Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.

Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10(-06) (false discovery rate ∼5%)] and one of eight biomarker associations at P < 8 × 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect

Ashcroft v. Iqbal: The Question of a Heightened Standard of Pleading in Qualified Immunity Cases

Background We have previously shown that Lactobacillus reuteri supplementation from pregnancy week 36 and to the infant through the first year of life decreased the prevalence of IgE-associated eczema at 2 years. The underlying immunological mechanisms are unknown, however. Objective To investigate the immunomodulatory effect of probiotic supplementation on allergen- and mitogen-induced immune responses in children until 2 years of age. Methods Blood mononuclear cells were collected at birth, 6, 12 and 24 months from 61 children (29 probiotic and 32 placebo treated) and cultured with ovalbumin, birch and cat extract and Phytohaemagglutinin (PHA). Cytokine and chemokine secretion was determined using an in-house multiplexed Luminex assay and ELISA. Real-time PCR was performed to investigate the Ebi3, Foxp3, GATA-3 and T-bet mRNA expression. Results Probiotic treatment was associated with low cat-induced Th2-like responses at 6 months (IL-5, P = 0.01, and IL-13, P = 0.009), with a similar trend for IL-5 at 12 months (P = 0.09). Cat-induced IFN-γ responses were also lower after probiotic than after placebo treatment at 24 months (P = 0.007), with similar findings for the anti-inflammatory IL-10 at birth (P = 0.001) and at 12 months (P = 0.009). At 24 months, Th2-associated CCL22 levels were lower in the probiotic than in the placebo group after birch stimulation (P = 0.02), with a similar trend after ovalbumin stimulation (P = 0.07). Lower CCL22 levels were recorded at 12 and 24 months (P = 0.03 and P = 0.01) after PHA stimulation. Conclusion and Clinical Relevance Lactobacillus reuteri supplementation decreases allergen responsiveness and may enhance immunoregulatory capacity during infancy. L. reuteri supplementation from week 36 and during the first year of life significantly decreases IgE-associated eczema and lowers allergen and mitogen responsiveness.Funding Agencies|Swedish Research Council|K2011-56X-21854-01-06|Ekhaga Foundation||Olle Engkvist Foundation||Heart and Lung foundation||Research Council for the South-East Sweden|F2000-106|Swedish Asthma and Allergy Association||Cancer and Allergy Association||BioGaia AB, Stockholm, Sweden||University Hospital of Linkoping, Sweden||</p

Index of an implicit differential equation

In this paper we introduce the concept of the index of an implicit differential equation F(x,y,p) = 0, where F is a smooth function, p = dy/dx, F(p) = 0 and F(pp) = 0 at an isolated singular point. We also apply the results to study the geometry of surfaces in R(5).FAPESP[06/50075-3]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma.

Lessons learnedThe safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.BackgroundSimtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.MethodsPatients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.ResultsIn total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.ConclusionThe addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8

Performance of the track matching

The procedure and the performance of the track matching algorithm at the time of DC'06 is described. The event-weighted efficiency is 79.3 % for all long tracks increasing to 86 % for tracks with p>5 GeV. An approach to tune the matching algorithm with real data is presented and a discussion on future improvements to the algorithm given

Prediction of Longitudinal White Matter Change in Healthy Elderly Individuals

Diffusion Tensor Imaging (DTI) studies have shown that significant alteration in white matter (WM) integrity differentiates healthy older adults from persons with Mild Cognitive Impairment (MCI) and Alzheimer\u27s disease (AD). Most studies, however, have been cross-sectional and have not related longitudinal DTI changes to cognitive change. Here we report changes in WM integrity and cognition in healthy older adults over an 18-month interval. Sixty-seven cognitively intact elders underwent neuropsychological testing and DTI at baseline to follow-up on the Rey Auditory Verbal Learning Test (recall sum across trials 1-5, delayed recall) and Mattis Dementia Rating Scale-2. Declining participants (N=21) showed a minimum of 1 SD reduction on at least one cognitive measure, while Stable participants (N=46) showed comparable scores at each time point. WM regions-of-interest were derived from Freesurfer. Hierarchical linear regression was used to predict fractional anisotropy (FA) change in regions frequently identified in DTI studies of MCI and AD including transentorhinal cortex, temporal lobe, and posterior cingulate. Groups did not differ at baseline in age, cognition, FA, or WM volume. After controlling for age and baseline FA, cognitive status (Declining, Stable) predicted the baseline to 18-month reduction in FA in the right hippocampal gyrus (p=.004) and left fusi-form gyrus (p=.01) with a trend in the left middle temporal gyrus (p=.06). Future research should examine WM changes in other brain regions and determine whether DTI diffusivity measures are related to cognitive decline

HUBUNGAN TINGKAT PENGETAHUAN IBU DENGAN KEJADIAN KARIES GIGI PADA BALITA DI RT 06 / RW 04 KELURAHAN BANYU URIP SURABAYA

Rendahnya pengetahuan ibu menyebabkan kurang menjaga kesehatan gigi balita sehingga mudah terkena karies gigi. Survey awal yang didapatkan peneliti dari hasil wawancara dengan kader posyandu terdapat 7 balita yang menderita karies gigi dari 22 balita. Tujuan penelitian ini untuk mengetahui hubungan tingkat pengetahuan ibu dengan terjadinya karies gigi pada balita usia 3-5 tahun di RT 06/RW 04 Kelurahan Banyu Urip Surabaya. Desain penelitian adalah analitik observasional. Populasi dalam penelitian ini sebanyak 22 ibu dan anak di RT 06/RW 04 Kelurahan Banyu Urip Surabaya dan besar sampel 20 responden ibu dan balita, cara pengambilan sampel dengan simple random sampling. Variabel penelitian adalah tingkat pengetahuan sebagai variabel independent dan karies gigi sebagai variabel dependen. Untuk mengumpulkan data dari responden digunakan instrumen kuesioner dan check list kemudian dilakukan uji Chi-Square dengan tingkat kemaknaan α=0,05. Berdasarkan tabel 5.7 didapatkan setengah (50%) responden berpengetahuan kurang dan dari tabel 5.8 didapatkan sebagian besar (65%) responden menderita karies gigi. Hasil uji Chi-Square menunjukkan p=0,001 < α=0,05, artinya ada hubungan tingkat pengetahuan ibu dengan terjadinya karies gigi pada balita usia 3-5 tahun di RT 06/RW 04 Kelurahan Banyu Urip Surabaya. Simpulan penelitian adalah semakin baik pengetahuan ibu maka semakin sedikit penderita karies gigi. Dengan demikian diharapkan para kader posyandu melakukan kegiatan penyuluhan tentang kesehatan gigi dan mulut secara periodik guna meningkatkan pengetahuan ibu

Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data.

BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). INTERPRETATION: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. FUNDING: UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health