Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections.

BACKGROUND: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1-5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. METHODS: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. RESULTS: The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. CONCLUSION: Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.

Supporting patients with heart failure with digital therapeutics-A pilot study in Germany.

Objective: Continuous monitoring and targeted behavioral interventions have been shown to improve health status and quality of life for heart failure patients. Digital therapeutics offer the possibility to make more frequent monitoring and targeted behavioral interventions available for more people. Methods: We conduct a pilot study with 71 patients who were given a smartphone app and wearables for a 3-month period. Clinical indicators as well as patient-reported outcomes were collected at entry and exit examinations. Results: The New York Heart Association class remained stable or improved. Most quantitative outcome measures improved (6-minute walk test distance + 21 m, Kansas City Cardiomyopathy Questionnaire summary score + 6.0 points, European Heard Failure Self-care Behavior Scale summary score + 6.6 points, correct answers in the Atlanta Heart Failure Knowledge Test + 2.1), although the changes were mainly not significantly different from zero. There was no change in EQ-5D weight and 9-item Shared Decision-Making Questionnaire summary score. Conclusions: This before-after comparison shows that an app-based intervention can work as a digital therapeutic for heart failure patients.

Is benzyl alcohol a significant contact sensitizer?

BACKGROUND: Benzyl alcohol is a widely used preservative, solvent and fragrance material. According to published data, it is a rare sensitizer in humans. OBJECTIVES: To identify characteristics and sensitization patterns of patients with positive patch test reactions to benzyl alcohol and to check the reliability of the patch test preparation benzyl alcohol 1% pet. PATIENTS AND METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2010-2019. RESULTS: Of 70 867 patients patch tested with benzyl alcohol 1% pet., 146 (0.21%) showed a positive reaction, most of them (89%) only weakly positive. The number of doubtful and irritant reactions significantly exceeded the number of positive reactions. Reproducibility of positive test reactions was low. Among benzyl alcohol-positive patients, compared to benzyl alcohol-negative patients, there were significantly more patients with leg dermatitis (17.8% vs. 8.6%), more patients aged 40 years or more (81.5% vs. 70.5%) and more patients who were tested because of a suspected intolerance reaction to topical medications (34.9% vs. 16.6%). Concomitant positive reactions were mainly seen to fragrances, preservatives and ointment bases. CONCLUSIONS: Sensitization to benzyl alcohol occurs very rarely, mainly in patients with stasis dermatitis. In view of our results, benzyl alcohol cannot be regarded as a significant contact allergen, and therefore marking it as skin sensitizer 1B and labelling it with H 317 is not helpful.

Short- and Long-term Outcome After Interventional VSD Closure: A Single-Center Experience in Pediatric and Adult Patients.

Interventional closure of congenital ventricular septal defects (VSD) is recording a continuous rise in acceptance. Complete atrioventricular block (cAVB) and residual shunting are major concerns during follow-up, but long-term data for both are still limited. We retrospectively evaluated the outcome of patients with interventional VSD closure and focused on long-term results (> 1 year follow-up). Transcatheter VSD closures were performed between 1993 and 2015, in 149 patients requiring 155 procedures (104 perimembranous, 29 muscular, 19 residual post-surgical VSDs, and 3 with multiple defects). The following devices were used: 65 × Amplatzer™ Membranous VSD Occluder, 33 × Duct Occluder II, 27 × Muscular VSD Occluder, 3 × Duct Occluder I, 24 × PFM-Nit-Occlud®, and 3 × Rashkind-Occluder. The median age at time of implantation was 6.2 (0.01-66.1) years, median height 117 (49-188) cm, and median weight 20.9 (3.2-117) kg. Median follow-up time was 6.2 (1.1-21.3) years and closure rate was 86.2% at last follow-up. Complications resulting in device explantation include one case of cAVB with a Membranous VSD occluder 7 days after implantation and four cases due to residual shunt/malposition. Six (4%) deaths occurred during follow-up with only one procedural related death from a hybrid VSD closure. Overall, our reported results of interventional VSD closure show favorable outcomes with only one (0.7%) episode of cAVB. Interventional closure offers a good alternative to surgical closure and shows improved performance by using softer devices. However, prospective long-term data in the current era with different devices are still mandatory to assess the effectiveness and safety of this procedure.

Use of impregnated catheters to decrease colonization rates in neonates - A randomized controlled pilot trial.

OBJECTIVE: Nosocomial infections increase mortality and morbidity in preterm infants. Central venous line colonization is a major risk factor for the development of such infections. In adults and children, antibiotic and antimycotic impregnated catheters have been demonstrated to reduce colonization. However, recently published data showed no significant difference in bloodstream infection in neonates when an impregnated catheter was used. We investigated the effect of impregnation of percutaneously inserted micro-catheters (PICC) on colonization in preterm and sick term infants in our unit. METHODS: Neonates were randomly assigned to receive either a standard (S-PICC; n = 34) or antibiotic and antimycotic impregnated (IP-PICC; n = 37) PICC. Catheters were placed and removed according to a standard procedure and subsequently examined by roll-out culture. The primary outcome was the rate of colonization defined as >15 colony-forming-units/ml. Additional outcomes were catheter associated or systemic infections. RESULTS: The rate of colonization was lower in neonates who received an IP-PICC as compared to S-PICC (5.6% vs. 12.1% respectively; p = 0.42). However, the difference was not significant. In IP-PICC vs S-PICC, catheter related local infection (CRI) although lower was not statistically significant (2.9% vs. 6.1%; p = 0.60). We observed no difference in catheter related systemic infection (CR-SI) (0% vs. 3.1%, p = 0.48). The neonates whose catheters were colonized were predominantly of a lower gestational age (median 254/7, p = 0.05) and males (100%, p = 0.01). In addition, the median colony count in the colonized IP-PICC catheters was lower as compared to S- PICC group (53 vs 250, p = 0.06). CONCLUSIONS: The use of antibiotic and antimycotic impregnated PICC-lines in neonates tended to decrease colonization rates in neonates in our centers but this difference was not significant. Lower gestational age and male sex are risk factors for catheter colonization.

Assessment of occupational exposure and spectrum of contact sensitization in metalworkers with occupational dermatitis: results of a cohort study within the OCCUDERM project.

BACKGROUND: Metalworkers occupationally exposed to metals, tools, metalworking fluids (MWFs), technical oils, gloves, skin care products etc. frequently suffer from occupational dermatitis (OD). OBJECTIVES: To investigate occupational exposure and to identify relevant occupational sensitizers in metalworkers with OD, and to evaluate suitability of current German patch test recommendations for this occupational group. PATIENTS AND METHODS: As part of the OCCUDERM project, occupational exposure of 230 metalworkers with suspected OD patch tested in the departments of dermatology in Göttingen and Osnabrück (both Lower Saxony, Germany) in 2012-2017 was recorded by questionnaire. These data, as well as results, of patch testing with standardized allergens and with workplace material were analysed. RESULTS: Metalworking fluids and skin care products were the most important exposures. Among MWF allergens, most frequently sensitizations to formaldehyde and formaldehyde releasers, colophony/abietic acid and monoethanolamine were observed. Sensitization to methylisothiazolinone (MI) was frequent, probably as part of the general European epidemic of contact allergy to MI in leave-on cosmetics. Sensitization to glove ingredients only played a minor role. CONCLUSIONS: The known occupational allergen spectrum could largely be confirmed. In order not to miss relevant sensitizations, patch testing with material from the patients' workplaces in parallel to baseline and MWF series is recommended. Sensitizations diagnosed could not always be linked to particular occupational exposures.

Effect of surfactant on the size and stability of PLGA nanoparticles encapsulating a protein kinase C inhibitor.

Nowadays many drugs with improved therapeutic efficacy are discovered but cannot be utilized due to their low solubility and insufficient bioavailability. An example of such a drug molecule is a protein kinase C inhibitor that influences an enzyme which plays an important role in several signal transduction cascades. The aim of this study was to formulate a stable nanoparticle dispersion of the PKC inhibitor encapsulated into PLGA nanoparticles (NPs). Encapsulation of the PKC inhibitor into PLGA NPs of 100-200 nm diameter should provide a targeted delivery to the inflammation sites. The NPs were prepared via nanoprecipitation and different surfactants were investigated: Fully and partially hydrolyzed poly(vinyl alcohol) (PVA, Mowiol X-88 and X-98), poloxamers (Pluronic F68 and F127) and polysorbates (Tween 20 and 80). From all surfactants tested, only NPs prepared with partially hydrolyzed PVA (Mowiol X-88) provided the desired stability throughout the downstream processes. These NPs were subsequently analyzed regarding their particle size, polydispersity, encapsulation efficiency and loading capacity. Dynamic light scattering results revealed that monodisperse NPs of 150-220 nm were formed, a size range that favors targeted delivery. The drug encapsulation efficiency varied from 31 to 75% with a drug loading of 1.3-2%. Moreover, the long-term stability was studied and the residual amount of PVA of the NP solutions was quantified via nuclear magnetic resonance (NMR) measurements. The shell-less hen's egg model was used to test toxic effects (hemorrhage, vascular lysis, thrombosis, hemolysis and lethality) of the NPs in a more complex biological system under dynamic flow conditions.

The frequency of specific contact allergies is reduced in patients with psoriasis.

BACKGROUND: Earlier studies suggested an inverse association between contact allergy and psoriasis, although the results of clinical studies have been inconsistent. Gene expression studies in human contact allergy focusing on immune responses revealed nickel being an inducer of T helper (Th)1/Th17 and some Th22 immune polarization, whereas fragrances were found to promote a Th2-dominated immune activation. OBJECTIVES: To investigate the epidemiological association between contact allergy and psoriasis in a large multicentre cohort and to analyse the sensitization profile to specific allergens in these patients. METHODS: Retrospective analysis of patch-tested patients from 56 departments of dermatology (1996-2015), including 2387 patients with psoriasis and 161 989 control patients. All patients with atopic dermatitis were excluded from both groups. RESULTS: The odds ratio (OR) for contact allergy was calculated to be 0·55 in patients with psoriasis (95% confidence interval 0·50-0·59). Logistic regression analyses with several independent variables indicated a 'protective effect' of having psoriasis for most allergens, independently of age, sex, affected body site and patch test indication. Fragrance mix II (OR 0·36) and lanolin alcohols (OR 0·38) were found to be among the least common allergens in patients with psoriasis. In contrast, the frequency of contact dermatitis to nickel was only marginally affected in patients with psoriasis compared with controls (OR 0·75). CONCLUSIONS: The inverse association between psoriasis and allergic contact sensitization is likely to be not exclusively mediated by psoriasis itself. The polarization of the activated immune response by specific allergens may influence the occurrence and significance of contact allergies in underlying immune-mediated diseases, eventually even beyond the skin.

Effects of mesenchymal stromal cells versus serum on tendon healing in a controlled experimental trial in an equine model.

BACKGROUND: Mesenchymal stromal cells (MSC) have shown promising results in the treatment of tendinopathy in equine medicine, making this therapeutic approach seem favorable for translation to human medicine. Having demonstrated that MSC engraft within the tendon lesions after local injection in an equine model, we hypothesized that they would improve tendon healing superior to serum injection alone. METHODS: Quadrilateral tendon lesions were induced in six horses by mechanical tissue disruption combined with collagenase application 3 weeks before treatment. Adipose-derived MSC suspended in serum or serum alone were then injected intralesionally. Clinical examinations, ultrasound and magnetic resonance imaging were performed over 24 weeks. Tendon biopsies for histological assessment were taken from the hindlimbs 3 weeks after treatment. Horses were sacrificed after 24 weeks and forelimb tendons were subjected to macroscopic and histological examination as well as analysis of musculoskeletal marker expression. RESULTS: Tendons injected with MSC showed a transient increase in inflammation and lesion size, as indicated by clinical and imaging parameters between week 3 and 6 (p < 0.05). Thereafter, symptoms decreased in both groups and, except that in MSC-treated tendons, mean lesion signal intensity as seen in T2w magnetic resonance imaging and cellularity as seen in the histology (p < 0.05) were lower, no major differences could be found at week 24. CONCLUSIONS: These data suggest that MSC have influenced the inflammatory reaction in a way not described in tendinopathy studies before. However, at the endpoint of the current study, 24 weeks after treatment, no distinct improvement was observed in MSC-treated tendons compared to the serum-injected controls. Future studies are necessary to elucidate whether and under which conditions MSC are beneficial for tendon healing before translation into human medicine.

[Type IV contact allergies in the food processing industry: an update]. / Typ-IV-Kontaktallergien in Nahrungsmittelberufen: Eine aktuelle Übersicht.

BACKGROUND: The food sector is one of the high-risk areas for occupational irritative and allergic contact eczema. OBJECTIVES: The present work provides an overview of the main allergens as well as sensitization frequencies and risk in various food industry occupations. METHODS: The literature on type IV sensitization in the food sector is summarized. RESULTS: The relative risk of developing a work-related eczema in food processing is increased by more than 3 times. The comparison group was calculated on the basis of the proportion of documented cases in the IVDK (Informationsverbund Dermatologischer Kliniken) network per 100,000 working persons in relation to the average of the years 2005 and 2010. For this purpose, the average risk of all patients was set as reference to 1. Bakers, pastry chefs, cooks and meat and fish processors are mainly affected. In addition to irritant contact eczema, allergic contact eczema and protein contact dermatitis often occur. Leading haptens (main allergens) are rubber ingredients, but also disinfectants and compositae. CONCLUSION: Only a few contact allergens are responsible for the majority of job-relevant sensitizations in the food industry.

[Pathogenesis of urinary tract infections : An update]. / Pathogenese der Harnwegsinfektion : Ein Update.

Urinary tract infections are among the most common bacterial infections worldwide. The management has become a public health concern of socioeconomic importance. Every second woman will experience at least one episode in her lifetime. Due to the emergence of multiresistant pathogens and the developmental void, treatment has become more challenging over the years. Deciphering the complex molecular interaction between host and pathogen is necessary to identify potent treatment targets for future approaches. The objective of this review is to present novel aspects on the pathogenesis of urinary tract infections and its relevance for clinical practice.

[New microbiological techniques]. / Neue mikrobiologische Techniken.

Microbiological diagnostic procedures have changed rapidly in recent years. This is especially true in the field of molecular diagnostics. Classical culture-based techniques are still the gold standard in many areas; however, they are already complemented by automated and also molecular techniques to guarantee faster and better quality results. The most commonly used techniques include real-time polymerase chain reaction (RT-PCR) based systems and nucleic acid hybridization. These procedures are used most powerfully from direct patient samples or in assays to detect the presence of nonculturable or fastidious organisms. Further techniques such as DNA sequencing are not yet used routinely for urological samples and can be considered experimental. However, in conjunction with dropping prices and further technical developments, these techniques promise to be used much more in the near future. Regarding bacterial identification from culture, mass spectrometry (MALDI-TOF MS) has become the technique of choice in recent years especially in Europe. It has tremendously shortened the time to result. This is now going to be extended to antibiotic susceptibility testing. This is of paramount importance in view of ever rising antimicrobial resistance rates. Techniques described in this review offer a faster and better microbiological diagnosis. Such continuous improvements are critical especially in times of cost pressure and rising antimicrobial resistance rates. It is in our interest to provide the best possible care for patients and in this regard a good and effective communication between the laboratory and the clinician is of vital importance.

Characterisation and intracellular labelling of mesenchymal stromal cells derived from synovial fluid of horses and sheep.

Multipotent mesenchymal stromal cells (MSCs) derived from synovial fluid (SF) are considered to be a promising cell type for therapeutic applications in joint disease. However, despite their potential relevance for clinical and experimental studies, there is insufficient knowledge about SF-derived MSCs isolated from horses and sheep. In this study, cells were recovered from healthy SF and bone marrow (BM) of sheep, and from healthy and osteoarthritic SF of horses. Ovine SF-MSCs were used to assess the efficiency of intracellular labelling with quantum dots (QDs). Colony forming units, generation times, trilineage differentiation potential and expression of CD73, CD90 and CD105 at mRNA level were assessed. QD labelling was efficient, with >98% positive cells directly after labelling at 10 nmol/L and >95% positive cells directly after labelling at 2 nmol/L. The label decreased over 7 days of culture, with more persistence at the higher labelling concentration. No significant differences in proliferation were observed. All MSCs had trilineage differentiation potential, but adipogenesis was more distinct in equine samples and chondrogenesis was most pronounced in ovine SF-MSCs. CD73, CD90 and CD105 were expressed in equine and ovine MSCs.

Pharmacodynamics of Finafloxacin, Ciprofloxacin, and Levofloxacin in Serum and Urine against TEM- and SHV-Type Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae Isolates from Patients with Urinary Tract Infections.

The pharmacodynamics of finafloxacin, ciprofloxacin, and levofloxacin against extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae isolates were compared. Since quinolones lose activity in acidic media, and particularly in urine, their activities were tested in parallel under conventional conditions and in acidic artificial urine. For this purpose, TEM- and SHV-type ESBL-producing Escherichia coli and Klebsiella pneumoniae strains and their wild-type counterparts were exposed in a modified Grasso model to simulated concentrations of drugs in serum and urine following oral doses of either finafloxacin at 800 mg once a day (q.d.), immediate-release ciprofloxacin at 500 mg twice a day (b.i.d.), extended-release ciprofloxacin at 1,000 mg q.d., or levofloxacin at 500 or 750 mg q.d. The concentrations of the drugs in urine were fitted by compartmental modeling. Bacteria were cultivated in Mueller-Hinton broth (MHB) at pH 7.2 or 5.8 or in artificial urine at pH 5.8. Bacteria were counted every 2 h until 10 h and at 24 h; the areas under the bacterial-count-versus-time curves were calculated. It was found that finafloxacin eliminated all strains within 2 h under all the conditions studied. At all doses studied, ciprofloxacin and levofloxacin were highly active against wild-type strains in MHB at pH 7.2 but lost activity in MHB, and particularly in urine, at pH 5.8. Viable counts of ESBL producers were reduced for 6 to 8 h by 3 log10 titers, but the bacteria regrew thereafter. Ciprofloxacin and levofloxacin were almost inactive against the SHV producer grown in artificial urine. We conclude that pharmacodynamic models using artificial urine may mirror the physiology of urinary tract infections more closely than those using conventional media. In contrast to ciprofloxacin and levofloxacin, finafloxacin gained activity in this model at an acidic pH, maintained activity in artificial urine, and was active against TEM and SHV producers.

Occupational contact sensitization in female geriatric nurses: Data of the Information Network of Departments of Dermatology (IVDK) 2005-2014.

BACKGROUND: Geriatric nurses (GN) have a high risk of occupational contact dermatitis (OCD), with chronic irritant contact dermatitis predominating. However, allergic contact dermatitis is an important issue as well. Little is known whether the relevant occupational allergen spectrum reported in the 1990s, including fragrances, preservatives, rubber chemicals and ingredients of surface disinfectants to be the most common sensitizers in GN, is still valid. OBJECTIVES: To monitor the current allergen spectrum in GN with OCD and verify the validity of the patch test recommendations (baseline-, preservative-, ointment base-, rubber-, disinfectant, series and fragrances) in GN with suspected OCD given by the German Contact Dermatitis Research Group (DKG). METHODS: Retrospective analysis of IVDK data (2005-2014) of 743 female GN with OCD, in comparison to 695 GN without OCD. RESULTS: GN with OCD reacted significantly more frequently to both fragrance mixes, hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC), thiuram mix, zinc diethyldithiocarbamate and mercaptobenzothiazole than GN without OCD. Reactions to MDBGN, methylchloroisothiazolinone/methylisothiazolinone and oil of turpentine occurred substantially, but not significantly more frequently among GN with OCD. The latter may be due to former use of a special alcoholic liniment in geriatric care. Among material from the patients' workplaces, tetrazepam was a frequent allergen, due to dust exposure from pill crushing. Furthermore, occupationally used protective gloves, body care products as well as surface disinfectants were often tested positively. CONCLUSIONS: The general allergen spectrum in GN with OCD is unchanged, so the DKG patch test recommendations are still valid. Prevention of occupational sensitization should focus on fragrance-free hygiene and body care products, usage of accelerator-free protective gloves and avoidance of drug dust exposure.

First case of Roussoella percutanea bursitis.

Roussoella percutanea is a novel opportunistic pathogen firstly identified in 2014. It is known to cause subcutaneous infection in immunosuppressed patients. We report on the first case of R. percutanea bursitis in a renal transplant patient. We provide new data about its identification, drug susceptibility, and treatment outcome. Here we demonstrate that R. percutanea is a potential human pathogen.

[Spondylodiscitis in children and adolescents]. / Spondylodiszitis im Kindes- und Jugendalter.

BACKGROUND: Spondylodiscitis in children is rare. The condition has an incidence of 2 to 4 % of all infectious skeletal diseases in children. AIM: Aim of the article is the presentation of epidemiology, the clinical signs, radiological findings as well the treatment options of non-specific and specific spondylodiscitis in children. METHODS: The available literature was reviewed. RESULTS: Non-specific spondylodiscitis in children is caused by haematogenous spread of pathogens. Staphylococcus aureus is the most frequently detected bacterium. The clinical signs are unspecific and an Magnetic Resonance Imaging of the spine is the standard radiological procedure to detect spondylodiscitis. In general, the treatment is conservative and includes an antibiotic therapy as well an immobilization of the spine. In endemic areas of the world, specific spondylodiscitis is more common and is caused by Mycobacterium tuberculosis or Brucellae. The treatment is also conservative. For all entities of spondylodiscitis in children, a surgical intervention is only necessary in the case of severe deformities due to the infection or in the case of neurological symptoms. CONCLUSION: Elevated infectious laboratory values and back pain or other unspecific symptoms can indicate spondylodiscitis in children. MRI of the spine is necessary to rule out spondylodiscitis.