Towards Subject and Diagnostic Identifiability in the Alzheimer’s Disease Spectrum Based on Functional Connectomes

Alzheimer’s disease (AD) is the only major cause of mortality in the world without an effective disease modifying treatment. Evidence supporting the so called “disconnection hypothesis” suggests that functional connectivity biomarkers may have clinical potential for early detection of AD. However, known issues with low test-retest reliability and signal to noise in functional connectivity may prevent accuracy and subsequent predictive capacity. We validate the utility of a novel principal component based diagnostic identifiability framework to increase separation in functional connectivity across the Alzheimer’s spectrum by identifying and reconstructing FC using only AD sensitive components or connectivity modes. We show that this framework (1) increases test-retest correspondence and (2) allows for better separation, in functional connectivity, of diagnostic groups both at the whole brain and individual resting state network level. Finally, we evaluate a posteriori the association between connectivity mode weights with longitudinal neurocognitive outcomes

Ethnic differences translate to inadequacy of high-risk screening for gestational diabetes mellitus in an Asian population: a cohort study

Background: universal and high-risk screening for gestational diabetes mellitus (GDM) has been widely studied and debated. Few studies have assessed GDM screening in Asian populations and even fewer have compared Asian ethnic groups in a single multi-ethnic population.Methods: 1136 pregnant women (56.7% Chinese, 25.5% Malay and 17.8% Indian) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study were screened for GDM by 75-g oral glucose tolerance test (OGTT) at 26–28 weeks of gestation. GDM was defined using the World Health Organization (WHO) criteria. High-risk screening is based on the guidelines of the UK National Institute for Health and Clinical Excellence.Results: universal screening detected significantly more cases than high-risk screening [crude OR 2.2 (95% CI 1.7-2.8)], particularly for Chinese women [crude OR = 3.5 (95% CI 2.5-5.0)]. Pre-pregnancy BMI > 30 kg/m2 (adjusted OR = 3.4, 95% CI 1.5-7.9) and previous GDM history (adjusted OR = 6.6, 95% CI 1.2-37.3) were associated with increased risk of GDM in Malay women while GDM history was the only significant risk factor for GDM in Chinese women (adjusted OR = 4.7, 95% CI 2.0-11.0).Conclusion: risk factors used in high-risk screening do not sufficiently predict GDM risk and failed to detect half the GDM cases in Asian women. Asian women, particularly Chinese, should be screened to avoid under-diagnosis of GDM and thereby optimize maternal and fetal outcome

Applying Optimal Stopping for Optimizing Queries to External Semantic Web Resources

The rapid increase in the amount of available information from various online sources poses new challenges for programs that endeavor to process these sources automatically and identify the most relevant material for a given application. This paper introduces an approach for optimizing queries to Semantic Web resources based on ideas originally proposed by MacQueen for optimal stopping in business economics. Modeling applications as decision makers looking for optimal action/answer sets, facing search costs for acquiring information, test costs for checking these information, and receiving a reward depending on the usefulness of the proposed solution, yields strategies for optimizing queries to external services. An extensive evaluation compares these strategies to a conventional coverage based approach, based on real world response times taken from popular Web services

Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight.

The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

The Coupling of Alternative Splicing and Nonsense-Mediated mRNA Decay

Most human genes exhibit alternative splicing, but not all alternatively spliced transcripts produce functional proteins. Computational and experimental results indicate that a substantial fraction of alternative splicing events in humans result in mRNA isoforms that harbor a premature termination codon (PTC). These transcripts are predicted to be degraded by the nonsense-mediated mRNA decay (NMD) pathway. One explanation for the abundance of PTC-containing isoforms is that they represent splicing errors that are identified and degraded by the NMD pathway. Another potential explanation for this startling observation is that cells may link alternative splicing and NMD to regulate the abundance of mRNA transcripts. This mechanism, which we call "Regulated Unproductive Splicing and Translation" (RUST), has been experimentally shown to regulate expression of a wide variety of genes in many organisms from yeast to human. It is frequently employed for autoregulation of proteins that affect the splicing process itself. Thus, alternative splicing and NMD act together to play an important role in regulating gene expression