Novel genotype-phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37.

Spinocerebellar ataxia subtype 37 (SCA37) is a rare disease originally identified in ataxia patients from the Iberian Peninsula with a pure cerebellar syndrome. SCA37 patients carry a pathogenic intronic (ATTTC)n repeat insertion flanked by two polymorphic (ATTTT)n repeats in the Disabled-1 (DAB1) gene leading to cerebellar dysregulation. Herein, we determine the precise configuration of the pathogenic 5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n SCA37 alleles by CRISPR-Cas9 and long-read nanopore sequencing, reveal their epigenomic signatures in SCA37 lymphocytes, fibroblasts, and cerebellar samples, and establish new molecular and clinical correlations. The 5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n pathogenic allele configurations revealed repeat instability and differential methylation signatures. Disease age of onset negatively correlated with the (ATTTC)n, and positively correlated with the 3'(ATTTT)n. Geographic origin and gender significantly correlated with age of onset. Furthermore, significant predictive regression models were obtained by machine learning for age of onset and disease evolution by considering gender, the (ATTTC)n, the 3'(ATTTT)n, and seven CpG positions differentially methylated in SCA37 cerebellum. A common 964-kb genomic region spanning the (ATTTC)n insertion was identified in all SCA37 patients analysed from Portugal and Spain, evidencing a common origin of the SCA37 mutation in the Iberian Peninsula originating 859 years ago (95% CI 647-1378). In conclusion, we demonstrate an accurate determination of the size and configuration of the regulatory 5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n repeat tract, avoiding PCR bias amplification using CRISPR/Cas9-enrichment and nanopore long-read sequencing, resulting relevant for accurate genetic diagnosis of SCA37. Moreover, we determine novel significant genotype-phenotype correlations in SCA37 and identify differential cerebellar allele-specific methylation signatures that may underlie DAB1 pathogenic dysregulation.

Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage.

Machado-Joseph disease (MJD/SCA3) is the most frequent dominant ataxia worldwide. It is caused by a (CAG)n expansion. MJD has two major ancestral backgrounds: the Machado lineage, found mainly in Portuguese families; and the Joseph lineage, present in all five continents, probably originating in Asia. MJD has been described in a few African and African-American families, but here we report the first diagnosed in Sudan to our knowledge. The proband presented with gait ataxia at age 24; followed by muscle cramps and spasticity, and dysarthria, by age 26; he was wheel-chair bound at 29 years of age. His brother had gait problems from age 20 years and, by age 21, lost the ability to run, showed dysarthria and muscle cramps. To assess the mutational origin of this family, we genotyped 30 SNPs and 7 STRs flanking the ATXN3_CAG repeat in three siblings and the non-transmitting father. We compared the MJD haplotype segregating in the family with our cohort of MJD families from diverse populations. Unlike all other known families of African origin, the Machado lineage was observed in Sudan, being shared with 86 Portuguese, 2 Spanish and 2 North-American families. The STR-based haplotype of Sudanese patients, however, was distinct, being four steps (2 STR mutations and 2 recombinations) away from the founder haplotype shared by 47 families, all of Portuguese extraction. Based on the phylogenetic network constructed with all MJD families of the Machado lineage, we estimated a common ancestry at 3211 ± 693 years ago.

Structured training program on confocal laser endomicroscopy for pancreatic cystic lesions: a multicenter prospective study among early-career endosonographers (with video).

BACKGROUND AND AIMS: Data on how to teach endosonographers needle-based confocal laser endomicroscopy (nCLE)-guided histologic diagnosis of pancreatic cystic lesions (PCLs) are limited. Hence, we developed and tested a structured educational program to train early-career endosonographers in nCLE-guided diagnosis of PCLs. METHODS: Twenty-one early-career nCLE-naïve endosonographers watched a teaching module outlining nCLE criteria for diagnosing PCLs. Participants then reviewed 80 high-yield nCLE videos, recorded diagnoses, and received expert feedback (phase 1). Observers were then randomized to a refresher feedback session or self-learning at 4 weeks. Eight weeks after training, participants independently assessed the same 80 nCLE videos without feedback and provided histologic predictions (phase 2). Diagnostic performance of nCLE to differentiate mucinous versus nonmucinous PCLs and to diagnose specific subtypes were analyzed using histopathology as the criterion standard. Learning curves were determined using cumulative sum analysis. RESULTS: Accuracy and diagnostic confidence for differentiating mucinous versus nonmucinous PCLs improved as endosonographers progressed through nCLE videos in phase 1 (P < .001). Similar trends were observed with the diagnosis of PCL subtypes. Most participants achieved competency interpreting nCLE, requiring a median of 38 assessments (range, 9-67). During phase 2, participants independently differentiated PCLs with high accuracy (89%), high confidence (83%), and substantial interobserver agreement (κ = .63). Accuracy for nCLE-guided PCL subtype diagnoses ranged from 82% to 96%. The learned nCLE skills did not deteriorate at 8 weeks and were not impacted by a refresher session. CONCLUSIONS: We developed a practical, effective, and durable educational intervention to train early-career endosonographers in nCLE-guided diagnosis of PCLs.

Endoscopic Retrograde Cholangiopancreatography Performed by Trainees Is Not Associated with Increased Immediate Adverse Events or Technical Failure Rates.

BACKGROUND/AIM: Training endoscopists to perform endoscopic retrograde cholangiopancreatography (ERCP) is critical to address the increasing patient population with pancreatobiliary diseases. Concerns remain about ERCP safety and success involving trainees. We compared the technical success and immediate adverse events between ERCP with and without trainee involvement. METHODS: Retrospective analysis of 28,271 ERCP procedures in a national sample of the United States over 12 years. Demographics, procedure and fluoroscopy time, visualization and cannulation of main structures, adverse events, and technical success rates were compared between ERCP with and without trainees. Categorical variables were compared using Pearson's chi-square test and continuous variables using a standard t-test. Univariate and multivariate regressions were performed adjusting for age, gender, ethnicity, US region, ASA class and clinical setting. RESULTS: Approximately 49.5% of ERCPs had a trainee involved. The ampulla was visualized in 97.4% with trainee vs. 97.3% without trainee involvement (P = 0.858). The common bile duct was visualized and cannulated in 90.4% with trainees vs. 91.7% without trainees involved (P < 0.001). The ERCP was incomplete in 5.9% of cases with trainees vs. 6.4% without trainees involved (P = 0.207). Trainee participation added 8.7 min to average procedure time (aOR: 1.02, P < 0.001) and 2.0 min to fluoroscopy time (aOR: 1.00, P = 0.796). Adverse events (aOR: 0.89, P = 0.704) and technical success (aOR: 0.83, P = 0.571) were similar in both groups. CONCLUSIONS: Trainee involvement leads to increased procedure duration but is not associated with increased immediate adverse events, or technical failure. Our study supports ERCP safety and success with trainee participation.

Model and Methodology to Characterize Phosphor-Based White LED Visible Light Communication Links.

LED lighting has become the standard solution for illumination purposes thanks to its energy efficiency. Nowadays, there is growing interest in the use of LEDs for data transmission to develop future-generation communication systems. The low cost and widespread deployment of phosphor-based white LEDs make them the best candidate for visible light communications (VLC), although they have a limited modulation bandwidth. This paper presents a simulation model of a VLC link based on phosphor-based white LEDs and a method to characterize the VLC setup used to perform the data transmission experiments. Specifically, the simulation model incorporates the frequency response of the LED, the noise levels coming from the lighting source and the acquisition electronics, and the attenuation due to both the propagation channel and the angular misalignment between the lighting source and the photoreceiver. In order to validate the suitability of the model for VLC, carrierless amplitude phase (CAP) and orthogonal frequency division multiplexing (OFDM) modulation signals were employed for data transmission, and simulations with the proposed model and measurements over the equivalent scenario show high agreement.

Histone H4 acetylation is dysregulated in active seminiferous tubules adjacent to testicular tumours.

STUDY QUESTION: Is histone H4 acetylation (H4ac) altered in the seminiferous tubules of patients affected by testicular tumours? SUMMARY ANSWER: A considerable dysregulation of H4ac was detected in the cells of the seminiferous tubules adjacent to testicular tumours of different aetiology and prior to any treatment, while no comparable alterations were observed in patients with disrupted spermatogenesis. WHAT IS KNOWN ALREADY: Altered H4ac levels have been associated with a variety of testicular pathological conditions. However, no information has been available regarding potential alterations in the spermatogenic cells adjacent to the neoplasia in testicular tumour patients. STUDY DESIGN, SIZE, DURATION: A retrospective analysis using testicular sections from 33 men aged between 21 and 74 years old was performed. Three study groups were defined and subjected to double-blind evaluation: a control group with normal spermatogenesis (n = 6), patients with testicular tumours (n = 18) and patients with spermatogenic impairments (n = 8). One additional sample with normal spermatogenesis was used as a technical internal control in all evaluations. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunohistochemistry against H4ac and, when needed, Placental-like alkaline phosphatase and CD117, was performed on testicular sections. The H4ac H-score, based on the percentage of detection and signal intensity, was used as the scoring method for statistical analyses. Protein expression data from the Human Protein Atlas were used to compare the expression levels of predicted secreted proteins from testicular tumours with those present in the normal tissue. MAIN RESULTS AND THE ROLE OF CHANCE: We revealed, for the first time, a dramatic disruption of the spermatogenic H4ac pattern in unaffected seminiferous tubule cells from different testicular tumour patients prior to any antineoplastic treatment, as compared to controls (P < 0.05). Since no similar alterations were associated with spermatogenic impairments and the in silico analysis revealed proteins potentially secreted by the tumour to the testicular stroma, we propose a potential paracrine effect of the neoplasia as a mechanistic hypothesis for this dysregulation. LIMITATIONS, REASONS FOR CAUTION: Statistical analyses were not performed on the hypospermatogenesis and Leydig cell tumour groups due to limited availability of samples. WIDER IMPLICATIONS OF THE FINDINGS: To the best of our knowledge, this is the first report showing an epigenetic alteration in cells from active seminiferous tubules adjacent to tumour cells in testicular tumour patients. Our results suggest that, despite presenting spermatogenic activity, the global epigenetic dysregulation found in the testicular tumour patients could lead to molecular alterations of the male germ cells. Since testicular tumours are normally diagnosed in men at reproductive age, H4ac alterations might have an impact when these testicular tumour patients express a desire for fatherhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the European Union Marie Curie European Training Network actions and by grants to R.O. from the 'Ministerio de Economía y Competividad (Spain)' (fondos FEDER 'una manera de hacer Europa', PI13/00699, PI16/00346 and PI20/00936) and from EU-FP7-PEOPLE-2011-ITN289880. J.C. was supported by the Sara Borrell Postdoctoral Fellowship, Acción Estratégica en Salud, CD17/00109. J.C. is a Serra Húnter fellow (Universitat de Barcelona, Generalitat de Catalunya). F.B. has received grants from the Ministerio de Educación, Cultura y Deporte para la Formación de Profesorado Universitario (Spain) (FPU15/02306). A.d.l.I. is supported by a fellowship of the Ministerio de Economía, Industria y Competitividad (Spain) (PFIS, FI17/00224). M.J. is supported by the Government of Catalonia (Generalitat de Catalunya, pla estratègic de recerca i innovació en salut, PERIS 2016-2020, SLT002/16/00337). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Assessment of automatic decision-support systems for detecting active T2 lesions in multiple sclerosis patients.

BACKGROUND: Active (new/enlarging) T2 lesion counts are routinely used in the clinical management of multiple sclerosis. Thus, automated tools able to accurately identify active T2 lesions would be of high interest to neuroradiologists for assisting in their clinical activity. OBJECTIVE: To compare the accuracy in detecting active T2 lesions and of radiologically active patients based on different visual and automated methods. METHODS: One hundred multiple sclerosis patients underwent two magnetic resonance imaging examinations within 12 months. Four approaches were assessed for detecting active T2 lesions: (1) conventional neuroradiological reports; (2) prospective visual analyses performed by an expert; (3) automated unsupervised tool; and (4) supervised convolutional neural network. As a gold standard, a reference outcome was created by the consensus of two observers. RESULTS: The automated methods detected a higher number of active T2 lesions, and a higher number of active patients, but a higher number of false-positive active patients than visual methods. The convolutional neural network model was more sensitive in detecting active T2 lesions and active patients than the other automated method. CONCLUSION: Automated convolutional neural network models show potential as an aid to neuroradiological assessment in clinical practice, although visual supervision of the outcomes is still required.

Assessment of 2D conventional and synthetic MRI in multiple sclerosis.

PURPOSE: To qualitatively and quantitatively compare synthetic and conventional MRI sequences acquired on a 1.5-T system for patients with multiple sclerosis (MS). METHODS: Prospective study that involved twenty-seven consecutive relapsing-remitting MS patients scanned on a 1.5-T MRI scanner. The MRI protocol included 2D transverse conventional spin-echo sequences: proton density-weighted (PD), T2-weighted, T2-FLAIR, and T1-weighted. Synthetic images were generated using 2D transverse QRAPMASTER and SyMRI software with the same voxel size, repetition, echo, and inversion times as the conventional sequences. Four raters performed a crosstab qualitative analysis that involved evaluating global image quality, contrast, flow artefacts, and confidence in lesion assessment introducing the concepts of predominance, agreement, and disagreement. A quantitative analysis was also performed and included evaluating the number of lesions (periventricular, juxtacortical, brainstem, and cerebellum) and the contrast-to-noise ratio between regions (CSF, white matter, grey matter, lesions). RESULTS: The global image quality assessment showed predominance for better scores for conventional sequences over synthetic sequences, whereas contrast, confidence in lesion assessment, and flow artefacts showed predominance for agreement between sequences. There was predominance for disagreement between all pairs of raters in most of the evaluated qualitative parameters. Synthetic PD and T2-FLAIR images showed higher contrast-to-noise ratios than the corresponding conventional images for most comparison between regions. There were no significant differences in the number of lesions detected for most of the study regions between conventional and synthetic images. CONCLUSION: Synthetic MRI can be potentially used as an alternative to conventional brain MRI sequences in the assessment of MS.

Pancreatic Disorders in Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) can involve multiple organ systems, and pancreatic manifestations of IBD are not uncommon. The incidence of several pancreatic diseases is more frequent in patients with Crohn's disease and ulcerative colitis than in the general population. Pancreatic manifestations in IBD include a heterogeneous group of disorders and abnormalities ranging from mild, self-limited disorders to severe diseases. Asymptomatic elevation of amylase and/or lipase is common. The risk of acute pancreatitis in patients with IBD is increased due to the higher incidence of cholelithiasis and drug-induced pancreatitis in this population. Patients with IBD commonly have altered pancreatic histology and chronic pancreatic exocrine dysfunction. Diagnosing acute pancreatitis in patients with IBD is challenging. In this review, we discuss the manifestations and possible causes of pancreatic abnormalities in patients with IBD.

H4K5 Butyrylation Coexist with Acetylation during Human Spermiogenesis and Are Retained in the Mature Sperm Chromatin.

Male germ cells experience a drastic chromatin remodeling through the nucleo-histone to nucleo-protamine (NH-NP) transition necessary for proper sperm functionality. Post-translational modifications (PTMs) of H4 Lys5, such as acetylation (H4K5ac), play a crucial role in epigenetic control of nucleosome disassembly facilitating protamine incorporation into paternal DNA. It has been shown that butyrylation on the same residue (H4K5bu) participates in temporal regulation of NH-NP transition in mice, delaying the bromodomain testis specific protein (BRDT)-dependent nucleosome disassembly and potentially marking retained nucleosomes. However, no information was available so far on this modification in human sperm. Here, we report a dual behavior of H4K5bu and H4K5ac in human normal spermatogenesis, suggesting a specific role of H4K5bu during spermatid elongation, coexisting with H4K5ac although with different starting points. This pattern is stable under different testicular pathologies, suggesting a highly conserved function of these modifications. Despite a drastic decrease of both PTMs in condensed spermatids, they are retained in ejaculated sperm, with 30% of non-colocalizing nucleosome clusters, which could reflect differential paternal genome retention. Whereas no apparent effect of these PTMs was observed associated with sperm quality, their presence in mature sperm could entail a potential role in the zygote.

The Increasing Proportion of Early-Stage Pancreatic Cancer between 2004-2013: A SEER Analysis.

Pancreatic cancer will become the second leading cause of cancer-related death in the United States by 2030. Survival improves when it is identified at an early-stage and resected. Increasing public attention and cross-section imaging may shift detection to earlier stages. We found a small total increase in the proportion of stage-I cancer relative to all stages and a significant increase compared to distant disease in the Surveillance, Epidemiology, and End Results (SEER) database. Despite this, our ability to screen and identify early-stage disease is still lacking. Additional research and population-based interventions are necessary to improve early detection.

Thirty-Day Readmission Among Patients with Alcoholic Acute Pancreatitis.

BACKGROUND/OBJECTIVES: Alcoholic acute pancreatitis (AAP) comprises the second most common cause of acute pancreatitis in the USA, and there is lack of data regarding 30-day specific readmission causes and predictors. We aim to identify 30-day readmission rate, causes, and predictors of readmission. METHODS: Retrospective analysis of the 2016 National Readmission Database of adult patients readmitted within 30 days after an index admission for AAP. RESULTS: Totally, 76,609 AAP patients were discharged from the hospital in 2016. The 30-day readmission rate was 12%. The main cause of readmission was another episode of AAP. Readmission was not associated with higher mortality (1.3% vs. 1.2%; P = 0.21) or prolonged length of stay (5.2 vs. 5.0 days; P = 0.06). The total health care economic burden was $354 million in charges and $90 million in costs. Independent predictors of readmission were having Medicaid insurance, a Charlson comorbidity index score ≥ 3, use of total parenteral nutrition, opioid abuse disorder, prior pancreatic cyst, chronic alcoholic pancreatitis, and other chronic pancreatitis. Obesity was associated with lower odds of readmission. CONCLUSION: Readmission rate for AAP is high and its primary cause are recurrent episodes of AAP. Alcohol and substance abuse pose a high burden on our health care system. Public health strategies should be targeted to provide alcohol abuse disorder rehabilitation and cessation resources to alleviate the burden on readmission, the health care system and to improve patient outcomes.

Feasibility Study of a Docosahexaenoic Acid-Optimized Nutraceutical Formulation on the Macular Levels of Lutein in a Healthy Mediterranean Population.

INTRODUCTION: Macular pigment optical density (MPOD) plays a pivotal role in maintaining macular structure and functioning. Research shows that daily consumption of lutein reduces the risk of eye diseases such as age-related macular degeneration. OBJECTIVE: This study analyzes the influence of a supplementation containing lutein and antioxidant vitamins either with or without docosahexaenoic acid (DHA), with the main objective of identifying MPOD changes in both eyes at the end of the follow-up using the Visucam®retinograph. The secondary end point was to determine variation in the lutein and DHA levels in plasma and red blood cell membranes (RBCMs), respectively. METHODS: One hundred healthy participants (200 eyes) aged 40-70 years (mean age 49.3 years, SEM = 13.7) were randomized in a 1:1 ratio to receive daily one of the following supplements for 3 months: lutein group (LT-G, n = 49) and lutein plus DHA group (LT/DHA-G, n = 51). The MPOD was measured at baseline and end of the follow-up by retinography (Visucam®retinograph). Lutein in plasma was determined by HPLC, and DHA in RBC membranes was analyzed by gas chromatograph/mass spectrometer. RESULTS: From baseline, MPOD showed significantly higher values in the LT/DHA-G than in the LT-G at the end of the study (p < 0.0001). Significantly higher lutein in plasma (p < 0.0001) and DHA (p < 0.0001) levels in the RBC membrane were seen in the LT/DHA-G than in the LT-G at the 3-month follow-up. CONCLUSION: Lutein supplementation improves MPOD in healthy subjects from a Mediterranean population being significantly increased in the presence of DHA. Therefore, our findings highlight the relevance of the adjunctive role of DHA for better lutein availability.

Increased Incidence and Mortality of Gastric Cancer in Immigrant Populations from High to Low Regions of Incidence: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Gastric cancer is the leading cause of infection-related cancer death and the third-leading cause of cancer death worldwide. The effect of immigration on gastric cancer risk is not well-defined but might be helpful for screening or surveillance endeavors. We performed a systematic review and meta-analysis to define the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions (including Western Europe, Australia, Brazil, Canada, Israel, and the United States). METHODS: We searched MEDLINE and EMBASE databases, from January 1980 to January 2019, for studies that identified immigrants from high-incidence regions of gastric cancer, provided clear definitions of immigrant and reference populations, and provided sufficient data to calculate gastric cancer incidence and gastric cancer-related mortality. We performed meta-analyses of standardized incidence ratios (SIR) for first-generation immigrants from high- to low-incidence regions, stratified by immigrant generation, sex, and anatomic and histologic subtype, when data were available. RESULTS: We identified 38 cohort studies that met our inclusion criteria. All 13 studies of 21 distinct populations reported significantly increased SIRs for gastric cancer in first-generation foreign-born immigrants (men SIR range, 1.24-4.50 and women SIR range, 1.27-5.05). The pooled SIR for immigrants with all types of gastric cancer was 1.66 (95% CI, 1.52-1.80) for men and 1.83 (95% CI, 1.69-1.98) for women. Nine studies from 2 high-incidence populations (the former Soviet Union and Japan) reported an increased gastric cancer standardized mortality ratio in first-generation immigrants who migrated to regions of low incidence (former Soviet Union immigrants, 1.44-1.91 for men and 1.40-2.56 for women). CONCLUSIONS: Immigrants from regions with a high incidence of gastric cancer to regions of low incidence maintain a higher risk of gastric cancer and related mortality, based on a comprehensive systematic review and meta-analysis. Assessment of immigrant generation along with other risk factors might help identify high-risk populations for prevention and therapeutic interventions.

COVID-19 polymerase chain reaction testing before endoscopy: an economic analysis.

BACKGROUND AND AIMS: The novel coronavirus disease 2019 (COVID-19) pandemic has limited endoscopy utilization, causing significant health and economic losses. We aim to model the impact of polymerase chain reaction (PCR) testing into resuming endoscopy practice. METHODS: We performed a retrospective review of endoscopy utilization during the COVID-19 pandemic for a baseline reference. A computer model compared 3 approaches: strategy 1, endoscopy for urgent indications only; strategy 2, testing for semiurgent indications; and strategy 3, testing all patients. Analysis was made under current COVID-19 prevalence and projected prevalence of 5% and 10%. Primary outcomes were number of procedures performed and/or canceled. Secondary outcomes were direct costs, reimbursement, personal protective equipment used, and personnel infected. Disease prevalence, testing accuracy, and costs were obtained from the literature. RESULTS: During the COVID-19 pandemic, endoscopy volume was 12.7% of expected. Strategies 2 and 3 were safe and effective interventions to resume endoscopy in semiurgent and elective cases. Investing 22 U.S. dollars (USD) and 105 USD in testing per patient allowed the completion of 19.4% and 95.3% of baseline endoscopies, respectively. False-negative results were seen after testing 4700 patients (or 3 months of applying strategy 2 in our practice). Implementing PCR testing over 1 week in the United States would require 13 and 64 million USD, with a return of 165 and 767 million USD to providers, leaving 65 and 325 healthcare workers infected. CONCLUSIONS: PCR testing is an effective strategy to restart endoscopic practice in the United States. PCR screening should be implemented during the second phase of the pandemic, once the healthcare system is able to test and isolate all suspected COVID-19 cases.

A novel SGCE variant is associated with myoclonus-dystonia with phenotypic variability.

Myoclonus-dystonia associated with epsilon-sarcoglycan gene (SGCE) is a rare disorder characterized by myoclonus involving the upper body (neck, trunk, upper limbs) and proximal muscles associated with dystonia in more than half of the patients. When the clinical picture is clearly identified, more than half of the cases are associated with mutations in the SGCE gene. We herein describe a family with myoclonus-dystonia associated with a novel mutation in exon 7 of SGCE, c.904A>T (p.Lys302Ter) [Chr7:(GRCh38):g.94600779 T>A], which was absent in a non-affected member. A video recording of two of the affected members is provided. While the index case presents a severe cervical dystonia even affecting back posture, his sibling shows a much milder phenotype with mild myoclonic jerks. None of them had alcohol responsiveness or psychiatric comorbidity.

Diagnostic Yield From Screening Asymptomatic Individuals at High Risk for Pancreatic Cancer: A Meta-analysis of Cohort Studies.

BACKGROUND & AIMS: There have been few studies of abdominal imaging screening of individuals at high risk for pancreatic cancer (based on family history or genetic variants). We performed a meta-analysis of prospective cohort studies to determine the diagnostic yield and outcomes of abdominal imaging screening for asymptomatic individuals at high risk. METHODS: Through a systematic review of multiple electronic databases and conference proceedings through July 2017, we identified prospective cohort studies (>20 patients) of asymptomatic adults determined to be at high-risk of pancreatic cancer (lifetime risk >5%, including specific genetic-associated conditions) who were screened by endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) to detect pancreatic lesions. Our primary outcome was identification of high-risk pancreatic lesions (high-grade pancreatic intraepithelial neoplasia, high-grade dysplasia, or adenocarcinoma) at initial screening, and overall incidence during follow up. Summary estimates were reported as incidence rates per 100 patient-years. RESULTS: We identified 19 studies comprising 7085 individuals at high risk for pancreatic cancer; of these, 1660 patients were evaluated by EUS and/or MRI. Fifty-nine high-risk lesions were identified (43 adenocarcinomas: 28 during the initial exam and 15 during follow-up surveillance) and 257 patients underwent pancreatic surgery. Based on our meta-analysis, the overall diagnostic yield screening for high-risk pancreatic lesions was 0.74 (95% CI, 0.33-1.14), with moderate heterogeneity among studies. The number needed to screen to identify 1 patient with a high-risk lesion was 135 (95% CI, 88-303). The diagnostic yield was similar for patients with different genetic features that increased risk, and whether patients were screened by EUS or MRI. CONCLUSIONS: Based on meta-analysis, 135 patients at high-risk for pancreatic cancer must be screened to identify 1 patient with a high-risk pancreatic lesion. Further studies are needed to determine whether screening reduces mortality and is cost effectiveness for individuals at high-risk of pancreatic cancer.

Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders.

BACKGROUND: Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations. METHODS: Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. RESULTS: Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. CONCLUSIONS: Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.

Esophageal Food Impaction: Causes, Elective Intubation, and Associated Adverse Events.

GOALS: The goal of this study is to examine the causes, type of adverse events (AE), and effects of elective intubation in outcomes associated with esophageal food impaction (EFI). BACKGROUND: EFI is a gastrointestinal emergency requiring immediate medical attention. STUDY: Retrospective review of all EFI cases presenting at 3 large tertiary centers from October 1, 2011 to October 31, 2014 and all cases registered in the Clinical Outcome Research Initiative (CORI) database from January 1, 2000 to December 31, 2012. Statistical analysis compared health care utilization, AEs, and outcomes in patients with or without elective intubation. RESULTS: A total of 214 cases presenting with EFI at our 3 referral hospitals and 4950 cases in the CORI database met inclusion criteria. Prevalence of structural disorders was similar in the Mayo Clinic and CORI datasets: 24.3% and 27.7% had strictures, and 3.8% and 2.5% had a tumor, respectively. AEs in the nonintubation group were 14.7% compared with 33.3% in the elective intubation group (P=0.003); however, 71.0% of these events were associated with EFI itself and not therapeutic procedure. Esophageal AEs were common (15.0%), followed by pulmonary and cardiovascular events with 3.0% and 1.4%, respectively. Severity of the AEs was influenced by the impaction-to-endoscopy time. CONCLUSIONS: Prevalence of structural esophageal disorders was similar to previous smaller studies. Elective intubation was associated with increased AEs; however, this is felt to be because of the nature of EFI itself and not by therapeutic endoscopy. Prolonged impaction-to-endoscopy time was associated with severe AEs.