Biotransformation and toxicokinetics of 2-phenoxyethanol after oral exposure in humans: a volunteer study.

2-Phenoxyethanol (PhE) is an aromatic glycol ether and is used in a variety of functions and applications, e.g., as preservative in pharmaceuticals, cosmetic and personal care products, as biocide in disinfectants (e.g. human hygiene), or as a solvent in formulations (e.g. coatings, functional fluids). Despite its widespread use, little is yet known on its biotransformation and toxicokinetics in humans. Therefore, a pilot study was conducted with oral administration of PhE (5 mg/kg body weight) to five volunteers. Blood and urine samples were collected and analyzed for PhE and three of its presumed metabolites up to 48 h post-exposure. Additionally, one volunteer was dermally exposed to PhE and monitored until 72 h post-exposure. PhE was rapidly resorbed following both oral and dermal application with tmax-levels in blood of about 1 h and 3 h, respectively. Metabolism of PhE was observed to be rather extensive with phenoxyacetic acid (PhAA) and 4-hydroxyphenoxyacetic acid (4-OH-PhAA) as the main metabolites found in blood and urine following oral and dermal exposure. PhE was excreted rapidly and efficiently via urine mostly in metabolized form: following oral exposure, on average 77% and 12% of the applied dose was excreted within 48 h as PhAA and 4-OH-PhAA, respectively. A similar metabolism pattern was observed following the single dermal exposure experiment. The obtained data on biotransformation and toxicokinetics of PhE in humans provide valuable information on this important chemical and will be highly useful for pharmacokinetic modelling and evaluation of human PhE exposure.

[Economic Relevance of Preventable Prohibitions of Employment in Bavarian Schools]. / Ökonomische Relevanz vermeidbarer Beschäftigungsverbote an Schulen in Bayern.

INTRODUCTION: According to the Maternity Protection Act, an occupational risk of infection (e. g. in childcare) - combined with individual immunity gaps - can result in an irresponsible risk for pregnant women in the workplace. If this risk cannot be eliminated by any other means, the employer must impose a prohibition of employment (PE) for the pregnant woman concerned. We classified PE as preventable if the underlying immunity gaps could have been closed by immunisation prior to pregnancy. METHODS: From 01.09.2016 to 25.03.2020, 1922 pregnant employees of Bavarian state schools obtained medical counselling on their occupational risk of infection as part of a research project. If the individual combination of occupational-risk profile and immunity status resulted in an irresponsible risk for the pregnancy, a PE was recommended by the attending physician. We determined the proportion of PE that would have theoretically been preventable by full immunisation prior to pregnancy and approximated the resulting - theoretically preventable - loss of working hours and personnel costs. RESULTS: In 425 cases (22%), a PE was deemed necessary by the attending physician, whereby 193 (45%) were retrospectively classified as theoretically preventable. Of these cases, 53 PE (27%) were temporary (valid until the 20th week of pregnancy) and 140 were long-term (valid for the complete duration of the pregnancy). Based on these results, we approximated a loss of 2,746 working weeks for our collective, which entails theoretically preventable personnel costs totalling 5,763,305 € for the observation period of our study (3.6 years). We then extrapolated estimates for all employees of Bavarian state schools and found a loss of 4,260 working weeks and theoretically preventable personnel costs amounting to almost 8,941,000 € per year during our observation period. CONCLUSION: Theoretically preventable PE caused by immunity gaps can entail a considerable loss of working hours and high personnel costs. Therefore, we should step up measures aimed at improving vaccination rates in women and increasing their willingness to be vaccinated. In view of the changes in legal and regulatory conditions in Germany since 2020, new investigations should be made as soon as there is sufficient data after the general employment prohibitions due to the SARS-CoV-2-pandemic have been lifted.

Human metabolism and excretion kinetics of benzotriazole UV stabilizer UV-327 after single oral administration.

UV-327 (2-(5-chloro-benzotriazol-2-yl)-4,6-di-(tert-butyl)phenol) is used as an ultraviolet (UV) absorber in plastic products and coatings. Due to its ubiquitous distribution in the environment, human exposure is conceivable. In the study presented herein, initial information on the human in vivo metabolism of UV-327 was obtained by single oral administration to three volunteers. Urine and blood samples were collected up to 72 h after exposure. One study participant additionally donated plasma samples. Maximum blood and plasma levels of UV-327 and its two monohydroxylated metabolites UV-327-6-mOH and UV-327-4-mOH were reached 6 h post-exposure. Almost the entire amount found in blood and plasma samples was identified as UV-327, whereas the two metabolites each accounted for only 0.04% of the total amount, indicating that UV-327 is well-absorbed from the intestine, but only partially metabolized. Plasma to blood ratios of UV-327, UV-327-6-mOH, and UV-327-4-mOH ranged from 1.5 to 1.6. Maximum urinary excretion rates of UV-327, UV-327-6-mOH, UV-327-4-mOH, and UV-327-4 + 6-diOH were reached 9-14 h post-exposure. However, only about 0.03% of the orally administered dose of UV-327 was recovered as UV-327 and its metabolites in urine, indicating that biliary excretion may be the major route of elimination of UV-327 and its hydroxylated metabolites. The present study complements the insight in the complex absorption, distribution, metabolism, and elimination (ADME) processes of benzotriazole UV stabilizers (BUVSs).

Syncarcinogenesis of natural UV radiation and polycyclic aromatic hydrocarbons in the development of squamous cell carcinomas of the skin?

Squamous cell carcinomas (SCC) of the skin can be induced by occupational exposures to polycyclic aromatic hydrocarbons (PAHs), as in tar and soot, or to UV radiation and can be recognized and compensated as occupational diseases. A possible syncarcinogenic effect of these exposures in the development of SCC in humans is under discussion. For the scientific validation of this question, a systematic literature search was conducted using the databases PubMed, Web of Science, and Scopus. Studies on individuals with SCC of the skin and their precursors as well as occupational, non-occupational, or therapeutic exposure to UV radiation and PAHs were selected. In addition, animal studies with exposure to UV radiation and PAHs were evaluated. After screening the abstracts of 510 identified studies, the full texts of 131 studies were reviewed. None of the epidemiological studies provided robust evidence for a syncarcinogenesis of PAHs and UV radiation in the development of SCC of the skin in humans. Nevertheless, as there are indications for a (super-)additive effect of UV radiation and PAH exposure from animal studies and mechanistic investigations, syncarcinogenesis seems possible. However, quantitative dose-response relationships are lacking which would allow comparison of the onset of an adverse effect between the different exposure levels.

Human metabolism and kinetics of the UV absorber 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) after oral administration.

2-(2H-Benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328; CAS: 25973-55-1) is an ultraviolet light (UV) absorber which belongs to the class of hydroxy phenol benzotriazoles. Therefore, UV 328 is added to plastics and other polymers due to its photostability to prevent discoloration and prolong product stability which may result in an exposure of consumers. However, information about the toxic effects on humans and the human metabolism are still lacking. In the present study, human metabolism pathways of UV 328 and its elimination kinetics were explored. For that purpose, three healthy volunteers were orally exposed to a single dose of 0.3 mg UV 328/kg bodyweight. UV 328 and its metabolites were investigated in blood and urine samples collected until 48 and 72 h after exposure, respectively. Thereby, previously published analytical procedures were applied for the sample analysis using dispersive liquid-liquid microextraction and subsequent measurement via gas chromatography coupled to tandem mass spectrometry with advanced electron ionization. UV 328 was found to be oxidized at its alkyl side chains leading to the formation of hydroxy and/or oxo function with maximum blood concentrations at 8-10 h after exposure for UV 328-6/3-OH, UV 328-4/3-OH and UV 328-4/3-CO. In contrast, a plateau for UV 328-4/3-CO-6/3-OH levels was reached around 10 h post-dosage. The highest blood levels were found for native UV 328 at 8 h after ingestion. Furthermore, biphasic elimination kinetics in blood were revealed for almost all detected metabolites. UV 328 and its metabolites did not occur in blood as conjugates. The renal elimination kinetics were very similar with the kinetics in blood. However, the prominence of the metabolites in urine was somewhat different compared to blood. In contrast, mostly conjugated metabolites occurred for renal elimination. In urine, UV 328-4/3-CO-6/3-OH was found to be the most dominant urinary biomarker followed by UV 328-6/3-OH and UV 328-4/3-OH. In total, approximately 0.1% of the orally administered dose was recovered in urine within 72 h. Although high levels of UV 328 in blood proved good resorption and high systemic availability of the substance in the human body, the urine results revealed a rather low quantitative metabolism and urinary excretion rate. Consequently, biliary excretion as part of the enterohepatic cycle and elimination via feces are assumed to be the preferred pathways instead of renal elimination.

Impact of Daily Antiperspirant Use on the Systemic Aluminum Exposure: An Experimental Intervention Study.

BACKGROUND AND OBJECTIVES: Adverse health effects such as neurotoxic and carcinogenic effects through aluminum from cosmetic products have been repeatedly discussed. The dermal uptake and impact on the systemic aluminum load is still poorly understood. Therefore, we investigated the effect of daily antiperspirant use on the systemic aluminum load under real-life conditions. METHODS: 21 healthy subjects meeting certain selection criteria to ensure a low systemic aluminum background load were asked to use a commercial aluminum-containing antiperspirant for 14 days. A questionnaire enquired about shaving habits and other sources of aluminum. Aluminum levels were measured before and after the exposure in 24-h urine and plasma using atomic absorption spectroscopy. Urine samples (n = 6) with <700 mg/day creatinine excretion or more than 30% difference in 24-h creatinine excretion were excluded from further analysis. RESULTS: No significant increase in plasma aluminum concentration or total excreted aluminum per day before and after exposure was measurable. No sample exceeded the reference values of the general population (maximum: 9.42 µg/g creatinine and 2.1 µg/L plasma). Shaving habits did not have a significant influence on the systemic aluminum load. Also, no correlation between the total amount of antiperspirant applied and the systemic aluminum level could be demonstrated. CONCLUSIONS: No measurable contribution to the overall systemically available aluminum load due to daily use of an antiperspirant for 14 days could be shown, but real-life data concerning long-term use or higher concentrations are still lacking. Considering toxicological occupational exposure data, adverse neurotoxic changes are unlikely in the case of urinary excretion of <50 µg aluminum/g creatinine (= no observed adverse effect level), even following long-term exposure.

Toxicokinetics of urinary 2-ethylhexyl salicylate and its metabolite 2-ethyl-hydroxyhexyl salicylate in humans after simulating real-life dermal sunscreen exposure.

Chemical UV filters are common components in sunscreens and cosmetic products. The question of adverse health risks is not completely resolved, partly owing to lacking human data from dermal exposure, which are essential for sound risk assessment. Therefore, we investigated the urinary toxicokinetics of 2-ethylhexyl salicylate (EHS) after a 1-day dermal real-life sunscreen application scenario. Twenty human volunteers were dermally exposed to a commercial sunscreen for 9 h under real-life conditions (2 mg/cm2 body surface area; double re-application; corresponding to 3.8 g EHS). Urine samples were analyzed for EHS and one of its specific metabolites 2-ethyl-5-hydroxyhexyl salicylate (5OH-EHS) using a two-dimensional liquid chromatographic electrospray-ionization tandem mass spectrometric procedure. EHS and 5OH-EHS were excreted after sunscreen application and reached up to 525 µg/g and 213 µg/g creatinine, respectively. The toxicokinetic models showed concentration peaks between 7 and 8 h after first application. First-phase terminal half-lives were 8-9 h. For 5OH-EHS, a second-phase terminal half-life could be determined (87 h). EHS and 5OH-EHS showed a faster elimination with 70-80% of the overall excretion occurring within 24 h after application compared to more lipophilic UV filters. Cumulative excreted amounts over 24 h reached up to 334 µg EHS and 124 µg of 5OH-EHS. Simulated real-life sunscreen use for 1 day leads to the bioavailability of the UV filter EHS in humans. The kinetic profiles with a prolonged systemic availability indicate a skin depot and make accumulation during consecutive multi-day exposure likely.

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype.

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

Retrospective evaluation of exposure to natural UV radiation: experiences with the online UV history tool in a field study.

BACKGROUND: Cutaneous squamous cell carcinoma and multiple actinic keratoses can be recognized as occupational diseases if the site affected has been subjected to additional occupational UV exposure of at least 40 %. An online UV history tool that allows for the quantification of occupational and recreational UV doses was now tested in a field study. PATIENTS AND METHODS: Ninety-nine patients with nonmelanoma skin cancer were examined. Patient history with respect to UV exposure was obtained using the online UV history tool. Initial validation was carried out with data from ten additional patients. In the context of a pilot study, the applicability of the tool was assessed using a questionnaire. RESULTS: Overall, patient history revealed a UV exposure between 3,792 and 53,163 SEDs. Patients with squamous cell carcinoma, actinic keratoses, or Bowen's disease (n  =  22) had significantly higher SED values and were significantly older (73 vs. 66 years) than patients with basal cell carcinoma (n  =  77). Occupational UV exposure was reported by 19 patients, two of whom showed an additional occupational UV exposure of more than 40 %, which prompted the filing of a (suspected) occupational disease report. With respect to validation, there was evidence of good inter-investigator reliability. The applicability of the tool was rated as good. CONCLUSIONS: The online UV history tool enables quick retrospective quantification of occupational and recreational UV exposure in case of suspicion of the occupational disease "cutaneous squamous cell carcinoma or multiple actinic keratoses caused by natural UV radiation".

Comprehensive assessment of the UV-filter 2-ethylhexyl salicylate and its phase I/II metabolites in urine by extended enzymatic hydrolysis and on-line SPE LC-MS/MS.

2-ethylhexyl salicylate (EHS) is used as a UV filter in personal-care products, such as sunscreen, to prevent skin damage through UV radiation. The application of EHS-containing products leads to systemic EHS absorption, metabolization and excretion. To measure EHS and its corresponding metabolite levels in urine, a comprehensive analytical procedure based on an extended enzymatic hydrolysis, on-line-SPE, and UPLC-MS/MS was developed. The method covers a large profile of seven metabolites (including isomeric structures) as well as EHS itself in a run time only of 18 min. Easy sample preparation, consisting of a 2-h hydrolysis step, followed by on-line enrichment and purification, add to the efficiency of the method. An update, compared to a previous method for the determination of EHS and metabolites in urine, is that, during hydrolysis, both glucuronide and sulfate conjugates are considered. The method was furthermore applied to urine samples after a real-life exposure scenario to EHS-containing sunscreen. The method is highly sensitive with limits of detection ranging from 6 to 65 ng/L. Moreover, it is characterized by good precision data, accuracy, and robustness to matrix influences. Application of the method to urine samples following dermal exposure to an EHS-containing sunscreen revealed EHS as the main biomarker after dermal exposure, followed by the major biomarkers 5OH-EHS, 5cx-EPS, 4OH-EHS and 5oxo-EHS. The expansion and optimization of this method decisively contributes to the research on the dermal metabolism of EHS and can be applied in exposure studies and for human biomonitoring.

Elevated aluminum excretion in patients by long-term subcutaneous immunotherapy - A cross-sectional case-control study.

BACKGROUND: Aluminum (Al) adjuvants have been used in vaccines and subcutaneous immunotherapy (SCIT) for decades. Despite indisputable neurotoxic properties of Al, there is no clear evidence of a causal relationship between their use and any neurotoxic side effects. However, recent rat studies have shown an accumulation of Al from adjuvants in tissues, especially in bones. OBJECTIVES: Since the human toxicokinetics of Al-adjuvants are poorly understood, this study aimed to evaluate whether up-dosed or long-term SCIT with Al-coupled extracts leads to increased Al load in humans. METHODS: This observational cross-sectional case-control study explored Al excretion in hymenoptera venom allergy patients recruited in 2020 before initiation (n = 10) and during ongoing (n = 12) SCIT with Al-based preparations. Urine samples were collected before and 24 h after the SCIT injections and analyzed for aluminum content by using atomic absorption spectrometry. The cumulative administered Al dose was extracted from patient records. Patients receiving long-term immunotherapy were treated between 2.8 and 13.6 years (mean 7.1). Other potential sources of Al exposure were surveyed. RESULTS: Patients who had received Al-coupled immunotherapy for several years showed significantly (p < 0.001) higher Al excretion than the controls at initiation of immunotherapy (mean 18.2 µg/gC vs. 7.9 µg/gC) and predominantly (73%) were above the 95th percentile of the general populations' exposure (>15 µg/gC), however, without reaching levels of toxicological concern (>50 µg/gC). Taking both groups together excreted Al levels correlated with the cumulative administered Al dose from SCIT (linear regression: Alurine = 8.258 + 0.133*Alcum; p = 0.001). DISCUSSION: These results suggest a relevant iatrogenic contribution of long-term SCIT to human internal Al burden and potential accumulation. Considering the medical benefits of Al-adjuvants and SCIT a differentiated risk-benefit analysis is needed. For certain scenarios of potential toxicological concern in clinical practice biomonitoring might be advisable.

Human urinary and blood toxicokinetics of beryllium after accidental exposure.

PURPOSE: Beryllium is known to have adverse health effects and is classified as carcinogenic to humans. However, data on systemic beryllium exposure in humans are rare and especially human toxicokinetics are largely uncharted. As such, the first reported multi-annual course of blood and urine concentrations after a high exposure scenario provides important new insights. METHODS: For a medical follow-up biomonitoring samples were collected for 56 months from a male subject after an accidental and multi-faceted high exposure. Sampling started on day 2 post-exposure for urine and day 147 for blood. The samples were analyzed by inductively coupled mass spectrometry (ICP-MS) and plotted longitudinally as a function of time. Terminal half-lives were calculated assuming a first-order elimination process. MAIN FINDINGS: Both matrices showed highly increased initial concentrations (about 100-fold), despite the 147-day delay in blood sampling, and a marked decline over time. In urine, a two-phase excretion process was suspected based on the longitudinal data. Calculations gave terminal half-lives of 117.5 days and 666.5 days for phases 1 and 2, respectively. Blood kinetics called for a terminal half-life of 103.5 days. Elimination kinetics in blood and urine were comparable, simultaneously gathered samples showed an excellent correlation (R² = 0.985). PRINCIPAL CONCLUSIONS: The long-term follow-up after a high initial exposure to beryllium provides the first detailed insights into the elimination course of systemically available beryllium in humans. Conform kinetics of beryllium in urine and blood and the strong correlation between both parameters indicate high data validity and support the good representation of the current systemically available beryllium by urine and blood concentration in humans. The relatively long terminal half-lives in both matrices suggest a possible accumulation in humans in case of repeated exposures.

Effect of an aluminum foil-processed diet on internal human aluminum burden.

BACKGROUND AND PURPOSE: Aluminum can be released into food by aluminum-containing food-contact materials (Al-FCM) during preparation or storage. There is considerable concern that extra aluminum intake may have negative effects on public health, especially with regard to its high background exposure and neurotoxic properties of aluminum in high exposures. Human in-vivo data on the additional aluminum load from Al-FCM, however, are lacking. As such, the objective of this study was to explore whether the consumption of a diet highly exposed to such products leads to an increased systemic Al load in real-world conditions. MATERIALS AND METHODS: An exploratory, single-arm intervention study with a partially standardized diet was designed and carried out with 11participants. The same 10-day sequence of dishes was repeated three times. Participants were exposed to Al-FCM from Days 11 to 20, whereas control-phase meals were prepared without Al-FCM during the first and last 10-day periods. Spot urine samples were collected each morning and evening and analyzed for their aluminum concentration; appropriate contamination countermeasures were taken. PRINCIPAL RESULTS: Urinary aluminum excretion showed a strong dependency on the creatinine concentration in urine and required adjustment in further analyses. The creatinine-adjusted aluminum excretion during the exposure phase (median 1.98 µg/g creatinine) was higher than in both control phases (1.78 µg/g creatinine each). Two different mixed-effects regression models showed a significant effect in the exposure phase. Considering a discrete time effect, the creatinine-adjusted mean increase in the exposure phase was estimated to be 0.19 µg/L (95% CI: 0.07-0.31; p = 0.0017). MAJOR CONCLUSIONS: This study demonstrated a measurable but fully reversible additional Al burden in humans from subacute Al-FCM exposure under real-world conditions. The estimated increase from Al-FCM corresponds to 8% of the baseline concentration. These data enable a more robust assessment of human health risks by Al-FCM.

Respiratory afflictions during hairdressing jobs: case history and clinical evaluation of a large symptomatic case series.

OBJECTIVES: Respiratory symptoms at work are common among hairdressers. Various working materials, most notably bleaching ingredients such as ammonium persulfate, have been made responsible. The objective of this study is to achieve a better understanding of work-related respiratory symptoms of hairdressers by describing common features in a large affected collective. METHODS: One hundred forty-eight hairdressers with respiratory symptoms at work presenting between 2012 and 2019 were consecutively included in a case series. Anamnestic and diagnostic data including pulmonary function and allergy testing were retrospectively compiled from records and analysed. Additionally, cases were categorised in five groups with respect to occupational causation certainty. RESULTS: 30% of the predominantly female collective had changed jobs or were on longer sick-leave. Besides respiratory symptoms, 10% also reported contact urticaria to blonde dyes. In 60% an obstructive airway disease was confirmed. A specific hypersensitivity reaction to ammonium persulfate was found in 15%. Group 1 with a proven immunological occupational causation showed significantly lower age (p < 0.001) and tenure time (p = 0.001), higher sensitization rates against environmental allergens as well as a higher total IgE (p = 0.015), compared to group 4 (obstructive airway disease, specific occupational causation unlikely). CONCLUSIONS: This case series contributes to a better characterization of work-related respiratory symptoms in hairdressing as one of the largest examined collectives of symptomatic hairdressers. Ammonium persulfate as the most common specific cause showed signs of a type-I-like hypersensitivity reaction with typical risk factors for atopy. Prick testing is recommended in all symptomatic cases. However, a specific occupational causation often cannot be proved.

First evaluation of a symbiotic food supplement in an allergen exposure chamber in birch pollen allergic patients.

BACKGROUND: Allergic rhinitis/rhinoconjunctivitis is the most common immune disease worldwide, but still largely underestimated, underdiagnosed, and undertreated. Dysbiosis and reduced microbial diversity is linked to the development of allergies, and the immunomodulatory effects of pro- and prebiotics might be used to counteract microbiome dysbiosis in allergy. Adequate symbiotic (multi-strain pro-, plus prebiotic) supplementation can be suggested as a complementary approach in the management of allergic rhinitis. OBJECTIVE: The effects of the daily intake of a symbiotic food supplement (combination of Lactobacillus acidophilus NCFM and Bifidobacterium lactis BL-04 with Fructo-Oligosaccharides) for 4 months in birch pollen allergic rhinoconjunctivitis patients were investigated for the first time in an allergen exposure chamber (AEC) allowing standardised, reproducible pollen exposure before and after intake. METHODS: Eligible patients were exposed to birch pollen (8000 pollen/m³ for 120 min) at the GA2LEN AEC, at baseline (V1) and final visit (V3) outside the season. The Total Symptom Score (TSS) and the scores for nose, eye, bronchial system, and others were evaluated every 10 min during exposure. Other secondary endpoints were the changes in well-being, Peak Nasal Inspiratory Flow (PNIF), lung function parameters, and safety. Co-primary endpoints were differences in Total Nasal Symptom Score (TNSS) and TSS after 120 min of exposure between both visits. Temporal evolution of symptom scores were analysed in an exploratory way using linear mixed effects models. RESULTS: 27 patients (mean age 45 years, 15% male) completed the study. Both co-primary endpoints showed significant improvement after intake of the symbiotic. Median TNSS and TSS were decreased 50% and 80% at 120 min (adjusted p-value = 0.025 and p < 0.01 respectively).All four symptom scores and the personal well-being, improved to a clinically relevant extent over time, visible by a weaker increase in symptoms during 120 min of the final birch pollen exposure. No relevant differences were observed for PNIF, PEF, and spirometry. There were no airway obstructions or lung restrictions before and after both exposures. Late phase reactions after exposure were reduced after V3, documenting a better birch pollen tolerability of the patients. The safety and tolerability profile of the symbiotic food supplement was excellent, no adverse events (AEs) were observed. CONCLUSIONS: This first evaluation of a symbiotic food supplement in an AEC in rhinoconjunctivitis patients with or without asthma induced by birch pollen revealed a significant beneficial effect, harnessing significant improvements of symptoms and well-being while maintaining an excellent safety and tolerability profile.

Chronic mucocutaneous candidiasis, from bench to bedside.

Chronic mucocutaneous candidiasis (CMC) defines a heterogeneous group of orphan and inherited syndromes characterised by chronic and recurrent infections of the skin and mucosa with the yeast Candida. Increasing evidence suggests that this inefficient defence against Candida species is reflected by a DC/T cell defect which results in an impaired Th17 and Th1 immune response and, consecutively, a failed immune instruction of tissue cells. Little is known about the incidence and prognosis of CMC. Clinically, the main complications are debilitating hands (Candida granuloma) and oesophageal stricture with potential mal-digestion/-absorption. Furthermore, the chronic infections are likely a risk factor for the development of squamous cell carcinoma. Since resistance to anti-mycotic drugs evolves rapidly, efficient and flexible therapeutic management is essential for CMC patients.

Psychosocial Risk Management in the Teaching Profession: A Systematic Review.

Teachers are facing various job demands with psychosocial aspects being fundamental due to the nature of the occupation. Although teachers' work is associated with different psychosocial health risks, little is known on how to identify and tackle those. Thus, a systematic literature search as per the PRISMA statement was conducted via MEDLINE (PubMed), PSYNDEX (PubPsych), and ScienceDirect. Two reviewers independently screened 2261 titles and abstracts and 169 full-texts. According to the inclusion criteria established a priori, articles from peer-reviewed journals (English or German) on psychosocial risk management in teachers were incorporated. Despite a comprehensive and sensitive search, only four publications could be identified, outlining a process to implement risk management and different assessment tools. Taken together, data presented in the articles were scarce. Recommendations for process steps and the assessment of psychosocial risks can be derived from the findings. To implement effective psychosocial risk management in the teaching profession, further research is needed, though. Effective and practicable approaches, which are accepted by the target group, should be further developed and investigated. Relevant causes of occupational strain in the teaching profession must be identified and assessed reliably. Low-threshold interventions should be implemented, and the outcome must be evaluated afterward.