Diagnostic Protocol for Detecting Otosclerosis on High-Resolution Temporal Bone CT.

OBJECTIVES: To present a systematic checklist to improve diagnosing otosclerosis (OS) on high-resolution computed tomography (HRCT) of the temporal bones and review this protocol's efficacy in diagnosing OS on HRCT. METHODS: A retrospective case series was performed at a University Referral Hospital in urban Chicago, Illinois. High-resolution computed tomographies of the temporal bone were reviewed including 17 ears in the test group with surgically confirmed OS and 21 ears in the control group surgically confirmed to not have OS. Preoperative HRCTs were evaluated by a single neuroradiologist using a systematic protocol created to assist in diagnosing OS. This looked for radiolucency at the fissula ante fenestram and pericochlear region, and new bone formation around the oval and round windows. RESULTS: The radiologist accurately diagnosed OS in all 17 test group ears and ruled out OS in all 21 control group ears using the protocol. All 17 test ears were read to have lucency at the fissula ante fenestram, 9 (53.0%) to have new bone formation, and 8 (47.1%) to have cochlear lucency. The radiologist was more confident in diagnosing OS when cochlear lucency was present with the fissula ante fenestram lucency. CONCLUSIONS: This HRCT checklist is a highly accurate tool for evaluating the presence of OS when images are reviewed in the systematic fashion described. Imaging prior to surgery aids in counseling patients, preparing surgically, and excluding other pathologies.

Differences in management outcome for first branchial cleft anomalies: A comparison of infants and toddlers to older children.

OBJECTIVE: First branchial cleft anomalies (FBCAs) are rare and often misdiagnosed, which can delay proper management and increase surgical risks. Complete excision often requires parotidectomy with facial nerve dissection. The literature reports that younger patients more often have lesions deep to the nerve with higher rates of nerve injury. We hypothesized that the rate of nerve injury and complications in children with FBCAs was not different in those ≤2 years of age compared to those >2 years of age. METHODS: Retrospective review of pediatric patients who underwent resection of histopathologically confirmed FBCAs between 2007 and 2017 at a tertiary care, pediatric hospital. Presenting symptoms, lesion classification, prior procedures, imaging techniques, extent of surgery performed, facial nerve position, and complications were reviewed and compared between patients ≤2 years of age and >2 years of age at time of surgery. RESULTS: 43 cases of FBCAs were included in the study: 12 in the younger group and 31 in the older group. There was no difference between groups regarding the presenting symptoms, gender breakdown, lesion classification, prior procedures performed, or extent of surgery. Lesions were more commonly deep to or running between branches of the facial nerve in the younger group (33.3% vs 9.7%, p = .0496). Rates of postoperative complications and facial nerve weakness were comparable between the younger and older groups (8.3% vs 25.8%, p = .206; 25.0% vs 16.1%, p = .503). In combining the age groups, FBCAs located deep to the facial nerve had increased risk of nerve weakness postoperatively (RR 7.2) and those with a history of prior incision and drainage or resection had increased risk of postoperative complications (RR 2.36). Imaging was obtained on all subjects with accuracy rates of 80-100%. CONCLUSION: Presenting characteristics of FBCAs in patients ≤2 years of age and >2 years of age are comparable, but lesions in younger subjects had a greater likelihood of being deep to or coursing between branches of the facial nerve. However, the rates of facial nerve injury and postoperative complications are comparable in younger and older children, owing likely to accurate preoperative imaging and appropriate surgical planning.

Genome-wide Significance Thresholds for Admixture Mapping Studies.

Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Based on this framework, we develop an analytical approach for obtaining genome-wide significance thresholds for admixture mapping studies. We validate our approach via analysis of simulated traits with real genotype data for 8,064 unrelated African American and 3,425 Hispanic/Latina women from the Women's Health Initiative SNP Health Association Resource (WHI SHARe). In an application to these WHI SHARe data, our approach yields genome-wide significant p value thresholds of 2.1 × 10-5 and 4.5 × 10-6 for admixture mapping studies in the African American and Hispanic/Latina cohorts, respectively. Compared to other commonly used multiple testing correction procedures, our method is fast, easy to implement (using our publicly available R package), and controls the family-wise error rate even in structured populations. Importantly, we note that the appropriate admixture mapping significance threshold depends on the number of ancestral populations, generations since admixture, and population structure of the sample; as a result, significance thresholds are not, in general, transferable across studies.

Admixture Mapping Identifies an Amerindian Ancestry Locus Associated with Albuminuria in Hispanics in the United States.

Increased urine albumin excretion is highly prevalent in Hispanics/Latinos. Previous studies have found an association between urine albumin excretion and Amerindian ancestry in Hispanic/Latino populations. Admixture between racial/ethnic groups creates long-range linkage disequilibrium between variants with different allelic frequencies in the founding populations and it can be used to localize genes. Hispanic/Latino genomes are an admixture of European, African, and Amerindian ancestries. We leveraged this admixture to identify associations between urine albumin excretion (urine albumin-to-creatinine ratio [UACR]) and genomic regions harboring variants with highly differentiated allele frequencies among the ancestral populations. Admixture mapping analysis of 12,212 Hispanic Community Health Study/Study of Latinos participants, using a linear mixed model, identified three novel genome-wide significant signals on chromosomes 2, 11, and 16. The admixture mapping signal identified on chromosome 2, spanning q11.2-14.1 and not previously reported for UACR, is driven by a difference between Amerindian ancestry and the other two ancestries (P<5.7 × 10-5). Within this locus, two common variants located at the proapoptotic BCL2L11 gene associated with UACR: rs116907128 (allele frequency =0.14; P=1.5 × 10-7) and rs586283 (C allele frequency =0.35; P=4.2 × 10-7). In a secondary analysis, rs116907128 accounted for most of the admixture mapping signal observed in the region. The rs116907128 variant is common among full-heritage Pima Indians (A allele frequency =0.54) but is monomorphic in the 1000 Genomes European and African populations. In a replication analysis using a sample of full-heritage Pima Indians, rs116907128 significantly associated with UACR (P=0.01; n=1568). Our findings provide evidence for the presence of Amerindian-specific variants influencing the variation of urine albumin excretion in Hispanics/Latinos.

Identity-by-descent estimation with population- and pedigree-based imputation in admixed family data.

BACKGROUND: In the past few years, imputation approaches have been mainly used in population-based designs of genome-wide association studies, although both family- and population-based imputation methods have been proposed. With the recent surge of family-based designs, family-based imputation has become more important. Imputation methods for both designs are based on identity-by-descent (IBD) information. Apart from imputation, the use of IBD information is also common for several types of genetic analysis, including pedigree-based linkage analysis. METHODS: We compared the performance of several family- and population-based imputation methods in large pedigrees provided by Genetic Analysis Workshop 19 (GAW19). We also evaluated the performance of a new IBD mapping approach that we propose, which combines IBD information from known pedigrees with information from unrelated individuals. RESULTS: Different combinations of the imputation methods have varied imputation accuracies. Moreover, we showed gains from the use of both known pedigrees and unrelated individuals with our IBD mapping approach over the use of known pedigrees only. CONCLUSIONS: Our results represent accuracies of different combinations of imputation methods that may be useful for data sets similar to the GAW19 pedigree data. Our IBD mapping approach, which uses both known pedigree and unrelated individuals, performed better than classical linkage analysis.

Estimating relationships between phenotypes and subjects drawn from admixed families.

BACKGROUND: Estimating relationships among subjects in a sample, within family structures or caused by population substructure, is complicated in admixed populations. Inaccurate allele frequencies can bias both kinship estimates and tests for association between subjects and a phenotype. We analyzed the simulated and real family data from Genetic Analysis Workshop 19, and were aware of the simulation model. RESULTS: We found that kinship estimation is more accurate when marker data include common variants whose frequencies are less variable across populations. Estimates of heritability and association vary with age for longitudinally measured traits. Accounting for local ancestry identified different true associations than those identified by a traditional approach. Principal components aid kinship estimation and tests for association, but their utility is influenced by the frequency of the markers used to generate them. CONCLUSIONS: Admixed families can provide a powerful resource for detecting disease loci, as well as analytical challenges. Allele frequencies, although difficult to adequately estimate in admixed populations, have a strong impact on the estimation of kinship, ancestry, and association with phenotypes. Approaches that acknowledge population structure in admixed families outperform those which ignore it.

Characterisation of the small RNAs in the biomedically important green-bottle blowfly Lucilia sericata.

BACKGROUND: The green bottle fly maggot, Lucilia sericata, is a species with importance in medicine, agriculture and forensics. Improved understanding of this species' biology is of great potential benefit to many research communities. MicroRNAs (miRNA) are a short non-protein coding regulatory RNA, which directly regulate a host of protein coding genes at the translational level. They have been shown to have developmental and tissue specific distributions where they impact directly on gene regulation. In order to improve understanding of the biology of L. sericata maggots we have performed small RNA-sequencing of their secretions and tissue at different developmental stages. RESULTS: We have successfully isolated RNA from the secretions of L. sericata maggots. Illumina small RNA-sequencing of these secretions and the three tissues (crop, salivary gland, gut) revealed that the most common small RNA fragments were derived from ribosomal RNA and transfer RNAs of both insect and bacterial origins. These RNA fragments were highly specific, with the most common tRNAs, such as GlyGCC, predominantly represented by reads derived from the 5' end of the mature maggot tRNA. Each library also had a unique profile of miRNAs with a high abundance of miR-10-5p in the maggot secretions and gut and miR-8 in the food storage organ the crop and salivary glands. The pattern of small RNAs in the bioactive maggot secretions suggests they originate from a combination of saliva, foregut and hindgut tissues. Droplet digital RT-PCR validation of the RNA-sequencing data shows that not only are there differences in the tissue profiles for miRNAs and small RNA fragments but that these are also modulated through developmental stages of the insect. CONCLUSIONS: We have identified the small-RNAome of the medicinal maggots L. sericata and shown that there are distinct subsets of miRNAs expressed in specific tissues that also alter during the development of the insect. Furthermore there are very specific RNA fragments derived from other non-coding RNAs present in tissues and in the secretions. This new knowledge has applicability in diverse research fields including wound healing, agriculture and forensics.

A systematic review of the extra-pancreatic infectious complications in acute pancreatitis.

BACKGROUND AND AIM: Extra-pancreatic infectious complications in acute pancreatitis increase morbidity, but their incidence and association with infected pancreatic necrosis is unknown. Half of bacterial cultures of pancreatic necrosis are of non-enteric origin, raising the possibility of other sources of infection. The aim of this systematic review was to assess the incidence of extra-pancreatic infectious complications in acute pancreatitis, their timing, and relation to severity of pancreatitis and mortality. METHODS: A systematic review was performed using Ovid MEDLINE, Embase and Cochrane Libraries, following PRISMA guidelines. Search terms were "Pancreatitis" AND "Infection" AND ("Complication" OR "Outcome"). RESULTS: 19 studies with 1741 patients were included. Extra-pancreatic infectious complication incidence was 32% (95% CI 23-41%), with the commonest being respiratory infection (9.2%) and bacteraemia (8.4%). Extra-pancreatic infectious complications were not associated with the predicted severity or the mortality of acute pancreatitis. Only 3 studies reported a relation of timing between extra-pancreatic and pancreatic infectious complications. CONCLUSIONS: This is the first systematic review to evaluate the incidence of extra-pancreatic infectious complications in acute pancreatitis, which a third of patients with acute pancreatitis will develop. Implications are vigilance and prompt treatment of extra-pancreatic infection, to reduce possibility of progression to infected pancreatic necrosis.

Successful Use of Erlotinib in Treating Recurrent Thymic Carcinoma: A Case Report.

Thymic carcinomas are rare and aggressive tumors. Primary treatment for these tumors consists of surgical resection, followed by adjuvant radiation therapy or platinum based chemotherapy. Unfortunately these tumors often exhibit a high incidence of local recurrence and metastasis despite treatment. Of recent interest are new targeted therapies such as Tarceva® (erlotinib), an epidermal growth factor receptor (EGFR) inhibitor, for treatment of recurrent thymic carcinoma. Unfortunately recent literature has shown little success with its use, except for a few isolated case reports. Here we present a unique case of progressive disease despite 4 cycles of cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) therapy, and subsequent treatment with 150mg erlotinib daily resulting in partial response at 6 months with tumor shrinking in size and resolution of many metastatic nodules.

Alanine transaminase rather than abdominal ultrasound alone is an important investigation to justify cholecystectomy in patients presenting with acute pancreatitis.

OBJECTIVES: The aims of this study were to investigate the predictive value of an elevated level of alanine transaminase (ALT) for biliary acute pancreatitis (AP) and to reconsider the role of abdominal ultrasound (AUS). METHODS: All patients admitted to Christchurch Public Hospital with AP between July 2005 and December 2008 were identified from a prospectively collected database. Peak ALT within 48 h of presentation was recorded. Aetiology was determined on the basis of history, AUS and other relevant investigations. RESULTS: A total of 543 patients met the inclusion criteria. Patients with biliary AP had significantly higher median (range) ALT than those with non-biliary causes (200 units/l [63-421 units/l] vs. 33 units/l [18-84 units/l]; P < 0.001). An ALT level of >300 units/l had a sensitivity of 36%, specificity of 94%, positive predictive value of 87% and positive likelihood ratio of 5.6 for gallstones. An elevated ALT and negative AUS had a probability of 21-80% for gallstones. CONCLUSIONS: An elevated ALT strongly supports a diagnosis of gallstones in AP. Abdominal ultrasound effectively confirms this diagnosis; however, a negative ultrasound in the presence of a raised ALT does not exclude gallstones. In some patients consideration could be given to proceeding to laparoscopic cholecystectomy based on ALT alone.

Closing the audit loop is necessary to achieve compliance with evidence-based guidelines in the management of acute pancreatitis.

AIM: The aim of this study was to assess the effect of the implementation of evidence-based guidelines and subsequent feedback to surgeons in the management of acute pancreatitis. METHOD: An evidence-based Pancreatitis Proforma was developed. Data were prospectively recorded (01/06/2005-30/09/2007). Audit feedback (AFB) was performed at 9 months. A final analysis was performed comparing outcomes pre- and post-audit feedback. RESULTS: 372 patients were included. Median age (range) was 57 (12-96) years. 168 (45.2%) patients were admitted pre-AFB. Post-AFB, there was a significant increase in the number of patients whose diagnosis was made within 48 hours (135/168 (80.4%) vs 189/204 (92.6%), p<0.001) and who underwent definitive treatment for mild biliary pancreatitis (33/61 (54.1%) vs 56/70 (80.0%), p=0.002). Post-AFB there was also a significant reduction in the number of computed tomography (CT) scans performed for patients with mild acute pancreatitis (23/85 (27.1%) vs 13/99 (13.1%), p=0.018). Mortality (9/168 (5.4%) vs 3/204 (1.4%), p=0.040) also decreased. On multivariate analysis, AFB was an independent factor for change in the use of CT scans (p=0.015) and management of patients with mild biliary pancreatitis (p=0.039). CONCLUSION: For evidence-based guidelines to be effective, feedback to surgeons is necessary.