Energy decomposition and waterswapping analysis to investigate the SNP associated DPD mediated 5-FU resistance.

5-fluorouracil is an essential component of systemic chemotherapy for colon, breast, head, and neck cancer patients. However, tumoral overexpression of the dihydropyrimidine dehydrogenase has rendered 5-FU clinically ineffective by inactivating it to 5'-6'-dihydro fluorouracil. The responses to 5-FU in terms of efficacy and toxicity greatly differ depending upon the population group, because of variability in the DPD activity levels. In the current study, key active site amino acids involved in the 5-FU inactivation were investigated by modelling the 3D structure of human DPD in a complex with 5-FU. The identified amino acids were analyzed for their possible missense mutations available in dbSNP database. Out of 12 missense SNPs, four were validated either by sequencing in the 1000 Genomes project or frequency/genotype data. The recorded validated missense SNPs were further considered to analyze the effect of their respective alterations on 5-FU binding. Overall findings suggested that population bearing the Glu611Val DPD mutation (rs762523739) is highly vulnerable to 5-FU resistance. From the docking, electrostatic complementarity, dynamics, and energy decomposition analyses it was found that the above mutation showed superior scores than the wild DPD -5FU complex. Therefore, prescribing prodrug NUC-3373 or DPD inhibitors (Gimeracil/3-Cyano-2,6-Dihydroxypyridines) as adjuvant therapy may overcome the 5-FU resistance.

Ambulatory management of common ENT emergencies - what's the evidence?

OBJECTIVES: The global pandemic of coronavirus disease 2019 has necessitated changes to 'usual' ways of practice in otolaryngology, with a view towards out-patient or ambulatory management of appropriate conditions. This paper reviews the available evidence for out-patient management of three of the most common causes for emergency referral to the otolaryngology team: tonsillitis, peri-tonsillar abscess and epistaxis. METHODS: A literature review was performed, searching all available online databases and resources. The Medical Subject Headings 'tonsillitis', 'pharyngotonsillitis', 'quinsy', 'peritonsillar abscess' and 'epistaxis' were used. Papers discussing out-patient management were reviewed by the authors. RESULTS: Out-patient and ambulatory pathways for tonsillitis and peritonsillar abscess are well described for patients meeting appropriate criteria. Safe discharge of select patients is safe and should be encouraged in the current clinical climate. Safe discharge of patients with epistaxis who have bleeding controlled is also well described. CONCLUSION: In select cases, tonsillitis, quinsy and epistaxis patients can be safely managed out of hospital, with low re-admission rates.

Neurobiological support to the diagnosis of ADHD in stimulant-naïve adults: pattern recognition analyses of MRI data.

OBJECTIVE: In adulthood, the diagnosis of attention-deficit/hyperactivity disorder (ADHD) has been subject of recent controversy. We searched for a neuroanatomical signature associated with ADHD spectrum symptoms in adults by applying, for the first time, machine learning-based pattern classification methods to structural MRI and diffusion tensor imaging (DTI) data obtained from stimulant-naïve adults with childhood-onset ADHD and healthy controls (HC). METHOD: Sixty-seven ADHD patients and 66 HC underwent high-resolution T1-weighted and DTI acquisitions. A support vector machine (SVM) classifier with a non-linear kernel was applied on multimodal image features extracted on regions of interest placed across the whole brain. RESULTS: The discrimination between a mixed-gender ADHD subgroup and individually matched HC (n = 58 each) yielded area-under-the-curve (AUC) and diagnostic accuracy (DA) values of up to 0.71% and 66% (P = 0.003) respectively. AUC and DA values increased to 0.74% and 74% (P = 0.0001) when analyses were restricted to males (52 ADHD vs. 44 HC). CONCLUSION: Although not at the level of clinically definitive DA, the neuroanatomical signature identified herein may provide additional, objective information that could influence treatment decisions in adults with ADHD spectrum symptoms.

State-dependent microstructural white matter changes in drug-naïve patients with first-episode psychosis.

BACKGROUND: Diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) microstructural abnormalities in schizophrenia. Whether or not such alterations could vary depending on clinical status (i.e. acute psychosis v. remission) remains to be investigated. METHODS: Twenty-five treatment-naïve first-episode psychosis (FEP) patients and 51 healthy-controls (HC) underwent MRI scanning at baseline. Twenty-one patients were re-scanned as soon as they achieved sustained remission of symptoms; 36 HC were also scanned twice. Rate-of-change maps of longitudinal DTI changes were calculated for in order to examine WM alterations associated with changes in clinical status. We conducted voxelwise analyses of fractional anisotropy (FA) and trace (TR) maps. RESULTS: At baseline, FEP presented reductions of FA in comparison with HC [p < 0.05, false-discovery rate (FDR)-corrected] affecting fronto-limbic WM and associative, projective and commissural fasciculi. After symptom remission, patients showed FA increase over time (p < 0.001, uncorrected) in some of the above WM tracts, namely the right anterior thalamic radiation, right uncinate fasciculus/inferior fronto-occipital fasciculus, and left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. We also found significant correlations between reductions in PANSS scores and FA increases over time (p < 0.05, FDR-corrected). CONCLUSIONS: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities in brain tracts are a key neurobiological feature of acute psychotic disorders, and recovery from such WM pathology can lead to amelioration of symptoms.

Volumetric Analysis from a Harmonized Multisite Brain MRI Study of a Single Subject with Multiple Sclerosis.

BACKGROUND AND PURPOSE: MR imaging can be used to measure structural changes in the brains of individuals with multiple sclerosis and is essential for diagnosis, longitudinal monitoring, and therapy evaluation. The North American Imaging in Multiple Sclerosis Cooperative steering committee developed a uniform high-resolution 3T MR imaging protocol relevant to the quantification of cerebral lesions and atrophy and implemented it at 7 sites across the United States. To assess intersite variability in scan data, we imaged a volunteer with relapsing-remitting MS with a scan-rescan at each site. MATERIALS AND METHODS: All imaging was acquired on Siemens scanners (4 Skyra, 2 Tim Trio, and 1 Verio). Expert segmentations were manually obtained for T1-hypointense and T2 (FLAIR) hyperintense lesions. Several automated lesion-detection and whole-brain, cortical, and deep gray matter volumetric pipelines were applied. Statistical analyses were conducted to assess variability across sites, as well as systematic biases in the volumetric measurements that were site-related. RESULTS: Systematic biases due to site differences in expert-traced lesion measurements were significant (P < .01 for both T1 and T2 lesion volumes), with site explaining >90% of the variation (range, 13.0-16.4 mL in T1 and 15.9-20.1 mL in T2) in lesion volumes. Site also explained >80% of the variation in most automated volumetric measurements. Output measures clustered according to scanner models, with similar results from the Skyra versus the other 2 units. CONCLUSIONS: Even in multicenter studies with consistent scanner field strength and manufacturer after protocol harmonization, systematic differences can lead to severe biases in volumetric analyses.

Relationship between APOE Genotype and Structural MRI Measures throughout Adulthood in the Study of Health in Pomerania Population-Based Cohort.

BACKGROUND AND PURPOSE: The presence of the apolipoprotein E ε4 allele is the strongest sporadic Alzheimer disease genetic risk factor. We hypothesized that apolipoprotein E ε4 carriers and noncarriers may already differ in imaging patterns in midlife. We therefore sought to identify the effect of apolipoprotein E genotype on brain atrophy across almost the entire adult age span by using advanced MR imaging-based pattern analysis. MATERIALS AND METHODS: We analyzed MR imaging scans of 1472 participants from the Study of Health in Pomerania (22-90 years of age). We studied the association among age, apolipoprotein E ε4 carrier status, and brain atrophy, which was quantified by using 2 MR imaging-based indices: Spatial Pattern of Atrophy for Recognition of Brain Aging (summarizing age-related brain atrophy) and Spatial Pattern of Abnormality for Recognition of Early Alzheimer Disease (summarizing Alzheimer disease-like brain atrophy patterns), as well as the gray matter volumes in several Alzheimer disease- and apolipoprotein E-related ROIs (lateral frontal, lateral temporal, medial frontal, and hippocampus). RESULTS: No significant association was found between apolipoprotein E ε4 carrier status and the studied ROIs or the MR imaging-based indices in linear regression models adjusted for age, sex, and education, including an interaction term between apolipoprotein E and age. CONCLUSIONS: Our study indicates that measurable apolipoprotein E-related brain atrophy does not occur in early adulthood and midlife and suggests that such atrophy may only occur more proximal to the onset of clinical symptoms of dementia.

Advanced brain aging: relationship with epidemiologic and genetic risk factors, and overlap with Alzheimer disease atrophy patterns.

We systematically compared structural imaging patterns of advanced brain aging (ABA) in the general-population, herein defined as significant deviation from typical BA to those found in Alzheimer disease (AD). The hypothesis that ABA would show different patterns of structural change compared with those found in AD was tested via advanced pattern analysis methods. In particular, magnetic resonance images of 2705 participants from the Study of Health in Pomerania (aged 20-90 years) were analyzed using an index that captures aging atrophy patterns (Spatial Pattern of Atrophy for Recognition of BA (SPARE-BA)), and an index previously shown to capture atrophy patterns found in clinical AD (Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease (SPARE-AD)). We studied the association between these indices and risk factors, including an AD polygenic risk score. Finally, we compared the ABA-associated atrophy with typical AD-like patterns. We observed that SPARE-BA had significant association with: smoking (P<0.05), anti-hypertensive (P<0.05), anti-diabetic drug use (men P<0.05, women P=0.06) and waist circumference for the male cohort (P<0.05), after adjusting for age. Subjects with ABA had spatially extensive gray matter loss in the frontal, parietal and temporal lobes (false-discovery-rate-corrected q<0.001). ABA patterns of atrophy were partially overlapping with, but notably deviating from those typically found in AD. Subjects with ABA had higher SPARE-AD values; largely due to the partial spatial overlap of associated patterns in temporal regions. The AD polygenic risk score was significantly associated with SPARE-AD but not with SPARE-BA. Our findings suggest that ABA is likely characterized by pathophysiologic mechanisms that are distinct from, or only partially overlapping with those of AD.

Working Length Determination of Root Canal of Young Permanent Tooth: An In vitro Study.

BACKGROUND: Determination of correct working length is one of the keys to success in endodontic therapy. AIM: The aim of this study was to evaluate the diagnostic efficacy of various methods to determine working length of root canal. MATERIALS AND METHODS: Tactile method was assessed using digital radiography and compared with electronic method using apex locator. A total sample of 30 single rooted young permanent teeth the (mandibular first premolars) with matured apices were selected for the study. Access cavity preparation was carried out. Working length was measured by tactile method using digital radiography and electronic method using apex locator with no 15 K file. Actual working length was established by grinding of cementum and dentine from the root apex and was observed under stereomicroscope. Data was collected and statistical analysis was carried out with the help of SPSS-15. RESULTS: The results of this study showed that there was a significant difference between tactile method assessed by digital radiography and electronic method using apex locator. CONCLUSION: Apex locator was found to be more reliable and accurate when compared with the actual length.

Development of an ENT undergraduate curriculum using a Delphi survey.

OBJECTIVE: To determine an ENT undergraduate syllabus. DESIGN: Two round Delphi survey. SETTING: Email questionnaire. PARTICIPANTS: Stakeholders with a vested interest in ENT undergraduate education. MAIN OUTCOMES MEASURED: Mode and median scores for 232 learning outcomes. RESULTS: The individual learning objectives that scored most highly were related to history taking and examination, red flag symptoms, common ENT conditions including all forms of otitis, acute and chronic rhinosinusitis, thyroid disease, pharyngeal infection and airway compromise and formulation of differential diagnoses. CONCLUSIONS: Using a Delphi technique, a structured, evidence-based curriculum has been developed. This should assist those medical schools who do not currently have ENT in their curriculum but wish to reinstate it to produce a high quality teaching programme. It may also assist those medical schools who do have ENT in their curriculum to continue to develop their curriculum.

Tracheostomy and laryngectomy survey: do front-line emergency staff appreciate the difference?

BACKGROUND: In an emergency scenario, it is vital to appreciate the difference between a laryngectomy and a tracheostomy so that oxygen can be administered in an appropriate manner. This survey aimed to ascertain the level of emergency healthcare personnel's knowledge with regards to distinguishing between a tracheostomy and a laryngectomy patient, and the emergency management of such patients. METHODS: Forty-four accident and emergency staff (28 doctors, nine nurses and seven paramedics) within one Foundation Trust were invited to complete a questionnaire to ascertain (1) their confidence at differentiating between a laryngectomy and tracheostomy stoma; (2) knowledge of the appropriate site for oxygen delivery if needed; and (3) overall level of training on this subject. RESULTS: There were significant gaps in knowledge, particularly with regards to fundamental differences between a tracheostomy and a laryngectomy; less than 5 per cent were able to describe the anatomical difference. Only 41 per cent correctly identified the route of oxygen administration in laryngectomy patients. CONCLUSION: In this cohort of emergency staff, the fundamental difference between a laryngectomy and a tracheostomy was poorly understood. This lack of awareness of front-line emergency staff needs to be addressed in order to maximise patient safety.

Determining the content of an educational ENT website using the Delphi technique.

The aim of this study was to develop an educational website (www.enttheatre.com) that showed common ENT operations and emergencies, in order to help improve the basic surgical ENT knowledge of medical students and junior doctors. A two-round Delphi survey was conducted to establish the contents of the website. 'Experts' who participated in the Delphi process included otolaryngology consultants and trainees, junior doctors, general practitioners, and medical students. First- and second-round Delphi response rates were 49 per cent (61/125) and 92 per cent (56/61), respectively. Our paper presents a consensus opinion on what basic surgical knowledge a medical student or junior doctor should be familiar with in otolaryngology.

Schwannoma of the ansa cervicalis.

Schwannomas are rare neoplasms that originate from Schwann cells. We present a case report of schwannoma of the ansa cervicalis in a patient where preoperative imaging suggested thyroid pathology. A 25-year-old man presented to the otolaryngology department with a one-year history of an asymptomatic, anterior triangle neck swelling. Imaging and FNA suggested a cystic lesion of the thyroid. However, intraoperatively, the lesion was found between the right sternohyoid and thyrohoid and histology showed findings consistent with a diagnosis of schwannoma, determined to originate from the ansa cervicalis based on its anatomical position. Schwannoma of the ansa cervicalis is extremely rare and there have only been four reported cases in the literature. Schwannomas are often misdiagnosed and confused for other lesions. In our case report we add to the sparse literature on this pathology and highlight common pitfalls in diagnosis and discuss the principles of management of this rare condition.

Recurrent facial nerve palsy: the role of surgery.

Repeated episodes of acute idiopathic facial paralysis present both a diagnostic and a management dilemma. We discuss these issues with reference to four adult cases managed between 1999 and 2008, thus adding to the sparse literature on this subject. For such cases, our unit performs decompression of geniculate, labyrinthine and meatal segments of the facial nerve via a middle fossa approach. A short video, available on The Journal of Laryngology & Otology website, demonstrates the key stages of the operation. We believe there is a role for surgical decompression in cases of recurrent acute facial weakness with three or more documented episodes, especially in the presence of progressive deterioration in function. Decompression of the geniculate, labyrinthine and meatal segments, via a middle fossa approach, is our favoured technique, and has achieved good results.

Diffusion-weighted magnetic resonance imaging: its uses in otolaryngology.

Over recent years, there has been an increase in otolaryngology publications concerning diffusion-weighted magnetic resonance imaging. The aims of this review paper are to summarise the basic principles of diffusion-weighted magnetic resonance imaging, and to provide an overview of current otolaryngological applications and areas of research. Diffusion-weighted magnetic resonance imaging is a radiological technique which has shown promising results in various areas of otolaryngology. However, studies of diffusion-weighted magnetic resonance imaging are difficult to compare, as different imaging parameters and techniques have been used. The role of this imaging modality within otolaryngology is yet to be fully elucidated. Diffusion-weighted magnetic resonance imaging may prove to be a useful adjunct in both the pre- and post-operative care of otolaryngology patients.

Acceptability of chlamydia screening using self-taken vaginal swabs.

In the first phase of the National Chlamydia Screening Programme (NCSP), the majority of sites involved offered testing with urine sample. Camden & Islington (C&I) were the first site to offer testing with self-taken vaginal swabs (SVS). SVS are appropriate specimens for diagnosing chlamydia by nucleic acid amplification tests. This study aimed to assess the uptake and acceptability of chlamydia screening using SVS within C&I contraceptive clinics. Data collected from women participating in the NCSP between June 2003 and April 2004 were analysed. Of the 3936 women who accepted screening, 90.4% provided a SVS and only 5.8% accepted the offer of providing a urine sample as an alternative to SVS. Women over 19 years and women from Asian ethnic groups were most likely to decline any screening. No woman stated a reluctance to provide a SVS as a reason for declining screening, confirming the acceptability of SVS for chlamydia screening.

Post-tonsillectomy morbidity statistics: are they underestimated?

BACKGROUND: Post-tonsillectomy morbidity statistics are obtained when patients present to hospital with complications. The two common morbidities are pain and haemorrhage. Hospital-recorded morbidity rates may be an underestimation, as some patients are treated by general practitioners and are therefore not included in hospital audits. METHODS: Prospective, cohort, questionnaire study to assess: the post-tonsillectomy haemorrhage rate (i.e. actual rate versus hospital recorded rate); and the number of patients with post-operative pain and/or bleeding who were treated with antibiotics by their general practitioner. RESULTS: The response rate was 76 per cent (70/92). The actual rate of secondary haemorrhage was three times that noted in the hospital records (15.7 vs 5.7 per cent, respectively). Fifteen patients (21 per cent) required extra analgesia after discharge. General practitioners prescribed antibiotics for pain alone in six patients (11 per cent). CONCLUSION: The actual post-tonsillectomy haemorrhage rate is much higher than that recorded in hospital statistics. General practitioners differ in their treatment of post-tonsillectomy patients presenting with pain alone; some prescribe antibiotics in addition to analgesia.