphine so that it could no longer cross the protective barrier that surrounds the brain. So MNTX blocks morphine’s peripheral side effects but does not interfere with its effect on pain, which is centered in the brain. It won FDA approval in 2008.
“These were patients with advanced cancer and a life expectancy of one to two months,” Moss recalled, “yet several lived for another five or six. It made us wonder whether this was just a consequence of better GI function or could there possibly be an effect on the tumors.”
So Singleton, Moss and colleagues, including Joe G.N. Garcia, MD, professor of medicine at the University of Chicago, began a series of studies looking at the many peripheral effects of opiates and the potential benefits of blocking those effects.
In laboratory studies, morphine can directly boost tumor-cell proliferation and inhibit the immune response. The researchers found that opiates also promote angiogenesis, the growth of new blood vessels, and decrease barrier function–effects that may exacerbate diseases involving vascular leakiness including acute lung injury in experimental models. In a surgical setting, decreased barrier function may make it easier for tumors to invade tissue and spread to distant sites. Increased angiogenesis helps cancers thrive in a new site.
In the studies to be presented Nov. 18, Singleton and colleagues focus on the mu opiate receptor as a regulator of tumor growth and metastasis and examine the ability of methylnaltrexone to attenuate these effects.
Using two different models of non-small cell lung cancer, the research teams showed that MNTX inhibited the tumor-promoting effects of opiates. In one study, using bronchioloalveolar carcinoma cells, MNTX blocked oncogenic signaling and prevented tumor-cell proliferation and migration.
In the other study, using Lewis lung carcinoma cells, mice without the mu opiate receptor did not develop the tumors that normal mice did when injected with cancer cells. The researchers further showed that MNTX reduced proliferation of cancer cells by 90 percent in normal mice. It also prevented invasion in cell culture and tumor growth and metastasis in mice.
The opioid receptor promotes Lewis lung cancer tumor growth, angiogenesis and metastasis, the authors conclude in a summary of the second study. “Methylnaltrexone attenuates these oncogenic effects.”
“In conjunction with previous studies on opiate-induced angiogenesis by our laboratory and others, these experimental data suggest a plausible explanation for the epidemiologic observations,” notes Moss, professor of anesthesiology and critical care at the University of Chicago. “If these laboratory studies are confirmed clinically, the selection of anesthetic technique used during the operative procedure and the possible use of opiate antagonists in the perioperative period may be important.”
Additional contributors to the project include Frances Lennon, PhD, Biji Mathew, PhD, and Ravi Salgia, MD, all of the University of Chicago.
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Painkillers are an important tool in the hospital. After major surgery, relieving a patient’s pain using morphine and other opiates helps their recovery and quality of life while the body heals. But these drugs are not without their side effects and risks, from the potential for dependence to symptoms such as nausea, constipation, and itching. More recently, researchers have found that morphine may have more serious consequences, such aspromoting tumor growth. A new study, conducted by surgeons from the University of Chicago Medicine, adds another warning to the list, revealing the bad influence of morphine upon normally harmless bacteria living in the human gut.
As discussed last week, the bacterial species Pseudomonas aeruginosa is a frequent inhabitant of the human body, usually colonizing the intestinal lining under peaceful conditions. But when that comfortable environment is disrupted by illness or surgery, what John Alverdy, professor of surgery at University of Chicago Medicine, calls “molecular diplomacy” can break down, causing the bacteria to turn violent and attack its host. Alverdy’s laboratory has studied various causes of this hostility, focusing primarily on the native biological signals that are thrown out of whack after the traumatic experience of surgery. But in a paper published last month in Annals of Surgery, Alverdy’s group found for the first time that a substance used to treat the after-effects of a procedure could also trigger P. aeruginosa virulence.
“Morphine is nothing we ever factored in,” Alverdy said. “The other triggers are endogenous signals, while morphine is both exogenous and endogenous. You make morphine-like substances from your body tissues, but we also give a boatload of them, clinically, and that’s the biggest difference.”
In the experiments, led by first author Trissa Babrowski, laboratory mice were given either morphine or placebo, and half of the animals in each group were inoculated with P. aeruginosa. The researchers then watched for signs of sepsis, the extreme immune response that accompanies the most serious infections. The difference between groups was striking — all of the mice given both the bacteria and morphine died within two days, while the mice who only received one or the other (or neither) survived.
Looking closer at the behavior of the bacteria when exposed to morphine, the researchers found a long chain of catastrophe. Activated by morphine, P. aeruginosa suppressed the natural production of mucus in the intestine, disrupted the epithelial cells that line the gut, and provoked the immune system to release various immune factors. In morphine-treated mice, the bacteria also released a protein called PA-IL and exhibited “clumping” behavior, signs that they had changed in personality from pacifists to aggressors.
But despite these worrisome results demonstrating the combustible mixture of morphine and P. aeruginosa, Alverdy said that there was no cause for alarm yet.
“Remember that most people get morphine, and most people have Pseudomonas, but most people don’t get an infection,” Alverdy said. “It’s easy to take away from a paper like this, ‘oh, if you have both, you’re dead meat.’ But not most of the time.”
Understanding why P. aeruginosa chooses to go berserk in some cases but not others will require a bit of bacterial psychoanalysis, Alverdy continued.
“We’ve discounted how the microbes are thinking,” he said. “We tend to think very simply there are microbes lurching everywhere trying to attack you at any minute. We’re just this giant defense system, and the minute our defenses go down, they attack. It just doesn’t happen that way.”
Nevertheless, if physicians want to prevent any potential negative influence of morphine on gut bacteria, there may already be a tool.
Methylnaltrexone, a drug developed in part by the University of Chicago Medicine’s Jonathan Moss, is a form of morphine that can be given at the same time to block the opiate’s effects outside of the nervous system, leaving only the pain relief minus the side effects. When mice given both P. aeruginosa and morphine were co-treated with methylnaltrexone, levels of the virulence protein PA-IL were reduced, suggesting an interruption of the morphine’s instigation of gut bacteria. Intriguingly, ina recent observational study of 7,000 patients treated with a drug similar to methylnaltrexone, postoperative infections were significantly reduced.
“These human findings…suggest that colonizing microbes can be shielded, in part, from the effects of host activating signals released during surgical injury by using opioid antagonists,” the authors wrote.
Regardless of how the mouse research translates to humans, Alverdy said that this new dangerous side effect of morphine should add even more caution to the use of opiate painkillers in the hospital and even more so in less regulated and monitored settings. Citing the recent deaths of Michael Jackson and Whitney Houston, both of which were thought to be caused by inappropriate use of prescription painkillers, Alverdy said that the potentially deadly influence of these drugs on gut bacteria offer yet another warning about their misuse.
“Our society is moving to becoming very dependent on pain medication. We have a whole group of pain clinics out there where people are getting Oxycontin and all these other things,” Alverdy said. “These are the things we worry about.”
Babrowski T, Holbrook C, Moss J, Gottlieb L, Valuckaite V, Zaborin A, Poroyko V, Liu DC, Zaborina O, & Alverdy JC (2012). Pseudomonas aeruginosa virulence expression is directly activated by morphine and is capable of causing lethal gut-derived sepsis in mice during chronic morphine administration.Annals of surgery, 255 (2), 386-93 PMID: 21989372
[Photo: A scanning electron micrograph (SEM) of a number of Pseudomonas aeruginosa bacteria. (CDC/ Janice Haney Carr)]
he gastrointestinal (GI) tract is a frequent source of blood-disseminated septic infections, which are anincreasing problem and common cause of death among already severely ill patients who spend time in intensive care units (ICUs). Sequence analyses of stool samples from ICU patients at University of Chicago hospitals revealed profound disruptions of gut microflora compared to healthy patients. In a study published today (September 23) in mBio, researchers also fed ICU patients’ “ultra-low-diversity” gut microbes to C. elegans roundworms. These experiments yielded insights into the origins of the microbes’ pathogenic behavior and potential paths to mitigate it.
Although a well-functioning human intestine teems with a variety of microbial life, serious illness, long-term intravenous feeding, and multiple rounds of antibiotics wipe out much of this diversity. Inspection of 16S rRNA sequences from stool samples showed that the guts of five healthy volunteers harbored at least 40 bacterial genera. In contrast, in five of the 14 ICU patients in the study, 90 percent of the bacterial sequences were from just one taxon—typically a known pathogen, such as Enterococcus or Staphylococcus.
When a patient spends a long time in ICU, “the gut undergoes near-complete ecologic collapse,” said study coauthor John Alverdy, a gastrointestinal surgeon and researcher at the University of Chicago’s Pritzker School of Medicine. In response to the “slash and burn” use of antibiotics, among other factors, “it’s like the Amazon rainforest. It falls apart.”
Because the microbial composition of the ICU patients’ guts was so simple, Alverdy and his colleagues were able to grow each bug in culture. The 16S rRNA sequences were specific to bacteria, but culture analysis also showed the presence of the fungus Candida albicans or C. glabrata in most patients. The researchers tested each cultured strain for resistance to various antibiotics or antifungal compounds. Not surprisingly, they found widespread antibiotic resistance, although in culture some strains were sensitive to drugs that were ineffective against the same infections in patients.
“It was so surprising that we found just two-member communities—only Candida and multidrug-resistant bacteria,” said microbiologist and study coauthor Olga Zaborina. “People have studied communication in these [simple] microbial communities, but even there, they never realized that it might happen in reality.”
To examine the disease-causing potential of the patients’ altered microflora, the researchers fed lab-grown cultures of six patients’ microbes to C. elegans roundworms—established models for studying the virulence activities of mammalian pathogens. Although individual bacterial taxa caused little harm to the worms on their own, most Candida isolates killed the worms within 40 hours of ingestion. The combination ofCandida and bacteria, however, appeared to keep pathogenesis in check.
“They actually considered the fungal component of the microbiome, which has been routinely ignored in hundreds of microbiome studies,” said Michael Lorenz, a microbiologist at the University of Texas Health Science Center at Houston who was not in involved in the study. “So the finding that there are these interactions between the bacterial and fungal components is one that people should be very aware of.”
To mimic the conditions in an ICU patient’s gut, the researchers grew the microbes in the presence of an opioid. Opioids often enter the gut in critically ill patients as part of a stress response, and are known to interact with the quorum-sensing signals that regulate bacterial virulence. Indeed, in two Candida-bacteria combinations, opioid treatment shifted bacterial behavior from commensal to pathogenic, killing a substantial proportion of worms.
On the other hand, Alverdy, Zaborina, and their colleagues previously showed that decreased phosphate concentrations in the C. elegans gut—much like the low-nutrient environment in an ICU patient’s GI tract—activate quorum-sensing signals that promote pathogenesis. Here, the team found that phosphate, when added to the opioid mix, rescued most of the worms.
Although this study was too small to assess statistical significance, the team found associations between the behavior of the bacterial communities in C. elegans and patient outcomes—whether they were discharged from the ICU or died after succumbing to a septic infection.
According to Mark Lyte, a neuroendocrinologist who studies interactions between microbes and host physiology at Texas Tech University Health Sciences Center, the study “gives clinicians important information that they’re to get the gut back to health as fast as they can. The quicker they can re-establish normal communities in the gut, the better it will be for the patient prognosis.”
While Alverdy and Zaborina continue to explore the antivirulence potential of phosphate treatment, they suggested that reconstituting a patient’s original community of gut microbes might be the best medicine. Before entering intensive care for organ transplants or other major procedures, patients may soon set aside their own healthy stool to be used for a future fecal transplant.
A. Zaborin et al., “Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness,” mBio, doi:10.1128/mBio.01361-14, 2014.
https://sciencelife.uchospitals.edu <<Science Life magazine
The research team recruited 358 adult subjects from the U.S., who were evaluated for IED, personality disorder, depression and other psychiatric disorders. Study participants were also scored on traits including anger, aggression and impulsivity. Participants fell into one of three groups. Roughly one third had IED. One third were healthy controls with no psychiatric history. The remaining third were individuals diagnosed with some psychiatric disorder, but not IED. This last group served as a control to distinguish IED from possible confounding psychiatric factors.
Hold your cats
The research team found that IED-diagnosed group was more than twice as likely to test positive for toxoplasmosis exposure (22 percent) as measured by a blood test, compared to the healthy control group (9 percent).
Around 16 percent of the psychiatric control group tested positive for toxoplasmosis, but had similar aggression and impulsivity scores to the healthy control group. IED-diagnosed subjects scored much higher on both measures than either control group.
Across all study subjects, toxoplasmosis-positive individuals scored significantly higher on scores of anger and aggression. The team noted a link between toxoplasmosis and increased impulsivity, but when adjusted for aggression scores, this link became non-significant. This finding suggests toxoplasmosis and aggression are most strongly correlated.
However, the authors caution that the study results do not address whether toxoplasmosis infection may cause increased aggression or IED.
“Correlation is not causation, and this is definitely not a sign that people should get rid of their cats,
Intermittent explosive disorder (IED) is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, as recurrent, impulsive, problematic outbursts of verbal or physical aggression that are disproportionate to the situations that trigger them. IED is thought to affect as many as 16 million Americans, more than bipolar disorder and schizophrenia combined.
As part of their pioneering research to improve diagnosis and treatment for IED and impulsive aggression, Coccaro and his colleagues examined possible connections to toxoplasmosis, an extremely common parasitic infection. Transmitted through the feces of infected cats, undercooked meat or contaminated water, toxoplasmosis is typically latent and harmless for healthy adults. However, it is known to reside in brain tissue, and has been linked to several psychiatric diseases, including schizophrenia, bipolar disorder and suicidal behavior.
“Our data confirm that IED is a brain disorder and not a disorder of ‘personality,’” said Coccaro. “The behaviors displayed by IED patients represent the expected consequence of altered brain structure and function underlying impulsive aggression in humans.”
IED is defined by the DSM-5 as recurrent, impulsive, problematic outbursts of aggression, disproportionate to the situation—extreme road rage, for example. It is thought to be more common than bipolar disorder and schizophrenia combined.
To study brain changes involved in IED, Coccaro and his colleagues performed high-resolution magnetic resonance imaging (MRI) scans in 168 people, including 57 who were diagnosed with IED, 53 healthy control subjects and another 58 control patients with psychiatric diagnoses.
The team discovered a direct correlation between history of impulsive aggressive behavior and gray matter volume in the frontolimbic region of the brain—an area known to play a central role in the regulation of emotions. Across all subjects, reduced gray matter volume directly correlated with increases in aggressive behavior. The inverse relationship was also observed.
Both CRP and IL-6 levels were higher, on average, in subjects with IED, compared to either psychiatric or normal controls. Average CRP levels, for example, were twice as high for those with IED as for normal healthy volunteers. Both markers were particularly elevated in subjects who had the most extensive histories of aggressive behaviors. Each marker independently correlated with aggression, the authors note, suggesting that “both have unique relations with aggression.”
Earlier studies have pointed to connections between an inflammatory response and depression or stress, said Coccaro. Healthy people who have been exposed to endotoxins — which set off a powerful immune reaction — have a much more robust brain reaction to exposure to social threat, such as photographs of an angry or fearful face, than those who were not exposed to endotoxin.
Overall, the findings reported in this new paper suggest that “medications that reduce inflammation may also drive down aggression,” Coccaro said. Anti-inflammatories such as Celebrex, or even aspirin, might make a difference for those with IED. Since available treatments bring less than 50 percent of patients into remission, the authors wrote, “additional strategies for the examination and intervention of human impulsive aggression are needed.”