Comparative Effectiveness Trial of an Obesity Prevention Intervention in EFNEP and SNAP-ED: Primary Outcomes

There is a need to disseminate evidence-based childhood obesity prevention interventions on a broader scale to reduce obesity-related disparities among underserved children. The purpose of this study was to test the comparative effectiveness of an evidence-based obesity prevention intervention, Hip-Hop to Health (HH), delivered through Expanded Food and Nutrition Education Program (EFNEP) and the Supplemental Nutrition Assistance Program-Education (SNAP-Ed) versus the standard curriculum delivered by the programs (Standard Nutrition Education (NE)). A nonequivalent control group design was delivered to compare the effectiveness of HH to NE on weight gain prevention and health behavior outcomes at EFNEP and SNAP-Ed sites. One hundred and fifty-three caregiver–child dyads (n = 103 in the HH group; n = 50 in the NE group) participated in the study. HH is an evidence-based dietary and physical activity intervention for low-income preschool children. The NE curriculum provided lessons for children that are consistent with the Dietary Guidelines for Americans 2010. Data were collected on demographics, anthropometrics, and behavioral variables for parent–child dyads at baseline and postintervention. Mixed model methods with random effects for site and participant were utilized. No differences in child or caregiver diet, physical activity, or screen time by group were found. No between-group differences in child BMI z-score were found; however, caregivers in the HH group lost significantly more weight than those in the NE group. Results from this trial can inform future dissemination efforts of evidenced-based programs for underserved families

Array comparative genomic hybridisation-based identification of two imbalances of chromosome 1p in a 9-year-old girl with a monosomy 1p36 related phenotype and a family history of learning difficulties: a case report

<p>Abstract</p> <p>Introduction</p> <p>Monosomy 1p36 is one of the most common terminal deletion syndromes, with an approximate incidence of 1 in every 5000 live births. This syndrome is associated with several pronounced clinical features including characteristic facial features, cardiac abnormalities, seizures and mental retardation, all of which are believed to be due to haploinsufficiency of genes within the 1p36 region. The deletion size varies from approximately 1.5 Mb to 10 Mb with the most common breakpoints located at 1p36.13 to 1p36.33. Over 70% of 1p36 deletion patients have a true terminal deletion. A further 7% have interstitial deletions and a proportion have a derivative chromosome 1 where the 1p telomere is replaced by material from another chromosome, either as a result of a de-novo rearrangement or as a consequence of malsegregation of a balanced parental translocation at meiosis.</p> <p>Case presentation</p> <p>Array comparative genomic hybridisation analysis of a 9-year-old Caucasian girl presenting with dysmorphic facial features and learning difficulties, for whom previous routine karyotyping had been normal, identified two submicroscopic rearrangements within chromosome 1p. Detection of both an insertional duplication of a region of 1p32.3 into the subtelomeric region of the short arm of a chromosome 1 homologue and a deletion within 1p36.32 of the same chromosome instigated a search for candidate genes within these regions which could be responsible for the clinical phenotype of the patient. Several genes were identified by computer-based annotation, some of which have implications in neurological and physical development.</p> <p>Conclusion</p> <p>Array comparative genomic hybridisation is providing a robust method for pinpointing regions of candidate genes associated with clinical phenotypes that extend beyond the resolution of the light microscope. This case report provides an example of how this method of analysis and the subsequent reporting of findings have proven useful in collaborative efforts to elucidate multiple gene functions from a clinical perspective.</p

Integrating shotgun proteomics and mRNA expression data to improve protein identification

Motivation: Tandem mass spectrometry (MS/MS) offers fast and reliable characterization of complex protein mixtures, but suffers from low sensitivity in protein identification. In a typical shotgun proteomics experiment, it is assumed that all proteins are equally likely to be present. However, there is often other information available, e.g. the probability of a protein's presence is likely to correlate with its mRNA concentration

Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type Diffuse Large B Cell Lymphoma

Despite the effectiveness of immuno-chemotherapy, 40\cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focussed attention on the changes in gene expression profile accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo DLBCL patients. Cell of origin remained stable from diagnosis to relapse in 80\ with only a single patient showing COO switching from ABC to GCB. Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC-DLBCLs derived from relapse-associated genes, that defined clinically distinct high and low risk subgroups in ABC-DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of \lt;60-year-old patients with superior PFS and OS treated with Ibrutinib-R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials

A cluster of multidrug-resistant Mycobacterium tuberculosis among patients arriving in Europe from the Horn of Africa: a molecular epidemiological study

SummaryBackground The risk of tuberculosis outbreaks among people fleeing hardship for refuge in Europe is heightened. We describe the cross-border European response to an outbreak of multidrug-resistant tuberculosis among patients from the Horn of Africa and Sudan. Methods On April 29 and May 30, 2016, the Swiss and German National Mycobacterial Reference Laboratories independently triggered an outbreak investigation after four patients were diagnosed with multidrug-resistant tuberculosis. In this molecular epidemiological study, we prospectively defined outbreak cases with 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) profiles; phenotypic resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, and capreomycin; and corresponding drug resistance mutations. We whole-genome sequenced all Mycobacterium tuberculosis isolates and clustered them using a threshold of five single nucleotide polymorphisms (SNPs). We collated epidemiological data from host countries from the European Centre for Disease Prevention and Control. Findings Between Feb 12, 2016, and April 19, 2017, 29 patients were diagnosed with multidrug-resistant tuberculosis in seven European countries. All originated from the Horn of Africa or Sudan, with all isolates two SNPs or fewer apart. 22 (76%) patients reported their travel routes, with clear spatiotemporal overlap between routes. We identified a further 29 MIRU-VNTR-linked cases from the Horn of Africa that predated the outbreak, but all were more than five SNPs from the outbreak. However all 58 isolates shared a capreomycin resistance-associated tlyA mutation. Interpretation Our data suggest that source cases are linked to an M tuberculosis clone circulating in northern Somalia or Djibouti and that transmission probably occurred en route before arrival in Europe. We hypothesise that the shared mutation of tlyA is a drug resistance mutation and phylogenetic marker, the first of its kind in M tuberculosis sensu stricto. Funding The Swiss Federal Office of Public Health, the University of Zurich, the Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the Medical Research Council, BELTA-TBnet, the European Union, the German Center for Infection Research, and Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG)

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

Investigation of reduced susceptibility to glycopeptides among meticillin-resistant Staphylococcus aureus recovered in Ireland (1998-2004)

THESIS 9261Meticillin-resistant Staphylococcus aureus (MRSA) isolates (n=3,189) from 2990 patients were studied by agar screening and the E-test? macromethod to investigate reduced susceptibility to glycopeptides among six collections of MRSA recovered between 1998 and 2004. No vancomycin-resistant S. aureus or glycopeptide-intermediate S. aureus (GISA) were detected but 178 isolates were confirmed by vancomycin population analysis profile (PAP)-area under the curve (vPAP-AUC) ratio determination and/or teicoplanin PAP (tPAP) methods as hetero-GISA (hGISA). Of 139 isolates detected using recommended E-test? macromethod cut-off values of ?8 mg/L for both vancomycin and teicoplanin or ?12 mg/L for teicoplanin alone, 73 were confirmed as hGlSA by vPAP- AUC, 95 by tPAP and 108 by both methods. Lowering the teicoplanin E-test? macromethod cut-off value to 8 mg/L detected a further 70 hGISA (17 were confirmed by vPAP-AUC and 70 by tPAP)

Investigation of Reduced Susceptibility to Glycopeptides among Methicillin-Resistant Staphylococcus aureus Isolates from Patients in Ireland and Evaluation of Agar Screening Methods for Detection of Heterogeneously Glycopeptide-Intermediate S. aureus▿

Methicillin-resistant Staphylococcus aureus (MRSA) isolates (n = 3,189) from 2,990 patients were investigated by agar screening and by the Etest macromethod for reduced susceptibility to glycopeptide. No vancomycin-resistant S. aureus or glycopeptide-intermediate S. aureus (GISA) isolates were detected, but 178 isolates were confirmed as hetero-GISA (hGISA) by vancomycin population analysis profile (vPAP)-area under the curve (AUC) ratio determination and/or teicoplanin PAP (tPAP) methods. Of 139 isolates detected using the recommended Etest macromethod cutoff values of ≥8 mg/liter for both vancomycin and teicoplanin or ≥12 mg/liter for teicoplanin alone, 73 were confirmed as hGISA by vPAP-AUC, 95 were confirmed as hGISA by tPAP, and 108 were confirmed as hGISA by both methods. An Etest macromethod cutoff value of 8 mg/liter for teicoplanin alone detected a further 70 hGISA (17 were confirmed by vPAP-AUC and 70 were confirmed by tPAP). Agar screening utilizing brain heart infusion (BHI) agar containing 6 mg of vancomycin/liter (BHIV6) and Mueller-Hinton (MH) agar containing 8 mg of teicoplanin/liter (MHT8) failed to detect hGISA. MH agar containing 5 mg of teicoplanin/liter (MHT5) and BHI containing 5 mg of teicoplanin/liter (BHIT5) were evaluated using 10-μl volumes of three inoculum concentrations (with densities equivalent to 0.5 and 2.0 McFarland turbidity standards and stationary-phase BHI broth subcultures [MHT50.5, MHT52.0, MHT5S, BHIT50.5, BHIT52.0, and BHIT5S]). The sensitivity of all methods except MHT50.5 and MHT52.0 was 100%. The specificity ranged from 4 to 82%. BHIT50.5 yielded the best performance, with a specificity of 84% for detecting isolates with teicoplanin Etest macromethod values of ≥8 mg/liter. Screening on BHIT50.5 is useful where screen-positive isolates are investigated with the Etest macromethod and confirmed by vPAP-AUC and tPAP. The prevalence of hGISA among patients with blood culture isolates recovered in Irish hospitals between 1999 and 2003 was 2.6%, whereas the prevalence among patients with isolates from all specimen sites collected during a 2-week survey in 1999 was 12%. The prevalence in one hospital decreased from 5.3% in 2003 to 1.5% in 2004

Modulation of human uterine smooth muscle cell collagen contractility by thrombin, y-27632, tnf alpha and indomethacin

Background: Preterm labour occurs in approximately 10% of pregnancies and is a major cause of infant morbidity and mortality. However, the pathways involved in regulating contractility in normal and preterm labour are not fully elucidated. Our aim was to utilise a human myometrial contractility model to investigate the effect of a number of uterine specific contractility agents in this system. Therefore, we investigated the contractile response of human primary uterine smooth muscle cells or immortalised myometrial smooth muscle cells cultured within collagen lattices, to known mediators of uterine contractility, which included thrombin, the ROCK-1 inhibitor Y-27632, tumour necrosis factor alpha (TNF alpha) and the non-steroidal anti-inflammatory indomethacin. Methods: Cell contractility was calculated over time, with the collagen gel contraction assay, utilising human primary uterine smooth muscle cells (hUtSMCs) and immortalised myometrial smooth muscle cells (hTERT-HM): a decrease in collagen gel area equated to an increase in contractility. RNA was isolated from collagen embedded cells and gene expression changes were analysed by real time fluorescence reverse transcription polymerase chain reaction. Scanning electron and fluorescence microscopy were employed to observe cell morphology and cell collagen gel interactions. Statistical analysis was performed using ANOVA followed by Tukey's post hoc tests. Results: TNF alpha increased collagen contractility in comparison to the un-stimulated collagen embedded hUtSMC cells, which was inhibited by indomethacin, while indomethacin alone significantly inhibited contraction. Thrombin augmented the contractility of uterine smooth muscle cell and hTERT-HM collagen gels, this effect was inhibited by the thrombin specific inhibitor, hirudin. Y-27632 decreased both basal and thrombin-induced collagen contractility in the hTERT-HM embedded gels. mRNA expression of the thrombin receptor, F2R was up-regulated in hUtSMCs isolated from collagen gel lattices, following thrombin-stimulated contractility. Conclusion: TNF alpha and thrombin increased uterine smooth muscle cell collagen contractility while indomethacin had the opposite effect. Thrombin-induced collagen contractility resulted in F2R activation which may in part be mediated by the ROCK-1 pathway. This study established the in vitro human myometrial model as a viable method to assess the effects of a range of uterotonic or uterorelaxant agents on contractility, and also permits investigation of the complex regulatory pathways involved in mediating myometrial contractility at labour