Mucosal Immunity to Gut Fungi in Health and Inflammatory Bowel Disease.

The gut microbiome is a diverse microbial community composed of bacteria, viruses, and fungi that plays a major role in human health and disease. Dysregulation of these gut organisms in a genetically susceptible host is fundamental to the pathogenesis of inflammatory bowel disease (IBD). While bacterial dysbiosis has been a predominant focus of research for many years, there is growing recognition that fungal interactions with the host immune system are an important driver of gut inflammation. Candida albicans is likely the most studied fungus in the context of IBD, being a near universal gut commensal in humans and also a major barrier-invasive pathogen. There is emerging evidence that intra-strain variation in C. albicans virulence factors exerts a critical influence on IBD pathophysiology. In this review, we describe the immunological impacts of variations in C. lbicans colonisation, morphology, genetics, and proteomics in IBD, as well as the clinical and therapeutic implications.

Antigen concentration, viral load, and test performance for SARS-CoV-2 in multiple specimen types.

The relationship between N-antigen concentration and viral load within and across different specimens guides the clinical performance of rapid diagnostic tests (RDT) in different uses. A prospective study was conducted in Porto Velho, Brazil, to investigate RDT performance in different specimen types as a function of the correlation between antigen concentration and viral load. The study included 214 close contacts with recent exposures to confirmed cases, aged 12 years and older and with various levels of vaccination. Antigen concentration was measured in nasopharyngeal swab (NPS), anterior nares swab (ANS), and saliva specimens. Reverse transcriptase (RT)-PCR was conducted on the NPS and saliva specimens, and two RDTs were conducted on ANS and one RDT on saliva. Antigen concentration correlated well with viral load when measured in the same specimen type but not across specimen types. Antigen levels were higher in symptomatic cases compared to asymptomatic/oligosymptomatic cases and lower in saliva compared to NPS and ANS samples. Discordant results between the RDTs conducted on ANS and the RT-PCR on NPS were resolved by antigen concentration values. The analytical limit-of-detection of RDTs can be used to predict the performance of the tests in populations for which the antigen concentration is known. The antigen dynamics across different sample types observed in SARS-CoV-2 disease progression support use of RDTs with nasal samples. Given lower antigen concentrations in saliva, rapid testing using saliva is expected to require improved RDT analytical sensitivity to achieve clinical sensitivity similar to rapid testing of nasal samples.

Recent advances in the detection and management of early gastric cancer and its precursors.

Despite declines in incidence, gastric cancer remains a disease with a poor prognosis and limited treatment options due to its often late stage of diagnosis. In contrast, early gastric cancer has a good to excellent prognosis, with 5-year survival rates as high as 92.6% after endoscopic resection. There remains an East-West divide for this disease, with high incidence countries such as Japan seeing earlier diagnoses and reduced mortality, in part thanks to the success of a national screening programme. With missed cancers still prevalent at upper endoscopy in the West, and variable approaches to assessment of the high-risk stomach, the quality of endoscopy we provide must be a focus for improvement, with particular attention paid to the minority of patients at increased cancer risk. High-definition endoscopy with virtual chromoendoscopy is superior to white light endoscopy alone. These enhanced imaging modalities allow the experienced endoscopist to accurately and robustly detect high-risk lesions in the stomach. An endoscopy-led staging strategy would mean biopsies could be targeted to histologically confirm the endoscopic impression of premalignant lesions including atrophic gastritis, gastric intestinal metaplasia, dysplasia and early cancer. This approach to quality improvement will reduce missed diagnoses and, combined with the latest endoscopic resection techniques performed at expert centres, will improve early detection and ultimately patient outcomes. In this review, we outline the latest evidence relating to diagnosis, staging and treatment of early gastric cancer and its precursor lesions.

Reliability of 3D dental and skeletal landmarks on CBCT images.

OBJECTIVES: To quantify reliability of three-dimensional skeletal landmarks and a comprehensive set of dental landmarks in cone-beam computed tomography (CBCT) and to determine the shapes of envelope of error. MATERIALS AND METHODS: Three judges located 31 skeletal landmarks and 60 dental landmarks on the pre- and posttreatment CBCT images of 22 patients. Landmark error was determined by calculating the distance of deviation of landmark locations around their average. Standard deviation and mean radial spherical error were calculated. Scatterplots were constructed to characterize envelope of error. RESULTS: The midline landmarks of the cranial base were highly reliable. Bilateral skeletal landmarks tended to have larger error than midline landmarks. Among the nonconventional landmarks, fronto-zygomatic suture, condyle, and mental foramen showed relatively high reliability. However, foramen spinosum and temporal fossa showed larger errors. Gonion was the least reliable landmark. Most dental landmarks were located more reliably than skeletal landmarks. The highest reliability was found at incisal edges. Mesiobuccal cusp of first molars also showed high reliability. CONCLUSIONS: There were differences in the size and shape of the distributions of errors of different landmarks. Most landmarks showed elongated envelopes. Bilateral structures tended to show greater errors than midline structures. Most dental landmarks were more reliable than skeletal landmarks.

Ectopic thyroid tissue presenting as a new neck mass in a pediatric patient.

Ectopic thyroid tissue is an uncommon, but well-documented condition. We present a case of an ectopic thyroid gland with an atypical presentation as a new neck mass in a 3-year-old female without symptoms of hypothyroidism. Imaging confirmed ectopic thyroid and suggested thyroiditis due to hyperemia and heterogeneity on ultrasound. However, there were no laboratory findings of hypothyroidism. An understanding of anatomy and sonographic features of ectopic thyroid gland allows the radiologist to provide a more accurate differential diagnosis in the setting of a neck mass.

Evaluation of O6-Benzylguanine-Potentiated Topical Carmustine for Mycosis Fungoides: A Phase 1-2 Clinical Trial.

Importance: In a phase 1 trial, single-dose O6-benzylguanine with topical carmustine for patients with early stage (stage IA through stage IIA) cutaneous T-cell lymphoma, mycosis fungoides (MF) type, resulted in clinical responses proportional to inhibition of O6-alkylguanine-DNA alkyltransferase activity, but a maximum tolerated dose (MTD) was not reached. Objective: To determine whether dose escalation of carmustine in combination with dual-dose O6-benzylguanine to prolong alkyltransferase inhibition could reach an MTD. Design, Setting, and Participants: A single-arm, phase 1-2 clinical trial conducted at a university teaching hospital enrolled 17 adults with stage IA through stage IIA cutaneous T-cell lymphoma, MF type, to evaluate treatment using topical carmustine plus 2 subsequent daily doses of intravenous O6-benzylguanine, administered every 2 weeks for up to 24 weeks (12 cycles). All patients who received treatment were included in an intent-to-treat analysis of the response rate. The study was conducted from February 17, 2010, to April 8, 2014. Data analysis was performed from May 1, 2014, to December 1, 2015. Interventions: Topical carmustine and intravenous O6-benzylguanine. Main Outcomes and Measures: Clinical disease response was assessed by the Severity-Weighted Assessment Tool (score range, 0-400; higher score indicates worse disease). Safety data were acquired by review of adverse events at study visits. Results: Of the 17 patients enrolled, 12 (71%) were men; mean (SD) age was 45.2 (14.6) years. There were 7 complete responses and 8 partial responses to combination carmustine and O6-benzylguanine treatment. The overall clinical response rate was 88%, with a mean (SD) duration of complete response of 14.43 (6.6) months. The MTD was 20 mg of carmustine applied once in combination with 2 daily doses of 120 mg/m2 of O6-benzylguanine. Most adverse events (112 [67%]) were grade I. Of 15 patients with dermatitis, 5 individuals (33%) demonstrated grade II dermatitis that was unresponsive to topical corticosteroid therapy. The dermatitis was characterized by high levels of macrophage activation, and clearance was associated with vitamin D3 administration. Conclusions and Relevance: Compared with single-dose O6-benzylguanine and carmustine, dual-dose O6-benzylguanine resulted in higher overall response rates and reduced total carmustine doses but was associated with more cutaneous adverse events. The MTD for dual-dose O6-benzylguanine plus carmustine was also ascertained. Trial Registration: clinicaltrials.gov Identifier: NCT00961220.

Phase I clinical trial of O6-benzylguanine and topical carmustine in the treatment of cutaneous T-cell lymphoma, mycosis fungoides type.

OBJECTIVES: To evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea] following intravenous O6-benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions. DESIGN: Open-label, dose-escalation, phase I trial. SETTING: Dermatology outpatient clinic and clinical research unit at a university teaching hospital. PATIENTS: A total of 21 adult patients (11 male, 10 female)with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine. INTERVENTION: Treatment once every 2 weeks with 120 mg/m(2) intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6-alkylguanine-DNA alkyltransferase activity. MAIN OUTCOME MEASURES: Clinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens. RESULTS: A minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyltransferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzylguanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P=.02) and inversely with area under the curve of O6-alkylguanine-DNA alkyltransferase over 1 week (P=.01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55-0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug. CONCLUSION: O6-benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses.

Physician-patient agreement in the assessment of allergen relevance.

BACKGROUND: The efficacy of patch testing may be enhanced by data allowing the physician to estimate the likelihood that results of a patch-test reading are relevant to a patient's dermatitis. OBJECTIVE: The goal of this study was to compare the rates of agreement between the physician's assessment of relevance at the time of final reading and the patients' report 3 months to 3 years later in regard to whether avoidance of an allergen was needed to remain free of dermatitis. We hypothesize that the agreement rates between the physician and patient relevance assessments will vary based on properties both intrinsic and extrinsic to the allergen in question. METHODS: We mailed 407 Institutional Review Board-approved questionnaires to patients and analyzed results for the 92 patients reporting greater than 80% improvement of their dermatitis. Cross-reacting allergens tested on the same patient were combined for analysis. Percent agreement was used to assess interrater concordance. RESULTS: Percent agreement regarding relevance for each allergen or group of allergens was as follows: formaldehyde and formaldehyde-releasing preservatives, 88%; neomycin sulfate, 78%; nickel sulfate hexahydrate, 71%; fragrance mix and related products, 65%; and gold sodium thiosulfate, 56%. CONCLUSION: Relevance varies between allergens. Physician assessment of relevance at the time of final reading is not the ideal method for determining allergen relevance. This has implications for when best to determine the relevance of certain allergens. For allergens with lower agreement, in particular, extended follow-up is recommended to accurately determine an allergen's contribution to a patient's allergic contact dermatitis, especially in those circumstances in which a patient's condition has not improved.

Relevance of doubtful ("equivocal") late patch-test readings.

BACKGROUND: Doubtful late patch-test readings are often not considered clinically relevant. As a result, allergens with doubtful late readings may not be disclosed to the patient, and relevant allergens may not be avoided. We hypothesize that doubtful late reactions at a day 7 reading may be relevant. OBJECTIVE: We compared the patients' assessments of relevance to the strength of reaction at the final reading 168 hours after patch test application to determine if doubtful late patch-test reactions are relevant. METHODS: Four hundred seven subjects who underwent patch testing from January 2005 to February 2008 were mailed a survey asking if their dermatitis was more than 80% better than before patch testing and whether they needed to avoid each of their positive patch-test allergens to remain free of dermatitis. Clinical charts of respondents who indicated their dermatitis was more than 80% improved were reviewed for strength of patch-test response at day 7 for each positive patch-test result, which was then compared to the patients' assessments of relevance formulated by the investigators' interpretation of the survey. RESULTS: On the basis of survey interpretation, 63% of negative (0) late readings, 79% of doubtful (?+) late readings, 85% of + late readings, 84% of ++ late readings, and 100% of +++ late readings were considered relevant. CONCLUSION: Study limitations included small sample size, lack of formal validation of questionnaire, and response bias. However, based on the patients' assessments of relevance, allergens with doubtful late reactions were considered relevant almost as frequently as were allergens with + late readings.

Clinical use of the ABO-Scoring Index: reliability and subtraction frequency.

This study tested the reliability and subtraction frequency of the study model-scoring system of the American Board of Orthodontists (ABO). We used a sample of 36 posttreatment study models that were selected randomly from six different orthodontic offices. Intrajudge and interjudge reliability was calculated using nonparametric statistics (Spearman rank coefficient, Wilcoxon, Kruskal-Wallis, and Mann-Whitney tests). We found differences ranging from 3 to 6 subtraction points (total score) for intrajudge scoring between two sessions. For overall total ABO score, the average correlation was .77. Intrajudge correlation was greatest for occlusal relationships and least for interproximal contacts. Interjudge correlation for ABO score averaged r = .85. Correlation was greatest for buccolingual inclination and least for overjet. The data show that some judges, on average, were much more lenient than others and that this resulted in a range of total scores between 19.7 and 27.5. Most of the deductions were found in the buccal segments and most were related to the second molars. We present these findings in the context of clinicians preparing for the ABO phase III examination and for orthodontists in their ongoing evaluation of clinical results.