Survey of rectal cancer MRI technique and reporting tumour descriptors in the UK: a multi-centre British Society of Gastrointestinal and Abdominal Radiology (BSGAR) audit.

AIM: To evaluate variation in magnetic resonance imaging (MRI) technique and reporting of rectal cancer staging examinations across the UK. MATERIALS AND METHODS: A retrospective, multi-centre audit was undertaken of imaging protocols and information documented within consecutive MRI rectal cancer reports between March 2020 and August 2021, which were compared against American and European guidelines. Inclusion criteria included histologically proven rectal adenocarcinoma and baseline staging MRI rectum only. RESULTS: Fully anonymised data from 924 MRI reports by 78 radiologists at 24 centres were evaluated. Thirty-two per cent of radiologists used template reporting, but these reports offered superior documentation of 13 out of 18 key tumour features compared to free-text reports including T-stage, relation to peritoneal reflection and mesorectal fascia (MRF), nodal status, and presence of extramural venous invasion (EMVI; p<0.027 in each). There was no significant differences in the remaining five features. Across all tumour locations, the tumour relationship to the MRF, the presence of EMVI, and the presence of tumour deposits were reported in 79.5%, 85.6%, and 44% of cases, respectively, and tumour, nodal, and distant metastatic stage documented in 94.4%, 97.7%, and 78.3%. In low rectal tumours, the relationship to the anal sphincter complex was reported in only 54.6%. CONCLUSION: Considerable variation exists in rectal cancer MRI acquisition and reporting in this sample of UK centres. Inclusion of key radiological features in reports must be improved for risk stratification and treatment decisions. Template reporting is superior to free-text reporting. Routine adoption of standardised radiology practices should now be considered to improve standards to facilitate personalised precision treatment for patients to improve outcomes.

The impact of endoscopic ultrasound on the management and outcome of patients with oesophageal cancer: an update of a systematic review.

AIM: To provide an updated systematic review concerning the impact of endoscopic ultrasound (EUS) in the modern era of oesophageal cancer staging. MATERIALS AND METHODS: To update the previous systematic review, databases including MEDLINE and EMBASE were searched and studies published from 2005 onwards were selected. Studies reporting primary data in patients with oesophageal or gastro-oesophageal junction cancer who underwent radiological staging and treatment, regardless of intent, were included. The primary outcome was the reported change in management after EUS. Secondary outcomes were recurrence rate and overall survival. Two reviewers extracted data from included articles. This study was registered with PROSPERO (CRD42021231852). RESULTS: Eighteen studies with 11,836 patients were included comprising 2,805 patients (23.7%) who underwent EUS compared to 9,031 (76.3%) without EUS examination. Reported change of management varied widely from 0% to 56%. When used, EUS fine-needle aspiration precluded curative treatment in 37.5%-71.4%. Overall survival improvements ranged between 121 and 639 days following EUS intervention compared to patients without EUS. Smaller effect sizes were observed in a randomised controlled trial, compared to larger differences reported in observational studies. CONCLUSION: Current evidence for the effectiveness of EUS in oesophageal cancer pathways is conflicting and of limited quality. In particular, the extent to which EUS adds value to contemporary cross-sectional imaging techniques is unclear and requires formal re-evaluation.

Coaching to enhance qualified surgeons' non-technical skills: a systematic review.

INTRODUCTION: The lack of an effective continuing professional development programme for qualified surgeons, specifically one that enhances non-technical skills (NTS), is an issue receiving increased attention. Peer-based coaching, used in multiple professions, is a proposed method to deliver this. The aim of this study was to undertake a systematic review of the literature to summarize the quantity and quality of studies involving surgical coaching of NTS in qualified surgeons. METHODS: A systematic search of the literature was performed through MEDLINE, EMBASE, Cochrane Collaboration and PsychINFO. Studies were selected based on predefined inclusion and exclusion criteria. Data for the included studies was independently extracted by two reviewers and the quality of the studies evaluated using the Medical Education and Research Study Quality Instrument (MERSQI). RESULTS: Some 4319 articles were screened from which 19 met the inclusion criteria. Ten studies involved coaching of individual surgeons and nine looked at group coaching of surgeons as part of a team. Group coaching studies used non-surgeons as coaches, included objective assessment of NTS, and were of a higher quality (average MERSQI 13.58). Individual coaching studies focused on learner perception, used experienced surgeons as coaches and were of a lower quality (average MERSQI 11.58). Individual coaching did not show an objective improvement in NTS for qualified surgeons in any study. CONCLUSION: Surgical coaching of qualified surgeons' NTS in a group setting was found to be effective. Coaching of individual surgeons revealed an overall positive learner perception but did not show an objective improvement in NTS for qualified surgeons.

Macrophage-derived multinucleated giant cells: hallmarks of the aging ovary.

Inflammaging is a state of chronic, low-grade inflammation associated with aging which contributes to age-related diseases. Recently, an age-associated increase in inflammation has been documented in the mammalian ovary, which is accompanied by a shift in the immune cell profile. In this Point of View article, we consider a unique population of macrophage-derived multinucleated giant cells, found in reproductively old mouse ovaries, as potential markers or functional drivers of inflammation in ovarian aging.

A national cross-sectional survey investigating the use of endoscopic ultrasound in the diagnosis and treatment of oesophageal cancer in the UK.

AIM: To evaluate variation in the pre-pandemic use of endoscopic ultrasound (EUS) for oesophageal cancer diagnosis and treatment planning up to 2019, and which factors contributed to this. MATERIALS AND METHODS: A UK-wide online survey of oesophagogastric multidisciplinary team lead clinicians was undertaken to determine perceptions towards, and the use of, EUS to aid staging and treatment planning in oesophageal cancer. RESULTS: Thirty-five responses were received, representing 97 UK National Health Service Trusts/Health Boards. A majority of centres (n=21, 60%) did not have formal written guidance for EUS use. Although all respondents had access to EUS, a perceived lack of utility (n=7) and concerns about delaying treatment start dates (n=8) each restricted EUS use for a fifth of respondents. For most centres (n=24, 68.6%), EUS use is case-specific, whereas for 10 (28.6%) EUS is used for all patients with potentially curable disease. A majority of centres use diagnostic positron-emission tomography for radiotherapy target volume delineation (TVD), whereas 22 (62.9%) use EUS. The factors contributing to decisions to use EUS for staging, TVD and surgical planning varied between centres. The proportion of centre respondents who would request EUS in each of six clinical scenarios varied considerably. CONCLUSION: There were substantial differences in the patient and disease characteristics that are perceived to be indications for EUS use for both staging and treatment planning. Research to clarify in which patients with oesophageal cancer EUS affords benefit is required, as is urgent standardisation of its role in the diagnostic pathway.

Opportunities in cancer imaging: a review of oesophageal, gastric and colorectal malignancies.

The incidence of gastrointestinal (GI) malignancy is increasing worldwide. In particular, there is a concerning rise in incidence of GI cancer in younger adults. Direct endoscopic visualisation of luminal tumour sites requires invasive procedures, which are associated with certain risks, but remain necessary because of limitations in current imaging techniques and the continuing need to obtain tissue for diagnosis and genetic analysis; however, management of GI cancer is increasingly reliant on non-invasive, radiological imaging to diagnose, stage, and treat these malignancies. Oesophageal, gastric, and colorectal malignancies require specialist investigation and treatment due to the complex nature of the anatomy, biology, and subsequent treatment strategies. As cancer imaging techniques develop, many opportunities to improve tumour detection, diagnostic accuracy and treatment monitoring present themselves. This review article aims to report current imaging practice, advances in various radiological modalities in relation to GI luminal tumour sites and describes opportunities for GI radiologists to improve patient outcomes.

Molecular basis for the faithful replication of 5-methylcytosine and its oxidized forms by DNA polymerase ß.

DNA methylation is an epigenetic mark that regulates gene expression in mammals. One method of methylation removal is through ten-eleven translocation-catalyzed oxidation and the base excision repair pathway. The iterative oxidation of 5-methylcytosine catalyzed by ten-eleven translocation enzymes produces three oxidized forms of cytosine: 5-hydroxmethylcytosine, 5-formylcytosine, and 5-carboxycytosine. The effect these modifications have on the efficiency and fidelity of the base excision repair pathway during the repair of opposing base damage, and in particular DNA polymerization, remains to be elucidated. Using kinetic assays, we show that the catalytic efficiency for the incorporation of dGTP catalyzed by human DNA polymerase ß is not affected when 5-methylcytosine, 5-hydroxmethylcytosine, and 5-formylcytosine are in the DNA template. In contrast, the catalytic efficiency of dGTP insertion decreases ∼20-fold when 5-carboxycytosine is in the templating position, as compared with unmodified cytosine. However, DNA polymerase fidelity is unaltered when these modifications are in the templating position. Structural analysis reveals that the methyl, hydroxymethyl, and formyl modifications are easily accommodated within the polymerase active site. However, to accommodate the carboxyl modification, the phosphate backbone on the templating nucleotide shifts ∼2.5 Å to avoid a potential steric/repulsive clash. This altered conformation is stabilized by lysine 280, which makes a direct interaction with the carboxyl modification and the phosphate backbone of the templating strand. This work provides the molecular basis for the accommodation of epigenetic base modifications in a polymerase active site and suggests that these modifications are not mutagenically copied during base excision repair.

Monotherapy for toenail onychomycosis: a systematic review and network meta-analysis.

BACKGROUND: Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts and nondermatophyte moulds that accounts for approximately 50% of all nail-related disease. OBJECTIVES: This study aims to assess the effectiveness and safety of monotherapy and combination treatments for toenail onychomycosis using a network meta-analysis (NMA). METHODS: Quality of evidence was assessed using Cochrane-compliant rules and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Efficacy and safety outcomes were compared using a random-effects NMA to estimate pooled odds ratios (ORs) of direct and indirect comparisons among oral and topical treatments (PROSPERO 2015: CRD42018086912). There were not enough eligible combination and device-based therapy trials to include in the NMA. RESULTS: Of 77 randomized controlled trials, 26 were included in the ORs (8136 patients). There were no significant inconsistencies between the direct and indirect evidence. Relative effects show that the odds of mycological cure with continuous terbinafine 250 mg or continuous itraconazole 200 mg are significantly greater than topical treatments. Fluconazole, pulse regimens of terbinafine and itraconazole, and topical treatments did not differ significantly in the odds of achieving mycological cure. The ORs of adverse events occurring with oral or topical treatments were not significantly different from each other. For mycological cure, evidence was of moderate or high quality while evidence ranged from very low to high quality for adverse events. CONCLUSIONS: Our review suggests that oral and topical treatments for toenail onychomycosis are safe and effective in producing mycological cure. What's already known about this topic? Topical treatments traditionally have lower success rates than oral treatments. Oral treatments have the advantage of shorter treatment durations, but also present challenges in cases of drug-drug interactions or immunosuppression. A network meta-analysis (NMA) gathers data from indirect evidence to gain confidence about all treatment comparisons and allows for estimation of comparative effects that have not been investigated in head-to-head randomized clinical trials (RCTs). What does this study add? This NMA of efficacy and safety includes all RCTs of oral, topical, combination and device-based treatments for toenail onychomycosis, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for NMA. The odds of achieving mycological cure with continuous terbinafine 250 mg or continuous itraconazole 200 mg were significantly greater than topical treatments. Fluconazole, pulse regimens of terbinafine and itraconazole, and topical treatments did not differ significantly in the odds of achieving mycological cure.

The efficacy and safety of pulse vs. continuous therapy for dermatophyte toenail onychomycosis.

BACKGROUND: Onychomycosis is a chronic, fungal infection of the nails. Complete cure remains challenging, but oral antifungal medications have been successful in managing the fungus for a significant proportion of patients. Treatment with these drugs can be continuous or intermittent, albeit the evidence on their relative efficacies remains unclear. OBJECTIVE: To determine the relative effectiveness and safety of pulse versus continuous administration, of three common oral therapies for dermatophyte onychomycosis, by conducting multiple-treatment meta-analysis. METHODS: This systematic review and network meta-analysis compared the efficacy (as per mycological cure) and adverse event rates of three oral antifungal medications in the treatment of dermatophyte toenail onychomycosis, namely terbinafine, itraconazole and fluconazole. A total of 30 studies were included in the systematic review, while 22 were included in the network meta-analysis. RESULTS: The likelihood of mycological cure was not significantly different between continuous and pulse regimens for each of terbinafine and itraconazole. Use of continuous terbinafine for 24 weeks - but not 12 weeks - was significantly more likely to result in mycological cure than continuous itraconazole for 12 weeks or weekly fluconazole for 9-12 months. Rank probabilities demonstrated that 24-week continuous treatment of terbinafine was the most effective. There were no significant differences in the likelihood of adverse events between any continuous and pulse regimens of terbinafine, itraconazole and fluconazole. Drug treatments were similar to placebo in terms of their likelihood of producing adverse events. CONCLUSION: More knowledge about the fungal life cycle and drugs' pharmacokinetics in nail and plasma could further explain the relative efficacy and safety of the pulse and continuous treatment regimens. Our results indicate that in the treatment of dermatophyte toenail onychomycosis, the continuous and pulse regimens for terbinafine and itraconazole have similar efficacies and rates of adverse events.

Evidence-Based Practices to Promote Tobacco Cessation During Pregnancy in a Sample of Romanian General Practitioners.

Changes in confidence in implementing smoking cessation support for pregnant women was assessed among Romanian General Practitioners (GPs) before and after a training program of evidence-based clinical practices to promote quitting. The total number of physicians participating in the study was 69. Before training, 51% of GPs felt somewhat/very confident asking pregnant women about tobacco use, 39% assisted smokers with a quit plan, 38% arranged follow-up for patients. After training, 85-90% found the training informative/very informative on: how to ask patients if they smoke (89%), advising patients to quit (88%), talking about the benefits of quitting (85%), assessing patients readiness to quit (87%), assisting patients in setting a quit date (87%).

Perceptions of Responsibility for Antibiotic Resistance: Implications for Stewardship Campaigns.

Widespread public engagement with antibiotic stewardship is essential to stem the rising incidence of antibiotic-resistant infections; however, campaigns that focus on increasing knowledge have not been effective. Beliefs about who is responsible for causing and solving antibiotic resistance (AR) likely influences engagement in antibiotic stewardship behaviors. This study assesses the U.S. public's AR causal and solution responsibility attributions and the capacity for changing these attributions to inform future antibiotic stewardship campaigns. U.S. participants (N= 1,014) diverse across race, education, and geographic region were surveyed on their beliefs about responsibility for AR for themselves, the general public, healthcare providers, scientists, and drug companies. Substantial percentages of participants held causal and solution beliefs about antibiotic resistance that likely inhibit antibiotic stewardship behaviors. Participants' beliefs that they and the general public are responsible for causing and solving AR were lower than their beliefs that healthcare providers, scientists, and drug companies are responsible. Beliefs about causal responsibility for any given person or group were significantly and positively associated with beliefs about solution responsibility for that same person or group. Responsibility beliefs differed by age, education level, and racial/ethnic background. Results highlight the need for antibiotic stewardship campaigns to incorporate responsibility attribution messaging to motivate stewardship.

Finasteride for androgenetic alopecia is not associated with sexual dysfunction: a survey-based, single-centre, controlled study.

BACKGROUND: The occurrence of sexual dysfunction side-effects associated with finasteride use in men with androgenetic alopecia (AGA) is thought to be less prevalent than is publicized. There is a need to investigate sexual dysfunction among finasteride users with population-based controls. OBJECTIVE: To evaluate the presence of sexual dysfunction in men using finasteride or not using finasteride. METHOD: Adult men visiting a dermatologist's office for any reason were asked to complete a survey including a modified version of the Arizona Sexual Experience Scale (ASEX) to assess the presence of sexual dysfunction with and without finasteride use. RESULTS: Data from 762 men aged 18-82 were collected: 663 finasteride users and 99 non-finasteride users. There were no significant differences between finasteride users and non-user controls in reporting sexual dysfunction using the ASEX. Regression analysis indicated that self-reporting libido loss and reduced sexual performance, not finasteride use, predict a higher ASEX score. CONCLUSION: The use of finasteride does not result in sexual dysfunction in men with AGA. These data are consistent with other large survey-based controlled studies.

Innovating Qualitative Framing Analysis for Purposes of Media Analysis Within Public Health Inquiry.

Public health is said to lack methodological diversity and creativity in media analysis. Although the framing paradigm offers important conceptual and operational insights for undertaking media analysis in public health research, frames are described as "elusive" to measure with their analysis a "methodological black box." With this article, we aim to foster creative thinking around media analysis in public health and to make the "black box" of framing analysis more transparent, by illustrating the innovation and application of a qualitative framing analysis technique in original public health research. We provide a "how to" guide for this framing analysis method and use data to illustrate methodological challenges encountered during the research. The findings drawn from this method are contrasted with findings gained from thematic analysis applied to the same data. The article concludes by considering the benefits of this type of framing analysis within public health scholarship.

Correction to: Differences in bone quality and strength between Asian and Caucasian young men.

The second name of the ninth author, X.E. Guo, was incorrectly coded as part of his surname. The publisher apologises for the inconvenience caused.

Additional value of EUS in oesophageal cancer patients staged N0 on PET/CT: validation of a prognostic model.

BACKGROUND: Lymph node metastases are a major prognostic indicator in oesophageal cancer. Radiological staging largely influences treatment decisions and is becoming more reliant on PET and CT. However, the sensitivity of these modalities is suboptimal and is known to under-stage disease. The primary aim of this study was to validate a published prognostic model in oesophageal cancer patients staged N0 with PET/CT, which showed that EUS nodal status was an independent predictor of survival. The secondary aim was to assess the prognostic significance of pathological lymph node metastases in this cohort. METHODS: An independent validation cohort included 139 consecutive patients from a regional upper gastrointestinal cancer network staged N0 with PET/CT between 1st January 2013 and 31st June 2015. Replicating the original study, two Cox regression models were produced: one included EUS T-stage and EUS N-stage, and one included EUS T-stage and EUS N0 versus N+. The primary outcome of the prognostic model was overall survival (OS). Kaplan-Meier analysis assessed differences in OS between pathological node-negative (pN0) and node-positive (pN+) groups. A p value of < 0.05 was considered statistically significant. RESULTS: The mean OS of the validation cohort was 29.8 months (95% CI 27.1-35.2). EUS T-stage was significantly and independently associated with OS in both models (p = 0.011 and p = 0.012, respectively). EUS N-stage and EUS N0 versus N+ were not significantly associated with OS (p = 0.553 and p = 0.359, respectively). There was a significant difference in OS between pN0 and pN+ groups (χ2 13.315, df 1, p < 0.001). CONCLUSION: Lymph node metastases have a significant detrimental effect on OS. This validation study did not replicate the results of the developed prognostic model but the continued benefit of EUS in patients staged N0 with PET/CT was demonstrated. EUS remains a valuable component of a multi-modality approach to oesophageal cancer staging.

Differences in bone quality and strength between Asian and Caucasian young men.

This is a cross-sectional study to assess differences in bone quality in young Asian and Caucasian (n = 30/group) men between 25 and 35 years. We found that Asians had smaller bones, thicker and denser cortices, and more plate-like trabeculae, but stiffness did not differ between groups. INTRODUCTION: We conducted a cross-sectional study to assess differences in bone quality in young Asian and Caucasian (n = 30/group) men between 25 and 35 years. METHODS: We measured bone mineral density (BMD) at the spine, total hip (TH), femoral neck (FN), and forearm by dual energy X-ray absorptiometry (DXA), and bone geometry, density, microarchitecture, and mechanical competence at the radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) with application of individual trabecula segmentation (ITS) and trabecular and whole bone finite element analysis (FEA). We measured load-to-strength ratio to account for differences in bone size and height, respectively. We used Wilcoxon rank sum and generalized linear models adjusted for height, weight, and their interaction for comparisons. RESULTS: Asians were 3.9 % shorter and weighed 6.5 % less than Caucasians. In adjusted models: by DXA, there were no significant race-based differences in areal BMD; by HR-pQCT, at the radius, Asians had smaller total and trabecular area (p = 0.003 for both), and denser (p = 0.01) and thicker (p = 0.04) cortices at the radius; by ITS, at the radius Asians, had more plate-like than rod-like trabeculae (PR ratio p = 0.01), greater plate trabecular surface (p = 0.009) and longer rod length (p = 0.002). There were no significant race-based differences in FEA or the load-to-strength ratio. CONCLUSIONS: Asians had smaller bones, thicker and denser cortices, and more plate-like trabeculae, but biomechanical estimates of bone strength did not differ between groups. Studies are needed to determine whether these differences persist later in life.

Accuracy of contemporary oesophageal cancer lymph node staging with radiological-pathological correlation.

AIM: To evaluate the accuracy of contemporary N-staging and provide radiological-pathological correlation in patients with lymph node metastases (LNMs) that were radiologically staged N0. MATERIALS AND METHODS: One hundred and twelve patients were included who underwent surgery alone (n=41) or neoadjuvant therapy (n=71) between October 2010 and December 2015. Contrast-enhanced computed tomography (CECT), endoscopic ultrasound (EUS), and combined positron-emission tomography (PET) and CT N-stage were compared to pathological N-stage [node-negative (N0) versus node-positive (N+) groups]. Fifty LNMs from 15 patients preoperatively staged as N0 were measured and the maximum size recorded. RESULTS: Accuracy, sensitivity, and specificity of N0 versus N+ disease with CECT, EUS, and PET/CT was 54.5%, 39.7% and 77.3%, 55.4%, 42.6% and 75%, and 57.1% 35.3%, and 90.9%, respectively. All techniques were more likely to under-stage nodal disease; CECT (X2 32.890, df=1, p<0.001), EUS (X2 28.471, df=1, p<0.001), and PET/CT (X2 50.790, df=1, p<0.001). PET/CT was more likely to under-stage nodal disease than EUS (p=0.031). Median LNM size was 3 mm, with 41 (82%) of LNMs measuring <6 mm and 22 (44%) classified as micro-metastases (≤2 mm). CONCLUSION: This study has demonstrated poor N-staging accuracy in the modern era of radiological staging. Eighty-two percent of LNMs measured <6 mm, making direct identification extremely challenging on medical imaging. Future research should focus on investigating and developing alternative surrogate markers to predict the likelihood of LNMs.

Are the 'rules' for times in set up and duration of red cell transfusion too strict?

OBJECTIVES: To discover if any adverse clinical effects have been reported to the UK haemovigilance scheme, Serious Hazards of Transfusion (SHOT) relating to delays in set up of transfusion or extended transfusion time for red cell units. BACKGROUND: Current guidance for duration of transfusion is based on outdated studies that do not reflect current UK Blood Service practices. Recent evidence suggests that the '30-min rule' could be extended without adverse effects. METHODS: Aggregated data from reports to SHOT covering a 5-year period (2010-2014) were reviewed in order to identify adverse clinical outcomes related to delay in set up of a red cell transfusion of more than 30 min after removal from cold storage, or total transfusion time of longer than 5 h. RESULTS: Five years of data from SHOT shows that there were no adverse clinical events related to delays in setting up transfusion or extended transfusion time between 2010 and 2014. There were a total of 382 reports which included 143 delays in set-up, and 239 episodes where transfusion took longer than 5 h. CONCLUSIONS: Delays in set up of transfusion and extended transfusion time did not result in any adverse clinical outcomes. Current guidance may be too stringent and lead to increased wastage.

The prevalence of unsuspected onychomycosis and its causative organisms in a multicentre Canadian sample of 30 000 patients visiting physicians' offices.

BACKGROUND: Onychomycosis is difficult to treat and a concern for many patients. Prevalence estimates of onychomycosis in North American clinic samples have been higher than what has been reported for general populations. OBJECTIVE: A large, multicentre study was conducted to estimate the prevalence of toenail onychomycosis in the Canadian population. METHODS: Patients were recruited from the offices of three dermatologists and one family physician in Ontario, Canada. Nail samples for mycological testing were obtained from normal and abnormal-looking nails. This sample of 32 193 patients includes our previous published study of 15 000 patients. RESULTS: Abnormal nails were observed in 4350 patients. Of these, the prevalence of culture-confirmed toenail onychomycosis was estimated to be 6.7% (95% CI, 6.41-6.96%). Following sex and age adjustments for the general population, the estimated prevalence of toenail onychomycosis in Canada was 6.4% (95% CI, 6.12%-6.65%). The distribution of fungal organisms in culture-confirmed onychomycosis was 71.9% dermatophytes, 20.4% non-dermatophyte moulds and 7.6% yeasts. Toenail onychomycosis was four times more prevalent in those over the age of 60 years than below the age of 60 years. CONCLUSION: The present data highlights that onychomycosis may be a growing medical concern among ageing patients.

Airway epithelial NF-κB activation promotes the ability to overcome inhalational antigen tolerance.

BACKGROUND: Inhalational antigen tolerance typically protects against the development of allergic airway disease but may be overcome to induce allergic sensitization preceding the development of asthma. OBJECTIVES: We examined in vivo whether pre-existing inhalational antigen tolerance could be overcome by activation of the transcription factor NF-κB in conducting airway epithelial cells, and used a combination of in vivo and in vitro approaches to examine the mechanisms involved. METHODS: Wild-type and transgenic mice capable of expressing constitutively active IκB kinase ß (CAIKKß) in airway epithelium were tolerized to inhaled ovalbumin. Twenty-eight days later, the transgene was transiently expressed and mice were exposed to inhaled OVA on Day 30 in an attempt to overcome inhalational tolerance. RESULTS: Following ovalbumin challenge on days 40-42, CAIKKß mice in which the transgene had been activated exhibited characteristic features of allergic airway disease, including airway eosinophilia and methacholine hyper-responsiveness. Increases in the CD103(+) and CD11b(HI) lung dendritic cell populations were present in CAIKKß mice on Day 31. Bronchoalveolar lavage from mice expressing CAIKKß mice induced CD4(+) T cells to secrete T(H)2 and T(H)17 cytokines, an effect that required IL-4 and IL-1 signalling, respectively. CAIKKß mice on Dox demonstrated increased numbers of innate lymphoid type 2 cells (ILC2) in the lung, which also exhibited elevated mRNA expression of the T(H)2-polarizing cytokine IL-4. Finally, airway epithelial NF-kB activation induced allergic sensitization in CAIKKß mice on Dox that required IL-4 and IL-1 signalling in vivo. CONCLUSIONS: Our studies demonstrate that soluble mediators generated in response to airway epithelial NF-κB activation orchestrate the breaking of inhalational tolerance and allergic antigen sensitization through the effects of soluble mediators, including IL-1 and IL-4, on pulmonary dendritic cells as well as innate lymphoid and CD4(+) T cells.