Adaptive control charts for attributes

We develop a general model for adaptive c, np, u and p control charts in which one, two or three design parameters (sample size, sampling interval and control limit width) switch between two values, according to the most recent process information. For a given in-control average sampling rate and a given false alarm rate, the adaptive chart detects changes in the process much faster than a chart with fixed parameters. Moreover, this study also offers general guidance on how to choose an effective design.

Gráfico de Hotelling com esquemas especiais de amostragem para o monitoramento de processos bivariados autocorrelacionados

Pós-graduação em Engenharia Mecânica - FEG

A Single Statistic for Monitoring the Covariance Matrix of Bivariate Processes

In this article, we present a new control chart for monitoring the covariance matrix in a bivariate process. In this method, n observations of the two variables were considered as if they came from a single variable (as a sample of 2n observations), and a sample variance was calculated. This statistic was used to build a new control chart specifically as a VMIX chart. The performance of the new control chart was compared with its main competitors: the generalized sampled variance chart, the likelihood ratio test, Nagao's test, probability integral transformation (v(t)), and the recently proposed VMAX chart. Among these statistics, only the VMAX chart was competitive with the VMIX chart. For shifts in both variances, the VMIX chart outperformed VMAX; however, VMAX showed better performance for large shifts (higher than 10%) in one variance.

Host risk factors for rifamycin-resistant clostridium difficile infection: A case control study

Objective. To evaluate the host risk factors associated with rifamycin-resistant Clostridium difficile (C. diff) infection in hospitalized patients compared to rifamycin-susceptible C.diff infection.^ Background. C. diff is the most common definable cause of nosocomial diarrhea affecting elderly hospitalized patients taking antibiotics for prolonged durations. The epidemiology of Clostridium difficile associated disease is now changing with the reports of a new hypervirulent strain causing hospital outbreaks. This new strain is associated with increased disease severity and mortality. The conventional therapy for C. diff includes metronidazole and vancomycin but high recurrence rates and treatment failures are now becoming a major concern. Rifamycin antibiotics are being developed as a new therapeutic option to treat C. diff infection after their efficacy was established in a few in vivo and in vitro studies. There are some recent studies that report an association between the hypervirulent strain and emerging rifamycin resistance. These findings assess the need for clinical studies to better understand the efficacy of rifamycin drugs against C. diff.^ Methods. This is a hospital-based, matched case-control study using de-identified data drawn from two prospective cohort studies involving C. diff patients at St Luke's Hospital. The C. diff isolates from these patients are screened for rifamycin resistance using agar dilution methods for minimum inhibitory concentrations (MIC) as part of Dr Zhi-Dong Jiang's study. Twenty-four rifamycin-rifamycin resistant C. diff cases were identified and matched with one rifamycin susceptible C. diff control on the basis of ± 10 years of age and hospitalization 30 days before or after the case. De-identified data for the 48 subjects was obtained from Dr Kevin Garey's clinical study at St Luke's Hospital enrolling C. diff patients. It was reviewed to gather information about host risk factors, outcome variables and relevant clinical characteristic.^ Results. Medical diagnosis at the time of admission (p = 0.0281) and history of chemotherapy (p = 0.022) were identified as a significant risk factor while hospital stay ranging from 1 week to 1 month and artificial feeding were identified as an important outcome variable (p = 0.072 and p = 0.081 respectively). Horn's Index assessing the severity of underlying illness and duration of antibiotics for cases and controls showed no significant difference.^ Conclusion. The study was a small project designed to identify host risk factors and understand the clinical implications of rifamycin-resistance. The study was underpowered and a larger sample size is needed to validate the results.^

Instrumental variable method for the causal relationship between soluble receptor for advanced glycation end-products (sRAGE) and risk of pancreatic cancer

This thesis project is motivated by the potential problem of using observational data to draw inferences about a causal relationship in observational epidemiology research when controlled randomization is not applicable. Instrumental variable (IV) method is one of the statistical tools to overcome this problem. Mendelian randomization study uses genetic variants as IVs in genetic association study. In this thesis, the IV method, as well as standard logistic and linear regression models, is used to investigate the causal association between risk of pancreatic cancer and the circulating levels of soluble receptor for advanced glycation end-products (sRAGE). Higher levels of serum sRAGE were found to be associated with a lower risk of pancreatic cancer in a previous observational study (255 cases and 485 controls). However, such a novel association may be biased by unknown confounding factors. In a case-control study, we aimed to use the IV approach to confirm or refute this observation in a subset of study subjects for whom the genotyping data were available (178 cases and 177 controls). Two-stage IV method using generalized method of moments-structural mean models (GMM-SMM) was conducted and the relative risk (RR) was calculated. In the first stage analysis, we found that the single nucleotide polymorphism (SNP) rs2070600 of the receptor for advanced glycation end-products (AGER) gene meets all three general assumptions for a genetic IV in examining the causal association between sRAGE and risk of pancreatic cancer. The variant allele of SNP rs2070600 of the AGER gene was associated with lower levels of sRAGE, and it was neither associated with risk of pancreatic cancer, nor with the confounding factors. It was a potential strong IV (F statistic = 29.2). However, in the second stage analysis, the GMM-SMM model failed to converge due to non- concaveness probably because of the small sample size. Therefore, the IV analysis could not support the causality of the association between serum sRAGE levels and risk of pancreatic cancer. Nevertheless, these analyses suggest that rs2070600 was a potentially good genetic IV for testing the causality between the risk of pancreatic cancer and sRAGE levels. A larger sample size is required to conduct a credible IV analysis.^

Weight-for-age percentile and its association to community acquired methicillin resistant Staphylococcus aureus among pediatric patients in Houston, TX

BACKGROUND: Weight has been implicated as a risk factor for symptomatic community-acquired methicillin resistant Staphylococcus Aureus (CA-MRSA). Information from Texas Children's Hospital (TCH) in Houston, TX was used to implement a case-control study to assess weight-for-age percentile (WFA), race and seasonal exposure as risk factors. ^ METHODS: A retrospective chart review to collect data from TCH was conducted covering the time period January 1st, 2008 to May 31st, 2011. Cases were confirmed and identified by the infectious disease department and were matched on a 1:1 ratio to controls that were seen by the emergency department for non-infected fractures from June 1st, 2008 to May 31st, 2011. Data abstraction was performed using TCH's electronic medical records (EMR) system (EPIC ®). ^ RESULTS: Of 702 CA-MRSA identified cases, ages 9 to 16.99, 564 (80.3%) had the variable `weight' present in their EMR, were not duplicates and not determined to be outliers. Cases were randomly matched to a pool of available controls (n=1864) according to age and gender, yielding 539 1:1 matched pairs (95.5% case matching success) with a total study sample size, N=1078. Case median age was 13.38 years with the majority being White (66.05%) and male (59.4%). Adjusted conditional logistic regression analysis of the matched pairs identified the following risk factors to presenting with CA-MRSA infection among pediatric patients, ages 9 to 16.99 years: a) Individual weight in the highest (75th-99.9th) WFA quartile (OR=1.36; 95% confidence interval [CI]=1.06-1.74; P= 0.016), b) Infection during summer months (OR: 1.69; 95% CI=1.2-2.38; P= 0.003), c) patients of African American race/ethnicity (OR= 1.48; 95% CI=1.13-1.95; P= 0.004). ^ CONCLUSIONS: Pediatric patients, 9 to 16.99 years of age, in the highest WFA quartile (75th-99.9th), or of African-American race had an associated increased risk of presenting with CA-MRSA infection. Furthermore, children in this population were at a higher risk of contracting CA-MRSA infection during the summer season.^

Effects of periodontal therapy on glycemic control and inflammatory markers

Background: Periodontitis, a complication of diabetes mellitus (DM), can induce or perpetuate systemic conditions. This double-masked, placebo-controlled study evaluated the effects of periodontal therapy (scaling and root planing [SRP]) on the serum levels of glycated hemoglobin (HbA1c) and on inflammatory biomarkers. Methods: Thirty subjects with type 2 DM and periodontitis were treated with SRP + placebo (SRP; N = 15) or with SRP + doxycycline (SRP+Doxy; N = 15), 100 mg/day, for 14 days. Clinical and laboratory data were recorded at baseline and at 3 months after treatment. Results: After 3 months, the reduction in probing depth Was 0.8 mm for the SRP group (P <0.01) and 1.1 mm for the SRP+Doxy group (P <0.01) followed by a 0.9% (SRP; P = 0.17) and 1.5% (SRP+Doxy; P<0.01) reduction in HbA1c levels. A significant reduction in interleukin (IL)-6; interferon-inducible protein 10; soluble fas ligand; granulocyte colony-stimulating factor; RANTES; and IL-12 p70 serum levels were also verified (N = 30). To our knowledge, this is the first report on the effects of periodontal therapy on multiple systemic inflammatory markers in DM. Conclusions: Periodontal therapy may influence the systemic conditions of patients with type 2 DM, but no statistical difference was observed with the adjunctive systemic doxycycline therapy. Moreover, it is possible that the observed improvement in glycemic control and in the reduction of inflammatory markers could also be due to diet, which was not controlled in our study. Therefore, a confirmatory study with a larger sample size and controlled diet is necessary.

Ultrassonografia torácica : impacto no diagnóstico e estadiamento do cancro do pulmão

RESUMO:RESUMO: Nos últimos anos a ultrassonografia emergiu como um instrumento importante no diagnóstico da patologia torácica. O progresso tecnológico possibilitou a conceção de novos equipamentos como a ecoendoscopia brônquica radial e linear. Verificou-se, igualmente, o aparecimento de indicações para a realização de ecografia transtorácica. Uma das principais doenças impulsionadoras da técnica ultrassonográfica no tórax foi o cancro do pulmão, primeira causa de morte oncológica a nível mundial. A aplicabilidade e conhecimento do papel dos ultrassons no âmbito do diagnóstico e estadiamento do cancro do pulmão não se encontram esgotados, persistindo focos de controvérsia e dúvida científica que se pretendem esclarecer. A presente tese foi organizada em cinco capítulos: o primeiro abordou de forma geral e introdutória o estado da arte referente à ultrassonografia torácica, cancro do pulmão e a sua conjugação; o segundo destacou os principais objetivos; o terceiro sumarizou a metodologia utilizada; o quarto englobou os cinco estudos publicados, descritos subsequentemente, e o quinto incluiu uma discussão concisa, as principais conclusões e perspetivas futuras. O primeiro estudo avaliou a rentabilidade diagnóstica, segurança e curva de aprendizagem num coorte de 179 doentes submetidos a ecoendoscopia brônquica linear. De acordo com as indicações para este procedimento os doentes foram subdivididos em três grupos: (1) diagnóstico, (2) diagnóstico e estadiamento e (3) estadiamento. Para o primeiro, segundo e terceiro grupos a sensibilidade da ecoendoscopia foi 86.1%, 86.7% e 95% respetivamente e a precisão técnica foi 87.5%, 93.1% e 97.7% respetivamente. O treino originou um aumento progressivo do número de locais puncionados por doente, com menor duração e sem complicações, comprovando a eficácia e segurança do método quando realizado na população Portuguesa por broncologistas com experiência. O segundo estudo foi conduzido para averiguar a eficácia e custo da ecoendoscopia brônquica linear realizada através da via aérea e/ou esófago no diagnóstico de lesões sugestivas de neoplasia do pulmão, após ineficácia das técnicas convencionais. Nos doentes incluídos prospetivamente alcançou-se um diagnóstico definitivo em 106 casos (87.6%). A sensibilidade global para o diagnóstico de cancro do pulmão foi 89.8%, a especificidade foi 100%, o valor preditivo positivo foi 100%, o valor preditivo negativo foi 20% e a precisão foi 90.1%. Esta estratégia ultrassonográfica abrangente evitou intervenções cirúrgicas diagnósticas em doentes anteriormente submetidos a broncoscopia flexível ou punção aspirativa transtorácica guiada por tomografia computorizada, proporcionando uma redução significativa dos custos. No terceiro estudo investigou-se a viabilidade e papel da conjugação da ecoendoscopia brônquica linear com técnicas moleculares na avaliação de antigénios tumorais e padrões de metastização ganglionar em doentes com cancro do pulmão de não-pequenas células (CPNPC). Os marcadores citoqueratina 19 (CK-19), antigénio carcinoembrionário (CEA), molécula de adesão celular epitelial (EPCAM), sialyl-Lewis X e CD44 foram determinados nos aspirados ganglionares de 33 doentes com neoplasia e 17 controlos 10 Ultrassonografia através de citometria de fluxo (CF) e reação em cadeia da polimerase em tempo real (RTPCR). Os doentes com CPNPC possuíam um compartimento celular epitelial significativamente aumentado e com marcação superior de CK-19 comparativamente ao grupo de controlo. O compartimento imune foi também analisado nestas amostras e revelou-se alterado no CPNPC com aumento da população de monócitos e diminuição das subpopulações linfocitárias. Os transcriptos de CK-19, CEA e EPCAM estavam elevados nos doentes com cancro do pulmão, identificando-se uma correlação positiva entre estes marcadores e o tamanho da lesão primária. Concluiu-se que a identificação de CK-19, CEA e EPCAM nas amostras obtidas por ecoendoscopia e avaliadas por CF e RTPCR foi viável, podendo auxiliar na deteção de metástases ganglionares no CPNPC. O quarto estudo envolveu a combinação da ecoendoscopia brônquica radial com uma criosonda para o diagnóstico de lesões pulmonares sólidas periféricas. Foi determinada a viabilidade, rentabilidade diagnóstica, tamanho das amostras e segurança do método. Lesões inferiores a 40mm foram localizadas por ultrassonografia sendo os doentes randomizados para a realização de biópsias transbrônquicas com pinça seguidas por criosonda ou vice-versa. Nos 39 casos incluídos a lesão foi visualizada pela minisonda em 31 doentes (79.5%), com 80.6% de prevalência de cancro do pulmão na amostra. A rentabilidade diagnóstica da pinça de biópsia foi 61.3% e da criosonda foi 74.2%. O tamanho do tecido adquirido pelas criobiópsias foi significativamente maior do que o alcançado por pinça (11.17mm2 vs. 4.69mm2, p<0.001). Ocorreu um único caso de hemorragia moderada, controlada através de medidas conservadoras. As biópsias transbrônquicas com criosonda sob orientação de ecoendoscopia radial foram seguras e eficazes na obtenção de amostras histológicas. O quinto estudo determinou o valor diagnóstico da ecografia transtorácica na identificação de malignidade em doentes com derrame pleural de natureza indeterminada. Foram examinados de forma prospetiva 154 doentes. Os resultados clínicos e radiológicos de cada caso foram ocultados ao executante do exame que gerou imagens estáticas e vídeos ultrassonográficos relevantes. Estes foram posteriormente visualizados, sendo as suas características classificadas por revisores independentes e comparadas com o diagnóstico definitivo. Em 66 casos o diagnóstico foi de derrame pleural maligno (68.2% com cancro do pulmão) e em 67 de derrame benigno. A ecografia torácica obteve 80.3% de sensibilidade, 83.6% de especificidade, 81.2% de valor preditivo negativo e 82.8% de valor preditivo positivo na deteção de malignidade. A nodularidade pleural ou diafragmática, espessamento pleural superior a 10mm e sinal de swirling foram significativamente diferentes (p<0.001) sendo sugestivos de derrame maligno. A existência de nodularidade pleural e ausência de broncograma aéreo ecográfico aumentaram a probabilidade de malignidade (OR 29.0 e OR 10.4, respetivamente). A ecografia transtorácica permitiu diferenciar derrame pleural maligno do benigno. A existência de nódulos pleurais constituiu o fator discriminador mais relevante. Em conclusão, os resultados desta tese possibilitam uma melhor compreensão do papel da ecoendoscopia brônquica (linear e radial) e ecografia transtorácica no diagnóstico e estadiamento do cancro do pulmão, com implicações e aplicabilidade na prática clínica.------------- ABSTRACT: In recent years ultrasonography has emerged as an important instrument in the diagnosis of thoracic diseases. Technological progress has enabled the design of new equipment such as radial and linear endobronchial ultrasound. In addition, indications for transthoracic echography were established. One of the main diseases responsible for the progression of chest sonography was lung cancer, the leading cause of cancer mortality worldwide. The applicability and knowledge of the role of ultrasonography in diagnosing and staging lung cancer is not depleted, persisting foci of controversy and scientific doubt that we intend to elucidate. The present thesis was organized into five chapters: the first included a general introduction regarding chest ultrasound, lung cancer and their combination; the second emphasized the main objectives; the third summarized the methodology used; the fourth encompassed the five published studies, subsequently described, and the fifth included a concise discussion, the main findings and future perspectives. The first study evaluated the diagnostic yield, safety and learning curve in a cohort of 179 patients submitted to linear endobronchial ultrasound. According to procedure indications, the patients were divided into three groups: (1) diagnosis, (2) diagnosis and staging, and (3) staging. For the first, second and third groups, endobronchial ultrasound sensitivity was 86.1%, 86.7% and 95% respectively and accuracy was 87.5%, 93.1% and 97.7% respectively. Practise led to an increase number of punctured sites per patient, in a shorter period of time and without complications, proving the safety and efficacy of the method when performed in the Portuguese population by expert echoscopists. The second study was conducted to determine the efficacy and cost of linear endobronchial ultrasound performed through the airway and/or oesophagus for diagnosis of lesions suggestive of lung cancer, after failure of conventional techniques. Of the patients prospectively enrolled a definitive diagnosis was reached in 106 cases (87.6%). The overall sensitivity for the diagnosis of lung cancer was 89.8%, specificity was 100%, positive predictive value was 100%, negative predictive value was 20% and accuracy was 90.1%. In conclusion, this global ultrasonographic strategy avoided diagnostic surgical procedures in patients that had undergone flexible bronchoscopy or computed tomography-guided transthoracic needle aspiration, providing a significant cost reduction. In the third study, the feasibility and role of linear endobronchial ultrasound combined with molecular techniques in the evaluation of tumour antigens and patterns of lymph node metastasis in patients with non-small cell lung cancer (NSCLC) was investigated. Cytokeratin 19 (CK-19), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), sialyl Lewis-X and CD44 were determined in lymph node aspirates of 33 lung cancer patients and 17 controls, using flow cytometry (FC) and reverse transcription polymerase chain reaction (RT-PCR). In patients with NSCLC the epithelial cell compartment was significantly increased nd showed brighter CK-19 staining, compared to the control group. In NSCLC patients the immune compartment revealed an increased monocyte population and decreased lymphocyte subsets. The transcripts of CK- 19, CEA and EPCAM were higher in lung cancer patients and a positive correlation between these markers and the size of the primary lesion was also found. We concluded that the identification of CK-19, CEA and EPCAM in endobronchial ultrasound samples, using RT-PCR and FC was feasible and might aid in the detection of NSCLC lymph node metastases. The fourth study involved the combination of the radial endobronchial ultrasound with the cryoprobe for diagnosing solid peripheral lung lesions. We determined the feasibility, diagnostic yield, sample size and safety of the method. Lesions less than 40mm were located by ultrasound and forceps or cryobiopsies were performed in a randomized order. Of the 39 cases included, the lesion could be visualized by the miniprobe in 31 patients (79.5%), and lung cancer prevalence was 80.6%. The diagnostic yield of the biopsy forceps was 61.3% and for the cryobiopsy was 74.2 %. Cryobiopsies were significantly larger than forceps biopsies (11.17mm2 vs. 4.69mm2, p<0.001). There was only one case of moderate bleeding that was controlled by conservative measures. Transbronchial cryobiopsies under radial endobronchial ultrasound guidance were safe and effective in obtaining histological samples. The fifth study determined the diagnostic value of transthoracic sonography in predicting malignancy in patients with an undiagnosed pleural effusion. One hundred and fifty four patients were prospectively scanned. Relevant ultrasound images and videos were generated by an operator blinded to clinical and radiological results. These were subsequently visualized, its characteristics classified by independent reviewers and compared to the final diagnosis. A malignant pleural effusion was diagnosed in 66 cases (68.2 % with lung cancer) and a benign effusion in 67 cases. Thoracic ultrasound had a sensitivity of 80.3 %, specificity of 83.6%, negative predictive value of 81.2 % and positive predictive value of 82.8% to detect malignancy. The presence of pleural or diaphragmatic nodularity, pleural thickening greater than 10mm and swirling signal were significantly different (p<0.001 ), being suggestive of malignant effusion. The existence of pleural nodularity and absence of lung air bronchogram were more likely to indicate malignancy (OR 29.0 and OR 10.4, respectively). Transthoracic ultrasonography permits the distinction between malignant and benign pleural effusions. Pleural nodules were the most relevant feature. In conclusion, the results of this thesis provide a better understanding of the role of endobronchial ultrasound (linear and radial) and transthoracic sonography in lung cancer diagnosis and staging, with direct implications and applicability in clinical practice.

RTOG 0525: Exploratory Subset Analysis from a Randomized Phase III Trial Comparing Standard (std) Adjuvant Temozolomide (TMZ) with a Dose-dense (dd) Schedule for Glioblastoma (GBM)

Purpose/Objective(s): RTwith TMZ is the standard for GBM. dd TMZ causes prolongedMGMTdepletion in mononuclear cells and possibly in tumor. The RTOG 0525 trial (ASCO 2011) did not show an advantage from dd TMZ for survival or progression free survival. We conducted exploratory, hypothesis-generating subset analyses to detect possible benefit from dd TMZ.Materials/Methods: Patients were randomized to std (150-200 mg/m2 x 5 d) or dd TMZ (75-100 mg/m2 x 21 d) q 4 weeks for 6- 12 cycles. Eligibility included age.18, KPS$ 60, and. 1 cm2 tissue for prospective MGMTanalysis for stratification. Furtheranalyses were performed for all randomized patients (''intent-to-treat'', ITT), and for all patients starting protocol therapy (SPT). Subset analyses were performed by RPA class (III, IV, V), KPS (90-100, = 50,\50), resection (partial, total), gender (female, male), and neurologic dysfunction (nf = none, minor, moderate).Results: No significant difference was seen for median OS (16.6 vs. 14.9 months), or PFS (5.5 vs. 6.7 months, p = 0.06). MGMT methylation was linked to improved OS (21.2 vs. 14 months, p\0.0001), and PFS (8.7 vs. 5.7 months, p\0.0001). For the ITT (n = 833), there was no OS benefit from dd TMZ in any subset. Two subsets showed a PFS benefit for dd TMZ: RPA class III (6.2 vs. 12.6 months, HR 0.69, p = 0.03) and nf = minor (HR 0.77, p = 0.01). For RPA III, dd dramatically delayed progression, but post-progression dd patients died more quickly than std. A similar pattern for nf = minor was observed. For the SPT group (n = 714) there was neither PFS nor OS benefit for dd TMZ, overall. For RPA class III and nf = minor, there was a PFS benefit for dd TMZ (HR 0.73, p = 0.08; HR 0.77, p = 0.02). For nf = moderate subset, both ITT and SPT, the std arm showed superior OS (14.4 vs. 10.9 months) compared to dd, without improved PFS (HR 1.46, p = 0.03; and HR 1.74, p = 0.01. In terms of methylation status within this subset, there were more methylated patients in the std arm of the ITT subset (n = 159; 32 vs. 24%). For the SPT subset (n = 124), methylation status was similar between arms.Conclusions: This study did not demonstrate improved OS for dd TMZ for any subgroup, but for 2 highly functional subgroups, PFS was significantly increased. These data generate the testable hypothesis that intensive treatment may selectively improve disease control in those most likely able to tolerate dd therapy. Interpretation of this should be considered carefully due to small sample size, the process of multiple observations, and other confounders.Acknowledgment: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI).

Sensitivity of predictive species distribution models to change in grain size

Predictive species distribution modelling (SDM) has become an essential tool in biodiversity conservation and management. The choice of grain size (resolution) of environmental layers used in modelling is one important factor that may affect predictions. We applied 10 distinct modelling techniques to presence-only data for 50 species in five different regions, to test whether: (1) a 10-fold coarsening of resolution affects predictive performance of SDMs, and (2) any observed effects are dependent on the type of region, modelling technique, or species considered. Results show that a 10 times change in grain size does not severely affect predictions from species distribution models. The overall trend is towards degradation of model performance, but improvement can also be observed. Changing grain size does not equally affect models across regions, techniques, and species types. The strongest effect is on regions and species types, with tree species in the data sets (regions) with highest locational accuracy being most affected. Changing grain size had little influence on the ranking of techniques: boosted regression trees remain best at both resolutions. The number of occurrences used for model training had an important effect, with larger sample sizes resulting in better models, which tended to be more sensitive to grain. Effect of grain change was only noticeable for models reaching sufficient performance and/or with initial data that have an intrinsic error smaller than the coarser grain size.

Impact of vaccines given during pregnancy on the offspring of women consulting a travel clinic: a longitudinal study

BACKGROUND: Little is known on the impact of travel vaccinations during pregnancy on child outcomes, in particular on the long-term psychomotor development. The objectives of the study were (1) to estimate the rate of premature births, congenital abnormalities, and mental and physical development problems of children born from mothers who had been vaccinated during pregnancy and (2) to compare these rates with those of children whose mothers had not been vaccinated during pregnancy. METHODS: Longitudinal study including (1) retrospectively pregnant women having attended our travel clinic before (vaccinated) and (2) prospectively mothers attending our clinic (nonvaccinated). We performed phone interviews with mothers vaccinated during pregnancy, up to 10 years before, and face-to-face interviews with nonvaccinated age-matched mothers, ie, women attending the travel clinic who had one child of about the same age as the one of the case to compare child development between both groups. RESULTS: Fifty-three women vaccinated during pregnancy were interviewed as well as 53 nonvaccinated ones. Twenty-eight (53%) women received their vaccination during the first trimester. The most frequent vaccine administered was hepatitis A (55% of the cases), followed by di-Te (34%), IM poliomyelitis (23%), yellow fever (12%), A-C meningitis (8%), IM typhoid (4%), and oral poliomyelitis (4%). Children were followed for a range of 1 to 10 years. Rates of premature births were 5.7% in both groups; congenital abnormalities were 1.9% in the vaccinated cohort versus 5.7% in the nonvaccinated one; children took their first steps at a median age of 12 months in both cohorts; among schoolchildren, 5% of the vaccinated cohort versus 7.7% of the nonvaccinated attended a lower level or a specialized school. CONCLUSION: In this small sample size, there was no indication that usual travel vaccinations, including the yellow fever one, had deleterious effect on child outcome and development

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Control de 6 respiròmetres i anàlisi de les dades

L’aplicació de tècniques respiromètriques és de recent innovació dins l’estudi dels tractaments d’aigües residuals. Aquest conjunt de tècniques ens permeten analitzar dos processos importants dins una planta de tractament biològic: el creixement de la biomassa i el consum del substrat. Això fa que siguin una eina amb gran potencial en l’avaluació dels sistemes de tractament biològic d’aigües residuals. L’objectiu principal d’aquest treball es la realització d’una aplicació capaç de controlar el funcionament de 6 respiròmetres, gestionant el procés del mostreig de les respirometries i l’anàlisi de les dades obtingudes, per obtenir el substrat ràpidament biodegradable (Ss) per a mostres d’aigua residual, i la taxa màxima de creixement específic per a mostres de compost. L’aplicació s’ha desenvolupat sobre l’entorn Microsoft Access, on s’integren la base de dades amb les mostres i els resultats de les respirometries, i els formularis de control que ens permeten gestionar i controlar els processos de mostreig i anàlisi. L’aplicació es comunica amb els sensors i actuadors dels respiròmetres a través del control ActiveX, ADS-OCX, subministrat per TwinCAT, que ens permet capturar les lectures dels sensors i controlar el funcionament dels actuadors. Aquests elements estan connectats a mòduls descentralitzats d’entrades i sortides, comunicats mitjançant el bus Ethernet amb el PC-Industrial, on s’executa l’aplicació. Un cop finalitzada l’aplicació, aquesta controla correctament el mostreig de les respirometries, registrant les lectures de les sondes a la base de dades i controlant l’activació de les vàlvules del respiròmetre. Partint de les mostres obtingudes, o de respirometries externes, importades des de Microsoft Excel, s’ha comprovat el correcte funcionament en el càlcul del substrat ràpidament biodegradable (Ss) i la taxa màxima de creixement específic. Amb l’aplicació desenvolupada, s’ha comprovat el funcionament i les possibilitats que ens ofereix TwinCAT alhora de controlar mòduls d’entrades i sortides, així com la seva comunicació amb aplicacions com Microsoft Access. Això pot afavorir a la utilització d’aquest tipus de tecnologia, per aplicacions futures.

Role of hepatitis C virus genotype 3 in liver fibrosis progression: a systematic review and meta-analysis.

The progression of liver fibrosis in chronic hepatitis C has long been considered to be independent from viral genotypes. However, recent studies suggest an association between Hepatitis C virus (HCV) genotype 3 and accelerated liver disease progression. We completed a systematic review and meta-analysis of studies evaluating the association between HCV genotypes and fibrosis progression. PubMed, Embase and ISI Web of Knowledge databases were searched for cohort, cross-sectional and case-control studies on treatment-naïve HCV-infected adults in which liver fibrosis progression rate (FPR) was assessed by the ratio of fibrosis stage in one single biopsy to the duration of infection (single-biopsy studies) or from the change in fibrosis stage between two biopsies (paired biopsies studies). A random effect model was used to derive FPR among different HCV genotypes. Eight single-biopsy studies (3182 patients, mean/median duration of infection ranging from 9 to 21 years) and eight paired biopsies studies (mean interval between biopsies 2-12 years) met the selection criteria. The odds ratio for the association of genotype 3 with accelerated fibrosis progression was 1.52 (95% CI 1.12-2.07, P = 0.007) in single-biopsy studies and 1.37 (95% CI 0.87-2.17, P = 0.17) in paired biopsy studies. In conclusion, viral genotype 3 was associated with faster fibrosis progression in single-biopsy studies. This observation may have important consequences on the clinical management of genotype 3-infected patients. The association was not significant in paired biopsies studies, although the latter may be limited by important indication bias, short observation time and small sample size.