APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.

BACKGROUND: Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies. PATIENTS AND METHODS: APOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance. RESULTS: APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis. CONCLUSIONS: APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

Current practice in the surgical management of parathyroid disorders: a United Kingdom survey.

PURPOSE: Surgery for primary hyperparathyroidism is undertaken by many specialties but predominantly endocrine and ear, nose and throat (ENT) surgeons. There is currently no consensus on the peri-operative management of primary hyperparathyroidism. We sought to determine current surgical practice and identify any inter-specialty variation in the United Kingdom (UK). METHODS: An online survey was disseminated to members of the British Association of Endocrine & Thyroid Surgeons (BAETS) in the UK. RESULTS: 78 surgeons responded (40 Endocrine, 37 ENT and 1 maxillofacial). 90% of surgeons used ultrasound and sestamibi for pre-operative localisation. Intraoperative frozen section (31%) and parathyroid hormone monitoring (41%) were the most common adjuncts used intraoperatively. 68% of surgeons did not use any wound drains. Nearly two-thirds of surgeons (64%) discharged patients from the clinic within 3 months, There were some significant differences (p < 0.05) in particular areas of practice between endocrine and ENT surgeons (%, p): use of single-photon emission computed tomography (SPECT) (Endocrine 25% vs. ENT 5%), preoperative laryngeal assessment (endocrine 58% vs. ENT 95%), intraoperative laryngeal nerve monitoring (endocrine 35% vs. ENT 68%), use of monopolar diathermy (endocrine 58% vs. ENT 22%), bipolar diathermy (endocrine 60% vs. 89%) and surgical ties (endocrine 48% vs. ENT 19%). CONCLUSION: Our study demonstrates some similarities as well as some notable differences in practice between endocrine and ENT surgeons, and therefore, highlights the need for national consensus with respect to some key areas in parathyroid surgery.

A Poly(ionic liquid) Gel Electrolyte for Efficient all Solid Electrochemical Double-Layer Capacitor.

Polyionic liquid based gels have stimulated significant interest due to their wide applications in flexible electronics, such as wearable electronics, roll-up displays, smart mobile devices and implantable biosensors. Novel supported liquid gel electrolyte using polymerisable ionic liquid and an acrylate monomer, has been developed in this work by entrapping ionic liquid during polymerisation instead of post polymerisation impregnation. The chemically crosslinked polyionic liquid gel electrolyte (PIL) is prepared using 2-hydroxyethylmethacrylate (HEMA) monomer and a polymerisable ionic liquid, 1,4-di(vinylimidazolium)butane bisbromide (DVIMBr) in an ionic liquid (IL- 1-butyl-3 methylimidazolium hexafluorophosphate) as the polymerisation solvent, which resulted in in-situ entrapment of the IL in the gel during polymerisation and crosslinking of the polymer. The supported liquid gel electrolyte (SLG) material was characterised with thermal analysis, infrared spectroscopy, and dynamic mechanical analysis, and was found to be stable with good mechanical properties. The electrochemical analysis showed that these chemically cross-linked PIL gel electrolyte-supported ILs are suitable for solid-state, flexible supercapacitor applications.

Developing a scalable training model in global mental health: pilot study of a video-assisted training Program for Generalist Clinicians in Rural Nepal.

BACKGROUND: In low- and middle-income countries, mental health training often includes sending few generalist clinicians to specialist-led programs for several weeks. Our objective is to develop and test a video-assisted training model addressing the shortcomings of traditional programs that affect scalability: failing to train all clinicians, disrupting clinical services, and depending on specialists. METHODS: We implemented the program -video lectures and on-site skills training- for all clinicians at a rural Nepali hospital. We used Wilcoxon signed-rank tests to evaluate pre- and post-test change in knowledge (diagnostic criteria, differential diagnosis, and appropriate treatment). We used a series of 'Yes' or 'No' questions to assess attitudes about mental illness, and utilized exact McNemar's test to analyze the proportions of participants who held a specific belief before and after the training. We assessed acceptability and feasibility through key informant interviews and structured feedback. RESULTS: For each topic except depression, there was a statistically significant increase (Δ) in median scores on knowledge questionnaires: Acute Stress Reaction (Δ = 20, p = 0.03), Depression (Δ = 11, p = 0.12), Grief (Δ = 40, p < 0.01), Psychosis (Δ = 22, p = 0.01), and post-traumatic stress disorder (Δ = 20, p = 0.01). The training received high ratings; key informants shared examples and views about the training's positive impact and complementary nature of the program's components. CONCLUSION: Video lectures and on-site skills training can address the limitations of a conventional training model while being acceptable, feasible, and impactful toward improving knowledge and attitudes of the participants.

Extended applications of the endoscopic modified Lothrop procedure.

OBJECTIVE: The endoscopic modified Lothrop procedure is mainly used for refractory frontal sinusitis. However, we have used it as an access procedure to facilitate treatment for an extended range of additional frontal sinus pathologies. METHODS: A retrospective review of patients who underwent the endoscopic modified Lothrop procedure for 'alternative' frontal sinus pathologies was conducted. Patient data were reviewed. The main outcome parameter measured was signs of recurrence. RESULTS: Twelve patients (6 males, 6 females) from a 7-year study period, with a mean age of 45.2 years (range, 16-78 years), were analysed. The surgical indications included frontoethmoidal mucoceles, cerebrospinal fluid leaks within the frontal sinus, cystic fibrosis, frontal sinus osteoma, frontal sinus ossifying fibroma and frontal silent sinus syndrome. The mean follow-up period was 33.3 months. There were no known recurrences. CONCLUSION: We have used the endoscopic modified Lothrop procedure for a range of frontal sinus pathologies, safely and effectively, with no peri-operative complications.

Longitudinal trends in global obesity research and collaboration: a review using bibliometric metadata.

The goal of this study was to understand research trends and collaboration patterns together with scholarly impact within the domain of global obesity research. We developed and analysed bibliographic affiliation data collected from 117,340 research articles indexed in Scopus database on the topic of obesity and published from 1993-2012. We found steady growth and an exponential increase of publication numbers. Research output in global obesity research roughly doubled each 5 years, with almost 80% of the publications and authors from the second decade (2003-2012). The highest publication output was from the USA - 42% of publications had at least one author from the USA. Many US institutions also ranked highly in terms of research output and collaboration. Fifteen of the top-20 institutions in terms of publication output were from the USA; however, several European and Japanese research institutions ranked more highly in terms of average citations per paper. The majority of obesity research and collaboration has been confined to developed countries although developing countries have showed higher growth in recent times, e.g. the publication ratio between 2003-2012 and 1993-2002 for developing regions was much higher than that of developed regions (9:1 vs. 4:1). We also identified around 42 broad disciplines from authors' affiliation data, and these showed strong collaboration between them. Overall, this study provides one of the most comprehensive longitudinal bibliometric analyses of obesity research. This should help in understanding research trends, spatial density, collaboration patterns and the complex multi-disciplinary nature of research in the obesity domain.

The outcome of septorhinoplasty surgery on olfactory function.

OBJECTIVES: To assess olfactory outcomes in patients undergoing septorhinoplasty surgery in our unit. DESIGN: Prospective cohort study. SETTING: The Royal National Throat Nose and Ear Hospital, London. PARTICIPANTS: Forty-three patients undergoing functional septorhinoplasty (Males = 26; mean age = 34.1 ± 12.2) were recruited into the study. MAIN OUTCOME MEASURES: The primary outcome of olfactory function was assessed using 'Sniffin sticks'. Our secondary outcomes were assessment of patient quality of life using the disease specific Sino-nasal Outcome Test-23 questionnaire (SNOT-23) and a visual analogue scale for sense of smell. These measures were repeated at 12 weeks post operatively. RESULTS: There was a significant change in the Sniffin' sticks score post-operatively (8.3 versus 9.6; P < 0.001). The SNOT-23 score also showed a significant improvement post-operatively (53.5 versus 40.4; P < 0.001). A significant improvement was not found in the smell/taste question (question 21) of the SNOT-23 questionnaire as well as the visual analogue scale for sense of smell. A difference in olfactory outcome was not found between open versus closed approaches, primary versus revision surgery and traumatic versus non traumatic cases. CONCLUSIONS: The results show a measured significant improvement in olfaction following functional Septorhinoplasty but not a subjective improvement in the patients perception of their sense of smell and hence not a clinically significant difference. The reasons for the measured improvement are not clear and are likely to be multifactorial.

The need for an objective measure in septorhinoplasty surgery: are we any closer to finding an answer?

OBJECTIVES: To assess the reliability of nasal inspiratory peak flow (NIPF) in providing a clinically accurate objective measure following functional septorhinoplasty by comparing it to the validated disease-specific quality-of-life questionnaire, SNOT-22. Studies so far have demonstrated poor correlation between bilateral NIPF and symptom-specific nasal questionnaires following septorhinoplasty. DESIGN: To perform a prospective comparative analysis between NIPF and the validated disease-specific quality-of-life questionnaire SNOT-22 and to determine whether a correlation exists following septorhinoplasty surgery. SETTING: The Royal National Throat Nose and Ear Hospital, London. PARTICIPANTS: A total of 122 patients (78 males, 44 females; mean age 33.5 ± 12.2 years) were recruited from the senior authors rhinology clinic and underwent functional septorhinoplasty surgery. MAIN OUTCOME MEASURES: Preoperative and postoperative nasal inspiratory peak flow (NIPF) measurements were performed in addition to the completion of three subjective quality-of-life and symptom assessment tool questionnaires; Sinonasal Outcome Test 22 (SNOT-22), Nasal Obstruction Symptom Evaluation (NOSE) and Visual Analogue Scale (VAS: 0-10). RESULTS: The mean preoperative NIPF was 88.2 L/min, and the postoperative value was 101.6 L/min and showed a significant improvement following surgery (P = 0.0064). The mean total SNOT-22 score improved significantly from 48.6 to 26.6 (P < 0.0001); the NOSE score from 14.1 to 6.6 (P < 0.0001); and the Visual Analogue Scale (VAS) blockage score from 6.9 to 3.2 (P < 0.0001). All individual domains assessed showed improvements postoperatively, but no correlation was found between the NIPF and SNOT-22 score. Equally, we did not find a correlation between NIPF and the symptom-specific NOSE questionnaire and the nasal blockage domain on the Visual Analogue Scale (VAS) scale. CONCLUSION: We have demonstrated that NIPF does not correlate with the SNOT-22 disease-specific questionnaire, although both outcomes significantly improve postoperatively. At present, we are still lacking a clinically accurate objective measure of nasal function for the evaluation of patients undergoing septorhinoplasty surgery.

Fabrication of highly elastic resilin/silk fibroin based hydrogel by rapid photo-crosslinking reaction.

A new type of hydrogel combining the highly elastic soft phase of Rec1-resilin and the mechanically strong hard phase Bombyx mori Silk fibroin has been reported using a rapid photo-crosslinking method. The improved elasticity and strength through the use of a resilin-based material and silk fibroin has been shown for the first time.

Detection and identification of red cell alloantibodies in multiply transfused thalassemia major patients: a prospective study.

Life long red blood transfusion remains the main treatment for ß thalassemia major patients. The development of alloantibodies complicates transfusion therapy in thalassemia patients. Alloimmunization to red cell antigens is one of the most important immunological transfusion reaction and causes delayed type of transfusion reaction. A prospective study was conducted from January 2007 to January 2010. This was a cohorts of 115 patients were selected from regular transfusion group and they were followed for two and half year. They were followed up for the effect of transfusion during study period. There was a decline in patient number from 115 to 96 due to mortality and transfer of patient. A total of 96 multiply transfused thalassemia patients were prospectively included in this study and three consecutive samples collected after every 6 months and investigated for the development of alloantibody to red cell antigens. Tests for antibody screening and identification were performed on preserved sample to investigate prevalence and development of red cell alloimmunization by standardized laboratory techniques by same person at Prathama Blood Centre. A total of 96 patients were included in the study. 63 patients were males and 33 females. A total of five single alloantibodies were formed in five patients out of them four (80 %) belonged to Kell blood group system and one (20 %) from Rh system. It was observed that two (1.92 %) of new thalassemia patients developed red cell alloantibodies during study period. Red cell alloimmunization should be kept in mind in the patients receiving multiple transfusions. In present study, alloimmunization rate was 5.21 %. Mean transfusion duration in these patients was 23.90 days, probably due to presence of alloantibody. RBC alloantibody detection on regular interval and corresponding antigen negative blood transfusion is strongly recommended in transfusion dependent thalassemia patients.

Scytalidium dimidiatum associated invasive fungal sinusitis in an immunocompetent patient.

BACKGROUND: Scytalidium dimidiatum is a soil and plant pathogen that frequently affects fruit trees, but can also cause human infection. There are only two reported cases of invasive fungal sinusitis involving this rare micro-organism. OBJECTIVE: This paper reports the first case of invasive fungal sinusitis caused by Scytalidium dimidiatum occurring in a young immunocompetent patient from a non-endemic region, and discusses potential sources of exposure and relevance of local factors. METHOD: Case report. RESULTS: The patient was treated successfully with a combination of functional endoscopic sinus surgery, and antifungal and corticosteroid treatment. CONCLUSION: This paper describes the first reported case of invasive fungal sinusitis secondary to Scytalidium dimidiatum in a young immunocompetent patient from a non-endemic region. Importance is placed on following a systematic process of investigation and management, and adhering to well-defined basic surgical principles.

Establishment of CYP2D6 reference samples by multiple validated genotyping platforms.

Cytochrome P450 2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6)), a highly polymorphic drug-metabolizing enzyme, is involved in the metabolism of one-quarter of the most commonly prescribed medications. Here we have applied multiple genotyping methods and Sanger sequencing to assign precise and reproducible CYP2D6 genotypes, including copy numbers, for 48 HapMap samples. Furthermore, by analyzing a set of 50 human liver microsomes using endoxifen formation from N-desmethyl-tamoxifen as the phenotype of interest, we observed a significant positive correlation between CYP2D6 genotype-assigned activity score and endoxifen formation rate (rs = 0.68 by rank correlation test, P = 5.3 × 10(-8)), which corroborated the genotype-phenotype prediction derived from our genotyping methodologies. In the future, these 48 publicly available HapMap samples characterized by multiple substantiated CYP2D6 genotyping platforms could serve as a reference resource for assay development, validation, quality control and proficiency testing for other CYP2D6 genotyping projects and for programs pursuing clinical pharmacogenomic testing implementation.

Evaluation of ophthalmic manifestations in patients with intracranial tumours.

The present study was done to observe the ophthalmic manifestations in patients with intracranial tumor. This was a prospective, purposive, consecutive, observational study conducted in patients with radiologically proven intracranial tumors in the department of Ophthalmology with collaboration of Department of Neuro-surgery of Bangabandhu Sheikh Mujib Medical University from January 2006 to December 2010. All cases had tissue histopathology confirmation post-operatively. The most common type of intracranial tumor was pituitary adenoma (58.04%), followed by craniopharyngioma (20.53%), posterior fossa tumour (12.50%) [medulloblestoma, ependymoma], meningioma (8.04%) [sphenoidalwing meningioma, petroclavel meningioma, oligodendroglioma] and others (0.89%) [nasopharyngial carcinoma, esthesio - astrocytoma]. Common neuro-ophthalmological findings were visual blur (91.07%), visual field defect (71.42%), optic disc changes (50%), pupillary light reaction defect (48.21%) and colour vision defect (46.42%). The study shows, pituitary adenoma is the most common tumor that impairs the visual pathway structures followed by craniopharyngioma, posterior fossa tumour & meningioma. Furthermore, decreased visual acuity, visual field defect, abnormal optic discs, relative afferent pupillary defect and ophthalmoplegia etc. are the common neuro-ophthalmic features that should be carefully examined for early detection of intracranial tumors.

Reference Ranges for Serum Uric Acid among Healthy Assamese People.

This study was designed to establish reference ranges for serum uric acid among healthy adult Assamese population. Samples from 1470 aged 35-86 years were used to establish age and sex related reference range by the centile method (central 95 percentile) for serum uric acid level. There were 51% (n = 754) males and 49% (n = 716) females; 75.9% (n = 1115) of them were from urban area and the rest 24.1% (n = 355) were from the rural area. Majority of the population were nonvegetarian (98.6%, n = 1450) and only 1.4% (n = 20) were vegetarian. The mean age, weight, height, and uric acid of the studied group were 53.6 ± 11.3 years, 62.6 ± 10.5 kg, 160 ± 9.4 cm, and 5.5 ± 1.4 mg/dL, respectively. There is a statistically significant difference in the mean value of the abovementioned parameters between male and female. The observed reference range of uric acid in the population is 2.6-8.2 mg/dL which is wider than the current reference range used in the laboratory. Except gender (P < 0.0001), we did not find any significant relation of uric acid with other selected factors.

Endoscopic airway management of acute upper airway obstruction.

The conventional treatment for patients with acute upper airway obstruction is tracheostomy, which is a safe, definitive procedure in most hands. Alternatively, a debulking procedure can be considered but this requires both surgical and anaesthetic skill and expertise. However, where possible, it provides a good alternative with the advantages of removing the cause of obstruction and yielding tissue for histopathological analysis, and avoiding the need for a tracheostomy, with its associated morbidity. We evaluated all patients who presented with acute upper airway obstruction and underwent endoscopic laser debulking surgery performed by the senior author, over a three and a half year period. We recorded patient demographic data, their underlying pathologies, complication rates associated with laser debulking surgery and the conversion to tracheostomy. Thirty patients were identified, including 19 males and 11 females, with a mean age of 57.10 ± 17.20 years (19-93 years). All patients underwent debulking procedures with carbon dioxide laser under general anaesthetic. All patients had their underlying diagnosis confirmed from their debulking surgery. Twelve patients were found to have benign pathology and 18 had malignant airway obstruction. There were no laser-associated complications. One patient required conversion to emergency tracheostomy, during their debulking surgery. Endoscopic laser assisted debulking surgery has successfully been used to establish a safe airway. It allows obtaining tissue specimens, to confirm the underlying diagnosis, thus avoiding the need for further biopsies under anaesthetic. For all malignant cases, patients were subsequently able to proceed to definitive treatment. It has obviated the need for emergency tracheostomy in almost all of the cases in our patient cohort.

Cerebellar abscess caused by Listeria monocytogenes in a liver transplant patient.

Brain abscesses are a rare but serious complication and have been documented in transplant recipients. Aspergillus is by far the most frequent etiology of post-transplant brain abscesses. Bacteria, apart from Nocardia, have a low association with brain abscesses in transplant recipients. We report herein the case of a 52-year-old man who had undergone orthotopic liver transplantation (OLT) for end-stage liver disease and hepatocellular carcinoma secondary to chronic hepatitis, and who developed a cerebellar abscess (CA) from Listeria monocytogenes. Three months after transplantation, he presented with a 1-week history of headache and vomiting. Computed tomography scan of the brain revealed a space-occupying lesion in the right cerebellum, which was further confirmed by magnetic resonance imaging. Emergency surgery was planned because of pressure effect on the surrounding structures. The patient recovered smoothly from the surgery. To our knowledge, no reports of Listeria CA following OLT have been published in the English literature. This case shows that, although extremely rare, L. monocytogenes may cause CA in liver transplant recipients, and clinicians should be aware of this, so that prompt diagnosis and treatment can be instituted before serious brain damage can occur.

Diffusion MRI improves the accuracy of preoperative diagnosis of common pediatric cerebellar tumors among reviewers with different experience levels.

BACKGROUND AND PURPOSE: Although utility of diffusion MR imaging in the preoperative diagnosis of common pediatric cerebellar tumors is generally recognized, its added value has not been systematically studied previously. The purpose of this study was to evaluate the impact of diffusion MR imaging on the accuracy of preoperative diagnosis of common pediatric cerebellar tumors among reviewers with different experience levels. MATERIALS AND METHODS: Review of the neuro-oncology data base yielded 96 patients whose preoperative brain MR imaging included both diffusion MR imaging (b = 1000 s/mm(2)) and ADC maps. There were 38 pilocytic astrocytomas, 33 medulloblastomas, 17 ependymomas, and 8 atypical teratoid/rhabdoid tumors. Six reviewers (4 residents, 2 neuroradiologists) evaluated the examinations. Two sessions were conducted with each reviewer, without and with diffusion MR imaging data on 2 separate days. The impact of diffusion MR imaging on accuracy of diagnoses was assessed. RESULTS: In choosing the correct diagnosis of the 4 alternatives, performances of 5 of the 6 reviewers improved significantly with inclusion of the diffusion MR imaging data, from 63%-77% (P = .0003-.0233). The performance of 1 reviewer also improved, but the difference did not attain statistical significance (P = .1944). Inclusion of diffusion MR imaging data improved the likelihood of rendering a correct diagnosis (odds ratio = 3.16, 95% confidence interval = 2.07-4.00) over all tumor types. When embryonal tumors were regarded as a single group, the rate of correct diagnosis increased from 66%-83% with diffusion MR imaging data, and performances of all of the reviewers improved significantly (P = .0001-.05). The improvement in performances resulted from increased correct diagnoses of pilocytic astrocytomas, medulloblastomas, and atypical teratoid/rhabdoid tumors. There was no improvement in the correct diagnoses of ependymomas with inclusion of the diffusion MR imaging data. CONCLUSIONS: Diffusion MR imaging improves accuracy of preoperative diagnosis of common pediatric cerebellar tumors significantly among reviewers with differing experience levels.