Representation of genetic association via attributable familial relative risks in order to identify polymorphisms functionally relevant to rheumatoid arthritis

The results from association studies are usually summarized by a measure of evidence of association (frequentist or Bayesian probability values) that does not directly reflect the impact of the detected signals on familial aggregation. This article investigates the possible advantage of a two-dimensional representation of genetic association in order to identify polymorphisms relevant to disease: a measure of evidence of association (the Bayes factor, BF) combined with the estimated contribution to familiality (the attributable sibling relative risk, λs). Simulation and data from the North American Rheumatoid Consortium (NARAC) were used to assess the possible benefit under several scenarios. Simulation indicated that the allele frequencies to reach the maximum BF and the maximum attributable λs diverged as the size of the genetic effect increased. The representation of BF versus attributable λs for selected regions of NARAC data revealed that SNPs involved in replicated associations clearly departed from the bulk of SNPs in these regions. In the 12 investigated regions, and particularly in the low-recombination major histocompatibility region, the ranking of SNPs according to BF differed from the ranking of SNPs according to attributable λs. The present results should be generalized using more extensive simulations and additional real data, but they suggest that a characterization of genetic association by both BF and attributable λs may result in an improved ranking of variants for further biological analyses

Development and diagnostic validation of the Brisbane Evidence-Based Language Test

Purpose: To describe the development and determine the diagnostic accuracy of the Brisbane Evidence-Based Language Test in detecting aphasia. Methods: Consecutive acute stroke admissions (n = 100; mean = 66.49y) participated in a single (assessor) blinded cross-sectional study. Index assessment was the ∼45 min Brisbane Evidence-Based Language Test. The Brisbane Evidence-Based Language Test is further divided into four 15–25 min Short Tests: two Foundation Tests (severe impairment), Standard (moderate) and High Level Test (mild). Independent reference standard included the Language Screening Test, Aphasia Screening Test, Comprehensive Aphasia Test and/or Measure for Cognitive-Linguistic Abilities, treating team diagnosis and aphasia referral post-ward discharge. Results: Brisbane Evidence-Based Language Test cut-off score of ≤ 157 demonstrated 80.8% (LR+ =10.9) sensitivity and 92.6% (LR− =0.21) specificity. All Short Tests reported specificities of ≥ 92.6%. Foundation Tests I (cut-off ≤ 61) and II (cut-off ≤ 51) reported lower sensitivity (≥ 57.5%) given their focus on severe conditions. The Standard (cut-off ≤ 90) and High Level Test (cut-off ≤ 78) reported sensitivities of ≥ 72.6%. Conclusion: The Brisbane Evidence-Based Language Test is a sensitive assessment of aphasia. Diagnostically, the High Level Test recorded the highest psychometric capabilities of the Short Tests, equivalent to the full Brisbane Evidence-Based Language Test. The test is available for download from brisbanetest.org. Implications for rehabilitation: Aphasia is a debilitating condition and accurate identification of language disorders is important in healthcare. Language assessment is complex and the accuracy of assessment procedures is dependent upon a variety of factors. The Brisbane Evidence-Based Language Test is a new evidence-based language test specifically designed to adapt to varying patient need, clinical contexts and co-occurring conditions. In this cross-sectional validation study, the Brisbane Evidence-Based Language Test was found to be a sensitive measure for identifying aphasia in stroke

The microwave spectrum, ab initio analysis, and structure of the fluorobenzene–hydrogen chloride complex

The fluorobenzene–hydrogen chloride π-hydrogen-bonded complex has been studied by high resolution microwave spectroscopy and ab initio calculations. Rotational spectra of the C6H5F–H35Cl,C6H5F–H35Cl, C6H5F–H37Cl,C6H5F–H37Cl, and C6D5F–H35ClC6D5F–H35Cl isotopomers were assigned using pulsed molecular beam techniques in a Fourier-transform microwave spectrometer. The spectra are consistent with a structure of the complex in which the HCl is above the fluorobenzene ring near the ring center, similar to the benzene–HCl prototype dimer. An analysis of the inertial data and the chlorine quadrupole coupling tensor results in two mathematically possible locations for the HCl subunit with respect to the fluorobenzene arising from sign ambiguities in interpreting the spectral constants. One structure has the HCl nearly perpendicular to the aromatic ring; the other has the HCl pointing toward the fluorine end of the ring. Spectral intensities for the μaμa and μbμb transitions favor the former configuration. Ab initio calculations (MP2/6-311++G(2df,2pd)+BSSE corrections) indicate that the position of the HCl is driven by electrostatic interactions with the π electrons of the benzene ring. HCl is shifted by 0.16 Å from the center of the ring toward the para-C atom, where the π density is significantly higher. In the equilibrium form, HCl is tilted by δ=14° from perpendicular to the ring with the hydrogen end toward the para-C atom. The H atom can perform an internal rotation or at least a half-circular libration (barriers smaller than 100 cm−1). An average δ value of 0.7° is estimated in reasonable agreement with the derived vibrationally averaged value of 3.8°. The complex binding energy ΔEΔE calculated at the CCSD(T)/6-311++G(2df,2pd)+CP(BSSE) level of theory is 2.8 kcal/mol, suggesting a lower ΔEΔE value for benzene–HCl than previously reported. Fluorobenzene–HCl possesses some charge transfer character; however, just 5.5 melectron are transferred from the benzene ring to HCl. In view of this, π–H bonding in fluorobenzene–HCl is predominantly electrostatic rather than covalent in character contrary to claims made in connection with benzene–HCl. © 2003 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71342/2/JCPSA6-118-20-9278-1.pd

Thyroid-Hormone-Induced Browning of White Adipose Tissue Does Not Contribute to Thermogenesis and Glucose Consumption.

Regulation of body temperature critically depends on thyroid hormone (TH). Recent studies revealed that TH induces browning of white adipose tissue, possibly contributing to the observed hyperthermia in hyperthyroid patients and potentially providing metabolic benefits. Here, we show that browning by TH requires TH-receptor β and occurs independently of the sympathetic nervous system. The beige fat, however, lacks sufficient adrenergic stimulation and is not metabolically activated despite high levels of uncoupling protein 1 (UCP1). Studies at different environmental temperatures reveal that TH instead causes hyperthermia by actions in skeletal muscle combined with a central body temperature set-point elevation. Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Dysphagia and Speech-Language Pathology Involvement Following Chemical Ingestion Injury: A Review of 44 Cases Admitted to a Quaternary Australian Hospital (2008-2012)

This study aimed to explore the clinical characteristics of an adult chemical ingestion population and examine the course of return to oral intake post injury and speech-language pathologist (SLP) involvement during the initial acute-care admission.A retrospective chart review of adults admitted to a quaternary hospital for the treatment of an acute chemical ingestion injury between 2008 and 2012 was conducted.Forty-four adults (23 men, 21 women) were identified as receiving treatment for ingestion injury, of whom 18 (40.91%) required altered oral intake. Of those requiring altered oral intake, 50% were referred to SLPs. Individuals requiring altered oral intake were significantly (p < .05) older, more likely to be men, and present with more severe injuries requiring longer ICU and hospital admissions following intentional chemical ingestions than those who were able to commence a normal oral diet without any alteration or nonoral supplementation. By discharge, 15.91% (n = 7) of the total cohort had not resumed normal oral intake.Return to oral intake post chemical ingestion injury can be protracted and complex. Referrals to SLPs were limited. These data may aid prognostic insight as well as provide (a) collateral information to assist discharge planning and follow-up and (b) background for evaluating the potential for SLP involvement

The challenges of dysphagia management and rehabilitation in two complex cases post chemical ingestion injury

Purpose: Dysphagia is common sequelae of chemical ingestion injury, resulting from damage to critical swallowing structures. From a speech-language pathology perspective, this study outlines the physiological deficits in 2 individuals with severe injury (1 woman, acid; 1 man, alkali) and the pattern of dysphagia rehabilitation and recovery

New host records for cotton leaf curl Gezira virus: capsicum and melon in Egypt

Cotton leaf curl Gezira virus (CLCuGeV), in association with a DNA-beta satellite, is reported as a causal agent of cotton leaf curl disease. This study reports CLCuGeV detection in field samples of Capsicum annuum and Cucumis melo from Egypt and represents an expansion of the virus host range beyond the Malvaceae family to the two plant families, Solanaceae and Cucurbitaceae