Prevalence of Powassan Virus Seropositivity Among People with History of Lyme Disease and Non-Lyme Community Controls in the Northeastern United States.

Introduction: Lyme disease (LD) affects ∼476,000 people each year in the United States. Symptoms are variable and include rash and flu-like symptoms. Reasons for the wide variation in disease outcomes are unknown. Powassan virus (POWV) is a tick-borne flavivirus that causes disease ranging from asymptomatic infection to encephalitis, neurologic damage, and death. POWV and LD geographic case distributions overlap, with Ixodes species ticks as the common vectors. Clinical ramifications of coinfection or sequential infection are unknown. Objectives: This study's primary objective was to determine the prevalence of POWV-reactive antibodies in sera samples collected from previously studied cohorts of individuals with self-reported LD history residing in the Northeastern United States. As a secondary objective, we studied clinical differences between people with self-reported LD history and low versus high POWV antibody levels. Methods: We used an enzyme-linked immunosorbent assay (ELISA) to quantify IgG directed at the POWV envelope (E) protein domain III in 538 samples from individuals with self-reported LD history and 16 community controls. The samples were also tested with an ELISA assay to quantify IgG directed at the POWV NS1 protein. Results: The percentage of individuals with LD history and possible evidence of POWV exposure varied depending on the assay utilized. We found no significant difference in clinical symptoms between those with low or high POWV IgG levels in the in-house assay. Congruence of the EDIII and NS1 assays was low with only 12% of those positive in the in-house EDIII ELISA testing positive in the POWV NS1 ELISA. Conclusions: The results highlight the difficulty in flavivirus diagnostic testing, particularly in the retrospective detection of flavivirus exposure. The findings suggest that a prospective study with symptomatic patients using approved clinical testing is necessary to address the incidence and clinical implications of LD and POWV co-infection or sequential infection.

Prevalence of virulence- and antibiotic resistance-associated genotypes and phenotypes in Staphylococcus aureus strains from the food sector compared to clinical and cow mastitis isolates.

Background: Infections by the pathogen Staphylococcus aureus currently represent one of the most serious threats to human health worldwide, especially due to the production of enterotoxins and the ability to form biofilms. These structures and the acquisition of antibiotic resistance limit the action of antibiotics and disinfectants used to combat this microorganism in the industry and the clinic. Methods: This work reports a comparative phenotypic and genotypic study of 18 S. aureus strains from different origins: clinical samples, milk from mastitic cows and food industry surfaces, most of which were isolated in Northern Spain. Results: Genetically, the strains were very diverse but, in most cases, a closer proximity was observed for those from the same source. Notably, the average number of virulence genes was not significantly different in strains from the food sector. Of the 18 strains, 10 coded for at least one enterotoxin, and four of them carried 6 or 7 enterotoxin genes. The latter were all veterinary or clinical isolates. Most strains carried prophages, plasmids and/or pathogenicity islands. Regarding antibiotic resistance, although phenotypically all strains showed resistance to at least one antibiotic, resistance genes were only identified in 44.5% of strains, being mastitis isolates those with the lowest prevalence. Virulence-related phenotypic properties such as haemolytic activity, staphyloxanthin production, biofilm-forming capacity and spreading ability were widely distributed amongst the isolates. Conclusions: Our results indicate that production of virulence factors, antibiotic resistance and biofilm formation can be found in S. aureus isolates from diverse environments, including the food industry, although some of these traits are more prevalent in strains isolated from infections in cows or humans. This emphasizes on the importance of monitoring the spread of these determinants not only in samples from the clinical environment, but also along the food chain, a strategy that falls under the prism of a one-health approach.

Cleavage of Carbon Dioxide C=O Bond Promoted by Nickel-Boron Cooperativity in a PBP-Ni Complex.

The synthesis and characterization of (tBu PBP)Ni(OAc) (5) by insertion of carbon dioxide into the Ni-C bond of (tBu PBP)NiMe (1) is presented. An unexpected CO2 cleavage process involving the formation of new B-O and Ni-CO bonds leads to the generation of a butterfly-structured tetra-nickel cluster (tBu PBOP)2 Ni4 (µ-CO)2 (6). Mechanistic investigation of this reaction indicates a reductive scission of CO2 by O-atom transfer to the boron atom via a cooperative nickel-boron mechanism. The CO2 activation reaction produces a three-coordinate (tBu P2 BO)Ni-acyl intermediate (A) that leads to a (tBu P2 BO)-NiI complex (B) via a likely radical pathway. The NiI species is trapped by treatment with the radical trap (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) to give (tBu P2 BO)NiII (η2 -TEMPO) (7). Additionally, 13 C and 1 H NMR spectroscopy analysis using 13 C-enriched CO2 provides information about the species involved in the CO2 activation process.

Understanding the Mechanisms That Drive Phage Resistance in Staphylococci to Prevent Phage Therapy Failure.

Despite occurring at the microscopic scale, the armed race between phages and their bacterial hosts involves multiple mechanisms, some of which are just starting to be understood. On the one hand, bacteria have evolved strategies that can stop the viral infection at different stages (adsorption, DNA injection and replication, biosynthesis and assembly of the viral progeny and/or release of the newly formed virions); on the other, phages have gradually evolved counterattack strategies that allow them to continue infecting their prey. This co-evolutionary process has played a major role in the development of microbial populations in both natural and man-made environments. Notably, understanding the parameters of this microscopic war will be paramount to fully benefit from the application of phage therapy against dangerous, antibiotic-resistant human pathogens. This review gathers the current knowledge regarding the mechanisms of phage resistance in the Staphylococcus genus, which includes Staphylococcus aureus, one of the most concerning microorganisms in terms of antibiotic resistance acquisition. Some of these strategies involve permanent changes to the bacterial cell via mutations, while others are transient, adaptive changes whose expression depends on certain environmental cues or the growth phase. Finally, we discuss the most plausible strategies to limit the impact of phage resistance on therapy, with a special emphasis on the importance of a rational design of phage cocktails in order to thwart therapeutic failure.

Management and Outcomes of Bleeding Within 30 Days of Colonic Polypectomy in a Large, Real-Life, Multicenter Cohort Study.

BACKGROUND & AIMS: Management of delayed (within 30 days) postpolypectomy bleeding (DPPB) has not been standardized. Patients often undergo colonoscopies that do not provide any benefit. We aimed to identify factors associated with therapeutic intervention and active bleeding after DPPB. METHODS: We performed a retrospective study of 548 patients with bleeding within 30 days after an index polypectomy (DPPB; 71.9% underwent colonoscopy, 2.6% underwent primary angiographic embolization, and 25.5% were managed without intervention) at 6 tertiary centers in Spain, from January 2010 through September 2018. We collected demographic and medical data from patients. The primary outcomes were the need for therapeutic intervention and the presence of active bleeding during colonoscopy. RESULTS: A need for therapeutic intervention was associated independently with the use of antithrombotic agents, hemoglobin decrease greater than 2 g/dL, hemodynamic instability, and comorbidities (P < .05). The bleeding point during colonoscopy was identified in 344 patients; 74 of these patients (21.5%) had active bleeding. Active use of anticoagulants (odds ratio [OR], 2.6; 95% CI, 1.5-4.5), left-sided polyps (OR, 1.95; 95% CI, 1-3.8), prior use of electrocautery (OR, 2.6; 95% CI, 1.1-6.1), and pedunculated polyp morphology (OR, 1.8, 95% CI, 1-3.2) significantly increased the risk of encountering active bleeding. We developed a visual nomogram to estimate the risk of active bleeding. Overall, 43% of the cohort did not require any hemostatic therapy. Rebleeding (<6%) and transfusion requirements were low in those managed without intervention. CONCLUSIONS: In a study of patients with DPPB, we found that almost half do not warrant any therapeutic intervention. Colonoscopy often is overused for patients with DPPB. We identified independent risk factors for active bleeding that might be used to identify patients most likely to benefit from colonoscopy.

Development of antibody-based assays for high throughput discovery and mechanistic study of antiviral agents against yellow fever virus.

Despite the availability of a highly effective yellow fever virus (YFV) vaccine, outbreaks of yellow fever frequently occur in Africa and South America with significant mortality, highlighting the pressing need for antiviral drugs to manage future outbreaks. To support the discovery and development of antiviral drugs against YFV, we characterized a panel of rabbit polyclonal antibodies against the three YFV structural proteins and five non-structural proteins and demonstrated these antibody reagents in conjunction with viral RNA metabolic labeling, double-stranded RNA staining and membrane floatation assays as powerful tools for investigating YFV polyprotein processing, replication complex formation, viral RNA synthesis and high throughput discovery of antiviral drugs. Specifically, the proteolytic processing of the viral polyprotein can be analyzed by Western blot assays. The predominant nuclear localization of NS5 protein as well as the relationship between intracellular viral non-structural protein distribution and foci of YFV RNA replication can be revealed by immunofluorescence staining and membrane flotation assays. Using an antibody against YFV NS4B protein as an example, in-cell western and high-content imaging assays have been developed for high throughput discovery of antiviral agents. A synergistic antiviral effect of an YFV NS4B-targeting antiviral agent BDAA and a NS5 RNA-dependent RNA polymerase inhibitor (Sofosbuvir) was also demonstrated with the high-content imaging assay. Apparently, the antibody-based assays established herein not only facilitate the discovery and development of antiviral agents against YFV, but also provide valuable tools to dissect the molecular mechanism by which the antiviral agents inhibit YFV replication.

Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody.

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. Here we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs.

A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques.

Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement (ADE) in vitro and extend their half-lives. Here we report on prophylactic coadministration of the Fc-modified antibodies to pregnant rhesus macaques challenged three times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission, protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV.

A multicentric Spanish study on the characteristics and survival of gastric adenocarcinoma under the age of 60 / Estudio multicéntrico español sobre las características y la supervivencia del adenocarcinoma gástrico en pacientes menores de 60 años

Introduction: In Europe, gastric adenocarcinoma (GADC) is commonly regarded as a disease of the elderly. This study aims to assess the proportion, characteristics, and survival of patients diagnosed with GADC under the age of 60. Materials and methods: This is a retrospective, multicentric, and analytical study conducted at four tertiary Spanish hospitals. All patients diagnosed with GADC between 2008 and 2015 were included. Demographic, clinical, endoscopic, histologic, and survival data were retrieved. A multivariate analysis was performed to compare GADC in young (age≤60 years) and elderly patients. Results: A total of 1374 patients with GADC were included. The mean age was 74 years (SD:11.1); 62.2% were males. There were 177 patients under the age of 60 (12.9%, 95% CI: 11.2-14.8%). GADC was frequently encountered as a metastatic disease in both young and elderly patients (Stage IV: 45.7% and 41%, respectively). In the multivariate analysis, alcohol abuse, ASA functional status I-II, diffuse subtype, neoadjuvant, and palliative therapy were independently associated (P<0.05) with age ≤60 years. No differences were found in 2-year survival (GADC ≤60: 39% vs. 35%, P=0.45). Curative-intent surgery, TNM stage I-II, body mass index<30kg/m2, and better functional status at diagnosis were independent predictors of survival in GADC under the age of 60. Conclusions: One out of eight cases of GADC were diagnosed under the age of 60. Metastatic disease was frequent at diagnosis and overall survival was poor regardless of age. Factors associated with localized disease correlated with improved survival in younger patients. Our results underline the need for early diagnosis strategies in our country

Introducción: En Europa, el adenocarcinoma gástrico (ADCG) afecta principalmente a pacientes de edad avanzada. Este estudio tiene como objetivo evaluar la proporción, las características y la supervivencia de los pacientes diagnosticados de ADCG menores de 60 años. Material y métodos: Estudio retrospectivo, multicéntrico y analítico realizado en 4 hospitales terciarios españoles. Se incluyeron todos los pacientes diagnosticados con ADCG entre los años 2008-2015. Se recogieron datos demográficos, clínicos, endoscópicos, histológicos y de supervivencia. Se realizó un análisis multivariante para comparar el ADCG en pacientes jóvenes (edad≤60 años) y de edad avanzada. Resultados: Se incluyeron un total de 1.374 pacientes con ADCG. La edad media fue de 74 años (DE: 11,1), el 62,2% varones. Ciento setenta y siete pacientes tenían menos de 60 años (12,9%, IC 95%: 11,2-14,8%). El ADCG se diagnosticó con frecuencia como enfermedad metastásica en pacientes jóvenes y ancianos (estadio IV: 45,7 y 41%, respectivamente). En el análisis multivariante, el abuso de alcohol, la clase funcional ASA I-II, el subtipo difuso, el tratamiento neoadyuvante y el tratamiento paliativo se asociaron de forma independiente (p<0,05) con una edad ≤60 años. No se encontraron diferencias en la supervivencia a 2 años (ADCG≤60: 39 vs. 35%; p=0,45). La cirugía con intención curativa, el estadio TNM I-II, el índice de masa corporal <30kg/m2 y un mejor estado funcional al diagnóstico fueron factores predictivos independientes de supervivencia en el subgrupo de pacientes menores de 60 años. Conclusiones: Uno de cada 8 casos de ADCG se diagnosticaron por debajo de los 60 años. Independientemente de la edad, la presencia de metástasis al diagnóstico fue frecuente y la supervivencia global baja. Los factores asociados a enfermedad localizada se correlacionaron con una mejor supervivencia en pacientes más jóvenes. Nuestros resultados apoyan la necesidad de implementar estrategias de diagnóstico temprano en nuestro país

A multicentric Spanish study on the characteristics and survival of gastric adenocarcinoma under the age of 60.

INTRODUCTION: In Europe, gastric adenocarcinoma (GADC) is commonly regarded as a disease of the elderly. This study aims to assess the proportion, characteristics, and survival of patients diagnosed with GADC under the age of 60. MATERIALS AND METHODS: This is a retrospective, multicentric, and analytical study conducted at four tertiary Spanish hospitals. All patients diagnosed with GADC between 2008 and 2015 were included. Demographic, clinical, endoscopic, histologic, and survival data were retrieved. A multivariate analysis was performed to compare GADC in young (age≤60 years) and elderly patients. RESULTS: A total of 1374 patients with GADC were included. The mean age was 74 years (SD:11.1); 62.2% were males. There were 177 patients under the age of 60 (12.9%, 95% CI: 11.2-14.8%). GADC was frequently encountered as a metastatic disease in both young and elderly patients (Stage IV: 45.7% and 41%, respectively). In the multivariate analysis, alcohol abuse, ASA functional status I-II, diffuse subtype, neoadjuvant, and palliative therapy were independently associated (P<0.05) with age ≤60 years. No differences were found in 2-year survival (GADC ≤60: 39% vs. 35%, P=0.45). Curative-intent surgery, TNM stage I-II, body mass index<30kg/m2, and better functional status at diagnosis were independent predictors of survival in GADC under the age of 60. CONCLUSIONS: One out of eight cases of GADC were diagnosed under the age of 60. Metastatic disease was frequent at diagnosis and overall survival was poor regardless of age. Factors associated with localized disease correlated with improved survival in younger patients. Our results underline the need for early diagnosis strategies in our country.

Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines.

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

ZAP's stress granule localization is correlated with its antiviral activity and induced by virus replication.

Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP's antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP's localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP's ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread.

Rate of missed oesophageal cancer at routine endoscopy and survival outcomes: A multicentric cohort study.

Background: Missed oesophageal cancer (MEC) at upper gastrointestinal endoscopy (UGE) is poorly documented. Objective: The objectives of this study were: (1) to assess the rate, predictors and survival of MEC; (2) to compare MEC and non-MEC tumours. Methods: This was a retrospective cohort study conducted at four tertiary centres. Oesophageal cancers (ECs) diagnosed between 2008 and 2015 were included. Patients with a premalignant condition (Barrett, achalasia), prior diagnosis of EC or oesophagogastric junction tumour of gastric origin were excluded. MEC was defined as EC detected within 36 months after negative UGE. Results: 123,395 UGEs were performed during the study period, with 502 ECs being diagnosed (0.4%). A total of 391 ECs were finally included. Overall MEC rate was 6.4% (95% confidence intervals (CI): 4.4-9.3%). The interval between negative and diagnostic UGE was less than 2 years in 84% of the cases. Multivariate analysis showed that a negative endoscopy was associated with proton pump inhibitor (PPI) therapy and less experienced endoscopists. MEC was smaller than non-MEC at diagnosis (25 versus 40 mm, p = 0.021), more often flat or depressed (p = 0.013) and less frequently diagnosed as metastatic disease (p = 0.013). Overall 2-year survival rate was similar for MEC (20%) and non-MEC (24.1%) (p = 0.95). Conclusions: MEC accounted for 6.4% of all ECs and was associated with poor survival. High-quality UGE and awareness of MEC may help to reduce its incidence.

Characteristics and consequences of missed gastric cancer: A multicentric cohort study.

BACKGROUND: Missed gastric cancer (MGC) is poorly documented in Mediterranean populations. AIMS: (1) To assess the rate, predictors and survival of MGC. (2) To compare MGC and non-MGC tumors. METHODS: This is a retrospective-cohort study conducted at four centers. MGC was defined as cancer detected within three years after negative esophagogastroduodenoscopy. Gastric adenocarcinomas diagnosed between 2008-2015 were included. Patients with no follow-up were excluded. RESULTS: During the study period 123,395 esophagogastroduodenoscopies were performed, with 1374 gastric cancers being diagnosed (1.1%). A total of 1289 gastric cancers were finally included. The overall rate of MGC was 4.7% (61/1289, 3.7-6%). A negative esophagogastroduodenoscopy in MGC patients was independently associated with PPI therapy (p < 0.001), previous Billroth II anastomosis (p = 0.002), and lack of alarm symptoms (p < 0.001). The most frequent location for MGC was the gastric body(52.4%). MGCs were smaller than non-MGCs (31 vs 41 mm, p = 0.047), more often flat or depressed (p = 0.003) and less likely to be encountered as advanced disease. Overall 2-year survival was similar between MGC (34.1%) and Non-MGC (35.3 %) (p = 0.59). CONCLUSION: MGC accounted for nearly five percent of newly-diagnosed gastric adenocarcinomas. Overall survival was poor and not different between MGC and non-MGC.

Morningness-eveningness in a large sample of German adolescents and adults.

People differ in their sleep-wake behavior. This individual difference is conceptualized in different aspects, such as wake up times, bed times, times of peak performance, as well as in morning affect. A total of 14,987 visitors of an exhibition in the LWL State Museum of Natural History, Münster (Germany), did the survey on chronotype and gave their consent that these data can be used for a scientific study. Age groups were coded into 5-year bins. Mean age (mean ± SD) was 28.2 ± 17.5 years. There were 8075 females (54%) and 6912 males in the sample. The German version of the rMEQ (reduced Morningness-Eveningness-Questionnaire) was used for data collection. The data showed clear age effects. Younger children are more morning oriented and become rapidly evening oriented during puberty, while the more attenuated turn towards morningness occurs from the age of 20 years. Then between the ages 25 to 30 morningness-eveningness remained rather stable. Significant gender differences existed in the reproductive age, i.e., the age groups 20 to 50 (corresponding to the age 16-50 years). In other age groups, no gender differences could be detected. Seasonal effects were also found. Chronotype score was lowest during the summer months (and more evening oriented). Based on the single item analysis of the five questions of the rMEQ, we found age group differences in all items. Gender differences occurred in all items except item 1, which deals with the preferred wake-up time. Men always scored significantly lower (i.e. more evening oriented) than women except in item 2 (tiredness after awakening). Seasonal effects were only significant in item 3, which is related to preferred bed times. People showed a later bed time preference during summer. The classification of chronotypes according to the cut-off scores provided by Adan and Almirall (1991) and by using the 20/80 percentile provided identical cut-off scores (values of 11 and below for evening types and 18 and above for morning types).

Pancreatitis aguda secundaria a déficit parcial de multidrug resistance 3 p-glycoprotein / Acute pancreatitis secondary to partial multidrug resistance 3 p-glycoprotein deficit

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