An Outbreak Investigation of Vibrio parahaemolyticus Infections in the United States Linked to Crabmeat Imported from Venezuela: 2018.

Vibrio parahaemolyticus is the leading cause of seafood-related foodborne illness globally. In 2018, the U.S. federal, state, and local public health and regulatory partners investigated a multistate outbreak of V. parahaemolyticus infections linked to crabmeat that resulted in 26 ill people and nine hospitalizations. State and U.S. Food and Drug Administration (FDA) laboratories recovered V. parahaemolyticus, Salmonella spp., and Listeria monocytogenes isolates from crabmeat samples collected from various points of distribution and conducted phylogenetic analyses of whole-genome sequencing data. Federal, state, and local partners conducted traceback investigations to determine the source of crabmeat. Multiple Venezuelan processors that supplied various brands of crabmeat were identified, but a sole firm was not confirmed as the source of the outbreak. Travel restrictions between the United States and Venezuela prevented FDA officials from conducting on-site inspections of cooked crabmeat processors. Based on investigation findings, partners developed public communications advising consumers not to eat crabmeat imported from Venezuela and placed potentially implicated firms on import alerts. While some challenges limited the scope of the investigation, epidemiologic, traceback, and laboratory evidence identified the contaminated food and country of origin, and contributed to public health and regulatory actions, preventing additional illnesses. This multistate outbreak illustrates the importance of adhering to appropriate food safety practices and regulations for imported seafood.

Burkholderia cepacia complex outbreak linked to a no-rinse cleansing foam product, United States - 2017-2018.

In March 2018, the US Food and Drug Administration (FDA), US Centers for Disease Control and Prevention, California Department of Public Health, Los Angeles County Department of Public Health and Pennsylvania Department of Health initiated an investigation of an outbreak of Burkholderia cepacia complex (Bcc) infections. Sixty infections were identified in California, New Jersey, Pennsylvania, Maine, Nevada and Ohio. The infections were linked to a no-rinse cleansing foam product (NRCFP), produced by Manufacturer A, used for skin care of patients in healthcare settings. FDA inspected Manufacturer A's production facility (manufacturing site of over-the-counter drugs and cosmetics), reviewed production records and collected product and environmental samples for analysis. FDA's inspection found poor manufacturing practices. Analysis by pulsed-field gel electrophoresis confirmed a match between NRCFP samples and clinical isolates. Manufacturer A conducted extensive recalls, FDA issued a warning letter citing the manufacturer's inadequate manufacturing practices, and federal, state and local partners issued public communications to advise patients, pharmacies, other healthcare providers and healthcare facilities to stop using the recalled NRCFP. This investigation highlighted the importance of following appropriate manufacturing practices to minimize microbial contamination of cosmetic products, especially if intended for use in healthcare settings.

A Series of Papaya-Associated Salmonella Illness Outbreak Investigations in 2017 and 2019: A Focus on Traceback, Laboratory, and Collaborative Efforts.

ABSTRACT: In 2017 and 2019, five outbreaks of infections from multiple strains of Salmonella linked to the consumption of whole, fresh Maradol papayas were reported in the United States, resulting in 325 ill persons. Traceback, laboratory, and epidemiologic evidence indicated papayas as the likely vehicle for each of these outbreaks and identified the source of papayas. State and U.S. Food and Drug Administration (FDA) laboratories recovered Salmonella from papaya samples from various points of distribution, including at import entry, and conducted serotyping, pulsed-field gel electrophoresis, and phylogenetic analyses of whole genome sequencing data. Federal and state partners led traceback investigations to determine the source of papayas. Four different suppliers of papayas were linked by traceback and laboratory results to five separate outbreaks of Salmonella infections associated with papayas. In 2017, multiple states tested papaya samples collected at retail, and Maryland and Virginia investigators recovered strains of Salmonella associated with one outbreak. FDA collected 183 papaya samples in 2017, and 11 samples yielded 62 isolates of Salmonella. Eleven serotypes of Salmonella were recovered from FDA papaya samples, and nine serotypes were closely related genetically by pulsed-field gel electrophoresis and whole genome sequencing to clinical isolates of four outbreaks, including the outbreak associated with positive state sample results. Four farms in Mexico were identified, and their names were released to the general public, retailers, and foreign authorities. In 2019, FDA collected 119 papaya samples, three of which yielded Salmonella; none yielded the 2019 outbreak strain. Investigators determined that papayas of interest had been sourced from a single farm in Campeche, Mexico, through traceback. This information was used to protect public health through public guidance, recalls, and import alerts and helped FDA collaborate with Mexican regulatory partners to enhance the food safety requirements for papayas imported from Mexico.

Integrating the Food and Drug Administration Office of the Coordinated Outbreak Response and Evaluation Network's foodborne illness outbreak surveillance and response activities with principles of the National Incident Management System.

The Food Safety Modernization Act mandates building a national Integrated Food Safety System, which represents a seamless partnership among federal, state, local, territorial, and tribal agencies. During multistate foodborne illness outbreak investigations, local and state partners, the Centers for Disease Control and Prevention, the United States Food and Drug Administration (FDA), or the United States Department of Agriculture Food Safety Inspection Service, depending on the regulated food product, become engaged and assist in coordinating the efforts between partners involved and determine the allocation of resources. The FDA Center for Food Safety and Applied Nutrition (CFSAN) Office of the Coordinated Outbreak Response and Evaluation (CORE) Network coordinates foodborne illness outbreak surveillance, response, and post-response activities related to incidents involving multiple illnesses linked to FDA-regulated human food, dietary supplements, and cosmetic products. FDA has implemented the National Incident Management System (NIMS) Incident Command System (ICS) principles across the agency to coordinate federal response efforts, and CORE has adapted NIMS ICS principles for the emergency management of multistate foodborne illness outbreaks. CORE's implementation of ICS principles has provided several benefits to the operational cycle of foodborne illness outbreak investigations, including establishing a consistent, standardized, and transparent step-by-step approach to outbreak investigations. ICS principles have been instrumental in the development of a national platform for rapid and systematic laboratory, traceback, and epidemiologic information sharing, data analysis, and decision-making. This allows for partners across jurisdictions to reach a consensus regarding outbreak goals and objectives, deploy resources, and take regulatory and public health actions.

An Overview of Traceback Investigations and Three Case Studies of Recent Outbreaks of Escherichia coli O157:H7 Infections Linked to Romaine Lettuce.

ABSTRACT: Leafy greens contaminated with Shiga toxin-producing Escherichia coli have continued to cause foodborne illness outbreaks in recent years and present a threat to public health. An important component of foodborne illness outbreak investigations is determining the source of the outbreak vehicle through traceback investigations. The U.S. Food and Drug Administration is home to traceback investigation experts who use a standardized process to initiate, execute, and interpret the results of traceback investigations in collaboration with the Centers for Disease Control and Prevention and state and local partners. Traceback investigations of three outbreaks of Shiga toxin-producing E. coli infections linked to romaine lettuce in 2018 and 2019 were examined to demonstrate challenges, limitations, and opportunities for improvement. The three outbreaks resulted in a total of 474 illnesses, 215 hospitalizations, and 5 deaths. These illnesses were linked to the consumption of romaine lettuce from three distinct growing regions in Arizona and California. Some of the challenges encountered included the time it took to initiate a traceback, limited product-identifying information throughout the supply chain, lack of interoperability in record-keeping systems, and comingling of product from multiple suppliers. These challenges led to time delays in the identification of the farm source of the leafy greens and the inability to identify the root cause of contamination. Implementation of technology-enabled traceability systems, testing of these systems, and future regulations to incentivize adoption of traceability systems are some of the initiatives that will help address these challenges by improving traceback investigations and ultimately preventing foodborne illnesses and future outbreaks from occurring.

Two multistate outbreaks of a reoccurring Shiga toxin-producing Escherichia coli strain associated with romaine lettuce: USA, 2018-2019.

Leafy green vegetables are a common source of Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) foodborne illness outbreaks. Ruminant animals, primarily cattle, are the major reservoir of STEC O157. Epidemiological, traceback and field investigations were conducted to identify potential outbreak sources. Product and environmental samples were tested for STEC. A reoccurring strain of STEC O157 caused two multistate outbreaks linked to romaine lettuce in 2018 and 2019, resulting in 234 illnesses in 33 states. Over 80% of patients interviewed consumed romaine lettuce before illness. The romaine lettuce was sourced from two California growing regions: Santa Maria and Salinas Valley in 2018 and Salinas Valley in 2019. The outbreak strain was isolated from environmental samples collected at sites >90 miles apart across growing regions, as well as from romaine-containing products in 2019. Although the definitive route of romaine contamination was undetermined, use of a contaminated agricultural water reservoir in 2018 and contamination from cattle grazing on adjacent land in 2019 were suspected as possible factors. Preventing lettuce contamination from growth to consumption is imperative to preventing illness. These outbreaks highlight the need to further understand mechanisms of romaine contamination, including the role of environmental or animal reservoirs for STEC O157.

Lessons Learned from a Decade of Investigations of Shiga Toxin-Producing Escherichia coli Outbreaks Linked to Leafy Greens, United States and Canada.

Shiga toxin-producing Escherichia coli (STEC) cause substantial and costly illnesses. Leafy greens are the second most common source of foodborne STEC O157 outbreaks. We examined STEC outbreaks linked to leafy greens during 2009-2018 in the United States and Canada. We identified 40 outbreaks, 1,212 illnesses, 77 cases of hemolytic uremic syndrome, and 8 deaths. More outbreaks were linked to romaine lettuce (54%) than to any other type of leafy green. More outbreaks occurred in the fall (45%) and spring (28%) than in other seasons. Barriers in epidemiologic and traceback investigations complicated identification of the ultimate outbreak source. Research on the seasonality of leafy green outbreaks and vulnerability to STEC contamination and bacterial survival dynamics by leafy green type are warranted. Improvements in traceability of leafy greens are also needed. Federal and state health partners, researchers, the leafy green industry, and retailers can work together on interventions to reduce STEC contamination.

A Multistate Outbreak of E Coli O157:H7 Infections Linked to Soy Nut Butter.

BACKGROUND: In 2017, we conducted a multistate investigation to determine the source of an outbreak of Shiga toxin-producing Escherichia coli (STEC) O157:H7 infections, which occurred primarily in children. METHODS: We defined a case as infection with an outbreak strain of STEC O157:H7 with illness onset between January 1, 2017, and April 30, 2017. Case patients were interviewed to identify common exposures. Traceback and facility investigations were conducted; food samples were tested for STEC. RESULTS: We identified 32 cases from 12 states. Twenty-six (81%) cases occurred in children <18 years old; 8 children developed hemolytic uremic syndrome. Twenty-five (78%) case patients ate the same brand of soy nut butter or attended facilities that served it. We identified 3 illness subclusters, including a child care center where person-to-person transmission may have occurred. Testing isolated an outbreak strain from 11 soy nut butter samples. Investigations identified violations of good manufacturing practices at the soy nut butter manufacturing facility with opportunities for product contamination, although the specific route of contamination was undetermined. CONCLUSIONS: This investigation identified soy nut butter as the source of a multistate outbreak of STEC infections affecting mainly children. The ensuing recall of all soy nut butter products the facility manufactured, totaling >1.2 million lb, likely prevented additional illnesses. Prompt diagnosis of STEC infections and appropriate specimen collection aids in outbreak detection. Child care providers should follow appropriate hygiene practices to prevent secondary spread of enteric illness in child care settings. Firms should manufacture ready-to-eat foods in a manner that minimizes the risk of contamination.

Outbreak of Salmonella Chailey Infections Linked To Precut Coconut Pieces - United States and Canada, 2017.

Foodborne salmonellosis causes an estimated 1 million illnesses and 400 deaths annually in the United States (1). In recent years, salmonellosis outbreaks have been caused by foods not typically associated with Salmonella. On May 2, 2017, PulseNet, CDC's national molecular subtyping network for foodborne disease surveillance, identified a cluster of 14 Salmonella Chailey isolates with a rare pulsed-field gel electrophoresis (PFGE) pattern. On May 29, Canadian health officials informed CDC that they were also investigating a cluster of five Salmonella Chailey infections in British Columbia with the same PFGE pattern. Nineteen cases were identified and investigated by CDC, U.S. state health departments, the Public Health Agency of Canada, and the British Columbia Centre for Disease Control. Isolates from all cases were highly related by whole genome sequencing (WGS). Illness onset dates ranged from March 10 to May 7, 2017. Initial interviews revealed that infected persons consumed various fresh foods and shopped at grocery chain A; focused questionnaires identified precut coconut pieces from grocery chain A as a common vehicle. The Canadian Food Inspection Agency (CFIA) and the U.S. Food and Drug Administration (FDA) conducted a traceback investigation that implicated a single lot of frozen, precut coconut as the outbreak source. Grocery chain A voluntarily removed precut coconut pieces from their stores. This action likely limited the size and scope of this outbreak.

Multistate Outbreak of Salmonella Virchow Infections Linked to a Powdered Meal Replacement Product-United States, 2015-2016.

Background: Nontyphoidal Salmonella is the leading cause of bacterial gastroenteritis in the United States. Meal replacement products containing raw and "superfood" ingredients have gained increasing popularity among consumers in recent years. In January 2016, we investigated a multistate outbreak of infections with a novel strain of Salmonella Virchow. Methods: Cases were defined using molecular subtyping procedures. Commonly reported exposures were compared with responses from healthy people interviewed in the 2006-2007 FoodNet Population Survey. Firm inspections and product traceback and testing were performed. Results: Thirty-five cases from 24 states were identified; 6 hospitalizations and no deaths were reported. Thirty-one of 33 (94%) ill people interviewed reported consuming a powdered supplement in the week before illness; of these, 30 (97%) reported consuming product A, a raw organic powdered shake product consumed as a meal replacement. Laboratory testing isolated the outbreak strain of Salmonella Virchow from leftover product A collected from ill people's homes, organic moringa leaf powder (an ingredient in product A), and finished product retained by the firm. Firm inspections at 3 facilities linked to product A production did not reveal contamination at the facilities. Traceback investigation identified that the contaminated moringa leaf powder was imported from South Africa. Conclusions: This investigation identified a novel outbreak vehicle and highlighted the potential risk with similar products not intended to be cooked by consumers before consuming. The company issued a voluntary recall of all implicated products. As this product has a long shelf life, the recall likely prevented additional illnesses.

The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement.

OBJECTIVE: Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE Pro(TM), a dietary supplement used for weight loss and/or muscle building. METHODS: Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA's Forensic Chemistry Center analyzed samples of OxyELITE Pro. RESULTS: From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required "new dietary ingredient" notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products. CONCLUSIONS: Vigilant surveillance is required for adverse events linked to the use of dietary supplements.

Outbreak of Salmonella Newport infections linked to cucumbers--United States, 2014.

In August 2014, PulseNet, the national molecular subtyping network for foodborne disease surveillance, detected a multistate cluster of Salmonella enterica serotype Newport infections with an indistinguishable pulse-field gel electrophoresis (PFGE) pattern (XbaI PFGE pattern JJPX01.0061). Outbreaks of illnesses associated with this PFGE pattern have previously been linked to consumption of tomatoes harvested from Virginia's Eastern Shore in the Delmarva region and have not been linked to cucumbers or other produce items. To identify the contaminated food and find the source of the contamination, CDC, state and local health and agriculture departments and laboratories, and the Food and Drug Administration (FDA) conducted epidemiologic, traceback, and laboratory investigations. A total of 275 patients in 29 states and the District of Columbia were identified, with illness onsets occurring during May 20-September 30, 2014. Whole genome sequencing (WGS), a highly discriminating subtyping method, was used to further characterize PFGE pattern JJPX01.0061 isolates. Epidemiologic, microbiologic, and product traceback evidence suggests that cucumbers were a source of Salmonella Newport infections in this outbreak. The epidemiologic link to a novel outbreak vehicle suggests an environmental reservoir for Salmonella in the Delmarva region that should be identified and mitigated to prevent future outbreaks.

Differentiation-related gene-1 decreases Bim stability by proteasome-mediated degradation.

Drg1 was identified as a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. Its expression is associated with resistance to irinotecan (CPT-11) therapy in preclinical colorectal cancer models both in vitro and in vivo. However, the functional significance of Drg1 in these processes is unknown. We have shown for the first time that Drg1 directly binds to the BH3-only proapoptotic protein Bim. Depletion of Drg1 by small interfering RNA induced up-regulation of Bim and its accumulation in the mitochondria, which correlated with loss of mitochondrial membrane potential and induction of apoptosis in cells exposed to SN-38. Further analyses revealed that Drg1 promotes degradation of Bim through the Cullin2/ElonginB-CIS ubiquitin-protein ligase complex. Conversely, in the absence of Drg1, Bim was stabilized and bound more abundantly to Hsp70. These results show that Drg1 renders cancer cells more resistant to chemotherapy through enhanced proteasome-mediated Bim degradation.

The cyclin-dependent kinase inhibitor flavopiridol potentiates the effects of topoisomerase I poisons by suppressing Rad51 expression in a p53-dependent manner.

The results of a phase I clinical trial of the topoisomerase I (Topo I) poison CPT-11 followed by the cyclin-dependent kinase inhibitor flavopiridol in patients with advanced solid tumors indicate that patients whose tumors were wild-type, but not mutant, for p53 obtained the most clinical benefit from this combination therapy. We elected to elucidate the mechanistic basis for this effect in isogenic-paired HCT116 colon cancer cells that were either wild-type (+/+) or null (-/-) for p53. With the combination therapy of SN-38 (the active metabolite of CPT-11) followed by flavopiridol, the induction of apoptosis was 5-fold greater in the p53+/+ cells compared with the p53-/- cells. This sequential treatment induced phosphorylation of p53 at Ser(15), which interacted with Rad51, a DNA repair protein involved in homologous recombination. Rad51 bound to p53-Ser(15) within the first 5 hours of combination therapy, and then was transcriptionally suppressed at 24 hours by flavopiridol only in p53+/+ cells. Microarray analysis also revealed suppression of Rad51 in a p53-dependent manner. Depletion of Rad51 by small interfering RNA (siRNA) sensitized both p53+/+ and p53-/- cells to SN-38-induced apoptosis with increase of gamma H2AX, a marker of DNA damage. Conversely, overexpression of Rad51 rescued p53+/+ cells from SN-->F-induced apoptosis. Because flavopiridol inhibits Cdk9, we found that inhibition of Cdk9 by DRB or by siRNA could recapitulate the flavopiridol effects, with suppression of Rad51 and induction of apoptosis only in p53+/+ cells. In conclusion, after DNA damage by Topo I poisons, flavopiridol targets homologous recombination through a p53-dependent down-regulation of Rad51, resulting in enhancement of apoptosis.

Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells.

Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a very poor prognosis and largely resistant to chemotherapy. MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1. In view of this, MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen-activated protein kinase pathway by the B-Raf inhibitor sorafenib. MPNST (MPNST and ST8814) and dedifferentiated liposarcoma (LS141 and DDLS) human tumor cell lines were characterized for Ras activation and B-Raf expression. Tumor cells were treated with sorafenib and examined for growth inhibition, inhibition of phospho-MEK, phospho-ERK, cell cycle arrest, and changes in cyclin D1 and pRb expression. MPNSTs were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G(1) cell cycle arrest. These effects were not seen in the liposarcoma cells, which either did not express B-Raf or showed decreased Ras activation. Small interfering RNA-mediated depletion of B-Raf in MPNSTs also induced a G(1) cell cycle arrest in these cells, with a marked inhibition of cyclin D1 expression and Rb phosphorylation, whereas depletion of C-Raf did not affect either. With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST.