Experience and expectations of patients on weight loss: The Learning Health System Network Experience

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152010/1/osp4364_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152010/2/osp4364.pd

NetDiff – Bayesian model selection for differential gene regulatory network inference

Differential networks allow us to better understand the changes in cellular processes that are exhibited in conditions of interest, identifying variations in gene regulation or protein interaction between, for example, cases and controls, or in response to external stimuli. Here we present a novel methodology for the inference of differential gene regulatory networks from gene expression microarray data. Specifically we apply a Bayesian model selection approach to compare models of conserved and varying network structure, and use Gaussian graphical models to represent the network structures. We apply a variational inference approach to the learning of Gaussian graphical models of gene regulatory networks, that enables us to perform Bayesian model selection that is significantly more computationally efficient than Markov Chain Monte Carlo approaches. Our method is demonstrated to be more robust than independent analysis of data from multiple conditions when applied to synthetic network data, generating fewer false positive predictions of differential edges. We demonstrate the utility of our approach on real world gene expression microarray data by applying it to existing data from amyotrophic lateral sclerosis cases with and without mutations in C9orf72, and controls, where we are able to identify differential network interactions for further investigation

Effects observed in the Latin American sector ionospheric F region during the intense geomagnetic disturbances in the early part of November 2004

The Sun was very active in the early part of November 2004. During the period of 8-10 November 2004, intense geomagnetic disturbances with two superstorms were observed. In this paper, we have investigated the generation and suppression of equatorial ionospheric irregularities and the daytime changes in the F region electron density in the Latin American sector during the period of intense geomagnetic disturbances. We present the ionospheric sounding observations carried out at Manaus and Sao Jose dos Campos, Brazil, during this geomagnetically disturbed period. Also, GPS observations obtained from several stations in Brazil, Argentina, and St. Croix, U.S. Virgin Islands, during the disturbed period are presented. During the main phase of the first superstorm, around the prereversal enhancement time (night of 7-8 November), prompt penetration of electric field was observed and the presence of equatorial ionospheric irregularities was detected from St. Croix, U.S. Virgin Islands (in the northern hemisphere) to Bahia Blanca, Argentina (in the southern hemisphere). The ionospheric sounding observations at Manaus indicate inhibition of prereversal enhancement on the nights of 9-10 and 10-11 November, possibly due to the disturbed thermospheric winds or disturbance electric fields. Virtually no phase fluctuations on the nights of 9-10 and 10-11 November were observed in the Latin American sector. During the daytime on 8 November, the vertical total electron content (VTEC) observations show a negative storm phase at Porto Alegre (Brazil) and Bahia Blanca (Argentina). Again during the daytime on 10 November, the VTEC observations show a negative storm phase from Brasilia (Brazil) to Bahia Blanca. These negative storm phases are associated with a decrease in the O/N2 ratio. During the daytime on 9 November, the VTEC observations show a positive storm phase extending from St. Croix to Porto Alegre, and again on 10 November, VTEC observations show a positive storm phase. These positive storm phases observed are possibly due to changes in large-scale wind circulation and an increase in the O/N2 ratio.Facultad de Ciencias Astronómicas y Geofísica

Effects observed in the Latin American sector ionospheric F region during the intense geomagnetic disturbances in the early part of November 2004

The Sun was very active in the early part of November 2004. During the period of 8-10 November 2004, intense geomagnetic disturbances with two superstorms were observed. In this paper, we have investigated the generation and suppression of equatorial ionospheric irregularities and the daytime changes in the F region electron density in the Latin American sector during the period of intense geomagnetic disturbances. We present the ionospheric sounding observations carried out at Manaus and Sao Jose dos Campos, Brazil, during this geomagnetically disturbed period. Also, GPS observations obtained from several stations in Brazil, Argentina, and St. Croix, U.S. Virgin Islands, during the disturbed period are presented. During the main phase of the first superstorm, around the prereversal enhancement time (night of 7-8 November), prompt penetration of electric field was observed and the presence of equatorial ionospheric irregularities was detected from St. Croix, U.S. Virgin Islands (in the northern hemisphere) to Bahia Blanca, Argentina (in the southern hemisphere). The ionospheric sounding observations at Manaus indicate inhibition of prereversal enhancement on the nights of 9-10 and 10-11 November, possibly due to the disturbed thermospheric winds or disturbance electric fields. Virtually no phase fluctuations on the nights of 9-10 and 10-11 November were observed in the Latin American sector. During the daytime on 8 November, the vertical total electron content (VTEC) observations show a negative storm phase at Porto Alegre (Brazil) and Bahia Blanca (Argentina). Again during the daytime on 10 November, the VTEC observations show a negative storm phase from Brasilia (Brazil) to Bahia Blanca. These negative storm phases are associated with a decrease in the O/N2 ratio. During the daytime on 9 November, the VTEC observations show a positive storm phase extending from St. Croix to Porto Alegre, and again on 10 November, VTEC observations show a positive storm phase. These positive storm phases observed are possibly due to changes in large-scale wind circulation and an increase in the O/N2 ratio.Facultad de Ciencias Astronómicas y Geofísica

Methodological standards in non-inferiority AIDS trials: moving from adherence to compliance

BACKGROUND: The interpretation of the results of active-control trials regarding the efficacy and safety of a new drug is important for drug registration and following clinical use. It has been suggested that non-inferiority and equivalence studies are not reported with the same quantitative rigor as superiority studies. METHODS: Standard methodological criteria for non-inferiority and equivalence trials including design, analysis and interpretation issues were applied to 18 recently conducted large non-inferiority (15) and equivalence (3) randomized trials in the field of AIDS antiretroviral therapy. We used the continuity-corrected non-inferiority chi-square to test 95% confidence interval treatment difference against the predefined non-inferiority margin. RESULTS: The pre-specified non-inferiority margin ranged from 10% to 15%. Only 4 studies provided justification for their choice. 39% of the studies (7/18) reported only intent-to-treat (ITT) analysis for the primary endpoint. When on-treatment (OT) and ITT statistical analyses were provided, ITT was favoured over OT for results interpretation for all but one study, inappropriately in this statistical context. All but two of the studies concluded there was "similar" efficacy of the experimental group. However, 9/18 had inconclusive results for non-inferiority. CONCLUSION: Conclusions about non-inferiority should be drawn on the basis of the confidence interval analysis of an appropriate primary endpoint, using the predefined criteria for non-inferiority, in both OT and ITT, in compliance with the non-inferiority and equivalence CONSORT statement. We suggest that the use of the non-inferiority chi-square test may provide additional useful information

Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

Whole genome functional analysis identifies novel components required for mitotic spindle integrity in human cells

A loss-of-function screen for siRNAs that arrest human cells in metaphase reveals genes involved in mitotic spindle integrity

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Trehalose-6-phosphate-mediated toxicity determines essentiality of OtsB2 in Mycobacterium tuberculosis in vitro and in mice

Trehalose biosynthesis is considered an attractive target for the development of antimicrobials against fungal, helminthic and bacterial pathogens including Mycobacterium tuberculosis. The most common biosynthetic route involves trehalose-6-phosphate (T6P) synthase OtsA and T6P phosphatase OtsB that generate trehalose from ADP/UDP-glucose and glucose-6-phosphate. In order to assess the drug target potential of T6P phosphatase, we generated a conditional mutant of M. tuberculosis allowing the regulated gene silencing of the T6P phosphatase gene otsB2. We found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection. By contrast, otsB2 is not essential for the chronic infection phase in mice, highlighting the substantial remodelling of trehalose metabolism during infection by M. tuberculosis. Blocking OtsB2 resulted in the accumulation of its substrate T6P, which appears to be toxic, leading to the self-poisoning of cells. Accordingly, blocking T6P production in a ΔotsA mutant abrogated otsB2 essentiality. T6P accumulation elicited a global upregulation of more than 800 genes, which might result from an increase in RNA stability implied by the enhanced neutralization of toxins exhibiting ribonuclease activity. Surprisingly, overlap with the stress response caused by the accumulation of another toxic sugar phosphate molecule, maltose-1-phosphate, was minimal. A genome-wide screen for synthetic lethal interactions with otsA identified numerous genes, revealing additional potential drug targets synergistic with OtsB2 suitable for combination therapies that would minimize the emergence of resistance to OtsB2 inhibitors

Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics

A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level