Systematic identification and annotation of multiple-variant compound effects at transcription factor binding sites in human genome

Publication date: Available online 7 July 2018

Source: Journal of Genetics and Genomics

Author(s): Si-Jin Cheng, Shuai Jiang, Fang-Yuan Shi, Yang Ding, Ge Gao

Abstract

Understanding the functional effects of genetic variants is crucial in modern genomics and genetics. Transcription factor binding sites (TFBSs) are one of the most important cis-regulatory elements. While multiple tools have been developed to assess functional effects of genetic variants at TFBSs, they usually assume that each variant works in isolation and neglect the potential "interference" among multiple variants within the same TFBS. In this study, we presented COPE-TFBS (Context-Oriented Predictor for variant Effect on Transcription Factor Binding Site), a novel method that considers sequence context to accurately predict variant effects on TFBSs. We systematically re-analyzed the sequencing data from both the 1000 Genomes Project and the Genotype-Tissue Expression (GTEx) Project via COPE-TFBS, and identified numbers of novel TFBSs, transformed TFBSs and discordantly annotated TFBSs resulting from multiple variants, further highlighting the necessity of sequence context in accurately annotating genetic variants. COPE-TFBS is freely available for academic use at http://cope.cbi.pku.edu.cn/.

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MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss

Abstract

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.

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Pediatric neuroanesthesia

Purpose of review Pediatric neuroanesthesia is a fascinating, yet challenging branch of anesthesia. This review highlights some of the recent insights into pediatric neuroanesthesia from the past 18 months. Recent findings Although there are incontrovertible evidences in animals suggesting that prolonged exposure to general anesthesia causes long-term neurological impairment, the translational relevance of these findings in humans is debatable. Early surgery for pediatric drug-refractory epilepsy is supported by emerging literature, but poses unique perioperative problems for the treating neuroanesthesiologist. Similarly, minimizing intraoperative blood loss and blood transfusion concerns every anesthesiologist managing small children. The usefulness of tranexamic acid in children is further enhanced by some studies in spine surgeries. Some pertinent issues related to intraoperative neuromonitoring are also discussed in the text. Summary There are several logistical and ethical problems of carrying out high-quality prospective studies in children but important findings on prevention of anesthetic neurotoxicity; minimizing intraoperative blood loss, intraoperative neurophysiological monitoring, examining optimal doses and choices of anesthetic agents in epilepsy surgery have been published recently. Correspondence to Dr Girija P. Rath, MBBS, MD, DM, Professor, Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India. Tel: +91 9810602272; e-mail: girijarath@yahoo.co.in Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Implementing the German model of work-related medical rehabilitation: Did the delivered dose of work-related treatment components increase?

Publication date: Available online 7 July 2018

Source: Archives of Physical Medicine and Rehabilitation

Author(s): Matthias Bethge, Miriam Markus, Marco Streibelt, Christian Gerlich, Michael Schuler

Abstract

Objective

Work-related components are an essential part of rehabilitation programs to support return to work of patients with musculoskeletal disorders. In Germany, a guideline for work-related medical rehabilitation was developed to increase work-related treatment components. In addition, new departments were approved to implement work-related medical rehabilitation programs. The aim of our study was to explore the state of implementation of the guideline's recommendations by describing the change in the delivered dose of work-related treatments.

Design

Nonrandomized controlled trial (cohort study).

Setting

59 German rehabilitation centers.

Participants

9,046 patients with musculoskeletal disorders were treated in work-related medical rehabilitation or common medical rehabilitation. Patients were matched one-to-one by propensity scores.

Interventions

Work-related medical rehabilitation in 2014 and medical rehabilitation in 2011

Main outcome measures

Treatment dose of work-related therapies.

Results

The mean dose of work-related therapies increased from 2.2 hours (95% CI: 1.6-2.8) to 8.9 hours (95% CI: 7.7-10.1). The mean dose of social counseling increased from 51 to 84 minutes, the mean dose of psychosocial work-related groups from 39 to 216 minutes, and the mean dose of functional capacity training from 39 to 234 minutes. The intraclass correlation of 0.67 (95% CI: 0.58-0.75) for the total dose of work-related therapies indicated that the variance explained by centers was high.

Conclusions

The delivered dose of work-related components was increased. However, there were discrepancies between the guideline's recommendations and the actual dose delivered in at least half of the centers. It is very likely that this will affect the effectiveness of work-related medical rehabilitation in practice.

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Editorial Board

Publication date: June 2018

Source: Archives of Physical Medicine and Rehabilitation, Volume 99, Issue 6

Author(s):

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Effects of Timing and Intensity of Neurorehabilitation on Functional Outcome After Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Publication date: June 2018

Source: Archives of Physical Medicine and Rehabilitation, Volume 99, Issue 6

Author(s): Marsh Königs, Eva A. Beurskens, Lian Snoep, Erik J. Scherder, Jaap Oosterlaan

Abstract

Objective

To systematically review evidence on the effects of timing and intensity of neurorehabilitation on the functional recovery of patients with moderate to severe traumatic brain injury (TBI) and aggregate the available evidence using meta-analytic methods.

Data Sources

PubMed, Embase, PsycINFO, and Cochrane Database.

Study Selection

Electronic databases were searched for prospective controlled clinical trials assessing the effect of timing or intensity of multidisciplinary neurorehabilitation programs on functional outcome of patients with moderate or severe TBI. A total of 5961 unique records were screened for relevance, of which 58 full-text articles were assessed for eligibility by 2 independent authors. Eleven articles were included for systematic review and meta-analysis.

Data Extraction

Two independent authors performed data extraction and risk of bias analysis using the Cochrane Collaboration tool. Discrepancies between authors were resolved by consensus.

Data Synthesis

Systematic review of a total of 6 randomized controlled trials, 1 quasi-randomized trial, and 4 controlled trials revealed consistent evidence for a beneficial effect of early onset neurorehabilitation in the trauma center and intensive neurorehabilitation in the rehabilitation facility on functional outcome compared with usual care. Meta-analytic quantification revealed a large-sized positive effect for early onset rehabilitation programs (d=1.02; P<.001; 95% confidence interval [CI], 0.56–1.47) and a medium-sized positive effect for intensive neurorehabilitation programs (d=.67; P<.001; 95% CI, .38–.97) compared with usual care. These effects were replicated based solely on studies with a low overall risk of bias.

Conclusions

The available evidence indicates that early onset neurorehabilitation in the trauma center and more intensive neurorehabilitation in the rehabilitation facility promote functional recovery of patients with moderate to severe TBI compared with usual care. These findings support the integration of early onset and more intensive neurorehabilitation in the chain of care for patients with TBI.

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Early Botulinum Toxin Injections in Infants With Musculoskeletal Disorders: A Systematic Review of Safety and Effectiveness

Publication date: June 2018

Source: Archives of Physical Medicine and Rehabilitation, Volume 99, Issue 6

Author(s): Jean-Sébastien Bourseul, Anais Molina, Mael Lintanf, Laetitia Houx, Emmanuelle Chaléat-Valayer, Christelle Pons, Sylvain Brochard

Abstract

Objective

To report current evidence regarding the safety of intramuscular botulinum toxin injection (BTI) in children with orthopedic- and neurologic-related musculoskeletal disorders >2 years of age.

Data Sources

PubMed, Cochrane Library, and ScienceDirect, Google Scholar, and Web of Science.

Study Selection

Two reviewers independently selected studies based on predetermined inclusion criteria.

Data Extraction

Data relating to the aim were extracted. Methodologic quality was graded independently by 2 reviewers using the Physiotherapy Evidence Database scale for randomized controlled trials (RCTs) and the Downs and Black evaluation tool for non-RCTs. Level of evidence was determined using the modified Sackett scale.

Data Synthesis

Data of 473 infants were analyzed. Fifty-five infants had cerebral palsy, 112 had obstetric brachial plexus palsy, 257 had clubfoot, and 44 had congenital torticollis. No studies reported any severe adverse event that could be attributed to the BTI. The rate of mild to moderate adverse events reported varied from 5% to 25%. Results regarding efficacy were preliminary, dependent on the pathology, and limited by the small number of studies and their low levels of evidence.

Conclusions

BTI is already widely used as an early treatment for this age group. The safety profile of BTI in infants appears similar to that of older children and risks appear more related to the severity of the pathology and the location of the injections than to the toxin itself. Regarding effectiveness, other studies with higher levels of evidence should be carried out for each specific pathology.

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