Citations

Abstract Background Acute kidney injury (AKI) carries a poor prognosis. Its incidence is increasing in the intensive care unit (ICU). Our purpose in this study is to develop and externally validate a model for predicting AKI in the ICU using patient data present prior to ICU admission. Methods We used data of 98 472 adult ICU admissions at Mayo Clinic between 1 January 2005 and 31 December 2017 and 51 801 encounters from Medical Information Mart for Intensive Care III (MIMIC-III) cohort. A gradient-boosting model was trained on 80% of the Mayo Clinic cohort using a set of features to predict AKI acquired in the ICU. Results AKI was identified in 39 307 (39.9%) encounters in the Mayo Clinic cohort. Patients who developed AKI in the ICU were older and had higher ICU and in-hospital mortality compared to patients without AKI. A 30-feature model yielded an area under the receiver operating curve of 0.690 [95% confidence interval (CI) 0.682–0.697] in the Mayo Clinic cohort set and 0.656 (95% CI 0.648–0.664) in the MIMIC-III cohort. Conclusions Using machine learning, AKI among ICU patients can be predicted using information available prior to admission. This model is independent of ICU information, making it valuable for stratifying patients at admission.

Objectives/HypothesisThe male singing voice through puberty undergoes many changes that present challenges for the singer and choral director. The purpose of this study was to discuss the endoscopic findings seen in prepubescent choir singers.Study DesignSingle‐institution prospective study.MethodsSubjects were recruited from the Cincinnati Boychoir and were described as Cooksey stage unchanged or mid‐voice I, as described by the Boychoir artistic director. Vocal history was obtained via questionnaire at the initial visit. Subjects with known laryngeal pathologies were excluded. Endoscopic laryngeal examinations were performed using videoendoscopy. During examination, each subject sang four discrete frequencies. Findings of the endoscopic exam were judged by a board‐certified pediatric otolaryngologist specializing in pediatric voice.ResultsWe evaluated 28 subjects prior to vocal maturation. Their age range was 8 to 13 years old (mean = 10.2 ± 1.2 years). The singing voice category of all 28 subjects was described as soprano vocal range by the Boychoir artistic director. The subjects had a mean of 1.7 ± 1.1 years in the Boychoir (0–5 years). None reported history of vocal issues or voice problems in the past; seven (25%) subjects had vocal fold lesions seen at one or more frequencies; 24 (85%) subjects had a posterior gap seen at one or more frequencies. Two subjects (7%) had a posterior gap at one frequency, C3 and G3, respectively. Five subjects (18%) had a posterior gap at two frequencies, seven subjects (25%) at three frequencies, and 10 subjects (36%) in all four frequencies.ConclusionsOur study aimed to describe the laryngeal examination of dedicated Boychoir singers prior to undergoing pubertal development and vocal maturation. In elite pediatric singers we found that vocal nodules are common (25%) and are not correlated with vocal symptoms. These findings may suggest that asymptomatic lesions may be more prevalent than previously thought. In these individuals, posterior glottic gap is common and can be considered a normal glottal configuration.Level of Evidence4 Laryngoscope, 131:592–597, 2021

We describe the phenotype of a patient with extensive aortic, carotid, and abdominal dissections. The proband was found to have a heterozygous deletion of exons 21–34 inMYLK, which is a rare finding, as deletions in this gene have been infrequently reported. We describe this finding following detection in a proband with an extensive history of aortic, carotid, and abdominal dissections. Neoteric molecular modeling techniques to help determine the impact of this deletion on protein function indicated loss of function due to lack of any kinase domain. We also provide the electrostatics calculations from the wild type and mutant variant. Through a combined multiomic approach of clinical, functional, and protein informatics, we arrive at a data fusion for determination of pathogenicity embedded within the genetic code for this particular genetic variant, which, as a platform, continues to broaden its scope across the field of variants of uncertain significance classification.

Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Abstract BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p<0.0001), HSP70 (p<0.0001) and skin unesterified cholesterol (p=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937).ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.Trial Registration: CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030; EudraCT 2014-005194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE. OR-REL-NPC-01: Unregistered.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Objectives: LMNA-associated familial partial lipodystrophy (FPLD) is a rare autosomal dominant A-type laminopathy characterized by variable loss and redistribution of subcutaneous adipose tissue, dyslipidemia, and insulin resistance. Though A-type lamins play a key role in nuclear membrane structure and regulation of cell proliferation, an association between cancer and LMNA-associated FPLD has not been reported. Methods and Results: This report outlines the case of two biological sisters with LMNA-associated FPLD who developed hypopharyngeal squamous cell carcinoma in the absence of any other risk factors for head and neck cancer. Conclusion: These observations prompt further investigation into the potential role of A-type lamins in the development and progression of head and neck cancers.

Abstract Background and Aims The correlation between genotype and phenotype is well described in ADPKD adults. PKD2 is milder than PKD1 disease, with end stage kidney disease (ESKD) occurring on average 20 years later, and patients with PKD1 truncating mutations having a more severe outcome than PKD1 non-truncating mutations. Still, large differences in outcome occur even within families carrying the same gene variation. Only a few cases series reported the genetic profile of severely affected ADPKD children and suggest an additional effect of hypomorphic genes. We therefore aim to analyse the geno-phenotype profile in a well characterized pediatric ADPKD cohort. Method Clinical, familial, biological and imaging data were collected longitudinally in children diagnosed with ADPKD. Genotypic analysis was done using a custom Agilent SureSelect gene panel containing 136 ciliopathy-associated genes, including PKD1 and PKD2. Mutations and/or variants identified were individually evaluated for pathogenicity. Results 57 ADPKD children from 44 families were diagnosed at a mean (± SD) age of 4.1 (±4.8) years. ADPKD diagnosis was made in 32 children (56%) because of asymptomatic screening as requested by the family; 7 (12%) due to presenting symptoms (6 due to urinary tract infection and 1 due to post-traumatic macroscopic hematuria); 9 (16%) due to a coincidental finding of renal cysts on US performed for another reason and in 9 cases (16%) a prenatal diagnosis was performed. Twenty-nine children (51%) met the definition of very-early onset (VEO) disease. We identified pathogenic mutations in 100% of our patients, in which the prevalence of PKD1 truncating, PKD1 non-truncating, PKD2 and GANAB mutations was 75%, 19%, 4%, and 2%, respectively. Four cases (7%) were due to a de novo mutation. Interestingly, in 29 patients (51%) the germline mutation was the only identified mutation. However, in the rest of the subjects additional variants were identified in other ciliopathy-associated genes. In 12 cases (21%) the additional identified variants found in either the PKD, PMM2, HNF1B, DNAJC1, CEP290, NEK1, MKKS, NPHP4 or PKHD1 genes were scored to have a potential phenotypic effect, which will be evaluated by continued follow-up of this cohort. Conclusion We report the first large cohort of genotyped ADPKD children, including an extensive panel of ciliopathy genes next to the PKD genes. Interestingly, we found a high prevalence of additional and potentially modifying variants in this young population.