Prevalence of dermatitis including allergic contact dermatitis from medical devices used by children and adults with Type 1 diabetes mellitus: A systematic review and questionnaire study.

Use of medical devices (MDs), that is, glucose sensors and insulin pumps, in patients with Type 1 diabetes mellitus (T1D) has proven an enormous advantage for disease control. Adverse skin reactions from these MDs may however hamper compliance. The objective of this study was to systematically review and analyse studies assessing the prevalence and incidence of dermatitis, including allergic contact dermatitis (ACD) related to MDs used in patients with T1D and to compare referral routes and the clinical investigation routines between clinics being part of the European Environmental and Contact Dermatitis Research Group (EECDRG). A systematic search of PubMed, EMBASE, CINAHL and Cochrane databases of full-text studies reporting incidence and prevalence of dermatitis in persons with T1D using MDs was conducted until December 2021. The Newcastle-Ottawa Scale was used to assess study quality. The inventory performed at EECRDG clinics focused on referral routes, patient numbers and the diagnostic process. Among the 3145 screened abstracts, 39 studies fulfilled the inclusion criteria. Sixteen studies included data on children only, 14 studies were on adults and nine studies reported data on both children and adults. Participants were exposed to a broad range of devices. Skin reactions were rarely specified. It was found that both the diagnostic process and referral routes differ in different centres. Further data on the prevalence of skin reactions related to MDs in individuals with T1D is needed and particularly studies where the skin reactions are correctly diagnosed. A correct diagnosis is delayed or hampered by the fact that, at present, the actual substances within the MDs are not declared, are changed without notice and the commercially available test materials are not adequately updated. Within Europe, routines for referral should be made more standardized to improve the diagnostic procedure when investigating patients with possible ACD from MDs.

A literature review and expert consensus statement on diagnostics in suspected metal implant allergy.

BACKGROUND: Although rare, allergic reactions to metal implants represent a diagnostic challenge in view of missing guidelines. OBJECTIVES: To develop an European expert consensus on characteristics of metal allergy reactions and the utility of various diagnostic tools in suspected metal implant allergy. METHODS: A nominal group technique (NGT) was applied to develop consensus statements. Initially an online literature database was created on a secure server to enable a comprehensive information. Twenty-three statements were formulated on potential aspects of metal implant allergy with a focus on diagnostics and grouped into five domains. For the consensus development, the panel of 12 experts initially did refine and reformulate those statements that were ambiguous or had unclear wording. By face-to-face (9/12) or virtual participation (3/12), an anonymous online voting was performed. RESULTS: Consensus (≥80% of agreement) was reached in 20/23 statements. The panel agreed that implant allergy despite being rare should be considered in case of persistent unexplained symptoms. It was, however, recommended to allow adequate time for resolution of symptoms associated with healing and integration of an implant. Obtaining questionnaire-aided standardized medical history and standardized scoring of patient outcomes was also considered an important step by all experts There was broad consensus regarding the utility/performance of patch testing with additional late reading. It was recognized that the lymphocyte transformation test (LTT) has to many limitations to be generally recommended. Prior to orthopaedic implant, allergy screening of patients without a history of potential allergy to implant components was not recommended. CONCLUSIONS: Using an expert consensus process, statements concerning allergy diagnostics in suspected metal implant allergy were created. Areas of nonconsensus were identified, stressing uncertainty among the experts around topics such as preoperative testing in assumed allergy, histological correlate of periimplant allergy and in vitro testing, which underscores the need for further research.

Long-term follow-up of hand eczema in hairdressers: a prospective cohort study of Danish hairdressers graduating from 1985 to 2007.

BACKGROUND: Occupational hand eczema is common among hairdressers and implementing effective preventive measures requires a good understanding of the disease's epidemiology. OBJECTIVE: To investigate the long-term development of hand eczema (HE) in hairdressers. METHODS: A prospective cohort study of all hairdressers graduating from Danish hairdressing vocational schools from 1985 to 2007 was conducted. A self-administered questionnaire was sent in 2009 with follow-up in 2020. Data from the Danish labour market supplementary pension scheme provided information on yearly affiliation with the hairdressing trade. RESULTS: The cumulative lifetime prevalence of HE increased from 42.3% at baseline to 45.2% at follow-up (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.0-1.2). The incidence rate decreased from 42.8 cases/1000 person-years (95% CI, 40.8-44.8) at baseline to 3.4 cases/1000 person-years (95% CI, 2.5-4.6) within the follow-up period. HE onset occurred within 8 years of beginning an apprenticeship for >90% of cases and occurred within the apprenticeship period for 68% of cases. The risk factors associated with having had HE at baseline were a previous positive patch test (adjusted OR [aOR], 5.3; 95% CI, 4.2-6.6), a history of atopic dermatitis (aOR, 3.4; 95% CI, 2.9-4.0) and female sex (aOR, 1.8; 95% CI 1.4-2.3). The most important risk factors at follow-up were previous HE (aOR, 10.1; 95% CI, 7.3-13.8) and a positive patch test within the follow-up period (aOR, 4.5; 95% CI, 3.0-6.8). Among the hairdressers who had HE at baseline, 65.5% exhibited remission, whereas 34.6% had persistent and often severe HE at follow-up. Hairdressers with persistent HE were the subgroup of the study population most frequently affected by the risk factors identified for HE. CONCLUSIONS: Primary prevention of HE should focus on hairdressing apprentices and fully trained hairdressers who have recently graduated. Approximately one-third of trained hairdressers develop persistent and often severe HE, emphasizing the need for early intervention.

Patch test informed consent form: position statement by European Academy of Dermatology and Venereology Task Force on Contact Dermatitis.

BACKGROUND: To our knowledge, an international consensus is lacking regarding the development of an adequate informed consent form for a patch test (PT) and the information that should be included in such document. OBJECTIVES: The aim of the study was to reach a consensus on the specific points that need to be addressed in a PT consent form. METHODS: A Delphi survey, comprising 2 rounds and 1 final discussion, was used to gather and analyse data, which was conducted over the Internet. Each statement that reached a consensus with the respondents (9 expert dermatologists from Europe) was defined as a median consensus score (MED) of ≥7 and agreement among panelists as an interquartile range (IQR) of ≤3. All study participants were members of the EADV task force on contact dermatitis. RESULTS: The expert panel addressed several topics that should be included in an informed consent form for a PT: introduction, preparation for PT, testing procedure, allowed activities, adverse events and additional authorizations. CONCLUSIONS: Our results assess recommendations regarding points to be contained in an informed consent form for a PR. Future actions towards standardization and harmonization of this specific consent form are needed.

Position statement: The need for EU legislation to require disclosure and labelling of the composition of medical devices.

BACKGROUND: In recent years, skin reactions secondary to the use of medical devices (MD), such as allergic contact dermatitis have increasingly been observed (e.g. to continuous blood sugar monitoring systems, insulin pumps, wound dressings, medical gloves, etc.): this is regarded as a developing epidemic. Lack of labelling of the composition of MD, as well as frequent lack of cooperation of manufacturers to disclose this relevant information, even when contacted by the clinician for the individual case of an established adverse reaction, significantly impede patient care. OBJECTIVES: To advocate for full ingredient labelling in the implementation of EU regulation for MD. METHODS: This position paper reviews the scientific literature, the current regulatory framework adopted for MD to date, and the likely impact, including some costs data in case of the absence of such labelling. RESULTS: Efforts made by several scientific teams, who are trying to identify the culprit of such adverse effects, either via asking for cooperation from companies, or using costly chemical analyses of MD, can only partly, and with considerable delay, compensate for the absence of meaningful information on the composition of MD; hence, patient management is compromised. Indeed, without knowing the chemical substances present, physicians are unable to inform patients about which substances they should avoid, and which alternative MD may be suitable/tolerated. CONCLUSION: There is an urgent need for full and accurate labelling of the chemical composition of MD in contact with the human body.

The epidemic of methylisothiazolinone contact allergy in Europe: follow-up on changing exposures.

BACKGROUND: Methylisothiazolinone (MI) has caused an unprecedented epidemic of contact allergy in Europe and elsewhere. Subsequently, regulatory action has been taken, at least in Europe, aiming at reducing risk of MI sensitization. OBJECTIVE: To follow-up on the prevalence of contact allergy to MI in consecutively patch tested patients and assess the spectrum of products containing MI or methylchloroisothiazolinone (MCI)/MI in patients positive to MI which elicited current allergic contact dermatitis. METHODS: A cross-sectional survey was performed in 2016 and 2017, including all adult patients patch tested with the baseline series (including MI 0.2% aq.) between 1 May and 31 October at 14 centres in 11 European countries. Patients with positive reactions (+ to +++) to MI were further examined regarding history, clinical characteristics and eliciting products, which were categorized into 34 types and 4 classes (leave-on, rinse-off, household, occupational). The results were compared with the reference year 2015. RESULTS: A total of 317 patients, n = 202 of 4278 tested in 2016 (4.72%) and n = 115 of 3879 tested in 2017 (2.96%), had positive reactions to MI; the previous result from 2015 was 5.97% (P < 0.0001). The share of currently relevant contact allergy among all positive reactions declined significantly as well (P = 0.0032). Concerning product classes, a relative decline of leave-on and a relative increase of rinse-off and household products was noted. CONCLUSION: The prevalence of MI contact allergy decreased by 50% from 2015 to 2017. As a consequence of regulation, the share of cosmetics products (leave-on in particular) eliciting allergic contact dermatitis is decreasing. The chosen method of analysing causative products in sensitized patients has proven useful to monitor effects of intervention.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. PATIENTS AND METHODS: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). RESULTS: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). CONCLUSION: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00145314.

Predictive value of a multi-biomarker disease activity score for clinical remission and radiographic progression in patients with early rheumatoid arthritis: a post-hoc study of the OPERA trial.

OBJECTIVES: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial. METHOD: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year. RESULTS: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01-1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96-1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003). CONCLUSION: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months.

Osteoradionecrosis of the mandible after radiotherapy for head and neck cancer: risk factors and dose-volume correlations.

Background: The project aimed at determining the incidence of mandibular osteoradionecrosis (ORN) after radiotherapy, possible risk factors, and mandibular dose-volume effects in a large cohort of head and neck cancer patients (HNC). Methods: The cohort consisted of 1224 HNC patients treated with 66-68 Gy in 2007-2015 predominantly with IMRT. ORN cases were defined from clinical observations at follow-up and through hospital code diagnostics after oral-maxillofacial surgery and cross-checked with the national Danish Head and Neck Cancer database. In a nested case-control study, patients with ORN cases were matched with two controls (1:2) and pre-RT dental procedures including surgery to the mandible were documented. Multivariable Cox regression analysis was applied using demographic and treatment variables including dental procedures, smoking and tumor characteristics, and combined with dosimetric data. Mean mandibular dose (Dmean) was pre-selected for the multivariable model. Results: ORN was recorded in 56 cases (4.6%) with a median time to event of 10.9 months (range 1.8-89.7) after RT, 90% occurred within 37.4 months. Median follow-up time was 22 months (0.3-95). Average Dmean was significantly higher in the ORN event cohort and significant dose-volume differences were observed for population mean DVH doses between 30 Gy and 60 Gy. In univariable analysis, smoking (HR = 1.69; CI 1.14-2.5), pre-RT surgery/tooth extraction (HR = 2.76; 1.48-5.14), and several dosimetric parameters including Dmean (HR = 1.05, 1.02-1.08) were all significantly associated with ORN. Dmean and surgery/tooth extraction remained significant predictors of ORN in multivariable analysis, HR = 1.04 (CI 1.01-1.07) and HR = 2.09 (CI 1.1-3.98), respectively, while smoking only retained its significance in an interaction analysis with pre-RT dental procedures. Conclusion: The onset of ORN of the mandible was early (median 10.8 months) and the incidence low (4.6%) after IMRT in HNC cancer patients. Surgery to the mandible and pre-RT tooth extraction, tobacco smoking, and treatment dose were associated with the development of ORN.

NTCP model validation method for DAHANCA patient selection of protons versus photons in head and neck cancer radiotherapy.

Introduction: Prediction models using logistic regression may perform poorly in external patient cohorts. However, there is a need to standardize and validate models for clinical use. The purpose of this project was to describe a method for validation of external NTCP models used for patient selection in the randomized trial of protons versus photons in head and neck cancer radiotherapy, DAHANCA 35. Material and methods: Organs at risk of 588 patients treated primarily with IMRT in the randomized controlled DAHANCA19 trial were retrospectively contoured according to recent international recommendations. Dose metrics were extracted using MatLab and all clinical parameters were retrieved from the DAHANCA database. The model proposed by Christianen et al. to predict physician-rated dysphagia was validated through the closed testing, where change of the model intercept, slope and individual beta's were tested for significant prediction improvements. Results: Six months prevalence of dysphagia in the validation cohort was 33%. The closed testing procedure for physician-rated dysphagia showed that the Christianen et al. model needed an intercept refitting for the best match for the Danish patients. The intercept update increased the risk of dysphagia for the validation cohort by 7.9 ± 2.5% point. For the raw model performance, the Brier score (mean squared residual) was 0.467, which improved significantly with a new intercept to 0.415. Conclusions: The previously published Dutch dysphagia model needed an intercept update to match the Danish patient cohort. The implementation of a closed testing procedure on the current validation cohort allows quick and efficient validation of external NTCP models for patient selection in the future.

Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer.

Background: Treatment of patients with locally advanced rectal cancer (LARC) is based on a combination of chemo-radiotherapy (CRT) and surgery. The rate of distant recurrences remains over 25%. Circulating cell-free DNA (cfDNA) in plasma is a mixture of normal and cancer-specific DNA segments and is a promising biomarker in patients with colorectal cancer. The aim of our study was to investigate plasma cfDNA as a prognostic marker for outcome in patients with LARC treated with neoadjuvant CRT and surgery. Patients and methods: In total, 123 patients with LARC were included in 2 biomarker studies. Patients were treated with neoadjuvant CRT before TME surgery. Fifty-two (42%) of the patients received induction chemotherapy with capecitabine + oxaliplatin. Total cfDNA was measured by direct fluorescent assay in EDTA plasma samples obtained at baseline, after induction chemotherapy, and after CRT. Serial samples 5 years after surgery were collected in 51 patients (41%). Results: Median follow-up was 55 months. Distant or local recurrence was seen in 30.9% of the patients. Patients with baseline cfDNA levels above the 75th quartile had a higher risk of local or distant recurrence and shorter time to recurrence compared with patients with plasma cfDNA below the 75th percentile (HR = 2.48, 95% CI: 1.3-4.8, P = 0.007). The same applied to disease-free survival (DFS) (HR = 2.43, 95% CI: 1.27-4.7, P = 0.015). In multivariate analysis, a high cfDNA level was significantly associated with time to progression and DFS. During follow-up, the association remained significant regardless of time point for sample analysis. Conclusion: We have demonstrated an association between a high baseline plasma level of cfDNA and increased risk of recurrence, shorter time to recurrence, and shorter DFS in patients with LARC. Consequently, cfDNA could potentially improve pre- and post-treatment risk assessment and facilitate individualized therapy for patients with LARC.

The challenges and possibilities of public access defibrillation.

Out-of-hospital cardiac arrest (OHCA) is a major health problem that affects approximately four hundred and thousand patients annually in the United States alone. It is a major challenge for the emergency medical system as decreased survival rates are directly proportional to the time delay from collapse to defibrillation. Historically, defibrillation has only been performed by physicians and in-hospital. With the development of automated external defibrillators (AEDs), rapid defibrillation by nonmedical professionals and subsequently by trained or untrained lay bystanders has become possible. Much hope has been put to the concept of Public Access Defibrillation with a massive dissemination of public available AEDs throughout most Western countries. Accordingly, current guidelines recommend that AEDs should be deployed in places with a high likelihood of OHCA. Despite these efforts, AED use is in most settings anecdotal with little effect on overall OHCA survival. The major reasons for low use of public AEDs are that most OHCAs take place outside high incidence sites of cardiac arrest and that most OHCAs take place in residential settings, currently defined as not suitable for Public Access Defibrillation. However, the use of new technology for identification and recruitment of lay bystanders and nearby AEDs to the scene of the cardiac arrest as well as new methods for strategic AED placement redefines and challenges the current concept and definitions of Public Access Defibrillation. Existing evidence of Public Access Defibrillation and knowledge gaps and future directions to improve outcomes for OHCA are discussed. In addition, a new definition of the different levels of Public Access Defibrillation is offered as well as new strategies for increasing AED use in the society.

Short contact with nickel causes allergic contact dermatitis: an experimental study.

BACKGROUND: Knowledge about the required duration of exposure for elicitation of allergic nickel dermatitis in nickel-allergic individuals is limited. However, it often has been proposed that short skin contact is safe. OBJECTIVES: To examine whether repeated skin contact with nickel over short time periods (3 × 10 min) can elicit allergic nickel dermatitis. METHODS: Sixteen nickel-allergic adults and 10 controls were exposed to, respectively, nickel- and aluminium-containing discs on each volar forearm and on each earlobe for 3 × 10 min. One arm was pretreated for 24 h with sodium lauryl sulfate (SLS) 0·5% under occlusion before exposure. One aluminium and one nickel exposure site were clinically evaluated, and blood flow was measured with laser Doppler flowmetry at day 2 and day 4. RESULTS: Ten of 16 (63%) nickel-allergic participants developed allergic nickel dermatitis on SLS-pretreated arm skin and three of 16 (19%) developed it on normal skin on the earlobe. On the SLS-pretreated arms of nickel-allergic participants, blood flow increased significantly more on the nickel-exposed skin than on the aluminium-exposed skin on days 2 and 4. No change in clinical reactivity or blood flow was found on normal forearm skin in nickel-allergic participants or on any skin in controls. CONCLUSIONS: This experimental study showed that relatively short repeated skin contact (3 × 10 min) with metallic nickel elicits allergic nickel dermatitis in irritated skin and at sites with previous dermatitis. The results support the restrictions in current nickel regulation.

Effect of atopic skin stressors on natural moisturizing factors and cytokines in healthy adult epidermis.

BACKGROUND: Epidermal deficiency of filaggrin, and the derived natural moisturizing factors (NMFs), is associated with increased risk of atopic dermatitis (AD). While filaggrin gene mutations cause filaggrin deficiency, there is limited insight into the causative environmental factors. OBJECTIVES: To explore the effect of selected exogenous skin stressors on NMF and skin cytokine levels in healthy adult epidermis. METHODS: Forty healthy volunteers (aged 18-49 years) were exposed to hard, soft and chlorinated water, 0·5% sodium lauryl sulfate, house dust mite, cat allergen, staphylococcal enterotoxin B (SEB), cooling and histamine. Participants were tape-stripped and biophysiological measurements performed. NMF was determined after 24 and 48 h, whereas skin cytokines were measured after 24 h for selected exposures. RESULTS: At 24 h, a significant decrease in NMFs was observed for soft (0·51 ± 0·19 g m-2 h-1 ) and hard water (0·61 ± 0·32 g m-2 h-1 ) compared with occlusion alone (0·71 ± 0·18 g m-2 h-1 ). Hard water led to increased levels of interleukin (IL)-4, interferon (IFN)-γ and IL-10. Exposure to house dust mite and SEB led to a significant decrease in NMFs after 24 h (0·77 ± 0·28 and 0·80 ± 0·28 g m-2 h-1 , respectively) compared with occlusion alone (1·00 ± 0·42 g m-2 h-1 ). House dust mite led to an increase in IFN-γ, IL-2 and IL-4 vs. the nonoccluded control site. CONCLUSIONS: Based on experimental exposure to selected atopic skin stressors, we conclude that NMFs levels are decreased along with increased secretion of various skin cytokines in healthy individuals. Our data highlight environmental factors that might play a role in AD pathophysiology.

The association between atopic dermatitis and hand eczema: a systematic review and meta-analysis.

BACKGROUND: Atopic dermatitis (AD) and hand eczema (HE) are common chronic and relapsing inflammatory skin conditions that often co-occur. OBJECTIVES: While several studies have addressed their relationship, the exact association estimate is unknown. METHODS: We systematically reviewed published literature on the association between AD and HE in PubMed, Embase and Web of Science using the following search terms: (atopic dermatitis OR atopic eczema) AND (hand dermatitis OR hand eczema). Meta-analyses were then performed to examine the association between AD and the point, 1-year and lifetime prevalence of HE, respectively. RESULTS: We identified 35 relevant studies, of which 26 were included in the meta-analyses. AD was associated with an increased prevalence of HE with regard to point [odds ratio (OR) 2·35; 95% confidence interval (CI) 1·47-3·76], 1-year (OR 4·29; 95% CI 3·13-5·88) and lifetime prevalence (OR 4·06; 95% CI 2·72-6·06). Furthermore, positive associations between AD and occupational HE were identified when assessing the 1-year (OR 4·31; 95% CI 2·08-8·91) and lifetime prevalence (OR 2·81; 95% CI 2·08-3·79). Similar positive associations were found in the general population studies, i.e. OR 4·19 (95% CI 3·46-5·08) and OR 5·69 (95% CI 4·41-7·36). CONCLUSIONS: Important study limitations include the wide use of questionnaire studies, and lack of prospective studies as well as poor clinical phenotype descriptions. In conclusion, our systematic review and meta-analysis showed that patients with AD had a strongly increased prevalence of HE. Clinicians should continue to guide patients with AD away from occupations with a high risk of HE.

Changes in filaggrin degradation products and corneocyte surface texture by season.

BACKGROUND: During the winter in northern countries, the risk of dermatitis is increased due to low temperature and humidity. Dermatitis is particularly common on weather-exposed skin such as the cheeks and hands. Recently, increased numbers of unidentified nanosized protrusions on the corneocyte surface were associated with dermatitis and deficiency of natural moisturizing factor (NMF). OBJECTIVES: To investigate the effect of season on NMF levels and corneocyte surface texture in cheek and hand skin of healthy adults. METHODS: Eighty healthy volunteers (40 male and 40 female) were recruited: 40 aged 18-40 years and 40 aged ≥ 70 years. Cheek and dorsal hand skin was tape stripped in the winter and summer. Analysis for NMF and corneocyte surface texture was done (Dermal Texture Index, DTI). Potential confounders were registered and adjusted for. RESULTS: In cheek skin, NMF levels were reduced and DTI elevated during the winter compared with the summer. Older participants had higher NMF levels than younger participants. In the summer, DTI level was dependent on self-reported ultraviolet exposure. In hand skin, NMF levels were higher during the winter than in the summer, and female participants had higher NMF levels than male participants. CONCLUSIONS: Seasonal effects on NMF and DTI on the cheeks and hands were found, suggesting an influence of climatic factors at the biochemical and ultrastructural levels. Significant variations were also observed regarding age and sex, making it difficult to draw firm conclusions. Our study adds new pieces to the puzzle of seasonal differences in xerosis and dermatitis.

Circulating serum interleukin-6, serum chitinase-3-like protein-1, and plasma vascular endothelial growth factor are not predictive for remission and radiographic progression in patients with early rheumatoid arthritis: post-hoc explorative and validation studies based on the CIMESTRA and OPERA trials.

OBJECTIVE: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs). METHOD: Treatment-naïve patients with early RA (< 6 months' duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers' relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman's correlation and logistic regression analyses. RESULTS: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study. CONCLUSION: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.

Importance of beta-blocker dose in prevention of ventricular tachyarrhythmias, heart failure hospitalizations, and death in primary prevention implantable cardioverter-defibrillator recipients: a Danish nationwide cohort study.

Aims: There is a paucity of studies investigating a dose-dependent association between beta-blocker therapy and risk of outcome. In a nationwide cohort of primary prevention implantable cardioverter-defibrillator (ICD) patients, we aimed to investigate the dose-dependent association between beta-blocker therapy and risk of ventricular tachyarrhythmias (VT/VF), heart failure (HF) hospitalizations, and death. Methods and results: Information on ICD implantation, endpoints, comorbidities, beta-blocker usage, type, and dose were obtained through Danish nationwide registers. The two major beta-blockers carvedilol and metoprolol were examined in three dose levels; low (metoprolol ≤ 25 mg; carvedilol ≤ 12.5 mg), intermediate (metoprolol 26-199 mg; carvedilol 12.6-49.9 mg), and high (metoprolol ≥ 200 mg; carvedilol ≥ 50 mg). Time to events was investigated utilizing multivariate Cox models with beta-blocker as a time-dependent variable. From 2007 to 2012, 2935 first-time ICD devices were implanted. During follow-up, 399 patients experienced VT/VF, 728 HF hospitalizations and 361 died. As compared with patients not on beta-blockers, low, intermediate, and high dose had significantly reduced risk of HF hospitalizations {hazard ratio (HR) = 0.68 [0.54-0.87], P = 0.002; HR = 0.53 [0.42-0.66], P < 0.001; HR = 0.43 [0.34-0.54], P < 0.001} and death (HR = 0.47 [0.35-0.64], P < 0.001; HR = 0.29 [0.22-0.39], P = 0.001; HR = 0.24 [0.18-0.33], P < 0.001). For the endpoint of VT/VF, only intermediate and high dose beta-blocker was associated with significantly reduced risk (HR = 0.58 [0.43-0.79], P < 0.001; HR = 0.53 [0.39-0.72], P < 0.001). No significant difference was found between comparable doses of carvedilol and metoprolol on any endpoint (P = 0.06-0.94). Conclusion: In primary prevention ICD patients, beta-blocker therapy was associated with significantly reduced risk of all endpoints, as compared with patients not on beta-blocker, with the suggestion of a dose-dependent effect. No detectable difference was found between comparable doses of carvedilol and metoprolol.

Implementation and effectiveness of a video-based debriefing programme for neonatal resuscitation.

BACKGROUND: Approximately 5%-10% of newly born babies need intervention to assist transition from intra- to extrauterine life. All providers in the delivery ward are trained in neonatal resuscitation, but without clinical experience or exposure, training competency is transient with a decline in skills within a few months. The aim of this study was to evaluate whether neonatal resuscitations skills and team performance would improve after implementation of video-assisted, performance-focused debriefings. METHODS: We installed motion-activated video cameras in every resuscitation bay capturing consecutive compromised neonates. The videos were used in debriefings led by two experienced facilitators, focusing on guideline adherence and non-technical skills. A modification of Neonatal Resuscitation Performance Evaluation (NRPE) was used to score team performance and procedural skills during a 7 month study period (2.5, 2.5 and 2 months pre-, peri- and post-implementation) (median score with 95% confidence interval). RESULTS: We compared 74 resuscitation events pre-implementation to 45 events post-implementation. NRPE-score improved from 77% (75, 81) to 89% (86, 93), P < 0.001. Specifically, the sub-categories "group function/communication", "preparation and initial steps", and "positive pressure ventilation" improved (P < 0.005). Adequate positive pressure ventilation improved from 43% to 64% (P = 0.03), and pauses during initial ventilation decreased from 20% to 0% (P = 0.02). Proportion of infants with heart rate > 100 bpm at 2 min improved from 71% pre- vs. 82% (P = 0.22) post-implementation. CONCLUSION: Implementation of video-assisted, performance-focused debriefings improved adherence to best practice guidelines for neonatal resuscitation skill and team performance.