Bartlett correction factors in logistic regression models

Bartlett correction factors for likelihood ratio tests of parameters in conditional and unconditional logistic regression models are calculated. The resulting tests are compared to the Wald, likelihood ratio, and score tests, and a test proposed by Moolgavkar and Venzon in Modern Statistical Methods in Chronic Disease Epidemiology. (Wiley, New York, 1986).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31011/1/0000686.pd

Maternal fecal microbiome predicts gestational age, birth weight and neonatal growth in rural Zimbabwe.

BACKGROUND: Preterm birth and low birth weight (LBW) affect one in ten and one in seven livebirths, respectively, primarily in low-income and middle-income countries (LMIC) and are major predictors of poor child health outcomes. However, both have been recalcitrant to public health intervention. The maternal intestinal microbiome may undergo substantial changes during pregnancy and may influence fetal and neonatal health in LMIC populations. METHODS: Within a subgroup of 207 mothers and infants enrolled in the SHINE trial in rural Zimbabwe, we performed shotgun metagenomics on 351 fecal specimens provided during pregnancy and at 1-month post-partum to investigate the relationship between the pregnancy gut microbiome and infant gestational age, birth weight, 1-month length-, and weight-for-age z-scores using extreme gradient boosting machines. FINDINGS: Pregnancy gut microbiome taxa and metabolic functions predicted birth weight and WAZ at 1 month more accurately than gestational age and LAZ. Blastoscystis sp, Brachyspira sp and Treponeme carriage were high compared to Western populations. Resistant starch-degraders were important predictors of birth outcomes. Microbiome capacity for environmental sensing, vitamin B metabolism, and signalling predicted increased infant birth weight and neonatal growth; while functions involved in biofilm formation in response to nutrient starvation predicted reduced birth weight and growth. INTERPRETATION: The pregnancy gut microbiome in rural Zimbabwe is characterized by resistant starch-degraders and may be an important metabolic target to improve birth weight. FUNDING: Bill and Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, and UNICEF

Mismatched single stranded antisense oligonucleotides can induce efficient dystrophin splice switching

<p>Abstract</p> <p>Background</p> <p>Antisense oligomer induced exon skipping aims to reduce the severity of Duchenne muscular dystrophy by redirecting splicing during pre-RNA processing such that the causative mutation is by-passed and a shorter but partially functional Becker muscular dystrophy-like dystrophin isoform is produced. Normal exons are generally targeted to restore the dystrophin reading frame however, an appreciable subset of dystrophin mutations are intra-exonic and therefore have the potential to compromise oligomer efficiency, necessitating personalised oligomer design for some patients. Although antisense oligomers are easily personalised, it remains unclear whether all patient polymorphisms within antisense oligomer target sequences will require the costly process of producing and validating patient specific compounds.</p> <p>Methods</p> <p>Here we report preclinical testing of a panel of splice switching antisense oligomers, designed to excise exon 25 from the dystrophin transcript, in normal and dystrophic patient cells. These patient cells harbour a single base insertion in exon 25 that lies within the target sequence of an oligomer shown to be effective at removing exon 25.</p> <p>Results</p> <p>It was anticipated that such a mutation would compromise oligomer binding and efficiency. However, we show that, despite the mismatch an oligomer, designed and optimised to excise exon 25 from the normal dystrophin mRNA, removes the mutated exon 25 more efficiently than the mutation-specific oligomer.</p> <p>Conclusion</p> <p>This raises the possibility that mismatched AOs could still be therapeutically applicable in some cases, negating the necessity to produce patient-specific compounds.</p

Predictive coding and representationalism

According to the predictive coding theory of cognition (PCT), brains are predictive machines that use perception and action to minimize prediction error, i.e. the discrepancy between bottom–up, externally-generated sensory signals and top–down, internally-generated sensory predictions. Many consider PCT to have an explanatory scope that is unparalleled in contemporary cognitive science and see in it a framework that could potentially provide us with a unified account of cognition. It is also commonly assumed that PCT is a representational theory of sorts, in the sense that it postulates that our cognitive contact with the world is mediated by internal representations. However, the exact sense in which PCT is representational remains unclear; neither is it clear that it deserves such status—that is, whether it really invokes structures that are truly and nontrivially representational in nature. In the present article, I argue that the representational pretensions of PCT are completely justified. This is because the theory postulates cognitive structures—namely action-guiding, detachable, structural models that afford representational error detection—that play genuinely representational functions within the cognitive system

Antisense PMO cocktails effectively skip dystrophin exons 45-55 in myotubes transdifferentiated from DMD patient fibroblasts

Antisense-mediated exon skipping has made significant progress as a therapeutic platform in recent years, especially in the case of Duchenne muscular dystrophy (DMD). Despite FDA approval of eteplirsen-the first-ever antisense drug clinically marketed for DMD-exon skipping therapy still faces the significant hurdles of limited applicability and unknown truncated protein function. In-frame exon skipping of dystrophin exons 45-55 represents a significant approach to treating DMD, as a large proportion of patients harbor mutations within this "hotspot" region. Additionally, patients harboring dystrophin exons 45-55 deletion mutations are reported to have exceptionally mild to asymptomatic phenotypes. Here, we demonstrate that a cocktail of phosphorodiamidate morpholino oligomers can effectively skip dystrophin exons 45-55 in vitro in myotubes transdifferentiated from DMD patient fibroblast cells. This is the first report of substantive exons 45-55 skipping in DMD patient cells. These findings help validate the use of transdifferentiated patient fibroblast cells as a suitable cell model for dystrophin exon skipping assays and further emphasize the feasibility of dystrophin exons 45-55 skipping in patients

A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and procontractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms

Illusions of Visual Motion Elicited by Electrical Stimulation of Human MT Complex

Human cortical area MT+ (hMT+) is known to respond to visual motion stimuli, but its causal role in the conscious experience of motion remains largely unexplored. Studies in non-human primates demonstrate that altering activity in area MT can influence motion perception judgments, but animal studies are inherently limited in assessing subjective conscious experience. In the current study, we use functional magnetic resonance imaging (fMRI), intracranial electrocorticography (ECoG), and electrical brain stimulation (EBS) in three patients implanted with intracranial electrodes to address the role of area hMT+ in conscious visual motion perception. We show that in conscious human subjects, reproducible illusory motion can be elicited by electrical stimulation of hMT+. These visual motion percepts only occurred when the site of stimulation overlapped directly with the region of the brain that had increased fMRI and electrophysiological activity during moving compared to static visual stimuli in the same individual subjects. Electrical stimulation in neighboring regions failed to produce illusory motion. Our study provides evidence for the sufficient causal link between the hMT+ network and the human conscious experience of visual motion. It also suggests a clear spatial relationship between fMRI signal and ECoG activity in the human brain