The Clinical Utility of Molecular Typing of Multiply-resistant Pseudomonas aeruginosa in Children with Cystic Fibrosis

Chronic infection with P. aeruginosa is expected in patients with cystic fibrosis (CF), but the ability to delay, prevent, or better manage infection with multiply-resistant P. aeruginosa (MRPA) can potentially increase quality of life and extend survival. The Texas Children’s Hospital CF Care Center has identified an endemic MRPA strain (dominant clone), and this study aimed to identify risk factors for acquisition of the clone as well as determine differences in patient outcome associated with subsequent infection with the clone. The study included 71 patients with CF with documented MRPA infection. Designation of patients as members of the dominant clone or a non-dominant clone group was based on molecular typing by rep-PCR of MRPA isolates from respiratory cultures. Patient data was collected from Port CF, the national patient registry of the CF Foundation. Patient demographic information and clinical parameters prior to MRPA infection were analyzed by logistic regression as potential risk factors. Differences in patient outcome including change in BMI, change in FEV1, and hospitalization rate were evaluated by MANOVA. Recent hospitalization (\u3c 90 days) was a statistically significant (p = 0.035) risk factor for acquisition of the dominant clone. Patients hospitalized \u3c 90 days prior to MRPA diagnosis were four times more likely to be infected with the dominant clone, and patients hospitalized 91-180 days prior were almost three times more likely. Increased hospitalization rates were seen in the dominant clone group both pre- (11 more days/year) and post-infection (14 more days/year) as compared to the non-dominant clone group. Patients infected with the endemic strain exhibited poorer outcomes in terms of nutritional status (3.73% decrease/year in BMI %ile) and lung function (3.7% decrease/year in FEV1 %ile). Significant overlap in hospitalization episodes of patients known to be infected with the dominant clone and patients subsequently infected with the dominant clone was observed. Recent hospitalization was a significant risk factor for infection with the dominant MRPA clone, and following infection, patients infected with the endemic strain exhibited declines in nutritional status and lung function and increased hospitalization rates. The results suggest potentially increased virulence and transmissibility of the endemic MRPA strain

Next-Generation Probiotics Targeting \u3ci\u3eClostridium difficile\u3c/i\u3e through Precursor- Directed Antimicrobial Biosynthesis

Integration of antibiotic and probiotic therapy has the potential to lessen the public health burden of antimicrobial-associated diseases. Clostridium difficile infection (CDI) represents an important example where the rational design of next-generation probiotics is being actively pursued to prevent disease recurrence. Because intrinsic resistance to clinically relevant antibiotics used to treat CDI (vancomycin, metronidazole, and fidaxomicin) is a desired trait in such probiotic species, we screened several bacteria and identified Lactobacillus reuteri to be a promising candidate for adjunct therapy. Human-derived L. reuteri bacteria convert glycerol to the broad-spectrum antimicrobial compound reuterin. When supplemented with glycerol, strains carrying the pocR gene locus were potent reuterin producers, with L. reuteri 17938 inhibiting C. difficile growth at a level on par with the level of growth inhibition by vancomycin. Targeted pocR mutations and complementation studies identified reuterin to be the precursor-induced antimicrobial agent. Pathophysiological relevance was demonstrated when the codelivery of L. reuteri with glycerol was effective against C. difficile colonization in complex human fecal microbial communities, whereas treatment with either glycerol or L. reuteri alone was ineffective. A global unbiased microbiome and metabolomics analysis independently confirmed that glycerol precursor delivery with L. reuteri elicited changes in the composition and function of the human microbial community that preferentially targets C. difficile outgrowth and toxicity, a finding consistent with glycerol fermentation and reuterin production. Antimicrobial resistance has thus been successfully exploited in the natural design of human microbiome evasion of C. difficile, and this method may provide a prototypic precursor-directed probiotic approach. Antibiotic resistance and substrate bioavailability may therefore represent critical new determinants of probiotic efficacy in clinical trials

Taking the Initiative? TLRP and Educational Research

Evaluating the effects of known subject traits on pediatric GI community structure and function. PCoA of the GI microbial communities of healthy children as a function of Bray-Curtis dissimilarities and 16S-based OTUs (A–D), WGS-based species (E–H), KO groups (I–L), and KEGG pathway profiles (M–P). Variation among profiles was evaluated with respect to known traits, and the percent variation captured by each axis is indicated in parenthesis. Adonis analysis results describe the significance of each trait to overall community variation. (TIF 1.58 kb

It’s not which school but which set you’re in that matters: the influence of ability-grouping practices on student progress in mathematics

The mathematics achievement of a cohort of 955 students in 42 classes in six schools in London was followed over a four-year period, until they took their GCSEs in the summer of 2000. All six schools were regarded by Ofsted as providing a good standard of education, and all were involved in teacher-training partnerships with universities. Matched data on key stage 3 test scores and GCSE grades were available for 709 students, and these data were analysed in terms of the progress from key stage 3 test scores to GCSE grades. Although there were wide differences between schools in terms of overall GCSE grades, the average progress made by students was similar in all six schools. However, within each school, the progress made during key stage 4 varied greatly from set to set. Comparing students with the same key stage 3 scores, students placed in top sets averaged nearly half a GCSE grade higher than those in the other upper sets, who in turn averaged a third of a grade higher than those in lower sets, who in turn averaged around a third of a grade higher than those students placed in bottom sets. In the four schools that used formal whole-class teaching, the difference in GCSE grades between top and bottom sets, taking key stage 3 scores into account, ranged from just over 1 grade at GCSE to nearly 3 grades. At the schools using small-group and individualised teaching, the differences in value-added between sets were not significant. In two of the schools, a significant proportion of working class students were placed into lower sets than would be indicated by their key stage 3 test scores

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Gut Microbiome and Inflammation: A Study of Diabetic Inflammasome-Knockout Mice

Aims. Diabetes is a proinflammatory state, evidenced by increased pattern recognition receptors and the inflammasome (NOD-like receptor family pyrin domain (NLRP)) complex. Recent reports have elucidated the role of the gut microbiome in diabetes, but there is limited data on the gut microbiome in NLRP-KO mice and its effect on diabetes-induced inflammation. Methods. Gut microbiome composition and biomarkers of inflammation (IL-18, serum amyloid A) were assessed in streptozotocin- (STZ-) induced diabetic mice on a NLRP3-knockout (KO) background versus wild-type diabetic mice. Results. SAA and IL-18 levels were significantly elevated in diabetic mice (STZ) compared to control (WT) mice, and there was a significant attenuation of inflammation in diabetic NLRP3-KO mice (NLRP3-KO STZ) compared to control mice (p<0.005). Principal coordinate analysis clearly separated controls, STZ, and NLRP3-KO STZ mice. Among the different phyla, there was a significant increase in the Firmicutes : Bacteroidetes ratio in the diabetic group compared to controls. When compared to the WT STZ group, the NLRP3-KO STZ group showed a significant decrease in the Firmicutes : Bacteroidetes ratio. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a crucial factor that could modify diabetes and complications

Microbiome signatures in neonatal central line associated bloodstream infections.

Neonates are at high risk for central line associated bloodstream infections (CLABSI). Biofilm formation is universal on indwelling catheters but why some biofilms seed the bloodstream to cause CLABSI is not clearly understood. With the objective to test the hypothesis that catheter biofilm microbiome in neonates with CLABSI differs than those without infection, we prospectively enrolled neonates (n = 30) with infected and uninfected indwelling central catheters. Catheters were collected at the time of removal, along with blood samples and skin swabs at the catheter insertion sites. Microbiomes of catheter biofilms, skin swabs and blood were evaluated by profiling the V4 region of the bacterial 16S rRNA gene using Illumina MiSeq sequencing platform. The microbial DNA load was higher from catheter biofilms of CLABSI patients without differences in alpha diversity when compared to that of the non-CLABSI neonates. Proteus and unclassified Staphylococcaceae were more abundant in infected catheter biofilms while Bradyrhizobium, Cloacibacterium, and Sphingomonas were more abundant in the uninfected catheters. A blood microbiome was detected in uninfected samples. The blood microbiome in CLABSI neonates clustered separately from the uninfected blood samples in beta diversity plots. We found that the microbiome signature in catheter biofilm and blood of neonates with CLABSI is different than the microbiomes of non-CLABSI neonates

A case-control study of human papillomavirus and cervical squamous intraepithelial lesions (SIL) in Harris County, Texas: differences among racial/ethnic groups Um estudo de caso-controle de infecção por papillomavirus humano e câncer de colo uterino em Harrys County, Texas

We conducted a case-control study of the association between SIL and HPV among whites (W), African Americans (AA), and Hispanics (H) in Harris County, Texas. Cases were identified at M.D. Anderson Cancer Center Colposcopy Clinic. Controls were identified among women obtaining routine Pap screening at two Harris County Health Department Clinics. HPV was detected by a PCR-based fluorescent assay. Dichotomous and polytomous logistic regression models were used to estimate adjusted odd ratios (AOR) and 95% confidence intervals (CI) for SIL among racial/ethnic groups and grade of disease. Prevalence of HPV infection was 64% in low grade SIL (LSIL), 84% in high grade SIL (HSIL), and 19% in controls. Risk of SIL was higher in H than in W and AA, AOR 29.5 (12.4-70.5), 15.3 (6.0-33.8), and 5.8 (2.6-12.6), respectively. Similarly, racial/ethnic differences were observed for both LSIL (AOR = 16.6, 7.7, and 4.3, respectively) and HSIL (AOR = 78.6, 34.6, and 14.2, respectively). Findings support the association between SIL and HPV and differences in the strength of the association with LSILs and HSILs. Data also suggest a higher risk for H and a lower risk for AA.Foi realizado um estudo caso-controle para analisar a associação entre lesões intra-epiteliais escamosas do colo uterino (SIL) e HPV entre mulheres brancas, negras e latinas em Harris County, Texas. Os casos foram identificados na M. D. Anderson Cancer Center Colposcopy Clinic, e os controles foram obtidos realizando-se exame de Papanicolau em duas clínicas do Departamento de Saúde. O HPV foi detectado por meio de ensaio de PCR (primer MY09/MY11). Foram construídos modelos de regressão logística para estimar as odds ratios ajustadas (AOR), e seus intervalos de confiança de 95% (IC) de SIL entre os grupos étnicos e graus da doença. A prevalência de HPV nas SIL de baixo grau (LSIL) foi de 64%; nas de alto grau (HSIL), 84%; e 19% nos controles. O risco de SIL foi maior em mulheres latinas que em brancas e negras, sendo observadas, respectivamente, as seguintes AOR: 29,5 (12,4-70,5); 15,3 (6,0-33,8); e 5,8 (2,6-12,6). De forma similar, foram observadas diferenças para ambos LSIL (AOR, respectivamente, de 16,6; 7,7 e 4,3) e HSIL (AOR de 78,6; 34,6 e 142). Os resultados apóiam a existência de associação entre SIL e HPV, diferenças na força de associação com SILs e HSILs, e sugerem risco mais elevado para mulheres latinas e menor para mulheres negras