Clostridium difficle, also known as "CDF/cdf", or "C. diff", is a species of Gram-positive bacteria of the genus Clostridium that causes severe diarrhea and other intestinal disease when competing bacteria in the gut flora have been wiped out by antibiotics.
Clostridia are anaerobic, spore-forming rods (bacilli). C. difficile is the most serious cause of antibiotic-associated diarrhea (AAD) and can lead to pseudomembranous colitis, a severe inflammation of the colon, often resulting from eradication of the normal gut flora by antibiotics.
In a very small percentage of the adult population, C. difficile bacteria naturally reside in the gut. Other people accidentally ingest spores of the bacteria while they are patients in a hospital, nursing home, or similar facility. When the bacteria are in a colon in which the normal gut flora has been destroyed (usually after a broad-spectrum antibiotic such as clindamycin has been used), the gut becomes overrun with C. difficile. This overpopulation is harmful because the bacteria release toxins that can cause bloating and diarrhea, with abdominal pain, which may become severe. C. difficile infections are the most common cause of pseudomembranous colitis, and in rare cases this can progress to toxic megacolon, which can be life-threatening.
Latent symptoms of C. difficile infection often mimic some flu-like symptoms and can mimic disease flare in patients with inflammatory bowel disease-associated colitis. Mild cases of C. difficile infection can often be cured by discontinuing the antibiotics responsible. In more serious cases, oral administration of, first, oral metronidazole and - if that fails - then, second, vancomycin and if unsucessful again, intravenous metronidazole can be used. Relapses of C. difficile AAD have been reported in up to 20% of cases.
SIGNS AND SYMPTOMS
In adults, a clinical prediction rule found the best signs to be: significant diarrhea ("new onset of > 3 partially formed or watery stools per 24 hour period"), recent antibiotic exposure, colitis (abdominal pain), fever (up to 40.5?C), and foul stool odour. In a population of hospitalized patients prior antibiotic treatment plus diarrhea or abdominal pain had a sensitivity of 86% and a specificity of 45%. In this study with a prevalence of positive cytotoxin assays of 14%, the positive predictive value was 20% and the negative predictive value was 95%.
With the introduction of broad-spectrum antibiotics and chemotherapeutic antineoplastic drugs in the second half of the twentieth century, antibiotic- (and chemotherapy-) associated diarrhea became more common. Pseudomembranous colitis was first described as a complication of C. difficile infection in 1978, when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.
The numerous spores formed by C. difficile are resistant to most routine cleaning methods that are used on surfaces (except for diluted bleach). Spores of these bacteria can remain viable outside of the human body for very long periods of time, and this means that patients in a medical facility are often exposed to situations where they end up accidentally ingesting spores. Extremely rigorous infection protocols are required in order to decrease or eliminate this risk.
C. difficile infection (CDI) can range in severity from asymptomatic to severe and life-threatening, especially among the elderly. People are most often nosocomially infected in hospitals, nursing homes, or other medical institutions, although C. difficile infection in the community, outpatient setting is increasing. The rate of C. difficile acquisition is estimated to be 13% in patients with hospital stays of up to 2 weeks, and 50% in those with hospital stays longer than 4 weeks. C. difficile-associated diarrhea (aka CDAD) is most strongly associated with fluoroquinolones. Fluoroquinolones are more strongly associated with C. difficile infections than other antibiotics including clindamycin, 3rd generation cephalosporins and beta-lactamase inhibitors. One study found that fluoroquinolones were responsible for 55% of C. difficile infections. In addition to previous use of antimicrobials, use of proton pump inhibitors [PPIs] is associated with a 2-fold increase in risk for C. difficile infection.
The European Center for Disease Prevention and Control recommend that fluoroquinolones and the antibiotic clindamycin be avoided in clinical practice due to their high association with subsequent Clostridium difficile infections. Frequency and severity of C. difficile colitis remains high and seems to be associated with increased death rates. Immunocompromised status and delayed diagnosis appear to result in elevated risk of death. Early intervention and aggressive management are key factors to recovery.
Increasing rates of community-acquired C. difficile infection are associated with the use of medication that suppress gastric acid production: H2-receptor antagonists increased the risk 1.5 fold, and proton pump inhibitors by 1.7 with once daily use and 2.4 with more than once daily use.
The emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as ciprofloxacin (Cipro) and levofloxacin (Levaquin), said to be causing geographically dispersed outbreaks in North America was reported in 2005. The Centers for Disease Control in Atlanta has also warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.
In 2005, molecular analysis led to the identification of the C. difficile strain type that was characterized as group BI by restriction endo nuclease analysis (REA), as North American pulse-field-type NAP1 by pulse-field gel electrophoresis (PFGE) and as ribotype 027; the differing terminology reflects the predominant techniques that were used for epidemiological typing and this strain is referred to as C. difficile BI/NAP1/027.
Some recent research suggests that the overuse of antibiotics in the raising of livestock for meat consumption is contributing to outbreaks of bacterial infections such as C. difficile.
Clostridia are motile bacteria that are ubiquitous in nature and are especially prevalent in soil. Under the microscope, clostridia appear as long, irregularly (often "drumstick" or "spindle") shaped cells with a bulge at their terminal ends. Under Gram staining, Clostridium difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. When stressed, the bacteria produce spores that can tolerate extreme conditions that the active bacteria cannot tolerate.
C. difficile is a commensal bacterium of the human intestine in 2-5% of the population. Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization. In small numbers, C. difficile does not result in significant disease. Antibiotics, especially those with a broad spectrum of activity (such as for example clindamycin) cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile, which flourishes under these conditions. This can lead to pseudomembranous colitis (PMC), the generalized inflammation of the colon and the development of pseudomembrane, a viscous collection of inflammatory cells, fibrin, and necrotic cells.
Pathogenic C. difficile strains produce several known toxins. The most well-characterized are enterotoxin (Clostridium difficile toxin A) and cytotoxin (Clostridium difficile toxin B), both of which are responsible for the diarrhea and inflammation seen in infected patients, although their relative contributions have been debated. Toxins A and B are glucosyltransferases that target and inactivate the Rho family of GTPases. Clostridium difficile toxin B (cytotoxin) induces actin depolymerization by a mechanism correlated with a decrease in the ADP-ribosylation of the low molecular mass GTP-binding Rho proteins. Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.
Antibiotic treatment of C. difficile infections can be difficult, due both to antibiotic resistance as well as physiological factors of the bacteria itself (spore formation, protective effects of the pseudomembrane) Pseudomembranous colitis caused by C. difficile is treated with specific antibiotics, for example, vancomycin (Vancocin) or metronidazole (Flagyl).
C. difficile is transmitted from person to person by the fecal-oral route. However, the organism forms large numbers of heat-resistant spores, and these are not killed by alcohol-based hand cleansers or routine cleaning of surfaces. Thus, these spores remain viable in the hospital or nursing home environment for long periods of time, and, because of this, the bacteria can be cultured from almost any surface in the hospital. Once spores are ingested by a patient, they pass through the stomach unscathed because of their acid-resistance. They germinate into vegetative cells in the colon upon exposure to bile acids, and multiply.
Several disinfectants commonly used in hospitals are ineffective against C. difficile spores, and may actually promote spore formation. However, disinfectants containing bleach are effective in killing the organisms.
C. difficile toxins have a cytopathic effect in cell culture, and neutralized with specific anti-sera is the practical gold standard for studies investigating new CDAD diagnostic techniques. Toxigenic culture, in which organisms are cultured on selective medium and tested for toxin production, remains the gold standard and is the most sensitive and specific test, although it is slow and labour-intensive.
Assessment of the A and B toxins by enzyme-linked immunosorbent assay (ELISA) for toxin A or B (or both) has a sensitivity of 63?99% and a specificity of 93?100%: At a prevalence of 15%, this leads to a positive predictive value (PPV) of 73% and a negative predictive value (NPV) of 96%.
Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative. However, recent evidence suggests that repeat testing during the same episode of diarrhea is of limited value and should be discouraged.C. difficile toxin should clear from the stool of previously infected patients if treatment is effective. However, many hospitals test only for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals, and ordering both toxins should occur. Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes.
OTHER STOOL TESTS
Stool leukocyte measurements and stool lactoferrin levels have also been proposed as diagnostic tests, but may have limited diagnostic accuracy.
In a recent study, a patient who received a diagnosis of Clostridium difficile colitis (CDC) on the basis of computed tomography (CT scan) had an 88% probability of testing positive on stool assay. Wall thickening is the key CT finding in this disease. Once colon wall thickening is identified as being 4 mm, the best ancillary findings were pericolonic stranding, ascites, and colon wall nodularity. The presence of wall thickness plus any one of these ancillary findings is 70% sensitive and 93% specific.
Using criteria of 10 mm or a wall thickness of 4 mm and any of the more-specific findings does not add significantly to the diagnosis but gives equally satisfactory results. In this study with a prevalence of positive C. difficile toxin of 54%, the PPV was 88%. Patients who have antibiotic-associated diarrhea with CT findings diagnostic of CDC merit consideration for treatment on that basis.
By the end of 2009, 3 different Real-Time PCR tests had achieved 510(k) clearance from the FDA. Cepheid's GeneXpert is by far the fastest and easiest of the three, but it is also the most expensive. Cepheid uses a cartridge-based kit that is tailored for small hospitals or labs without the ability to batch large numbers of samples together. In fact, batching is not required since the extraction occurs in the same vial as amplification of the target, positive, and negative controls. The reported time from sample to result is 45 minutes.
Prodesse offers another kit-based IVD Real-Time PCR test (ProGastro Cd), which uses an external extraction and purification on the Roche MagnaPure. Prodesse (Gen-Probe) tech support claims that this external separation produces higher yields than the BD GeneOhm. The Prodesse technique is similar in price to the BD GeneOhm technique after one includes the price of the extraction and takes about three hours from sample to result.
The final IVD Clostridium difficile Real Time PCR test on the market since 2009 is from BD GeneOhm. The protocol uses a glass-bead lysis rather than an extraction, but results are reported to be good and the method shaves a little over an hour off the protocol time (about 1 hour 45 minutes from sample to result). Total costs for the Prodesse and BD GeneOhm tests are approximately the same.
For each test, sensitivities are generally reported as 88-91% and specificities as 96-97%, depending on the tests, prevalence of the disease and the size of the patient pool.
The most effective method for preventing CDAD is proper antimicrobial prescribing. In the hospital setting, where CDAD is most common, nearly all patients that develop CDAD are exposed to antimicrobials. Although proper antimicrobial prescribing sounds easy to do, approximately 50% of antimicrobial use is considered inappropriate. This is consistent whether in the hospital, clinic, community, or academic setting. Several studies have demonstrated a decrease in CDAD by limiting antibiotics most strongly associated with CDAD or by limiting unnecessary antimicrobial prescribing in general, both in outbreak and non-outbreak settings.
In Britain, the testing of all hospital inpatients over the age of 65 with diarrhea for C. difficile became a compulsory NHS practice in January 2008, when it became evident that many UK outbreaks were being disguised as Norovirus by hospital risk managers. Risk managers can be dismissed by the Department of Health if C. difficile infection rates are too high, but they cannot be dismissed as a result of a Norovirus outbreak. Patients most at risk are those with recent broad-spectrum antibiotic or proton-pump inhibitor treatments.
Infection control measures, such as wearing gloves when caring for patients with CDAD, have been proven to be effective at prevention. This works by limiting the spread of C. difficile in the hospital setting. In addition, washing with soap and water will eliminate the spores from contaminated hands, but alcohol-based hand rubs are ineffective. Bleach wipes containing 0.55 percent sodium hypochlorite have been shown to kill the spores and prevent transmission between patients.
Soil-containing potted plants can serve as a reservoir for the development of multidrug-resistant bacteria and fungi, and, for this reason, many hospital systems restrict the use of soil-containing potted plants. To help mitigate serious infections and development of multidrug-resistant organisms in long-term and acute hospital settings, soil-containing potted plants should not be used, especially in areas of direct patient care, such as offices, rooms, and hallways of hospital wards. Alternatives to soil-containing plants are available.
Treatment with various oral supplements containing live bacteria has been studied in efforts to prevent Clostridium difficile-associated infection/disease. A randomized controlled trial using a probiotic drink containing Lactobacillus casei, L bulgaricus, and Streptococcus salivarius subsp. thermophilus was reported to have some efficacy. This study was sponsored by the company that produces the drink studied. Although intriguing, several other studies have been unable to demonstrate any benefit of oral supplements of similar bacteria at preventing CDAD. Of note, patients on the antibiotics most strongly associated with CDAD were excluded from this study.
Hydrogen peroxide vapor (HPV) systems used to sterilize a patient room post discharge has been shown to reduce infection rates and to reduce risk of infection to subsequent patients. One study (Boyce et al. 2008) showed that incidence of CDAD was reduced by 53% though use of HPV. A second study (Manian et al. 2010) showed only a 42% reduction in CDAD rates through use of HPV.
In a limited clinical trial, a C. difficile anti-toxoid vaccine was reported to improve patient outcomes. Further testing will be required to validate this trial. Recent advancements have been made at the University of Guelph by Professor Monteiro on a polysaccharide vaccine currently in its pre-clinical stage.
symptomatic colonization with C. difficile is common. Treatment in asymptomatic patients is controversial, also leading into the debate of clinical surveillance and how it intersects with public health policy. In general, mild cases do not require specific treatment.
Patients should be treated as soon as possible when the diagnosis of Clostridium difficile colitis (CDC) is made to avoid frank sepsis or bowel perforation. To reduce complications, physicians often begin treatment based on clinical presentation before definitive results are available. Knowledge of the local epidemiology of intestinal flora of a particular institution can guide therapy. In addition, oral rehydration therapy (ORT) is useful in retaining fluids during the duration of diarrhea.
Three antibiotics are specifically effective against C. difficile. With the available agents more or less equally effective.
Metronidazole is the drug of choice, because of lower price and comparable efficacy.
Oral vancomycin (125 mg four times daily) is second-line therapy, but is often avoided due to concerns of converting intestinal flora into vancomycin-resistant organisms. Vancomycin is the treatment of choice in the following cases: no response to oral metronidazole; the organism is resistant to metronidazole; the patient is allergic to metronidazole; the patient is either pregnant, breastfeeding, or younger than 10 years of age. Vancomycin must be administered orally because intravenous administration does not achieve gut lumen minimum therapeutic concentration. Patients unresponsive to Metronidazole can be placed on 14 days of Vancomycin followed by Rifaximin for another 14 days.
A more recent study by Zar and others showed no difference between vancomycin and metronidazole in mild disease, but that vancomycin was superior to metronidazole for treating severe disease. In this study, severe disease was defined on a point score: One point each was given for age >60 years, temperature >38.3?C, albumin level <2.5 mg/dL, or peripheral WBC count >15,000 cells/mm3 within 48 h of enrollment. Two points were given for endoscopic evidence of pseudomembranous colitis or treatment in the intensive care unit. Severe disease was defined as 2 or more points on this score. The main criticism of this study is that a low, non-standard dose of metronidazole (250 mg) was used instead of (500 mg).
Fidaxomicin has been found to be equally effective as vancomycin In March 2012, 'The Lancet Infectious Diseases' published a double blind study made at the University of Cologne proving that the enduring treatment success of Fidaxomicin is better than the previous medication. Its tolerability showed as good as Vancomycin. Fidaxomicin has been approved in the USA since May 2011 and in Europe since December 2011 for the treatment of adults with CDI.
Drugs used to stop diarrhea frequently worsen the course of C. difficile-related pseudomembranous colitis. Loperamide, diphenoxylate and bismuth compounds are contraindicated: slowing of fecal transit time is thought to result in extended toxin-associated damage.
Cholestyramine, a powder drink (an ion exchange resin), which is occasionally used to lower cholesterol, is effective in binding both Toxin A and B, slowing bowel motility and helping prevent dehydration. The dosage can be 4 grams daily, to up to four doses a day; however caution should be exercised to prevent constipation, or drug interactions, most notably the binding of drugs by cholestyramine, preventing their absorption. Cholestyramine is not an anti-infective; it dramatically reduces many of the symptoms of a C. difficile infection, but it is not appropriate to use by itself, as it does not change the infection status. Cholestyramine is usually used in concert with vancomycin. Powdered banana flakes given twice daily are an alternative to cholestyramine, and allow for stool bulking.
Treatment with probiotics ("good" intestinal flora) has also been shown effective. Provision of Saccharomyces boulardii (Florastor) or Lactobacillus acidophilus twice daily times 30 days along with antibiotics has been clinically shown to shorten the duration of diarrhea. A last-resort treatment in immunosuppressed patients is intravenous immunoglobulin (IVIG).
Fecal bacteriotherapy, known in colloquial terms as stool transplant, a procedure related to probiotic research, has preliminarily been shown to cure the disease. It involves infusion of bacterial flora acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection. In fecal transplantation, donor stool is collected from a close relative who has been tested for a wide array of bacterial, viral, and parasitic pathogens. The stool is often mixed with saline or milk to achieve the desired consistency, then delivered through a colonoscope or retention enema, or through a nasogastric or nasoduodenal tube. The procedure replaces normal, healthy colonic flora that had been wiped out by antibiotics, and reestablishes the patient's resistance to colonization by Clostridium difficile. However, there is often patient resistance due to the perceived unpleasantness of the procedure that must be overcome first before proceeding with this often-effective treatment.
In those patients that develop systemic symptoms of CDC, colectomy may improve the outcome if performed before the need for vasopressors.
There are currently over 150 published reports dating back to 1958, though many more have been performed. It has a success rate of about 90%. A guide was released in 2010 for home fecal transplantation.
The evolution of protocols for patients with recurrent C. difficile diarrhea also present a challenge: There is no known proper length of time or universally accepted alternative drugs with which one should be treated. However, re-treatment with metronidazole or vancomycin at the previous dose for 10 to 14 days is generally successful. The addition of rifampin to vancomycin also has been effective.
PrognosisAfter a first treatment with metronidazole or vancomycin, Clostridium difficile recurs in about 20% of people. This increases to 40% and 60% with subsequent recurrences.
Initially named Bacillus difficilis by Hall and O'Toole in 1935 because it was resistant to early attempts at isolation and grew very slowly in culture, it was renamed in 1970.
SOCIETY AND CULTURE
June 4, 2003, two outbreaks of a highly virulent strain of this bacterium were reported in Montreal, Quebec and Calgary, Alberta, in Canada. Sources put the death count as low as 36 and as high as 89, with approximately 1,400 cases in 2003 and within the first few months of 2004. C. difficile infections continued to be a problem in the Quebec healthcare system in late 2004. As of March 2005, it had spread into the Toronto, Ontario area, hospitalizing 10 people. One died while the others were being discharged.
A similar outbreak took place at Stoke Mandeville Hospital in the United Kingdom between 2003 and 2005. The local epidemiology of C. difficile may offer clues on how its spread may relate to the amount of time a patient spends in hospital and/or a rehabilitation center. It also samples institutions' ability to detect increased rates, and their capacity to respond with more aggressive hand-washing campaigns, quarantine methods, and availability of yogurt containing live cultures to patients at risk for infection.
It has been suggested that both the Canadian and English outbreaks were related to the seemingly more virulent Strain NAP1/027 of bacterium. This novel strain, also known as Quebec strain, has also been implicated in an epidemic at two Dutch hospitals (Harderwijk and Amersfoort, both 2005). A theory for explaining the increased virulence of 027 is that it is a hyperproducer of both toxins A and B, and that certain antibiotics may actually stimulate the bacteria to hyperproduce.
October 1, 2006, C. difficile was said to have killed at least 49 people at hospitals in Leicester, England over eight months, according to a National Health Service investigation. Another 29 similar cases were investigated by coroners. A UK Department of Health memo leaked shortly afterwards revealed significant concern in government about the bacterium, described as being "endemic throughout the health service"
October 27, 2006, 9 deaths were attributed to the bacterium in Quebec, Canada.
November 18, 2006, the bacterium was reported to have been responsible for 12 deaths in Quebec, Canada. This 12th reported death was only two days after the St. Hyacinthe's Honor? Mercier announced that the outbreak was under control. Thirty-one patients were diagnosed with Clostridium difficile and four (as of Sat. Nov 18th) were still under observation. Cleaning crews took measures in an attempt to clear the outbreak.
C. difficile was mentioned on 6,480 death certificates in 2006 in UK.
February 27, 2007, a new outbreak was identified at Trillium Health Centre in Mississauga, Ontario, where 14 people were diagnosed with the bacteria. The bacteria were of the same strain as the one in Quebec. Officials have not been able to determine whether C. difficile was responsible for deaths of four patients over the prior two months.
Between February and June 2007, three patients at Loughlinstown Hospital in Dublin, Ireland were found by the coroner to have died as a result of C. difficile infection. In an inquest, the Coroner's Court found that the hospital had no designated infection control team or consultant microbiologist on staff.
Between June 2007 and August 2008, Northern Health & Social Care Trust Northern Ireland. Anrtim Area, Braid Valley, Mid Ulster Hospitals. During the enquiry expert reviewers concluded that C DIFF was implicated in 31 of these deaths, as the underlying cause in 15 and as a contributory cause in 16. During the time period the review also noted 375 instances of C DIFF infection in patients.
October 2007, Maidstone and Tunbridge Wells NHS Trust was heavily criticized by the Healthcare Commission regarding its handling of a major outbreak of C. difficile in its hospitals in Kent from April 2004 to September 2006. In its report, the Commission estimated that about 90 patients "definitely or probably" died as a result of the infection.
November 2007, the 027 strain has spread into several hospitals in southern Finland, with ten deaths out of 115 infected patients reported on 2007-12-14.
November 2009, four deaths at Our Lady of Lourdes Hospital in Ireland, have possible links to Clostridium difficile infection. A further 12 patients tested positive for infection, and another 20 show signs of infection, 10 November 2009.
March 2010, From February 2009 to February 2010 199 patients at Herlev hospital in Denmark was suspected of being infected with the 027 strain. In the first half of 2009, 29 died in hospitals in Copenhagen after they were infected with the bacterium
May 2010, A total of 138 patients at four different hospitals in Denmark infected with the 027 strain ( Herlev, Amager, Gentofte and Hvidovre) plus some isolated occurrences at other hospitals.
May 28, 2011 an outbreak in Ontario, Canada has been reported, with 26 fatalities as of July 24, 2011.
The first complete genome sequence of a Clostridium difficile strain was first published in 2005 by Sanger Institute in the UK. This was of the C. difficile strain 630, a virulent and multidrug-resistant strain isolated in Switzerland in 1982. Scientists at Sanger Institute have also recently sequenced genomes of about 30 Clostridium difficile isolates using next generation sequencing technologies from 454 Life Sciences and Illumina.
Researchers at McGill University in Montreal, Quebec sequenced the genome of the highly virulent Quebec strain of C. difficile in 2005 using ultra-high-throughput sequencing technology. The tests involved doing 400,000 DNA parallel-sequencing reactions of the bacterium's genome, which had been fragmented for sequencing. These sequences were assembled computationally to form a complete genome sequence.
CDA-1 and CDB-1 (also known as MDX-066/MDX-1388 and MBL-CDA1/MBL-CDB1) is an investigational, monoclonal antibody combination co-developed by Medarex and Massachusetts Biologic Laboratories (MBL) to target and neutralize C. difficile toxins A and B, for the treatment of CDI. Merck & Co., Inc. gained worldwide rights to develop and commercialize CDA-1 and CDB-1 through an exclusive license agreement signed in April 2009. It is intended as an add-on therapy to one of the existing antibiotics to treat CDI.
Nitazoxanide is a synthetic nitrothiazolyl-salicylamide derivative indicated as an antiprotozoal agent (FDA-approved for the treatment of infectious diarrhea caused by Cryptosporidium parvum and Giardia lamblia) and is also currently being studied in C. difficile infections vs. vancomycin.
Rifaximin, is a clinical-stage semi synthetic, rifamycin-based non-systemic antibiotic for CDI. It is FDA-approved for the treatment of infectious diarrhea and being developed by Salix Pharmaceuticals.
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