Search

OBJECTIVE: The aim of this study was to describe a series of 10 cases of oral-maxillofacial myiasis, discussing its main features, demographic distribution, and treatment aspects. STUDY DESIGN: A retrospective study was carried out involving male and female patients of any age with oral-maxillofacial myiasis. The sample was determined by spontaneous demand at the emergency ward of a hospital between January 2005 and January 2011 (6 years). After treatment of each case, data were gathered on the presence of associated systemic disorders, time elapsed since onset of the disease, and treatment established. A review of the literature on this topic was also carried out. RESULTS: The sample was made up of 10 patients, all treated with surgical debridement whether or not associated with the use of oral ivermectin. Mean time elapsed since the onset of the disease ranged from 4 to 36 months. The middle third of the face was the most frequently affected region (7 cases). Oral-maxillofacial myiasis predominantly affected the male gender (70%). CONCLUSIONS: Oral-maxillofacial myiasis affects individuals with poor hygiene and neurologic and/or psychologic alterations. It occurs predominantly in countries near the tropics. The treatment of choice is surgical debridement. [ABSTRACT FROM AUTHOR]

Objective: Psoriatic disease remains underdiagnosed and undertreated. We developed and validated a suite of novel, sensor-based smartphone assessments (Psorcast app) that can be self-administered to measure cutaneous and musculoskeletal signs and symptoms of psoriatic disease., Methods: Participants with psoriasis (PsO) or psoriatic arthritis (PsA) and healthy controls were recruited between June 5, 2019, and November 10, 2021, at 2 academic medical centers. Concordance and accuracy of digital measures and image-based machine learning models were compared to their analogous clinical measures from trained rheumatologists and dermatologists., Results: Of 104 study participants, 51 (49%) were female and 53 (51%) were male, with a mean age of 42.3 years (SD 12.6). Seventy-nine (76%) participants had PsA, 16 (15.4%) had PsO, and 9 (8.7%) were healthy controls. Digital patient assessment of percent body surface area (BSA) affected with PsO demonstrated very strong concordance (Lin concordance correlation coefficient [CCC] 0.94 [95% CI 0.91-0.96]) with physician-assessed BSA. The in-clinic and remote target plaque physician global assessments showed fair-to-moderate concordance (CCC erythema 0.72 [0.59-0.85]; CCC induration 0.72 [0.62-0.82]; CCC scaling 0.60 [0.48-0.72]). Machine learning models of hand photos taken by patients accurately identified clinically diagnosed nail PsO with an accuracy of 0.76. The Digital Jar Open assessment categorized physician-assessed upper extremity involvement, considering joint tenderness or enthesitis (AUROC 0.68 [0.47-0.85])., Conclusion: The Psorcast digital assessments achieved significant clinical validity, although they require further validation in larger cohorts before use in evidence-based medicine or clinical trial settings. The smartphone software and analysis pipelines from the Psorcast suite are open source and freely available., (Copyright © 2024 by the Journal of Rheumatology.)

Aim: The purpose of this study is to undertake an integrative literature review in order to determine the prevalence, etiology, and reactivation of oral HSV infection in patients receiving chemotherapy (CT)., Methods: The study was carried out in the PubMed/MEDLINE, Embase, Virtual Health Library, and Scopus databases, using the descriptors "Herpes Simplex", "Viral Diseases", "Mouth", and "Antineoplastic Agents"., Results: The findings suggest that HSV infection is widespread in this group of patients and can be severe. HSV infection is frequent in CT patients, and treatment should begin as soon as it is feasible, utilizing antivirals to avoid future difficulties, as patients are immunocompromised., Conclusion: It is critical for health professionals to be fully informed on the dangers and treatment choices available, with the most appropriate therapy for each circumstance. Furthermore, more recent research with acceptable methodological rigor is required to better quantify the prevalence of HSV in these patients., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Carvalho et al.)

Background: Myocardial perfusion defect (MPD) is common in chronic Chagas cardiomyopathy (CCC) and is associated with inflammation and development of left ventricular systolic dysfunction. We tested the hypothesis that pentoxifylline (PTX) could reduce inflammation and prevent the development of MPD in a model of CCC in hamsters., Methods and Results: We investigated with echocardiogram and rest myocardial perfusion scintigraphy at baseline (6-months after T. cruzi infection/saline) and post-treatment (after additional 2-months of PTX/saline administration), female Syrian hamsters assigned to 3 groups: T. cruzi-infected animals treated with PTX (CH + PTX) or saline (CH + SLN); and uninfected control animals (CO). At the baseline, all groups showed similar left ventricular ejection fraction (LVEF) and MPD areas. At post-treatment evaluation, there was a significant increase of MPD in CH + SLN group (0.8 ± 1.6 to 9.4 ± 9.7%), but not in CH + PTX (1.9 ± 3.0% to 2.7 ± 2.7%) that exhibited MPD area similar to CO (0.0 ± 0.0% to 0.0 ± 0.0%). The LVEF decreased in both infected groups. Histological analysis showed a reduced inflammatory infiltrate in CH + PTX group (395.7 ± 88.3 cell/mm 2 ), as compared to CH + SLN (515.1 ± 133.0 cell/mm 2 ), but larger than CO (193.0 ± 25.7 cell/mm 2 ). The fibrosis and TNF-α expression was higher in both infected groups., Conclusions: The prolonged use of PTX is associated with positive effects, including prevention of MPD development and reduction of inflammation in the chronic hamster model of CCC., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Objective: The role of oestrogen in craniofacial growth still remains unclear. Therefore, the present study aimed to assess the effect of oestrogen deficiency on maxilla and mandible dimensions., Setting and Sample Population: The study was conducted at the Department of Pediatric Dentistry at the School of Dentistry of Ribeirão Preto, University of São Paulo, and used forty female Wistar rats., Material and Methods: Ovariectomy (OVX) and placebo surgery (Sham) were performed when animals were twenty-one days old (prepubertal stage). Dimensions of the maxilla and mandible were assessed by craniometric analysis using radiographs, during and after puberty of the animals (45 and 63 days old, respectively). Quantitative real-time PCR and immunohistochemical analyses were performed to determine the expression and localization, respectively, of oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERβ) in different growth sites of the evaluated structures at puberty. The differences between the groups for each outcome were evaluated using the t test with an established alpha error of 5%., Results: There were significant differences between the OVX and Sham groups for horizontal and vertical linear measurements in the maxilla and the mandible at both pubertal and post-pubertal stages (P < .05). The ovariectomized rats showed significantly greater measures for all dimensions assessed. No differences in gene expression of ERα and ERβ were identified at the different growth sites between the OVX and Sham groups (P > .05). Immunohistochemical analyses revealed the presence of both oestrogen receptors in osteoblasts and chondrocytes in the midpalatal suture and mandibular condyle, respectively, in the OVX and Sham groups., Conclusion: Our results suggest that oestrogen deficiency from the prepubertal stage might increase the growth of the maxilla and mandible in female rats., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

There are many approaches to maintaining wellness, including taking a simple vacation to attending highly structured wellness retreats, which typically regulate the attendee's personal time and activities. In a healthy English-speaking cohort of 112 women and men (aged 30-80 years), this study examined the effects of participating in either a 6-days intensive wellness retreat based on Ayurvedic medicine principles or unstructured 6-days vacation at the same wellness center setting. Heart rate variability (HRV) was monitored continuously using a wearable ECG sensor patch for up to 7 days prior to, during, and 1-month following participation in the interventions. Additionally, salivary cortisol levels were assessed for all participants at multiple times during the day. Continual HRV monitoring data in the real-world setting was seen to be associated with demographic [HRV ALF : β Age = 0.98 (95% CI = 0.96-0.98), false discovery rate (FDR) < 0.001] and physiological characteristics [HRV PLF : β = 0.98 (95% CI = 0.98-1), FDR =0.005] of participants. HRV features were also able to quantify known diurnal variations [HRV LF/HF : β ACT:night vs. early-morning = 2.69 (SE = 1.26), FDR < 0.001] along with notable inter- and intraperson heterogeneity in response to intervention. A statistically significant increase in HRV ALF [β = 1.48 (SE = 1.1), FDR < 0.001] was observed for all participants during the resort visit. Personalized HRV analysis at an individual level showed a distinct individualized response to intervention, further supporting the utility of using continuous real-world tracking of HRV at an individual level to objectively measure responses to potentially stressful or relaxing settings., (Copyright © 2020 Pratap, Steinhubl, Neto, Wegerich, Peterson, Weiss, Patel, Chopra and Mills.)

Digital technologies such as smartphones are transforming the way scientists conduct biomedical research. Several remotely conducted studies have recruited thousands of participants over a span of a few months allowing researchers to collect real-world data at scale and at a fraction of the cost of traditional research. Unfortunately, remote studies have been hampered by substantial participant attrition, calling into question the representativeness of the collected data including generalizability of outcomes. We report the findings regarding recruitment and retention from eight remote digital health studies conducted between 2014-2019 that provided individual-level study-app usage data from more than 100,000 participants completing nearly 3.5 million remote health evaluations over cumulative participation of 850,000 days. Median participant retention across eight studies varied widely from 2-26 days (median across all studies = 5.5 days). Survival analysis revealed several factors significantly associated with increase in participant retention time, including (i) referral by a clinician to the study (increase of 40 days in median retention time); (ii) compensation for participation (increase of 22 days, 1 study); (iii) having the clinical condition of interest in the study (increase of 7 days compared with controls); and (iv) older age (increase of 4 days). Additionally, four distinct patterns of daily app usage behavior were identified by unsupervised clustering, which were also associated with participant demographics. Most studies were not able to recruit a sample that was representative of the race/ethnicity or geographical diversity of the US. Together these findings can help inform recruitment and retention strategies to enable equitable participation of populations in future digital health research., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

High-fat diet increase two to three times the plasma lipopolysaccharide (LPS) levels and induce subclinical inflammation. Diet can modify gene expression due to epigenetic processes related to MicroRNAs (miRNAs). MicroRNAs (miRNAs) play important role in the post-transcriptional mechanisms involved in regulation of expression of genes related to the inflammatory response. Also, diet can indirectly induce post-transcriptional regulation of gene expression by miRNAs, which may affect the risk for the development of chronic diseases., Objective: This study investigated the effect of high-fat high-saturated meal ingestion on plasma miRNA expression and LPS levels during the postprandial period in healthy women., Methods: An interventional study was carried out in which a high-fat breakfast (1067.45 kcal), composed mainly of saturated fatty acids (56 g), and 500 mL of water, was offered. Blood samples were collected at baseline and 1, 3 and 5 h after meal intake. The studied population consisted of healthy women (n = 11), aged between 20 and 40 years, and body mass index (BMI) between 18.5 and 25 kg/m 2 . Plasma levels of lipid profile, cytokines, adhesion molecules, and LPS were measured at the 3 time points. A profile of 752 human plasma miRNA expression was analyzed by real-time PCR assay. These analyzes were performed for all blood collection time-points., Results: Expression profile analysis revealed 33 differentially expressed plasma circulating miRNAs compared to that of the control group. MiR-145-5p and miR-200 were differentially modulated in all time-points post meal consumption. In addition, there was a significant increase in plasma LPS, triglycerides, myristic and palmitic saturated fatty acids levels at the 3 time-points in comparison with the control basal levels. We also observed increased levels of the plasma tumor necrosis factor alpha (TNF-α) cytokine and the vascular cell adhesion molecule 1 (VCAM-1) levels after 5 h post meal ingestion., Conclusion: Ingestion of high-fat high-saturated meal was able to induce metabolic endotoxemia and increase the expression of pro-inflammatory molecules such as TNF-alpha and VCAM-1, as well as modulating circulating miRNAs possibly controlling inflammatory and lipid metabolism proteins at the postprandial period., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.

Ventilator-induced lung injury is well recognized, and appropriate arterial saturation target is unknown, so gentle modes of ventilation and minimizing oxidative stress have been well studied. Our objective was to analyze any association between the oxygen levels at blood sampling and plasma levels of the interleukins IL-6, IL-1 β , IL-10, and IL-8 and TNF- α in preterm newborns under mechanical ventilation (MV) in their first two days. Methods . Prospective cohort including neonates with severe respiratory distress. Blood samples were collected right before and 2 hours after invasive MV. For analysis purposes, newborns were separated according to oxygen requirement: low oxygen (≤30%) and high oxygen (>30%) groups. Interleukins were measured using a commercially available kit. Results . 20 neonates (gestational age 32.2 ± 3 weeks) were evaluated. Median O 2 saturation levels pre-MV were not different in both oxygen groups. In the high oxygen group, IL-6, IL-8, and TNF- α plasma levels increased significantly after two hours under MV. Conclusions . Despite the small sample studied, data showed that there is a relationship between VILI, proinflammatory cytokines, and oxygen-induced lung injury, but a study considering oxidative marker measurements is needed. It seems that less oxygen may keep safer saturation targets playing a less harmful role.

Objective: To histologically assess the hard and soft tissue changes after insertion of cleaned and activated titanium implants using plasma of argon., Materials and Methods: Eight dogs were included in this study. The mandibular premolars and first molars were extracted. For each hemi-mandible, four implants, 7 mm long and 3.3 mm of diameter, with a ZirTi surface were used. The surface of two implants was randomly treated with argon plasma (test), while the other two implants were left untreated (control). After 1 month, the same procedure was performed in the contralateral hemi-mandible. The amount of old bone, new bone, overall value of old bone plus new bone, and soft tissue was histologically evaluated., Results: After 1 month of healing, high percentages of new bone in close contact with the implant surface were found at both the treated (60.1% ± 15.6%; 95% CI 56.5%-78.0%) and untreated (57.2% ± 13.1%; 95% CI 49.3%-67.5%) implants. Low percentages of old bone were found at this stage of healing, at both the treated (4.4% ± 3.0%; 95% CI 1.2%-5.4%) and untreated (3.4% ± 3.1%; 95% CI 0.6%-4.9%) implants. Not statistically significant differences were found between groups (p > .05). After 2 months of healing, treated implants presented a significantly higher (p = .012) new bone formation (72.5% ± 12.4%; 95% CI 69.6%-86.8%) compared to untreated sites (64.7% ± 17.3%; 95% CI 59.4%-83.3%). Controversially, no difference (p = .270) in terms of old bone was present between treated (3.1% ± 1.7%, 95% CI 1.8%-4.2%) and untreated implants (3.8% ± 1.9%, 95% CI 3.2%-5.8%). Significant differences (p = .018) in terms of total mineralized bone were found between treated (75.6% ± 13.0%, 95% CI 73.3%-91.3%) and untreated implants (68.4% ± 16.8%; 95% CI 64.2%-87.6%)., Conclusions: Implants treated using plasma of argon was demonstrated to reach a higher bone-to-implant contact when compared to untreated implants., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Docetaxel has a demonstrated survival benefit for patients with metastatic castration-resistant prostate cancer (mCRPC); however, 10% to 20% of patients discontinue docetaxel prematurely because of toxicity-induced adverse events, and the management of risk factors for toxicity remains a challenge., Patients and Methods: The comparator arms of four phase III clinical trials in first-line mCRPC were collected, annotated, and compiled, with a total of 2,070 patients. Early discontinuation was defined as treatment stoppage within 3 months as a result of adverse treatment effects; 10% of patients discontinued treatment. We designed an open-data, crowd-sourced DREAM Challenge for developing models with which to predict early discontinuation of docetaxel treatment. Clinical features for all four trials and outcomes for three of the four trials were made publicly available, with the outcomes of the fourth trial held back for unbiased model evaluation. Challenge participants from around the world trained models and submitted their predictions. Area under the precision-recall curve was the primary metric used for performance assessment., Results: In total, 34 separate teams submitted predictions. Seven models with statistically similar area under precision-recall curves (Bayes factor ≤ 3) outperformed all other models. A postchallenge analysis of risk prediction using these seven models revealed three patient subgroups: high risk, low risk, or discordant risk. Early discontinuation events were two times higher in the high-risk subgroup compared with the low-risk subgroup. Simulation studies demonstrated that use of patient discontinuation prediction models could reduce patient enrollment in clinical trials without the loss of statistical power., Conclusion: This work represents a successful collaboration between 34 international teams that leveraged open clinical trial data. Our results demonstrate that routinely collected clinical features can be used to identify patients with mCRPC who are likely to discontinue treatment because of adverse events and establishes a robust benchmark with implications for clinical trial design.

Lysosomal storage diseases (LSDs) are genetic disorders, clinically heterogeneous, mainly caused by defects in genes encoding lysosomal enzymes that degrade macromolecules. Several LSDs already have specific therapies that may improve clinical outcomes, especially if introduced early in life. With this aim, screening methods have been established and newborn screening (NBS) for some LSDs has been developed. Such programs should include additional procedures for the confirmation (or not) of the cases that had an abnormal result in the initial screening. We present here the methods and results of the additional investigation performed in four babies with positive initial screening results in a program of NBS for LSDs performed by a private laboratory in over 10,000 newborns in Brazil. The suspicion in these cases was of Mucopolysaccharidosis I - MPS I (in two babies), Pompe disease and Gaucher disease (one baby each). One case of pseudodeficiency for MPS I, 1 carrier for MPS I, 1 case of pseudodeficiency for Pompe disease and 1 carrier for Gaucher disease were identified. This report illustrates the challenges that may be encountered by NBS programs for LSDs, and the need of a comprehensive protocol for the rapid and precise investigation of the babies who have an abnormal screening result.

Fresh frozen bone allografts (FFB) have become an alternative for bone augmentation in the past decades, especially because of the absence of recent reports of disease transmission or immunologic reactions when it is used. The aim of this prospective controlled study is to evaluate volumetric changes of newly created bone following reconstruction of the atrophic posterior mandible. Twenty consecutive patients presenting for reconstruction of posterior mandibular alveolar bone ridge width ≤6.0 mm and/or height ≤6.0 who met all inclusion and exclusion criteria were included. FFB blocks were used. The main outcome variable investigated was bone volume dynamics. Vertical, horizontal, and 3-dimensional bone gain data were measured from computerized tomography scans. The main predictor variable was time evaluated at 3 points: immediately after surgery (T1), at implant placement (T2), and 1 year after functional loading (T3). Secondary outcome parameters evaluated were implant survival, histologic findings, and microtomographic morphometry. The study included 28 hemi-mandibles, 50 FFB bone blocks, and 15 female and 5 male patients (mean age, 51.8 years). Block and implant survival rates were 100% and 96%, respectively, after 31.75 months of follow-up. Vertical and horizontal bone gain at T2 was 5.15 and 6.42 mm, respectively. Volumetric resorption was 31% at T2, followed by an additional 10% reduction at T3. Histologic evaluation showed newly formed vital bone in intimate contact with the remaining FFB. Microtomography revealed 31.8% newly formed bone, 14.5% remaining grafted bone, and 53.7% connective tissue and bone marrow. Thus, FFB blocks may lead to new bone formation and consolidation, with satisfactory volumetric bone maintenance, allowing implant-supported rehabilitation with high success rates.

Background: Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease., Methods: Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone., Findings: 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·39-4·62, p<0·0001; reference model: 2·56, 1·85-3·53, p<0·0001). The new model was validated further on the ENTHUSE M1 cohort with similarly high performance (iAUC 0·768). Meta-analysis across all methods confirmed previously identified predictive clinical variables and revealed aspartate aminotransferase as an important, albeit previously under-reported, prognostic biomarker., Interpretation: Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer., Funding: Sanofi US Services, Project Data Sphere., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced β-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote β-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. β-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates β-cell proliferation in both mouse and human islets., Competing Interests: The authors have declared that no competing interests exist.

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA&#95;Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2)=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.

Clinical success of implant therapy is directly related to titanium (Ti) surface properties and the quality of bone tissue. The treatment of Ti implants with H2SO4/H2O2 is a feasible, reproducible, and low-cost technique to create surface nanotopography (Ti-Nano). As this nanotopography induces osteoblast differentiation, we hypothesized that it may affect bone response to Ti. Thus, this study was designed to evaluate the bone response to a machined Ti implant treated with H2SO4/H2O2 to generate Ti-Nano and to compare it with a commercially available microtopographic Ti implant (Ti-Porous). Implants were placed in rabbit tibias and evaluated after 2 and 6 weeks, and the bone tissue formed around them was assessed by microtomography to record bone volume, bone surface, specific bone surface, trabecular number, trabecular thickness, and trabecular separation. Undecalcified histological sections were used to determine the percentages of bone-to-implant contact, bone area formed between threads, and bone area formed in the mirror area. At the end of 6 weeks, the removal torque was evaluated using a digital torque gauge. The results showed bone formation in close contact with both Ti-Nano and Ti-Porous implants without relevant morphological and morphometric differences, in addition to a similar removal torque irrespective of surface topography. In conclusion, our results have shown that a simple and low-cost method using H2SO4/H2O2 is highly efficient for creating nanotopography on Ti surfaces, which elicits a similar bone response compared with microtopography presented in a commercially available Ti implant.

Current measures of health and disease are often insensitive, episodic, and subjective. Further, these measures generally are not designed to provide meaningful feedback to individuals. The impact of high-resolution activity data collected from mobile phones is only beginning to be explored. Here we present data from mPower, a clinical observational study about Parkinson disease conducted purely through an iPhone app interface. The study interrogated aspects of this movement disorder through surveys and frequent sensor-based recordings from participants with and without Parkinson disease. Benefitting from large enrollment and repeated measurements on many individuals, these data may help establish baseline variability of real-world activity measurement collected via mobile phones, and ultimately may lead to quantification of the ebbs-and-flows of Parkinson symptoms. App source code for these data collection modules are available through an open source license for use in studies of other conditions. We hope that releasing data contributed by engaged research participants will seed a new community of analysts working collaboratively on understanding mobile health data to advance human health.

This work presents a systematic review of techniques for the 3D automatic detection of pulmonary nodules in computerized-tomography (CT) images. Its main goals are to analyze the latest technology being used for the development of computational diagnostic tools to assist in the acquisition, storage and, mainly, processing and analysis of the biomedical data. Also, this work identifies the progress made, so far, evaluates the challenges to be overcome and provides an analysis of future prospects. As far as the authors know, this is the first time that a review is devoted exclusively to automated 3D techniques for the detection of pulmonary nodules from lung CT images, which makes this work of noteworthy value. The research covered the published works in the Web of Science, PubMed, Science Direct and IEEEXplore up to December 2014. Each work found that referred to automated 3D segmentation of the lungs was individually analyzed to identify its objective, methodology and results. Based on the analysis of the selected works, several studies were seen to be useful for the construction of medical diagnostic aid tools. However, there are certain aspects that still require attention such as increasing algorithm sensitivity, reducing the number of false positives, improving and optimizing the algorithm detection of different kinds of nodules with different sizes and shapes and, finally, the ability to integrate with the Electronic Medical Record Systems and Picture Archiving and Communication Systems. Based on this analysis, we can say that further research is needed to develop current techniques and that new algorithms are needed to overcome the identified drawbacks., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aim: To study the sequential events in osseointegration at implants with highly hydrophilic surfaces., Material and Methods: All premolars and the first molars were bilaterally extracted in 12 Beagle dogs. After 3 months, full-thickness flaps were elevated and two different implants systems with various surfaces were randomly installed in the edentulous premolar region in one side of the mandible. One surface was acid etched and further modified with calcium ions (UnicCa(®)), while the other was sandblasted with large grits and acid etched (SLActive(®)). The flaps were sutured to allow a fully submerged healing. The surgery on the other side of the mandible and the sacrifices were planned in such a way to obtain biopsies representing the healing after 1, 2, 4, and 8 weeks (n = 6 per period)., Results: After one week of healing, new bone apposition was found at both surfaces with percentages of 6.9 ± 3.3% and 6.1 ± 4.6% at UnicCa(®) and SLActive(®), respectively. After 2 weeks, the percentages had increased to 29.1 ± 11.9% and 21.6 ± 14.3%, respectively. After 4 and 8 weeks of healing, mean values of 46.3 ± 7.3% and 58.7 ± 15.1% at UnicCa(®) and 51.2 ± 16.1% and 68.9 ± 15.4% at SLActive(®) surfaces were found, respectively. None of the differences in percentages were statistically significant. Concomitantly, the old bone was resorbed at both surfaces from about 21-22% after 1 week to about 4-6% after 8 weeks of healing., Conclusions: The osseointegration process onto moderately rough titanium implant surfaces of high hydrophilicity was very similar for two implant systems that were both nanotechnologically modified., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gaucher disease (GD) is one of the most prevalent lysosomal storage disorders and the disorder that has the greatest immune system involvement. Pathologic lipid accumulation in macrophages accounts for a small amount of the additional tissue mass in the liver and spleen. The additional increase may be related to an inflammatory response because Gaucher cells secrete inflammatory mediators. Osteopontin (OPN) is a protein identified in cancer cells and in bone cells that is produced by several types of immune cells including T-cells and macrophages. We report here elevated OPN levels in the plasma of type 1 GD patients and its sensitive response to enzyme replacement therapy. The mean OPN value of GD patients receiving ERT was similar to the values of controls and patients with other lysosomal disorders. When comparing untreated and treated GD patients, the p value was <0.001. In GD, OPN appears to be more sensitive to ERT than chitotriosidase and can be used during the follow-up of patients who are chitotriosidase deficient. Additional extended studies are required to relate variations in the OPN levels to clinical findings and response to therapy in GD patients.

Aim: Compare the intima-media thickness (IMT) of the internal carotid artery with the IMT of the common and external carotid, vertebral and femoral arteries and the abdominal aorta to assess the possibility of using these arteries as markers of atherosclerotic disease., Methods: Fifty patients with atherosclerosic risk factors were examined and the IMT was determined in the carotid arteries and compared with the values of IMT of the vertebral and femoral arteries and the abdominal aorta. The Spearman correlation coefficient and Kappa index were used for statistical analysis., Results: Considering IMT equal or greater than 0,8mm, there was positive and significant correlation between the values obtained for the examined arteries. The best agreement was found between the external and common carotid artery as compared to the internal carotid. (accuracy of 73.5% and 79.2%, respectively). For all arteries the was a positive correlation of the values of the EMI., Conclusion: There is positive and significant correlation between the IMT of the internal carotid artery and the vertebral and femoral arteries and abdominal aorta. Routine examinations of either one of these arteries can ad important findings regarding early diagnosis for higher risk patients concerning atherosclerotic disease.

Introduction: Early nCPAP seems to prevent ventilator-induced lung injury in humans, although the pathophysiological mechanisms underlying this beneficial effect have not been clarified yet., Objective: To evaluate plasma levels IL-1β, IL-6, IL-8, IL-10, and TNF-α immediately before the start of nCPAP and 2 hours later in preterm infants., Methods: Prospective cohort including preterm infants with 28 to 35 weeks gestational age with moderate respiratory distress requiring nCPAP. Extreme preemies, newborns with malformations, congenital infections, sepsis, surfactant treatment, and receiving ventilatory support in the delivery room were excluded. Blood samples were collected right before and 2 hours after the start of nCPAP., Results: 23 preterm infants (birth weight 1851±403 grams; GA 32.3±1.7 weeks) were treated with nCPAP. IL-1β, IL-10, TNF-α levels were similar, IL-8 levels were reduced in 18/23 preterm infants and a significant decrease in IL-6 levels was observed after 2 hours of nCPAP. All newborns whose mothers received antenatal steroids had lower cytokine levels at the onset of nCPAP than those whose mothers didn't receive it; this effect was not sustained after 2 hours of nCPAP., Conclusion: Early use nCPAP is not associated with rising of plasma pro-inflammatory cytokines and it seems to be a less harmful respiratory strategy for preterm with moderate respiratory distress.

Mutations in the GBA gene are related to an increased risk of developing neurodegenerative diseases. The exact molecular mechanisms involved in the interaction between GBA and α-synuclein, a protein that has been associated with several neurological diseases, remain unsolved. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is important for the normal development of the peripheral and central nervous system, and it plays a key role in neuronal survival and synaptic plasticity in the adult brain. A reduction in BDNF expression has been reported in patients with Parkinson's disease, Alzheimer's disease and dementia with Lewy bodies. We analyzed BDNF levels in the plasma of Gaucher Disease (GD) patients who were not being treated with enzyme replacement therapy (ERT) and then subsequently following ERT; we compared the levels to those of healthy controls. We demonstrated that BDNF levels were remarkably diminished in GD patients who were under no specific treatment and these levels increased following ERT. This is the first study that demonstrates a variation in the plasma levels of a neurotrophic factor in GD type 1 patients. Further studies are required to correlate BDNF level variations with the clinical findings and the response to therapy in GD patients. Low levels of BDNF are associated with neurodegenerative diseases; therefore, BDNF could provide a new therapeutic target for GD patients with neurological symptoms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Finding the most effective method of minimizing the gap effect in alveolar crest remodeling constitutes a clinical challenge for immediate implant technique., Purpose: To evaluate the effectiveness of osseoconductive xenografts with different porosities in the crestal bone region, with and without guided bone regeneration, over immediate implant installation., Materials and Methods: Five bone defects (6 mm in diameter/4 mm depth) were prepared on one side of the mandibles of twelve dogs. Implants of 3.3 × 10 mm were installed on the mesial side of each defect, providing a 2.7-mm distal gap. Defects were randomly filled with autogenous bone, coagulum, a deproteinized bovine bone mineral (DBBM) block, a DBBM sponge, or DBBM granules. The same procedures were performed on the opposite side after 8 weeks. Collagen membranes were used to cover the defects on half of the sides. The animals were sacrificed after 8 weeks. The outcomes were evaluated by histology, histomorphometric analysis, resonance frequency analysis, and micro-CT analysis., Results: The histomorphometry showed the DBBM sponge to provide similar bone formation to autogenous bone at 8 weeks without a membrane. The coagulum rendered better bone formation at 16 weeks (membrane) (p < .05). The DBBM block exhibited the poorest results between treatments (8 and 16 weeks, with or without membrane). Micro-CT analysis revealed increasing bone surface values in sites with DBBM granules, followed by the DBBM sponge (8 weeks without membrane) and autogenous bone at 8 weeks with membrane (p < .05). Porosity analysis of the biomaterials showed the highest number, volume, and surface area of closed pores in DBBM granules. The DBBM block presented the highest volume of open pores, open porosity, and total porosity., Conclusions: The high-porosity block (DBBM block) failed to provide greater bone repair within the defect. Biomaterials with lower porosity (DBBM sponge and granules) showed similar or higher bone formation when compared with autogenous bone., (© 2013 Wiley Periodicals, Inc.)

The intracellular protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a serious disorder that affects millions of people in Latin America. Cell invasion by T. cruzi and its intracellular replication are essential to the parasite's life cycle and for the development of Chagas disease. Here, we present evidence suggesting the involvement of the host's cyclooxygenase (COX) enzymes during T. cruzi invasion. Pharmacological antagonists for COX-1 (aspirin) and COX-2 (celecoxib) caused marked inhibition of T. cruzi infection when rat cardiac cells were pretreated with these nonsteroidal anti-inflammatory drugs (NSAIDs) for 60 min at 37°C before inoculation. This inhibition was associated with an increase in the production of NO and interleukin-1β and decreased production of transforming growth factor β (TGF-β) by cells. Taken together, these results indicate that COX-1 more than COX-2 is involved in the regulation of anti-T. cruzi activity in cardiac cells, and they provide a better understanding of the influence of TGF-β-interfering therapies on the innate inflammatory response to T. cruzi infection and may represent a very pertinent target for new therapeutic treatments of Chagas disease., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Biotinidase deficiency (BD) is an inborn error of metabolism in which some genetic variants correlate with the level of enzyme activity. Biotinidase activity, however, may be artifactually low due to enzyme lability, premature birth, and jaundice; this hinders both phenotypic classification and the decision to implement therapy. This study sought to characterize the clinical and genetic profile of a sample of Brazilian patients exhibiting reduced biotinidase activity., Methods: This observational, multicenter study used a convenience sampling strategy, with sequencing of exons 2, 3, and 4 of the BTD gene., Results: The sample comprised 38 individuals with biochemical phenotypes defined a priori on the basis of biotinidase activity in serum/plasma (2 with profound deficiency, 9 with partial deficiency, 15 heterozygous, 1 borderline between partial deficiency and heterozygosity, 2 borderline between heterozygous and normal) or dried blood spot sample (n = 9, all with unspecified deficiency). Most patients were from Southern Brazil (n = 29/38) and were identified by neonatal screening (n = 33/38). Parental consanguinity was reported in two cases. The most commonly found genetic variants were c.1330G > C (p.D444H), c.755A > G (p.D252G), and c.[511G > A;1330G > C] (p.[A171T;D444H]), with allele frequencies of 50%, 9.4%, and 5.4% respectively. Three novel pathogenic variants were identified (c.119 T > C or p.L40P, c.479G > A or p.C160Y, and c.664G > A or p.D222N). Twenty-nine patients had two pathogenic variants detected (with cis/trans status ascertained in 26/29), six had only one variant, and three had no pathogenic variants detected. Genotyping confirmed the original phenotypic classification based on enzyme activity in 16/26 cases. Three polymorphic variants were identified in control individuals, of which two were nonpathogenic (c.1171C > T or p.P391S and c.1413 T > C or p.C471C, with a frequency of 1.5% and 5.5% respectively) and one pathogenic (c.1330G > C, frequency 4%)., Conclusions: Our findings suggest that partial BD is the most common form of BD in Brazil, and expand current knowledge on the allelic heterogeneity of this condition.

Computational efficiency is important for learning algorithms operating in the "large p, small n" setting. In computational biology, the analysis of data sets containing tens of thousands of features ("large p"), but only a few hundred samples ("small n"), is nowadays routine, and regularized regression approaches such as ridge-regression, lasso, and elastic-net are popular choices. In this paper we propose a novel and highly efficient Bayesian inference method for fitting ridge-regression. Our method is fully analytical, and bypasses the need for expensive tuning parameter optimization, via cross-validation, by employing Bayesian model averaging over the grid of tuning parameters. Additional computational efficiency is achieved by adopting the singular value decomposition reparametrization of the ridge-regression model, replacing computationally expensive inversions of large p × p matrices by efficient inversions of small and diagonal n × n matrices. We show in simulation studies and in the analysis of two large cancer cell line data panels that our algorithm achieves slightly better predictive performance than cross-validated ridge-regression while requiring only a fraction of the computation time. Furthermore, in comparisons based on the cell line data sets, our algorithm systematically out-performs the lasso in both predictive performance and computation time, and shows equivalent predictive performance, but considerably smaller computation time, than the elastic-net.

Large-scale pharmacogenomic screens of cancer cell lines have emerged as an attractive pre-clinical system for identifying tumor genetic subtypes with selective sensitivity to targeted therapeutic strategies. Application of modern machine learning approaches to pharmacogenomic datasets have demonstrated the ability to infer genomic predictors of compound sensitivity. Such modeling approaches entail many analytical design choices; however, a systematic study evaluating the relative performance attributable to each design choice is not yet available. In this work, we evaluated over 110,000 different models, based on a multifactorial experimental design testing systematic combinations of modeling factors within several categories of modeling choices, including: type of algorithm, type of molecular feature data, compound being predicted, method of summarizing compound sensitivity values, and whether predictions are based on discretized or continuous response values. Our results suggest that model input data (type of molecular features and choice of compound) are the primary factors explaining model performance, followed by choice of algorithm. Our results also provide a statistically principled set of recommended modeling guidelines, including: using elastic net or ridge regression with input features from all genomic profiling platforms, most importantly, gene expression features, to predict continuous-valued sensitivity scores summarized using the area under the dose response curve, with pathway targeted compounds most likely to yield the most accurate predictors. In addition, our study provides a publicly available resource of all modeling results, an open source code base, and experimental design for researchers throughout the community to build on our results and assess novel methodologies or applications in related predictive modeling problems.

Current efforts in systems genetics have focused on the development of statistical approaches that aim to disentangle causal relationships among molecular phenotypes in segregating populations. Reverse engineering of transcriptional networks plays a key role in the understanding of gene regulation. However, transcriptional regulation is only one possible mechanism, as methylation, phosphorylation, direct protein-protein interaction, transcription factor binding, etc., can also contribute to gene regulation. These additional modes of regulation can be interpreted as unobserved variables in the transcriptional gene network and can potentially affect its reconstruction accuracy. We develop tests of causal direction for a pair of phenotypes that may be embedded in a more complicated but unobserved network by extending Vuong's selection tests for misspecified models. Our tests provide a significance level, which is unavailable for the widely used AIC and BIC criteria. We evaluate the performance of our tests against the AIC, BIC, and a recently published causality inference test in simulation studies. We compare the precision of causal calls using biologically validated causal relationships extracted from a database of 247 knockout experiments in yeast. Our model selection tests are more precise, showing greatly reduced false-positive rates compared to the alternative approaches. In practice, this is a useful feature since follow-up studies tend to be time consuming and expensive and, hence, it is important for the experimentalist to have causal predictions with low false-positive rates.

Background: The soluble cell adhesion molecules and adipokines are elevated in patients with obesity, hypertension, type 2 diabetes mellitus, breast cancer and atherosclerosis., Objective: To investigate the relationship between anthropometric profile, dietary intake, lipid profile and fasting glycemia with serum levels of adipokines (adiponectin and PAI-1) and adhesion molecules (ICAM-1 and VCAM-1) in women without breast cancer undergoing routine mammographic screening., Design: Transversal study., Subjects: One hundred and forty-five women over 40-years old participated in this study., Results: In 39.3% of cases the BMI was above 30 kg/m2; 46.9% had hypertension, 14.5% had type 2 Diabetes Mellitus, 31.7% had dyslipidemia and 88.3% presented a waist-to-hip ratio ≥ 0.8. A linear correlation was found between serum levels of PAI-1 and triglycerides, between serum levels of PAI-1 and WHR and between serum levels of VCAM-1 and BMI., Conclusion: We found a high prevalence of obesity and metabolic syndrome. PAI-1 and VCAM-1 levels were correlated with clinical indicators of obesity and overweight.

Quantitative trait loci (QTL) hotspots (genomic locations affecting many traits) are a common feature in genetical genomics studies and are biologically interesting since they may harbor critical regulators. Therefore, statistical procedures to assess the significance of hotspots are of key importance. One approach, randomly allocating observed QTL across the genomic locations separately by trait, implicitly assumes all traits are uncorrelated. Recently, an empirical test for QTL hotspots was proposed on the basis of the number of traits that exceed a predetermined LOD value, such as the standard permutation LOD threshold. The permutation null distribution of the maximum number of traits across all genomic locations preserves the correlation structure among the phenotypes, avoiding the detection of spurious hotspots due to nongenetic correlation induced by uncontrolled environmental factors and unmeasured variables. However, by considering only the number of traits above a threshold, without accounting for the magnitude of the LOD scores, relevant information is lost. In particular, biologically interesting hotspots composed of a moderate to small number of traits with strong LOD scores may be neglected as nonsignificant. In this article we propose a quantile-based permutation approach that simultaneously accounts for the number and the LOD scores of traits within the hotspots. By considering a sliding scale of mapping thresholds, our method can assess the statistical significance of both small and large hotspots. Although the proposed approach can be applied to any type of heritable high-volume "omic" data set, we restrict our attention to expression (e)QTL analysis. We assess and compare the performances of these three methods in simulations and we illustrate how our approach can effectively assess the significance of moderate and small hotspots with strong LOD scores in a yeast expression data set.

Purpose: The aim of the present study was to compare pain, edema, and trismus in the postoperative period following third molar surgery using 8 mg of dexamethasone administered either orally or through local injection., Methods: A prospective, controlled, randomized trial was carried out involving 60 lower third molar surgeries in 67 patients between October 2008 and June 2009. The sample was randomly divided into three groups: group A (local injection), group B (tablets), and group C (control). In all cases, either ostectomy or crown sectioning was employed. On the second and seventh day following surgery, linear edema was determined using facial landmarks, and maximal mouth opening measurements were performed. Postoperative pain was recorded using a visual analog scale., Results: Patient age ranged from 14 to 37 years (mean, 21.0 years). With regard to pain, edema, and trismus, the two administration routes tested (local injection and tablets) demonstrated similar efficacy, and both methods achieved better results in comparison to the control group., Conclusion: Both the oral administration and local injection of dexamethasone proved effective in reducing pain, edema, and trismus compared to control group following lower third molar surgeries, achieving similar results.

We sought to determine cytokine response in term and late preterm newborn infants on phototherapy. Twenty newborn infants with gestational age > or = 35 weeks and birth weight > or = 2000 g in the first week of life had serum interleukin (IL)-6, IL-8, IL-10, IL-1beta, and tumor necrosis factor (TNF)-alpha measured immediately prior to and after 24 hours on phototherapy. Exclusion criteria were newborns with severe congenital malformations, congenital infections, birth asphyxia, sepsis, hemolytic anemia that required blood transfusion, maternal-infant Rh incompatibility and those who required exchange transfusion or intravenous immunoglobulin treatment for hyperbilirubinemia. Median IL-6 concentrations significantly decreased after 24 hours on phototherapy (18.3 pg/mL and 7.85 pg/mL, respectively, p = 0.005). IL-6 concentrations decreased in 17 out of the 20 newborns. There were no statistical differences in IL-8, IL-10, IL-1beta, and TNF-alpha concentrations before and after 24 hours on phototherapy. There was a statistically significant correlation between IL-6 decline and irradiance (r = 0.57, p = 0.009). The finding that serum IL-6 decreases in newborn under phototherapy suggests that phototherapy possibly has an anti-inflammatory effect, although the clinical implications of this study deserve further studies., (Copyright Thieme Medical Publishers.)

Background: Colonic interposition is one of the surgical options in children when esophageal replacement is necessary, especially when the stomach is not suitable as a conduit. Conventional open surgery and blind mediastinal dissections present reasonable morbidity, which can be reduced by videosurgery. The authors present novel techniques and the preliminary results of the first series of laparoscopically assisted esophagectomies and colonic interpositions (LECIN) in children., Methods: Five children aged 19 months to 4 years underwent LECIN. Indications were complicated esophageal atresia and severe caustic esophagitis. The patients were operated on laparoscopically using 3 ports, including the gastrostomy site. Transhiatal esophagectomy was carried out, followed by pyloroplasty and mobilization of the transverse colon maintaining a double blood supply from the left pedicle. The stomach at the gastrostomy site was freed and closed in 3 cases. The colon was exteriorized through this 2- to 3-cm site or through the umbilicus, and the conduit was fashioned extracorporeally, including the colocolic and gastrocolic anastomosis. The colon was pulled up along the retromediastinal tunnel for the coloesophageal anastomosis through a cervical incision., Results: Operative times ranged from 3 to 4.3 hours; there were no conversions and no complications related to laparoscopy. There were no cardiorespiratory problems, and 4 were extubated immediately after operation. Feedings could be started by day 3 to 4. Postoperative complications included atelectasis (1), pneumonia (1), and cervical stenosis because of persistent fibrotic esophagus, requiring cervical revision (1). One needed dilatations for mild dysphagia. After a follow-up period of 10 to 29 months, all patients are asymptomatic, gaining weight, and feeding well., Conclusions: These preliminary data suggest that LECIN is feasible and can be safely performed with very low morbidity in children. Further studies with larger series and follow-up are expected., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Causal inference approaches in systems genetics exploit quantitative trait loci (QTL) genotypes to infer causal relationships among phenotypes. The genetic architecture of each phenotype may be complex, and poorly estimated genetic architectures may compromise the inference of causal relationships among phenotypes. Existing methods assume QTLs are known or inferred without regard to the phenotype network structure. In this paper we develop a QTL-driven phenotype network method (QTLnet) to jointly infer a causal phenotype network and associated genetic architecture for sets of correlated phenotypes. Randomization of alleles during meiosis and the unidirectional influence of genotype on phenotype allow the inference of QTLs causal to phenotypes. Causal relationships among phenotypes can be inferred using these QTL nodes, enabling us to distinguish among phenotype networks that would otherwise be distribution equivalent. We jointly model phenotypes and QTLs using homogeneous conditional Gaussian regression models, and we derive a graphical criterion for distribution equivalence. We validate the QTLnet approach in a simulation study. Finally, we illustrate with simulated data and a real example how QTLnet can be used to infer both direct and indirect effects of QTLs and phenotypes that co-map to a genomic region.

Objective: To evaluate plasma levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha in newborn infants immediately before and after 2 hours of mechanical ventilation., Study Design: Term and late preterm neonates with no history of mechanical ventilation and/or ventilatory support were studied prospectively. Exclusion criteria were congenital malformations, congenital infections, use of nitric oxide, resuscitation with positive-pressure ventilation, and any procedure in the delivery room or neonatal intensive care unit that resulted in tracheal intubation. Blood samples for IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha levels were collected before intubation and mechanical ventilation and 2 hours later., Results: Nineteen newborn infants with gestational age 35.8 +/- 1.9 weeks and birth weight 2280 +/- 370 g were included. Pro-inflammatory cytokines increased: IL-8 (2.5-fold), IL-1beta (7.5-fold), and TNF-alpha (10-fold), and the anti-inflammatory cytokine IL-10 decreased by 90%. Although median IL-6 levels were similar between before and after ventilation, IL-6 increased in 89.4% of infants., Conclusions: A short period of mechanical ventilation promotes an imbalance of plasma levels of pro-inflammatory and anti-inflammatory cytokines. The systemic alteration of cytokines in response to mechanical ventilation may lead to ventilator-induced lung injury.

Congenital hypothyroidism and congenital adrenal hyperplasia are included in many newborn screening (NBS) panels worldwide and in all state-sponsored programs in the United States. Both conditions meet the fundamental prerequisites for NBS: high incidence in the population; biomarkers in the dried blood specimen that are easily detected; and, effective therapies to lessen, if not prevent, the sequelae of late or no treatment. In this review, the history of NBS is discussed for these 2 conditions. The technologies and protocols used in their detection, and related subjects such as genetics, and treatment and outcomes, are also discussed.