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Obesity, metabolic syndrome, and type 2 diabetes are major public health challenges. Recently, interest has surged regarding the possible role of the intestinal microbiota as potential novel contributors to the increased prevalence of these 3 disorders. Recent advances in microbial DNA sequencing technologies have resulted in the widespread application of whole-genome sequencing technologies for metagenomic DNA analysis of complex ecosystems such as the human gut. Current evidence suggests that the gut microbiota affect nutrient acquisition, energy harvest, and a myriad of host metabolic pathways. Advances in the Human Microbiome Project and human metagenomics research will lead the way toward a greater understanding of the importance and role of the gut microbiome in metabolic disorders such as obesity, metabolic syndrome, and diabetes.

A death due to mpox in an immunocompromised patient in the United States is described. Evaluation revealed disseminated viral infection.

Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H(2) receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases.

Abstract Objectives This study aimed to assess whether the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Epsilon variant (B.1.429/427) is more virulent, leading to more hospitalization and more severe disease requiring intensive care unit (ICU) admission. Methods SARS-CoV-2 genomic surveillance was performed on respiratory samples from 231 unique patients, collected at a single large health system in Southern California between November 2020 and March 2021 during the winter surge. Results The frequencies of the Epsilon variant among outpatients, hospitalized patients, and ICU patients were indifferent. Conclusions Our study suggests that the Epsilon variant is not associated with increased hospitalization and ICU admission.

Remdesivir is the first FDA-approved drug for treating severe SARS-CoV-2 infection and targets RNA-dependent RNA polymerase (RdRp) that is required for viral replication. To monitor for the development of mutations that may result in remdesivir resistance during prolonged treatment, we sequenced SARS-CoV-2 specimens collected at different treatment time points in two transplant patients with severe COVID-19. In the first patient, an allogeneic hematopoietic stem cell transplant recipient, a transient RdRp catalytic subunit mutation (nsp12:A449V) was observed that has not previously been associated with remdesivir resistance. As no in vitro study had been conducted to elucidate the phenotypic effect of nsp12:A449V, its clinical significance is unclear. In the second patient, two other transient RdRp mutations were detected: one in the catalytic subunit (nsp12:V166A) and the other in an accessory subunit important for processivity (nsp7:D67N). This is the first case report for a potential link between the nsp12:V166A mutation and remdesivir resistance in vivo, which had only been previously described by in vitro studies. The nsp7:D67N mutation has not previously been associated with remdesivir resistance, and whether it has a phenotypic effect is unknown. Our study revealed SARS-CoV-2 genetic dynamics during remdesivir treatment in transplant recipients that involved mutations in the RdRp complex (nsp7 and nsp12), which may be the result of selective pressure. These results suggest that close monitoring for potential resistance during the course of remdesivir treatment in highly vulnerable patient populations may be beneficial. Development and utilization of diagnostic RdRp genotyping tests may be a future direction for improving the management of chronic COVID-19.

Bacterial‐derived compounds from the intestinal microbiome modulate host mucosal immunity. Identification and mechanistic studies of these compounds provide insights into host–microbial mutualism. Specific Lactobacillus reuteri strains suppress production of the proinflammatory cytokine, tumor necrosis factor (TNF), and are protective in a mouse model of colitis. Human‐derived L. reuteri strain ATCC PTA 6475 suppresses intestinal inflammation and produces 5,10‐methenyltetrahydrofolic acid polyglutamates. Insertional mutagenesis identified the bifunctional dihydrofolate synthase/folylpolyglutamate synthase type 2 (folC2) gene as essential for 5,10‐methenyltetrahydrofolic acid polyglutamate biosynthesis, as well as for suppression of TNF production by activated human monocytes, and for the anti‐inflammatory effect of L. reuteri 6475 in a trinitrobenzene sulfonic acid‐induced mouse model of acute colitis. In contrast, folC encodes the enzyme responsible for folate polyglutamylation but does not impact TNF suppression by L. reuteri. Comparative transcriptomics between wild‐type and mutant L. reuteri strains revealed additional genes involved in immunomodulation, including previously identified hdc genes involved in histidine to histamine conversion. The folC2 mutant yielded diminished hdc gene cluster expression and diminished histamine production, suggesting a link between folate and histadine/histamine metabolism. The identification of genes and gene networks regulating production of bacterial‐derived immunoregulatory molecules may lead to improved anti‐inflammatory strategies for digestive diseases. The bifunctional dihydrofolate synthase/folylpolyglutamate synthase type 2 (folC2) gene is necessary for 5,10‐methenyltetrahydrofolic acid production by Lactobacillus reuteri, while the folC gene encodes the enzyme responsible for polyglutamylation of 5,10‐methenyltetrahydrofolate. The folC2 gene is important for suppression of the proinflammatory cytokine, tumor necrosis factor (TNF), in vitro, and for protection against trinitrobenzene sulfonic acid (TNBS)‐induced colitis and mucosal inflammation in vivo. In addition, there is a link between 5,10‐methenyltetrahydrofolic acid production and histamine, a known potent immunoregulatory molecule produced by probiotics. Specifically, the folC2 mutant yields diminished expression of the hdc gene cluster, which is responsible for the conversion of l‐histidine to histamine as well as diminished histamine production.

Background Historically, endemic Klebsiella pneumoniae carbapenemase (KPC) has accounted for the majority of carbapenem-resistant Enterobacteriaceae (CRE) in Los Angeles County (LAC). The LAC Department of Public Health (DPH) initiated enhanced CRE surveillance in 2016 to determine CRE prevalence and track emerging non-KPC resistance mechanisms (IMP, NDM, OXA, and VIM) among CRE to describe characteristics and identify local epidemiology for novel multi-drug-resistant organism (N-MDRO) infection and colonization. Methods CRE isolates were voluntarily submitted by local clinical laboratories for mechanism detection by LAC Public Health Laboratory via MALDI-TOF and Nanosphere BC-GN. Baseline isolates were collected in 2016. Results are then presented by year through 2018. For N-MDRO cases, LACDPH interviewed healthcare facility (HCF) staff and cases to obtain case characteristics. Data were analyzed via Microsoft Access and SAS. Results CRE surveillance isolates were voluntarily submitted by 31 labs representing 34% (34/96) LAC hospitals and 1 large regional lab serving 60% of skilled nursing facilities from January 2016 to December 2018. LACDPH tested 1438 CRE isolates during the study period, 1168 (81%) were carbapenemase producing (CP). The proportion of CP CRE and KPC CRE declined over the study period (Table 1). NDM was the most common non-KPC (n = 30) followed by OXA (n = 28). The proportion of CRE with no genotypic marker increased over the course of the study. Case characteristics were obtained from 41 non-KPC CP CRE cases; median age was 66 years (range: 6–94 years); 12 (29%) expired. Among the 41 cases, 20 (49%) had a central line; 11 (27%) had surgery; 14 (34%) had antibiotics in the 6 months prior to culture date. Of the 41 cases, 11 (27%) had international healthcare exposure within 12 months with an invasive procedure and/or antibiotics. Conclusion Surveillance in a large urban setting suggests the molecular epidemiology of CRE is changing, with declining prevalence of KPC, increasing metallo-β-lactamase CP, and large proportion of isolates without resistance markers detected. Given the worrisome trends in non-KPC CRE, more systematic surveillance is warranted, potentially using more robust molecular epidemiology. Disclosures All authors: No reported disclosures.

Fungal infections in the central nervous system (CNS) are associated with significant morbidity and death. Transient fungemia in immunocompetent patients without any other risk factors for fungemia has been suggested as a possible mechanism that may lead to serious fungal ventriculoperitoneal (VP) shunt infections, but evidence is lacking. The clinical spectrum, diagnosis, and optimal therapy of Cyberlindnera fabianii infections remain to be determined. We describe the first case of CNS infection due to C. fabianii that occurred in an immunocompetent adult with a VP shunt. Spontaneous translocation with yeast that is not part of the normal gastrointestinal flora in the setting of ingestion of multiple servings of a fermentation product was the likely source from which Cyberlindnera fabianii gained entrance into the VP shunt system, causing meningitis in this patient. The authors conclude that, in view of the high morbidity associated with yeast infection of the CNS, long-term antifungal therapy should be strongly considered in cases where the VP shunt cannot be completely removed. Transient fungemia may lead to invasive disease in an immunocompetent host with VP shunt, even in the absence of any other risk factors for fungemia and even after remote placement of the VP shunt.

Los Angeles County comprises 4,058 square miles and is home to approximately 10 million residents, an estimated 59,000 (0.6%) of whom experience homelessness on a given night. In late 2018, Los Angeles County Department of Public Health was notified of a case of hepatitis A virus infection in a person experiencing homelessness. Here, Haddix et al determine the source of infection, identify additional cases, and identify contacts for postexposure prophylaxis.