Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Quality of care transition, patient safety incidents, and patients' health status: a structural equation model on the complexity of the discharge process.

BACKGROUND: The transition of patients between care contexts poses patient safety risks. Discharges to home from inpatient care can be associated with adverse patient outcomes. Quality in discharge processes is essential in ensuring safe transitions for patients. Current evidence relies on bivariate analyses and neglects contextual factors such as treatment and patient characteristics and the interactions of potential outcomes. This study aimed to investigate the associations between the quality and safety of the discharge process, patient safety incidents, and health-related outcomes after discharge, considering the treatments' and patients' contextual factors in one comprehensive model. METHODS: Patients at least 18 years old and discharged home after at least three days of inpatient treatment received a self-report questionnaire. A total of N = 825 patients participated. The assessment contained items to assess the quality and safety of the discharge process from the patient's perspective with the care transitions measure (CTM), a self-report on the incidence of unplanned readmissions and medication complications, health status, and sociodemographic and treatment-related characteristics. Statistical analyses included structural equation modeling (SEM) and additional analyses using logistic regressions. RESULTS: Higher quality of care transition was related to a lower incidence of medication complications (B = -0.35, p < 0.01) and better health status (B = 0.74, p < 0.001), but not with lower incidence of readmissions (B = -0.01, p = 0.39). These effects were controlled for the influences of various sociodemographic and treatment-related characteristics in SEM. Additional analyses showed that these associations were only constant when all subscales of the CTM were included. CONCLUSIONS: Quality and safety in the discharge process are critical to safe patient transitions to home care. This study contributes to a better understanding of the complex discharge process by applying a model in which various contextual factors and interactions were considered. The findings revealed that high quality discharge processes are associated with a lower likelihood of patient safety incidents and better health status at home even, when sociodemographic and treatment-related characteristics are taken into account. This study supports the call for developing individualized, patient-centered discharge processes to strengthen patient safety in care transitions.

[Sarcoidosis in head and neck area - a diagnostic challenge using the example of skin manifestations]. / Sarkoidose im Kopf-Hals-Bereich ­ eine diagnostische Herausforderung am Beispiel lokaler Hautmanifestationen.

BACKGROUND: Sarcoidosis is a granulomatous multisystem disease of unknown etiology and relatively rare. The heterogeneous clinical picture is a diagnostic challenge. We are investigating whether the superficially visible cutaneous lesions can lead to the differential diagnosis of sarcoidosis and what systemic manifestations are present. MATERIAL AND METHODS: As part of our exploratory retrospective investigation (eight years) a total of 32 patients with cutaneous sarcoidosis were identified and analyzed. RESULTS AND CONCLUSION: In many cases the dermatologists considered the differential diagnosis of sarcoidosis even before biopsy (71.8%); in our previous study with ENT-patients the diagnosis wasn't considered in a single case by the attending doctors at this time and without any prevoius suspicion. Sarcoidosis of the skin in the head and neck area is the second most common cutaneous manifestation. After biopsy (Gold standard) the search for further possible organ manifestations is essential (e.g. lungs, heart) to treat them in an early stage and to prevent complications of a possible chronic course (including cardiac arrhythmias, pulmonary fibrosis).

[Facial necrosis caused by orthopoxvirus : Differential diagnosis and dermatohistopathological correlation of infectious facial ulcers]. / Faziale Nekrose durch Orthopoxviren : Differenzialdiagnosen und dermatohistopathologische Korrelation infektiöser fazialer Ulzera.

This article reports the remarkable course of a facial ulcer in a patient receiving prednisolone for Crohn's disease. Based on the initially unclear origin of the ulcer the patient received a triple anti-infective treatment (antiviral, antibiotic, antimycotic) but the lesion showed a rapid progression. An orthopoxvirus infection could be verified later by extensive diagnostics and relevant differential diagnoses could be ruled out. Extensive necrotic changes were observed in the first weeks resulting in cicatricial healing after months. Human cowpox infections have been repeatedly reported in Germany and are a relevant zoonosis. Cats and rodents are main carriers. The differential diagnoses include infections caused by other bacterial, mycobacterial, mycotic and parasitic agents that are thoroughly discussed here both clinically and histopathologically. Especially cutaneous leishmaniasis must be named as the incidence is continuously rising. With inadequate treatment infectious facial ulcers may give rise to life-threatening complications and extensive disfiguring scarring, therefore treatment must be initiated in a timely manner.

Slope-deviation measurement of Fresnel-shaped mold surfaces.

Molds are used to dictate their shape to other materials in embossing or filling processes. In optics fabrication especially, the exact surface slope of the polymer replica is of high relevance. The quality control of molds is challenging: non-invasive, optical metrologies struggle with shiny surfaces that minimize the scattering of light. In addition, the inspection of complex shaped molds with a stepped optical surface can be difficult. In response, the authors show a backward ray-tracing approach combined with fringe-reflection technique to determine the slopes of a Fresnel-shaped mold surface with topography features in the magnitude order of a quarter millimeter. The error is kept small by stitching together several measurements with different sample rotations.

Calibration function for an experimental setup for the measurement of irradiance distributions via a transmitting diffuser.

We describe a procedure to estimate the calibration function for an experimental setup that contains a transmitting diffuser whose bidirectional transmittance distribution function for light transmitted in normal direction is nearly independent of the incidence angle. This type of diffusing screen may be used in experimental setups to measure the irradiance distribution in the focal plane of concentrator optics that have large angles of incidence in the focal plane. It is shown that the influence of this screen and of the remaining components on the irradiance distribution may be described empirically by a Gaussian function and thus may be corrected for. Furthermore, it is demonstrated that the correction is necessary to avoid an underestimation of the concentrator optics' ability to concentrate the incoming radiation.

Light diffraction by concentrator Fresnel lenses.

Fresnel lenses are widely used in concentrating photovoltaic (CPV) systems as primary optical elements focusing sunlight onto small solar cells or onto entrance apertures of secondary optical elements attached to the solar cells. Calculations using the Young-Maggi-Rubinowicz theory of diffraction yield analytical expressions for the amount of light spilling outside these target areas due to diffraction at the edges of the concentrator Fresnel lenses. Explicit equations are given for the diffraction loss due to planar Fresnel lenses with small prisms and due to arbitrarily shaped Fresnel lenses. Furthermore, the cases of illumination by monochromatic, polychromatic, totally spatially coherent and partially spatially coherent light (e.g. from the solar disc) are treated, resulting in analytical formulae. Examples using realistic values show losses due to diffraction of up to several percent.

Measuring transitional patient safety: Adaptation and validation of the German version of the Care Transitions Measure.

INTRODUCTION: The transition between different care contexts, especially during discharge from inpatient treatment to home, is associated with risks for patient safety. Internationally established, the Care Transitions Measure (CTM) is used to assess the quality and safety of this transition from the patients' perspective. A systematic and standardized assessment of quality and safety in the discharge process from the patients' perspective has not been possible in German-speaking countries due to the lack of a German adaptation and validation of the CTM. This study aims to translate, adapt, and validate the CTM for use in German-speaking countries METHODS: The German version of the CTM was developed based on internationally accepted recommendations for translating and adapting questionnaires. Patients of all departments (except pediatric departments) of a German university hospital who were discharged home after at least three days of inpatient treatment received the questionnaire by mail between May and August 2022. A total of 806 patients participated in the survey. The validity of the CTM was tested by factor analyses. For this purpose, different factor models were compared. In addition, the measurement invariance of the instrument was examined. RESULTS: The construct validity of the long version of the CTM (15items) with a two-factorial model structure was confirmed with good model fit indices. The two subscales had excellent internal consistency. In addition, the one short version with four items achieved excellent model fit indices and high internal consistency. For the long version of the CTM, measurement invariance was confirmed for all sociodemographic, care-related, and survey response characteristics examined. The measurement invariance of the short version was only partially confirmed. DISCUSSION: The validity and reliability of the German version of the CTM were confirmed. In its long version, the instrument is measurement invariant across various characteristics and thus allows valid interpretation of group differences. The short version is partially measurement invariant and is suitable as a screening instrument for assessing the quality and safety of discharge processes due to its high validity and reliability. CONCLUSIONS: With a validated and standardized German version of the CTM, an instrument is now available to assess the quality and safety of the discharge process from the patients' perspective. Thus, this study provides an essential tool for systematically investigating and optimizing patient safety in the discharge process.

Preoperative characterization of basal cell carcinoma comparing tumour thickness measurement by optical coherence tomography, 20-MHz ultrasound and histopathology.

Optical coherence tomography (OCT) is a new imaging method with promising results for several dermatological indications, including preoperative skin tumour characterization. While high-frequency ultrasound (HFUS) is frequently used for this purpose, overestimation of tumour thickness is a problem, due to subtumoral inflammatory infiltration that cannot be differentiated from tumour tissue. The aim of this single-centre study was to describe OCT features of basal cell carcinoma (BCC) and to determine vertical tumour thickness accurately, including a comparison with HFUS and histopathology. Tumour thickness values of 10 BCCs measured by OCT did not differ significantly from those measured by histopathology (median difference 0.12 mm). By contrast, the difference between HFUS and histopathology was greater (median difference 0.3 mm). A Pearson's correlation coefficient of 0.83 showed a stronger correlation of OCT in measuring tumour thickness compared with HFUS (0.59). Bland-Altman plots revealed a better agreement of OCT and histopathology concerning tumour thickness measurements. On the basis of this explorative study cohort, OCt was more exact than HFUS in preoperative tumour thickness estimation of BCCs compared with histopathological measurements.

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes.

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.

Assessment of tumor thickness in melanocytic skin lesions: comparison of optical coherence tomography, 20-MHz ultrasound and histopathology.

BACKGROUND: Accurate assessment of vertical tumor size is important for surgical treatment planning of melanocytic skin lesions. High-frequency ultrasound (HFUS) is frequently used for this purpose, but overestimation of tumor thickness is known as a problem especially in thin melanocytic lesions. Optical coherence tomography (OCT) as a new imaging technique might be a promising alternative. OBJECTIVE: To evaluate the ability of OCT to accurately determine the vertical tumor thickness of melanocytic skin lesions and to compare it with HFUS and histopathology in order to improve surgical planning. METHODS: In this single-center study, 26 melanocytic lesions were imaged by OCT and HFUS. Vertical lesion dimensions of both methods were compared with histopathological measurements. RESULTS: Bland-Altman plots for OCT and histopathology as well as for HFUS and histopathology revealed better agreement for OCT and histopathology concerning tumor thickness measurements. Tumor thickness values for the melanocytic lesions measured by OCT presented a median tumor thickness of 0.31 mm (range 0.10-0.77) compared to a median tumor thickness of 0.25 mm (range 0.06-1.5) measured by histopathology. The median tumor thickness of HFUS was 0.44 mm (range 0.23-1.1). A Spearman correlation procedure including the correlation coefficient (r) showed a stronger relationship between OCT and histopathology (r = 0.734) compared to HFUS and histopathology (r = 0.390). CONCLUSIONS: On the basis of this smaller study cohort, OCT seems to be more exact than HFUS as far as thickness determination of thin melanocytic skin lesions is concerned.

Detection and Characterization of Clinical Bordetella trematum Isolates from Chronic Wounds.

Bordetella trematum is a relatively newly discovered and potentially frequently overlooked Bordetella species, mostly isolated from chronic wounds and predominantly in those of the lower extremities. Its susceptibility profile and clinical significance is still debated, given the limited amount of available data. We contribute providing a molecular and phenotypical analysis of three unique clinical B. trematum isolates detected between August 2019 and January 2020 to aid the matter. Cryo-conserved isolates were subcultured and re-identified using various routine means of identification. Bacterial genomes were fully Illumina-sequenced and phenotypical susceptibility was determined by broth microdilution and gradient-strip tests. All isolates displayed increased susceptibility to piperacillin-tazobactam (<2/4 mg/L), imipenem (<1 mg/L), and meropenem (<0.047 mg/L), whereas they displayed decreased susceptibility to all tested cephalosporins and fluoroquinolones (according to PK-PD, EUCAST 10.0 2020). One isolate carried a beta-lactamase (EC 3.5.2.6) and a sulfonamide resistance gene (sul2) and cells displayed resistance to ampicillin, ampicillin/sulbactam, and trimethoprim/sulfamethoxazole. All isolates carried genes conferring decreased susceptibility to aminoglycosides (aadA), fosfomycin (fosA) and fluoroquinolones (gyrB EC 5.99.1.3). Awareness that B. trematum can be resistant to trimethoprim/sulfamethoxazole is warranted.

Association between miRNA signatures in serum samples from epidermal growth factor inhibitor treated patients and skin toxicity.

OBJECTIVE: Epidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers. MATERIALS AND METHODS: Five candidate miRNAs were selected, based on an earlier in vitro next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients (n = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash. RESULTS: In our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (p-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (p-value 9.01e-06 linear-trend-test). CONCLUSIONS: This suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.