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.

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.

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.

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.

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.

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.