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Ear and HearingA multisite clinical trial was conducted to obtain cochlear implant (CI) efficacy data in adults with asymmetric hearing loss (AHL) and establish an evidence-based...
OBJECTIVE
A multisite clinical trial was conducted to obtain cochlear implant (CI) efficacy data in adults with asymmetric hearing loss (AHL) and establish an evidence-based framework for clinical decision-making regarding CI candidacy, counseling, and assessment tools. Study hypotheses were threefold: (1) 6-month postimplant performance in the poor ear (PE) with a CI will be significantly better than preimplant performance with a hearing aid (HA), (2) 6-month postimplant performance with a CI and HA (bimodal) will be significantly better than preimplant performance with bilateral HAs (Bil HAs), and (3) 6-month postimplant bimodal performance will be significantly better than aided, better ear (BE) performance.
DESIGN
Forty adults with AHL from four, metropolitan CI centers participated. Hearing criteria for the ear to be implanted included (1) pure-tone average (PTA, 0.5, 1, 2 kHz) of >70 dB HL, (2) aided, monosyllabic word score of ≤30%, (3) duration of severe-to-profound hearing loss of ≥6 months, and (4) onset of hearing loss ≥6 years of age. Hearing criteria for the BE included (1) PTA (0.5, 1, 2, 4 kHz) of 40 to 70 dB HL, (2) currently using a HA, (3) aided, word score of >40%, and (4) stable hearing for the previous 1-year period. Speech perception and localization measures, in quiet and in noise, were administered preimplant and at 3-, 6-, 9-, and 12-months postimplant. Preimplant testing was performed in three listening conditions, PE HA, BE HA, and Bil HAs. Postimplant testing was performed in three conditions, CI, BE HA, and bimodal. Outcome factors included age at implantation and length of deafness (LOD) in the PE.
RESULTS
A hierarchical nonlinear analysis predicted significant improvement in the PE by 3 months postimplant versus preimplant for audibility and speech perception with a plateau in performance at approximately 6 months. The model predicted significant improvement in postimplant, bimodal outcomes versus preimplant outcomes (Bil HAs) for all speech perception measures by 3 months. Both age and LOD were predicted to moderate some CI and bimodal outcomes. In contrast with speech perception, localization in quiet and noise was not predicted to improve by 6 months when comparing Bil HAs (preimplant) to bimodal (postimplant) outcomes. However, when participants' preimplant everyday listening condition (BE HA or Bil HAs) was compared with bimodal performance, the model predicted significant improvement by 3 months for localization in quiet and noise. Lastly, BE HA results were stable over time; a generalized linear model analysis revealed bimodal performance was significantly better than performance with a BE HA at all postimplant intervals for most speech perception measures and localization.
CONCLUSIONS
Results revealed significant CI and bimodal benefit for AHL participants by 3-months postimplant, with a plateau in CI and bimodal performance at approximately 6-months postimplant. Results can be used to inform AHL CI candidates and to monitor postimplant performance. On the basis of this and other AHL research, clinicians should consider a CI for individuals with AHL if the PE has a PTA (0.5, 1, 2 kHz) >70 dB HL and a Consonant-Vowel Nucleus-Consonant word score ≤40%. LOD >10 years should not be a contraindication.
Topics: Adult; Humans; Cochlear Implants; Prospective Studies; Cochlear Implantation; Hearing Loss; Hearing Aids; Speech Perception; Treatment Outcome
PubMed: 37018114
DOI: 10.1097/AUD.0000000000001354 -
European Journal of Human Genetics :... Aug 2019Language is a uniquely human ability, and failure to attain this ability can have a life-long impact on the affected individuals. This is particularly true for...
Language is a uniquely human ability, and failure to attain this ability can have a life-long impact on the affected individuals. This is particularly true for individuals with specific language impairment (SLI), which is defined as an impairment in normal language development in the absence of any other developmental disability. Although SLI displays high heritability, family-based linkage studies have been hampered by an unclear mode of Mendelian segregation, variable disease penetrance, and heterogeneity of diagnostic criteria. We performed genome-wide parametric linkage analysis and homozygosity mapping in 14 consanguineous families from Pakistan segregating SLI. Linkage analysis revealed a multipoint LOD score of 4.18 at chromosome 2q in family PKSLI05 under a recessive mode of inheritance. A second linkage score of 3.85 was observed in family PKSLI12 at a non-overlapping locus on chromosome 2q. Two other suggestive linkage loci were found in family PKSLI05 on 14q and 22q with LOD scores of 2.37 and 2.23, respectively, that were also identified in homozygosity mapping. Reduction to homozygosity was observed on chromosomes 2q, 5p, 8q, 14q, 17q, and 22q. Each homozygosity region occurred in multiple PKSLI families. We report new SLI loci on chromosomes 2 and 8 and confirm suggestive SLI linkage loci on chromosomes 5, 14, 17, and 22 reported previously in the population of Robinson Crusoe Island. These findings indicate that linkage and homozygosity mapping in consanguineous families can improve genetic analyses in SLI and suggest the involvement of additional genes in the causation of this disorder.
Topics: Chromosome Mapping; Consanguinity; Family Health; Female; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Lod Score; Male; Pakistan; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Specific Language Disorder
PubMed: 30976110
DOI: 10.1038/s41431-019-0398-1 -
Nature Communications Sep 2021Evolutionary constraints may significantly bias phenotypic change, while "breaking" from such constraints can lead to expanded ecological opportunity. Ray-finned fishes...
Evolutionary constraints may significantly bias phenotypic change, while "breaking" from such constraints can lead to expanded ecological opportunity. Ray-finned fishes have broken functional constraints by developing two jaws (oral-pharyngeal), decoupling prey capture (oral jaw) from processing (pharyngeal jaw). It is hypothesized that the oral and pharyngeal jaws represent independent evolutionary modules and this facilitated diversification in feeding architectures. Here we test this hypothesis in African cichlids. Contrary to our expectation, we find integration between jaws at multiple evolutionary levels. Next, we document integration at the genetic level, and identify a candidate gene, smad7, within a pleiotropic locus for oral and pharyngeal jaw shape that exhibits correlated expression between the two tissues. Collectively, our data show that African cichlid evolutionary success has occurred within the context of a coupled jaw system, an attribute that may be driving adaptive evolution in this iconic group by facilitating rapid shifts between foraging habitats, providing an advantage in a stochastic environment such as the East African Rift-Valley.
Topics: Animals; Biological Evolution; Cichlids; Ecosystem; Feeding Behavior; Female; Jaw; Lod Score; Male; Mouth; Pharynx; Quantitative Trait Loci; Sequence Analysis, DNA; X-Ray Microtomography
PubMed: 34531386
DOI: 10.1038/s41467-021-25755-5 -
NPJ Genomic Medicine Aug 2023Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive...
Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chicken molecular development studies, we demonstrated that this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity. We thus delineate an Ihh enhancer active in mammalian eye development whose variant causes human microphthalmia, anophthalmia and ocular coloboma. The findings highlight disease causation by an intronic variant affecting the expression of a neighboring gene, delineating molecular pathways of eye development.
PubMed: 37580330
DOI: 10.1038/s41525-023-00364-x -
Food Research International (Ottawa,... Nov 2021Ageing is a time-consuming step in Baijiu manufacture, stimulating an urgent requirement of optimization. Variation of artificial aged Feng-flavor Baijiu by...
Ageing is a time-consuming step in Baijiu manufacture, stimulating an urgent requirement of optimization. Variation of artificial aged Feng-flavor Baijiu by inhomogeneous alternating magnetic field was investigated through quantitative foodomics combined with confirmed ultra high performance liquid chromatography quadrupole-orbitaltrap high resolution mass spectrometry (UHPLC-Q-Orbitrap). A total of 153 substances were identified with significant variables (p < 0.05, VIP > 1) and 16 metabolic pathways related to Feng-flavor Baijiu functions were obtained. The method showed good accuracy with recovery values between 80.4% and 117.4% and precision lower than 9.8% for all characteristic substances. Limit of detection (LOD) was ranging between 1.6 and 10.0 μg/L with R ≥ 0.99. Factor analysis demonstrated that ageing degree of magnetized samples increased with rise of magnetic field intensity and the maximum effect was equivalent to 12.81 years of natural ageing. The results of stoichiometric analysis revealed that regulation of magnetic field on proportion in Baijiu was mainly performed through entropy and the hydrogen bond strength of Baijiu molecules. Sensory evaluation illustrated that score of Baijiu samples reached the highest at 150 mT, demonstrating that magnetic field treatment can be considered as an optimized ageing means for Feng-flavor Baijiu.
Topics: Chromatography, High Pressure Liquid; Flavoring Agents; Magnetic Fields; Taste
PubMed: 34600683
DOI: 10.1016/j.foodres.2021.110681 -
Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene.Movement Disorders : Official Journal... Dec 2020In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney...
BACKGROUND
In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction.
OBJECTIVE
To demonstrate linkage and to identify the underlying genetic cause of disease.
METHODS
Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed.
RESULTS
Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS.
CONCLUSIONS
Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.
Topics: Chorea; Humans; LIM-Homeodomain Proteins; Nail-Patella Syndrome; Skull; Transcription Factors
PubMed: 32949189
DOI: 10.1002/mds.28244 -
Toxins Dec 2022Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory...
INTRODUCTION
Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory phospholipase A (sPLA) that can be administered orally via its prodrug, varespladib-methyl. Extensive preclinical data support clinical evaluation of varespladib as a treatment for snakebite envenoming (SBE). The protocol reported here was designed to evaluate varespladib-methyl for SBE from any snake species in multiple geographies.
METHODS AND ANALYSIS
BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite) is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study to evaluate the safety, tolerability, and efficacy of oral varespladib-methyl plus standard of care (SoC) vs. SoC plus placebo in patients presenting with acute SBE by any venomous snake species. Male and female patients 5 years of age and older who meet eligibility criteria will be randomly assigned 1:1 to varespladib-methyl or placebo. The primary outcome is the Snakebite Severity Score (SSS) that has been modified for international use. This composite outcome is based on the sum of the pulmonary, cardiovascular, nervous, hematologic, and renal systems components of the updated SSS.
ETHICS AND DISSEMINATION
This protocol was submitted to regulatory authorities in India and the US. A Clinical Trial No Objection Certificate from the India Central Drugs Standard Control Organisation, Drug Controller General-India, and a Notice to Proceed from the US Food and Drug Administration have been obtained. The study protocol was approved by properly constituted, valid institutional review boards or ethics committees at each study site. This study is being conducted in compliance with the April 1996 ICH Guidance for Industry GCP E6, the Integrated Addendum to ICH E6 (R2) of November 2016, and the applicable regulations of the country in which the study is conducted. The trial is registered on Clinical trials.gov, NCT#04996264 and Clinical Trials Registry-India, 2021/07/045079 000062.
Topics: Humans; Male; Female; Snake Bites; Phospholipases A2, Secretory; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase II as Topic
PubMed: 36668842
DOI: 10.3390/toxins15010022 -
Bone Oct 2019Syndactyly type II (synpolydactyly, SPD) is a rare autosomal dominant inherited disease with higher incomplete penetrance. Currently, several variants in HOXD13 and one...
BACKGROUND
Syndactyly type II (synpolydactyly, SPD) is a rare autosomal dominant inherited disease with higher incomplete penetrance. Currently, several variants in HOXD13 and one deletion in FBLN1 have been associated with SPD. However, the causative variants in several SPD families and their etiological mechanism are still largely unknown.
METHODS
Whole exome and PCR-sanger sequencing followed by two-point linkage analysis were performed to identify the pathogenic variant in a six-generation Chinese pedigree. Homology modeling in combination with the RNAi and qRT-PCR experiments was used for revealing the pathogenic mechanism of the TTC30B variant.
RESULTS
A six-generation SPD family was reported. The affected subjects in this family had no other clinical malformation beyond SPD. A rare missense variant c.1157C>T [p.Ala375Val] (chr2:178416368, hg19) in TTC30B was demonstrated to be responsible for this SPD family. The modeling structure indicated that the Ala375 was evolutionarily and structurally conserved. The variant p.Ala375Val was predicted to be deleterious for protein structure and/or stability. Two-point linkage analysis resulted in a maximum LOD score of 3.1444 (P = 0.000071). Furthermore, we found that TTC30B was regulated by the Shh signaling pathway and the abnormal expression of TTC30B will affect the activation of the Shh signaling pathway in human retinal pigment epithelial cells.
CONCLUSIONS
This study demonstrates for the first time that an IFT (intraflagellar transport) - related gene TTC30B is implicated with SPD.
Topics: Amino Acid Sequence; Asian People; Base Sequence; Conserved Sequence; Cyclohexylamines; Cytoskeletal Proteins; Evolution, Molecular; Female; Hedgehog Proteins; Humans; Male; Models, Molecular; Mutation; Pedigree; Signal Transduction; Syndactyly; Thiophenes
PubMed: 31306809
DOI: 10.1016/j.bone.2019.07.012 -
Journal of Medical Genetics Jan 2022Strabismus is a common condition, affecting 1%-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the...
Strabismus is a common condition, affecting 1%-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis. Among these, nine are affected and four are unaffected. A single linkage signal has been identified at an 8.5 Mb region of chromosome 14q12 with a multipoint LOD (logarithm of the odds) score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next-generation sequencing and in-depth bioinformatic analyses, a 4 bp non-coding deletion was prioritised as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of , which encodes a transcription factor of the Forkhead family. Suggestive of an autoregulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. Future study of this specific deletion may shed light on the regulation of expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.
Topics: Adolescent; Aged; Aged, 80 and over; Animals; Forkhead Transcription Factors; Genetic Linkage; High-Throughput Nucleotide Sequencing; Humans; Middle Aged; Nerve Tissue Proteins; Pedigree; Rett Syndrome; Sequence Deletion; Strabismus; Exome Sequencing; Whole Genome Sequencing; Young Adult
PubMed: 33257509
DOI: 10.1136/jmedgenet-2020-107226 -
ACS Omega Feb 2021Rapid, accurate, and low-cost detection of SARS-CoV-2 is crucial to contain the transmission of COVID-19. Here, we present a cost-effective smartphone-based device...
Rapid, accurate, and low-cost detection of SARS-CoV-2 is crucial to contain the transmission of COVID-19. Here, we present a cost-effective smartphone-based device coupled with machine learning-driven software that evaluates the fluorescence signals of the CRISPR diagnostic of SARS-CoV-2. The device consists of a three-dimensional (3D)-printed housing and low-cost optic components that allow excitation of fluorescent reporters and selective transmission of the fluorescence emission to a smartphone. Custom software equipped with a binary classification model has been developed to quantify the acquired fluorescence images and determine the presence of the virus. Our detection system has a limit of detection (LoD) of 6.25 RNA copies/μL on laboratory samples and produces a test accuracy of 95% and sensitivity of 97% on 96 nasopharyngeal swab samples with transmissible viral loads. Our quantitative fluorescence score shows a strong correlation with the quantitative reverse transcription polymerase chain reaction (RT-qPCR) Ct values, offering valuable information of the viral load and, therefore, presenting an important advantage over nonquantitative readouts.
PubMed: 33553890
DOI: 10.1021/acsomega.0c04929