A common variant association study reveals novel susceptibility loci for low HDL‐cholesterol levels in ethnic Arabs

The genetic susceptibility to acquiring low high density lipoprotein‐cholesterol (LHDLC) levels is not completely elucidated yet. In this study, we performed a common variant association study for harboring this trait in ethnic Arabs. We employed the Affymetrix high‐density Axiom Genome‐Wide ASI Array (Asian population) providing a coverage of 598,000 single nucleotide variations (SNPs) to genotype 5495 individuals in a two‐phase study involving discovery and validation sets of experiments. The rs1800775 [1.31 (1.22–1.42); p = 3.41E‐12] in the CETP gene and rs359027 [1.26 (1.16–1.36); p = 2.55E‐08] in the LMCD1 gene were significantly associated with LHDLC levels. Furthermore, rs3104435 [1.26 (1.15–1.38); p = 1.19E‐06] at the MATN1 locus, rs9835344 [1.16 (1.08–1.26); p = 8.75E‐06] in the CNTN6 gene, rs1559997 [1.3 (1.14–1.47); p = 9.48E‐06] in the SDS gene and rs1670273 [1.2 (1.1–1.31); p = 4.81E‐06] in the DMN/SYNM gene exhibited suggestive association with the disorder. Seven other variants including rs1147169 in the PLCL1 gene, rs10248618 in the DNAH11, rs476155 in the GLIS3, rs7024300 in the ABCA1, intergenic rs10836699, rs11603691 in P2RX3 and rs750134 in CORO1C gene exhibited borderline protective properties. Validation and joint meta‐analysis resulted in rs1800775, rs3104435 and rs359027 retaining their predisposing properties, while rs10836699 and rs11603691 showed protective properties. Our data show several predisposing variants across the genome for LHDLC levels in ethnic Arabs.     

Maintaining the ties that bind: the role of an intermediate visual memory store in the persistence of awareness

Segregation and feature binding are essential to the perception and awareness of objects in a visual scene. When a fragmented line-drawing of an object moves relative to a background of randomly oriented lines, the previously hidden object is segregated from the background and consequently enters awareness. Interestingly, in such shape-from-motion displays, the percept of the object persists briefly when the motion stops, suggesting that the segregated and bound representation of the object is maintained in awareness. Here, we tested whether this persistence effect is mediated by capacity-limited working-memory processes, or by the amount of object-related information available. The experiments demonstrate that persistence is affected mainly by the proportion of object information available and is independent of working-memory limits. We suggest that this persistence effect can be seen as evidence for an intermediate, form-based memory store mediating between sensory and working memory.     

Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson's disease

Cervical dystonia (CD) is a movement disorder that involves involuntary turning and twisting of the neck caused by abnormal muscle contraction. Deep brain stimulation (DBS) in the globus pallidus internus (GPi) is used to treat both CD and the motor symptoms of Parkinson's disease (PD). It has been suggested that the differing motor symptoms in CD and PD may arise from a decreased GPi output in CD and elevation of output in PD. To test this hypothesis, extracellular recordings of GPi neuronal activity were obtained during stereotactic surgery for the implantation of DBS electrodes in seven idiopathic CD and 14 PD patients. The mean GPi neuronal firing rate recorded from CD patients was lower than that in PD patients (P < 0.001; means +/- SE: 71.4 +/- 2.2 and 91.7 +/- 3.0 Hz, respectively). Furthermore, GPi neurons fired in a more irregular pattern consisting of more frequent and longer pauses in CD compared with PD patients. When comparisons were done based on locations of recordings, these differences in firing rates and patterns were limited to the ventral portion of the GPi. In contrast, no difference in firing rate or pattern was observed in the globus pallidus externus between the two groups. These findings suggest that alterations in both firing rate and firing pattern may underlie the differing motor symptoms associated with these two movement disorders.     

Number magnitude potentiates action judgements

Motor actions can be simulated and generated through the perception of objects and their characteristics. Such functional characteristics of objects with given action capabilities are called affordances. Here we report an interaction between the perception of affordances and the processing of numerical magnitude, and we show that the numerical information calibrates the judgement of action even when no actual action is required. In Experiment 1, participants had to judge whether they would be able to grasp a rod lengthways between their thumb and index finger. The presentation of the rod was preceded by a number or a non-numerical symbol. When a small number preceded the rod, participants overestimated their grasp; conversely, when a large number preceded the rods, they underestimated their grasp. In Experiment 2, participants were requested to judge if two successive rods had the same length, a judgement that did not involve any grasping. The numerical primes had no effect on this judgement, showing that the magnitude/affordance interaction was not due to a simple perceptual effect. Finally, Experiment 3 showed that the interaction was not present with a non-numerical ordered sequence, thereby eliminating sequence order as a potentially confounding variable.     

Glecaprevir + pibrentasvir for treatment of hepatitis C

Introduction: Glecaprevir/pibrentasvir is a fixed-dose combination regimen of a new generation NS3/4A inhibitor and an NS5A inhibitor with potent antiviral activity against all hepatitis C virus (HCV) genotypes. This regimen offers a shorter course of therapy (8 weeks) for selected patients regardless of genotype and has demonstrated high virological efficacy for retreatment of individuals who previously failed an NS5A containing regimen. Glecaprevir and pibrentasvir are minimally excreted by the kidneys; thus this regimen can safely be used in individuals with severe chronic kidney disease (CKD), including those undergoing hemodialysis.

Areas covered: This review covers the mechanism of action, pharmacokinetics, clinical applications, efficacy, and safety profile of glecaprevir/pibrentasvir. It also covers key phase 2 and 3 clinical trials that led to licensure of this regimen.

Expert opinion: Glecaprevir/pibrentasvir is the latest antiviral regimen licensed in the United States for treatment of HCV infection. Although several other direct-acting antiviral agents (DAAs) are currently available, glecaprevir/pibrentasvir has some unique characteristics that expand treatment options for HCV infection, including patients with comorbidities such as advanced stage CKD or prior treatment failure to antiviral regimens containing other DAAs.     

Efficient Screening for Impairments in Peer Functioning Among Mid-to-Late Adolescents Receiving Clinical Assessments for Social Anxiety

Background

Impairments in peer relations comprise a core feature of social anxiety, particularly among adolescents. Yet, these impairments may also stem from concerns that commonly co-occur with social anxiety, namely depressive symptoms and attention-deficit/hyperactivity disorder (ADHD) symptoms.

Objective

Although peer-related impairments spike during adolescence, we know relatively little about efficiently screening for peer-related impairments that specifically index those impairments relevant to adolescent social anxiety.

Method

We recruited 89 adolescents (M?=?14.5 years, 64% female, 65.1% African American) who varied on evaluation-seeking status (30 evaluation-seeking; 59 community control). On a preliminary phone screen, parents provided reports on three peer-related impairment items identified in prior work as particularly discriminative: number of friends, trouble making friends, and trouble keeping friends. Parents and adolescents completed survey measures of social anxiety and mental health concerns commonly linked to social anxiety (i.e., depressive symptoms, ADHD symptoms).

Results

Increased peer-related impairments were uniquely related to increased social anxiety, controlling for depressive symptoms and ADHD symptoms. Increased peer-related impairments also predicted increased risk for being above the clinical cut score on measures of social anxiety, depressive symptoms, and ADHD symptoms. The number of peer-related impairments significantly distinguished adolescents on evaluation-seeking status.

Conclusions

Using a short list of three items assessing peer-related impairments (number of friends, trouble making friends, and trouble keeping friends) one can efficiently screen for peer-related impairments of specific relevance to adolescent social anxiety. These findings have important implications for leveraging efficient, evidence-based screening devices when clinically assessing adolescent social anxiety, particularly in low-resource mental health settings.

     

Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group

OBJECTIVE: To provide a uniform platform from which to study acute liver failure, the U.S. Acute Liver Failure Study Group has sought to standardize the management of patients with acute liver failure within participating centers. METHODS: In areas where consensus could not be reached because of divergent practices and a paucity of studies in acute liver failure patients, additional information was gleaned from the intensive care literature and literature on the management of intracranial hypertension in non-acute liver failure patients. Experts in diverse fields were included in the development of a standard study-wide management protocol. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure monitoring is recommended in patients with advanced hepatic encephalopathy who are awaiting orthotopic liver transplantation. At an intracranial pressure of > or =25 mm Hg, osmotic therapy should be instituted with intravenous mannitol boluses. Patients with acute liver failure should be maintained in a mildly hyperosmotic state to minimize cerebral edema. Accordingly, serum sodium should be maintained at least within high normal limits, but hypertonic saline administered to 145-155 mmol/L may be considered in patients with intracranial hypertension refractory to mannitol. Data are insufficient to recommend further therapy in patients who fail osmotherapy, although the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation. Empirical broad-spectrum antibiotics should be administered to any patient with acute liver failure who develops signs of the systemic inflammatory response syndrome, or unexplained progression to higher grades of encephalopathy. Other recommendations encompassing specific hematologic, renal, pulmonary, and endocrine complications of acute liver failure patients are provided, including their management during and after orthotopic liver transplantation. CONCLUSIONS: The present consensus details the intensive care management of patients with acute liver failure. Such guidelines may be useful not only for the management of individual patients with acute liver failure, but also to improve the uniformity of practices across academic centers for the purpose of collaborative studies.     

Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods

Voriconazole (VRC) is a broad-spectrum antifungal triazole with nonlinear pharmacokinetics. The utility of measurement of voriconazole blood levels for optimizing therapy is a matter of debate. Available high-performance liquid chromatography (HPLC) and bioassay methods are technically complex, time-consuming, or have a narrow analytical range. Objectives of the present study were to develop new, simple analytical methods and to assess variability of voriconazole blood levels in patients with invasive mycoses. Acetonitrile precipitation, reverse-phase separation, and UV detection were used for HPLC. A voriconazole-hypersusceptible Candida albicans mutant lacking multidrug efflux transporters (cdr1Delta/cdr1Delta, cdr2Delta/cdr2Delta, flu1Delta/flu1Delta, and mdr1Delta/mdr1Delta) and calcineurin subunit A (cnaDelta/cnaDelta) was used for bioassay. Mean intra-/interrun accuracies over the VRC concentration range from 0.25 to 16 mg/liter were 93.7% +/- 5.0%/96.5% +/- 2.4% (HPLC) and 94.9% +/- 6.1%/94.7% +/- 3.3% (bioassay). Mean intra-/interrun coefficients of variation were 5.2% +/- 1.5%/5.4% +/- 0.9% and 6.5% +/- 2.5%/4.0% +/- 1.6% for HPLC and bioassay, respectively. The coefficient of concordance between HPLC and bioassay was 0.96. Sequential measurements in 10 patients with invasive mycoses showed important inter- and intraindividual variations of estimated voriconazole area under the concentration-time curve (AUC): median, 43.9 mg x h/liter (range, 12.9 to 71.1) on the first and 27.4 mg x h/liter (range, 2.9 to 93.1) on the last day of therapy. During therapy, AUC decreased in five patients, increased in three, and remained unchanged in two. A toxic encephalopathy probably related to the increase of the VRC AUC (from 71.1 to 93.1 mg x h/liter) was observed. The VRC AUC decreased (from 12.9 to 2.9 mg x h/liter) in a patient with persistent signs of invasive aspergillosis. These preliminary observations suggest that voriconazole over- or underexposure resulting from variability of blood levels might have clinical implications. Simple HPLC and bioassay methods offer new tools for monitoring voriconazole therapy.     

Sarcoidosis (Heerfordt syndrome): a case report

We report the case of a 22-year-old woman who is suspected of having primary Sj?gren s syndrome. She complaining of bilateral swelling of eyelids and the parotid glands of three weeks duration. Physical examination revealed a bilateral enlargement of both parotid glands, which were solid and painful. Sj?gren s syndrome was suspected at that stage, and the serologic and specific analysis were done. All these tests didn t find any autoimmune or visceral features typical of Sj?gren s syndrome and autoantibodies were negative. During follow-up time the right facial nerve palsy developed. Pulmonary radiography revealed bihilar lymphadenopathy and labial salivary gland biopsy revealed non-caseating granuloma. The patient was classified as having stage I sarcoidosis. This case demonstrates the importance of being aware of the leading clinical signs and symptoms in case of Heerfordt syndrome.