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BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

BACKGROUND: Hazardous drug exposure is an occupational health hazard to oncology nurses. Sparse data are available regarding the frequency and characteristics of hazardous drug spills. OBJECTIVES: This article aims to describe nurses hazardous drug exposures and use of personal protective equipment during drug spills. METHODS: The Drug Exposure Feedback and Education for Nurses Safety study launched in March 2015. When drug spills occurred, consented RNs administering chemotherapy in ambulatory infusion settings completed brief questionnaires. Descriptive statistics were used to summarize equipment use and spill events. FINDINGS: Spills were common, despite the use of closed-system transfer devices. Over two years, 51 nurses from 12 participating academic infusion centers reported 61 unique spills. Spills commonly involved highly toxic drugs. Personal protective equipment use during drug spills was suboptimal. These foundational data reveal gaps in clinical practice.

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

We describe an 11-year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X-inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Objectives/hypothesisTo objectively assess the initial and long-term retention of robotic surgical skills of otolaryngology residents.Study designThis study was performed in an academic otolaryngology residency training program. Between October 2015 and November 2016, residents were invited to complete a prospective, multiphase robotic surgical skills training course: 1) online da Vinci Surgical System Assessment and didactic, 2) faculty-supervised robotic simulator training, 3) robotic docking and draping training, 4) robotic dry-lab exercises. To optimize surgical skill retention, the training laboratory was repeated 2 weeks after the initial training session.MethodsTwenty otolaryngology residents were included. Primary outcome was measured as robotic skill assessment scores on three tasks: camera targeting, peg board, and needle targeting. Skill assessments were completed prior to training, between the two training sessions, and at 1 month and 6 months after training. Residents were also asked to complete a self-assessment questionnaire.ResultsCamera targeting scores were improved at midtraining (P

PurposeNeurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.MethodsA total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.ResultsNone of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.ConclusionWe demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Objectives/hypothesisDetermine the rate, diagnoses, and risk factors associated with 30-day nonelective readmissions for patients undergoing surgery for oropharyngeal cancer.Study designRetrospective cohort study.MethodsWe analyzed the Nationwide Readmissions Database for patients who underwent oropharyngeal cancer surgery between 2010 and 2014. Rates and causes of 30-day readmissions were determined. Multivariate logistic regression was used to identify risk factors for readmission.ResultsAmong 16,902 identified cases, the 30-day, nonelective readmission rate was 10.2%, with an average cost per readmission of $14,170. The most common readmission diagnoses were postoperative bleeding (14.1%) and wound complications (12.6%) (surgical site infection [8.6%], dehiscence [2.3%], and fistula [1.7%]). On multivariate regression, significant risk factors for readmission were major ablative surgery (which included total glossectomy, pharyngectomy, and mandibulectomy) (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.06-1.60), advanced Charlson/Deyo comorbidity (OR: 2.00, 95% CI: 1.43-2.79), history of radiation (OR: 1.58, 95% CI: 1.15-2.17), Medicare (OR: 1.34, 95% CI: 1.06-1.69) or Medicaid (OR: 1.82, 95% CI: 1.32-2.50) payer status, index admission from the emergency department (OR: 1.19, 95% CI: 1.02-1.40), and length of stay ≥6 days (OR: 1.57, 95% CI: 1.19-2.08).ConclusionsIn this large database analysis, we found that approximately one in 10 patients undergoing surgery for oropharyngeal cancer is readmitted within 30 days. Procedural complexity, insurance status, and advanced comorbidity are independent risk factors, whereas postoperative bleeding and wound complications are the most common reasons for readmission.Level of evidence4. Laryngoscope, 129:910-918, 2019.

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

ObjectivesTo determine the incidence of dysphagia and aspiration pneumonia following transcatheter aortic valve replacement (TAVR) performed with either general anesthesia (GA) or moderate sedation (MS).DesignRetrospective study.SettingTertiary care university hospital.ParticipantsOne hundred ninety-seven patients undergoing TAVR from 2012 to 2016 INTERVENTIONS: After Institutional Review Board approval, 197 consecutive patients undergoing TAVR from 2012 to 2016 at the authors' institution were identified for analysis and placed into groups depending on method of anesthesia received (GA: n = 139 v MS: n = 58). Groups then were compared with respect to baseline characteristics, operative details, primary outcome variables (dysphagia, pneumonia), and secondary outcome variables.Measurement and main resultsAny patient who failed the institution's postprocedure bedside swallow test subsequently underwent a fiberoptic endoscopic evaluation of swallowing test, confirming the diagnosis of dysphagia. GA patients were significantly more likely to develop dysphagia, which occurred in 10 GA patients and no MS patients (p = 0.04). MS patients also were found to have significantly reduced operative durations and spent less time in the intensive care unit and hospital (p < 0.001).ConclusionsPatients who underwent TAVR with moderate sedation were less likely to develop dysphagia. Use of MS may be particularly suitable in patients predisposed to swallowing dysfunction.

Congenital sodium diarrhea is a rare and life-threatening disorder characterized by a severe, secretory diarrhea containing high concentrations of sodium, leading to hyponatremia and metabolic acidosis. It may occur in isolation or in association with systemic features such as facial dysmorphism, choanal atresia, imperforate anus, and corneal erosions. Mutations in the serine protease inhibitor, Kunitz-Type 2 (SPINT2) gene have been associated with congenital sodium diarrhea and additional syndromic features. We present a child with congenital sodium diarrhea, cleft lip and palate, corneal erosions, optic nerve coloboma, and intermittent exotropia who was found to have biallelic mutations in SPINT2. One mutation, c.488A > G, predicting p.(Tyr163Cys), has been previously associated with a syndromic form of congenital sodium diarrhea. The other mutation, c.166_167dupTA, predicting p.(Asn57Thrfs*24) has not previously been reported and is likely a novel pathogenic variant for this disorder. We found only one other report of an optic nerve coloboma associated with SPINT2 mutations and this occurred in a patient with congenital tufting enteropathy. Our patient confirms an association of ocular coloboma with presumed loss of SPINT2 function.

Several cases of phenotypic variability among family members with mucopolysaccharidosis type II (MPS II) have been reported, but the data are limited. Data from patients enrolled in the Hunter Outcome Survey (HOS) were used to investigate intrafamilial variability in male siblings with MPS II. As of July 2015, data were available for 78 patients aged ≥5 years at last visit who had at least one affected sibling (39 sibling pairs). These patients were followed prospectively (i.e., they were alive at enrollment in HOS). The median age at the onset of signs and symptoms was the same for the elder and younger brothers (2.0 years); however, the younger brothers were typically diagnosed at a younger age than the elder brothers (median age, 2.5 and 5.1 years, respectively). Of the 39 pairs, eight pairs were classified as being discordant (the status of four or more signs and symptoms differed between the siblings); 21 pairs had one, two, or three signs and symptoms that differed between the siblings, and 10 pairs had none. Regression status of the majority of the developmental milestones studied was generally concordant among siblings. Functional classification, a measure of central nervous system involvement, was the same in 24/28 pairs, although four pairs were considered discordant as functional classification differed between the siblings. Overall, this analysis revealed similarity in the clinical manifestations of MPS II among siblings. This information should help to improve our understanding of the clinical presentation of the disease, including phenotype prediction in affected family members.

ObjectiveTo evaluate the association between racial residential segregation, a prominent manifestation of systemic racism, and the White-Black survival gap in a contemporary cohort of adults, and to assess the extent to which socioeconomic inequality explains this association.DesignThis was a cross sectional study of White and Black men and women aged 35-75 living in 102 large US Core Based Statistical Areas. The main outcome was the White-Black survival gap. We used 2009-2013 CDC mortality data for Black and White men and women to calculate age-, sex- and race adjusted White and Black mortality rates. We measured segregation using the Dissimilarity index, obtained from the Manhattan Institute. We used the 2009-2013 American Community Survey to define indicators of socioeconomic inequality. We estimated the CBSA-level White-Black gap in probability of survival using sequential linear regression models accounting for the CBSA dissimilarity index and race-specific socioeconomic indicators.ResultsBlack men and women had a 14% and 9% lower probability of survival from age 35 to 75 than their white counterparts. Residential segregation was strongly associated with the survival gap, and this relationship was partly, but not fully, explained by socioeconomic inequality. At the lowest observed level of segregation, and with the Black socioeconomic status (SES) assumed to be at the White SES level scenario, the survival gap is essentially eliminated.ConclusionWhite-Black differences in survival remain wide notwithstanding public health efforts to improve life expectancy and initiatives to reduce health disparities. Eliminating racial residential segregation and bringing Black socioeconomic status (SES) to White SES levels would eliminate the White-Black survival gap.

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs*2, and p.Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.

ImportanceOptimal management of subglottic stenosis has not been established. Endoscopic techniques include balloon dilation, radial incisions with carbon dioxide laser or cold knife, and combinations of techniques. Adjunctive measures include mitomycin application and glucocorticoid injection.ObjectiveTo determine whether surgical technique or adjunctive measures are associated with duration between surgical procedures.Design, setting, and participantsAdult patients with subglottic stenosis treated endoscopically between 1995-2015 at a quaternary academic medical center were identified. Patients with isolated subglottic (cricotracheal) stenosis 18 years and older were included. Patients with prior open surgical procedures, prior laryngeal surgical procedures, glottic stenosis, or vocal fold paralysis were excluded.InterventionsPatients underwent endoscopic procedures including laser radial incisions, balloon dilation, or both, with some patients receiving topical mitomycin, glucocorticoid injection, or both.Main outcomes and measuresTime interval between endoscopic treatments.ResultsA total of 101 patients (mean [SD] age, 52.3 [15.9] years; 77.2% female) were included in the analysis, with etiologies including idiopathic (47 [46.5%]), intubation (31 [30.7%]), granulomatosis with polyangiitis (9 [8.9%]), and other autoimmune diseases (6 [5.9%]). Among the 219 operations, both laser and balloon dilation were used in 117 (53.4%), while balloon dilation alone was used in 96 (43.8%) and laser alone in 6 (2.7%). Mitomycin application and steroid injection were used in 144 (65.8%) and 93 (42.5%) cases, respectively. Mitomycin application was associated with improvement in the mean interval to next procedure from 317 to 474 days (absolute difference, 157 days; 95% CI, 15-299 days). Advanced grade of stenosis, dilation technique, and steroid injection did not significantly alter the surgical intervals.Conclusions and relevanceEndoscopic surgery for subglottic stenosis is a critical aspect of patient management. Neither surgical technique nor grade of stenosis was seen to alter the surgical intervals. Mitomycin application was associated with an extended time interval between endoscopic treatments.

BackgroundSevere combined immunodeficiency (SCID) is characterized by arrested T-lymphocyte production and by B-lymphocyte dysfunction, which result in life-threatening infections. Early diagnosis of SCID through population-based screening of newborns can aid clinical management and help improve outcomes; it also permits the identification of previously unknown factors that are essential for lymphocyte development in humans.MethodsSCID was detected in a newborn before the onset of infections by means of screening of T-cell-receptor excision circles, a biomarker for thymic output. On confirmation of the condition, the affected infant was treated with allogeneic hematopoietic stem-cell transplantation. Exome sequencing in the patient and parents was followed by functional analysis of a prioritized candidate gene with the use of human hematopoietic stem cells and zebrafish embryos.ResultsThe infant had "leaky" SCID (i.e., a form of SCID in which a minimal degree of immune function is preserved), as well as craniofacial and dermal abnormalities and the absence of a corpus callosum; his immune deficit was fully corrected by hematopoietic stem-cell transplantation. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The resulting BCL11B protein had dominant negative activity, which abrogated the ability of wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration; this revealed a previously unknown function of BCL11B. The patient's abnormalities, when recapitulated in bcl11ba-deficient zebrafish, were reversed by ectopic expression of functionally intact human BCL11B but not mutant human BCL11B.ConclusionsNewborn screening facilitated the identification and treatment of a previously unknown cause of human SCID. Coupling exome sequencing with an evaluation of candidate genes in human hematopoietic stem cells and in zebrafish revealed that a constitutional BCL11B mutation caused human multisystem anomalies with SCID and also revealed a prethymic role for BCL11B in hematopoietic progenitors. (Funded by the National Institutes of Health and others.).

ObjectiveWhen total laryngectomy is not required, organ preservation surgery or radiotherapy is considered the standard of care for primary glottic cancer. These accepted treatment options are available for early and advanced glottic cancers due to equivalent locoregional control and survival rates. However, in today's climate of accountable care, the financial burden of treatment choices continues to increase in significance. We therefore compared hospital charges and treatment-related morbidity between organ-preserving surgery and radiation with or without chemotherapy-herein, (chemo)radiation-in the primary treatment of glottic cancer.Study designNationwide Inpatient Sample Database was analyzed to assess clinical and financial information.SettingPopulation-based analysis.SubjectsPatients (N = 5499) with primary glottic cancer undergoing treatment with laryngeal preservation strategies.MethodsPatients were subdivided by ICD-9 codes into 3 treatment groups: endoscopic resection, open partial laryngectomy, and (chemo)radiation. Treatment-related outcomes, charges, and length of hospitalization were analyzed among treatment groups.ResultsWhen adjusting for sex, age, race, comorbidity, and primary payer, (chemo)radiotherapy was associated with increased direct charges (P < .001; coefficient, $23,658.99; 95% confidence interval [95% CI]: $10,227.15-$37,090.84) and length of hospitalization (P < .001; hazard ratio, 0.593; 95% CI: 0.502-0.702) when compared with endoscopic surgery. As compared with open surgery, endoscopic surgery was associated with reduced hospital charges (P = .012; coefficient, $11,967.01; 95% CI: $2,784.17-$21,249.85) and duration of hospitalization (P < .001; hazard ratio, 0.749; 95% CI: 0.641-0.876).ConclusionsThis analysis suggests that increased utilization of endoscopic surgery in patients with primary glottic cancer not requiring total laryngectomy may lead to reduced financial burden and duration of hospitalization when compared with open surgery or (chemo)radiation therapy.

Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE Exome(TM) (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401-1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1-associated disorders described here.

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies.

Objectives/hypothesisThe direct study of human phonation is limited by the invasive and painful nature of human laryngeal neuromuscular manipulation. As a platform for the study of human phonation, indirect models have been utilized for decades such as animal, cadaveric, and computational. We sought to develop a research method allowing direct scientific control of virtually living larynges to expand our ability to understand human phonation.Study designCanine and porcine models.MethodsNineteen canine larynges were surgically removed and reperfused with progressively adapting methodologies to create ex vivo phonation.ResultsFull neuromuscular stimulation and phonation were ultimately achieved in the ex vivo larynx. As compared with alternative perfusate solutions, heparinized whole blood was found to result in the most robust neuromuscular response. Modification of the reperfusion technique from a continuous flow to a pulsatile pump system resulted in dramatic increases in neuromuscular response and longevity of the organ. The experimental findings were repeated to demonstrate reliability of the ex vivo model.ConclusionsThe ex vivo larynx model is demonstrated to be a repeatable platform for phonatory research. The process of development has been comprehensively described in the present report. Although the described experimental model was designed for phonatory research, this model can be readily adapted for investigations of organ transplant preservation techniques, effects of organ ischemia, and neuromuscular reinnervation capabilities.Level of evidenceNA.

ImportanceThis study reviews a single center's experience of performing staged laryngotracheoplasty (LTP) for the treatment of laryngotracheal stenosis with the ultimate goal of attaining long-term airway patency without restenosis.ObjectiveTo identify staged LTP as an efficacious surgical treatment option for laryngotracheal stenosis.Design, setting, and participantsFrom January 2000 to January 2012, patients at a tertiary care academic institution presenting with diagnoses of laryngeal or laryngotracheal stenosis were retrospectively identified. Medical records from adult patients were inspected, and patient demographics, clinical data, and clinical outcomes were recorded. All patients undergoing staged LTP were initially included. Patients with history of head and neck malignant neoplasm were excluded.InterventionsStaged LTP.Main outcomes and measuresThe primary outcome was long-term decannulation, defined as decannulation for duration of at least 6 months.ResultsSixty-one patients were included in this study. The mean (SD) patient age was 47.1 (16.7) at the time of first-stage LTP and had a mean (range) follow-up of 5.32 (0.5-17.3) years from the first-stage reconstruction. Etiology of stenosis included prolonged intubation in 27 patients (44%), autoimmune disease in 9 (15%), idiopathic causes in 11 (18%), blunt laryngeal trauma in 10 (16%), and other causes in 4 (7%). Forty-nine patients (80%) were successfully decannulated, while to date 12 (20%) remain tracheostomy or tympanostomy tube dependent. Univariate analyses showed no significant association between decannulation and age (P = .35), sex (P = .52), history of intubation (P = .22), surgeon (P = .20), etiology of stenosis (P = .91), or length of stenosis (P = .31). Multivariate logistic regression analysis showed a significant inverse relationship between grade of stenosis and probability of decannulation (P = .01).Conclusions and relevanceStaged LTP is an option for the reconstruction laryngotracheal stenosis. Our experience shows excellent decannulation rates in the selected patients with stenosis, many of whom have failed treatment with other surgical modalities.

BackgroundPreliminary case series have reported clinical feasibility and safety of a transoral minimally invasive technique to approach parapharyngeal space masses. With the assistance of the surgical robotic system, tumors within the parapharyngeal space can now be excised safely without neck incisions. A detailed technical description is included.MethodsAfter developing compressive symptoms from a parapharyngeal space lipomatous tumor, the patient was referred by his primary otolaryngologist because of poor open surgical access to the nasopharyngeal component of the tumor.ResultsTransoral robotic assisted resection of a 54- × 46-mm parapharyngeal space mass was performed, utilizing 97 minutes of robotic surgical time. Pictorial demonstration of the robotic resection is provided.ConclusionParapharyngeal space tumors have traditionally been approached via transcervical skin incisions, typically including blunt dissection from tactile feedback. The transoral robotic approach offers magnified 3D visualization of the parapharyngeal space that allows for complete and safe resection.

Background and objectiveSurvival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.MethodsWe analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).ResultsIn the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10(-7)), rs981621 (p=1.65×10(-7)) and rs16861827 (p=3.75×10(-7)), respectively. 131 SNPs with p≤10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis.ConclusionsGermline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

Through bound apolipoprotein A-I (apoA-I), high-density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD) have low apoA-I and endothelial dysfunction, we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C and improves vascular function in SCD. Twenty-seven patients with SCD with levels of HDL-C

ObjectiveAlthough high-speed imaging (HSI) has been identified as a valuable tool in phonatory biomechanics research, to date, there have only been a selected number of reports investigating the clinical utility of HSI. We aim to elucidate the role of HSI in the diagnosis of the dysphonic patient.MethodsThe video files from 28 consecutive dysphonic patients with concurrently acquired videostroboscopy and HSI were retrospectively collected. Stroboscopy video files were edited to include vibratory motion only. Videos were then anonymously and randomly presented to four academic laryngologists. Experts were asked to assign a single best diagnosis for each video file. Assigned diagnoses were then compared with treatment diagnoses conferred based on medical history, phonatory evaluation, laryngeal examination, and response to treatment.ResultsInterrater analysis for the four laryngologists demonstrated significant and meaningful correlations for the diagnoses of polyps, cysts, nodules, and normal examination using stroboscopy (kappa > 0.40, P < 0.001). The experts demonstrated significant and meaningful correlations for the diagnoses of polyps, presbyphonia, and normal examination using HSI (kappa > 0.40, P < 0.001). Combined intrarater analysis performed by comparing single rater's diagnosis for single patient across both modalities resulted in poor correlation without statistical significance (kappa = 0.30, P = 0.07). Both stroboscopy- and HSI-assigned diagnoses matched the treatment diagnoses at equal predicted frequencies (32.3%), as demonstrated through multivariate logistic regression analysis (P < 0.001).ConclusionOverall, HSI did not improve the diagnostic accuracy above stroboscopy alone. Although specific laryngeal states such as presbyphonia may be better diagnosed with HSI, further studies are required to define HSI's precise role in the clinical setting.

PurposeDiabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).MethodsThe pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (

The literature has consistently reported no association between low to moderate alcohol consumption and pancreatic cancer; however, a few studies have shown that high levels of intake may increase risk. Most single studies have limited power to detect associations even in the highest alcohol intake categories or to examine associations by alcohol type. We analyzed these associations using 1,530 pancreatic cancer cases and 1,530 controls from the Pancreatic Cancer Cohort Consortium (PanScan) nested case-control study. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression, adjusting for potential confounders. We observed no significant overall association between total alcohol (ethanol) intake and pancreatic cancer risk (OR = 1.38, 95% CI = 0.86-2.23, for 60 or more g/day vs. >0 to

BackgroundObesity has been proposed as a risk factor for pancreatic cancer.MethodsPooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, or = 35.0). Models were adjusted for potential confounders.ResultsIn all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile, 1.33; 95% CI, 1.12-1.58; P(trend) < .001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% CI, 1.04-1.69; P(trend) < .03), and in women it was 1.34 (95% CI, 1.05-1.70; P(trend) = .01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% CI, 1.31-2.69; P(trend) = .003) but less so in men.ConclusionsThese findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women.

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Smoking is an established risk factor for pancreatic cancer; however, detailed examination of the association of smoking intensity, smoking duration, and cumulative smoking dose with pancreatic cancer is limited. The authors analyzed pooled data from the international Pancreatic Cancer Cohort Consortium nested case-control study (1,481 cases, 1,539 controls). Odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression. Smoking intensity effects were examined with an excess odds ratio model that was linear in pack-years and exponential in cigarettes smoked per day and its square. When compared with never smokers, current smokers had a significantly elevated risk (odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.38, 2.26). Risk increased significantly with greater intensity (> or =30 cigarettes/day: OR = 1.75, 95% CI: 1.27, 2.42), duration (> or =50 years: OR = 2.13, 95% CI: 1.25, 3.62), and cumulative smoking dose (> or =40 pack-years: OR = 1.78, 95% CI: 1.35, 2.34). Risk more than 15 years after smoking cessation was similar to that for never smokers. Estimates of excess odds ratio per pack-year declined with increasing intensity, suggesting greater risk for total exposure delivered at lower intensity for longer duration than for higher intensity for shorter duration. This finding and the decline in risk after smoking cessation suggest that smoking has a late-stage effect on pancreatic carcinogenesis.