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Background and objectives A recent generation of 5,500 nm wavelength carbon monoxide (CO) lasers could serve as a novel tool for applications in medicine and surgery. At this wavelength, the optical penetration depth is about three times higher than that of the 10,600 nm wavelength carbon dioxide (CO2 ) laser. As the amount of ablation and coagulation is strongly influenced by the wavelength, we anticipated that CO lasers would provide extended coagulation zones, which could be beneficial for several medical applications, such as tissue tightening effects after laser skin resurfacing. Until now, the 1,940 nm wavelength thulium fiber (Tm:fiber) laser is primarily known as a non-ablative laser with an optical penetration depth that is eight times higher than that of the CO2 laser. The advantage of lasers with shorter wavelengths is the ability to create smaller spot sizes, which has a determining influence on the ablation outcome. In this study, the ablation and coagulation characteristics of a novel CO laser and a high power Tm:fiber laser were investigated to evaluate their potential application for fractional ablation of the skin. Study design/materials and methods Laser-tissue exposures were performed using a novel CO laser, a modified, pulse-width-modulated CO2 laser, and a Tm:fiber laser. We used discarded ex vivo human skin obtained from abdominoplasty as tissue samples. Similar exposure parameters, such as spot size (108-120 μm), pulse duration (2 milliseconds), and pulse energy (~10-200 mJ) were adjusted for the different laser systems with comparable temporal pulse structures. Laser effects were quantified by histology. Results At radiant exposures 10-fold higher than the ablation threshold, the CO laser ablation depth was almost two times deeper than that of the CO2 laser. At 40-fold of the ablation threshold, the CO laser ablation was 47% deeper. The ablation craters produced by the CO laser exhibited about two times larger coagulation zones when compared with the CO2 laser. In contrast, the Tm:fiber laser exhibited superficial ablation craters with massive thermal damage. Conclusions The tissue ablation using the Tm:fiber laser was very superficial in contrast to the CO laser and the CO2 laser. However, higher etch depths should be obtainable when the radiant exposure is increased by using higher pulse energies and/or smaller spot sizes. At radiant exposures normalized to the ablation threshold, the CO laser was capable of generating deeper ablation craters with extended coagulation zones compared with the CO2 laser, which is possibly desirable depending on the clinical goal. The effect of deep ablation combined with additional thermal damage on dermal remodeling needs to be further confirmed with in vivo studies. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Continuous subcutaneous insulin infusion (CSII) is a widely used treatment for diabetes patients. Insulin infusion sets (CSII-catheters) are continuously optimized regarding size, handling and safety, but recurring dysfunction (kinking or occlusion), due to different user situations, behavior or chain of events, demand new ways to improve the functionality and safety in patients experiencing these issues. A novel CSII-catheter design (Lantern) features additional lateral perforations, which guarantee functionality even in case of kinking or occlusion. This study aimed to compare functionality, insulin distribution, and failure rate of Lantern and standard catheters using excised human adipose tissue samples. Novel Lantern CSII-catheters (open and artificially occluded) and commercially available standard CSII-catheters were inserted into adipose tissue samples. A mixture of insulin and contrast agent was infused as single bolus (7 IU) with an insulin infusion pump at highest flow rate (1 IU/s). Microtomography images and surface-to-volume ratios were used to assess insulin distribution and depot volume indicating the functionality of CSII-catheters. Failure rate was measured by flow-stop alerts of the pump. We found no difference in the volume of insulin depots compared with the nominal volume of 70 μL. Surface-to-volume ratios showed no significant difference among CSII-catheters. None of the catheters triggered any flow-stop alarm. The novel Lantern CSII-catheter design achieved similar insulin distribution as commercially available CSII-catheters. Moreover, functionality of Lantern CSII-catheters was guaranteed during occlusion, which is an improvement compared with standard CSII-catheters. We conclude that the novel CSII-catheter design has the potential to provide a valuable contribution to patient well-being and safety.

Background/objectives Standard optical coherence tomography angiography (OCTA) has been limited to imaging blood vessels actively undergoing perfusion, providing a temporary picture of surface microvasculature. Capillary perfusion in the skin is dynamic and changes in response to the surrounding tissue's respiratory, nutritional, and thermoregulatory needs. Hence, OCTA often represents a given perfusion state without depicting the actual extent of the vascular network. Here we present a method for obtaining a more accurate anatomic representation of the surface capillary network in human skin using OCTA, along with proposing a new parameter, the Relative Capillary Capacity (RCC), a quantifiable proxy for assessing capillary dilation potential and permeability. Methods OCTA images were captured at baseline and after compression of the skin. Baseline images display ambient capillary perfusion, while images taken upon capillary refill display the network of existing capillaries at full capacity. An optimization-based automated vessel segmentation method was used to automatically analyze and compare OCTA image sequences obtained from two volunteers. RCC was then compared with visual impressions of capillary viability. Results Our OCTA imaging sequence provides a method for mapping cutaneous capillary networks independent of ambient perfusion. Differences between baseline and refill images clearly demonstrate the shortcomings of standard OCTA imaging and produce the RCC biometric as a quantifiable proxy for assessing capillary dilation potential and permeability. Conclusion Future dermatological OCTA diagnostic studies should implement the Capillary Refill Methods over standard imaging techniques and further explore the relevance of RCC to differential diagnosis and dermatopathology. Lasers Surg. Med. © The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Arztinnen und Arzte werden im Rahmen ihrer Berufsausubung zunehmend mit rechtlichen Fragen konfrontiert. Aufgrund einer Starkung der Patientenrechte durch die Vorschriften zum Behandlungsvertrag (§§ 630a ff. BGB), aber auch einer umfangreichen Rechtsprechung, Gesetzen oder Leitlinien ist eine starke Reglementierung der Medizin zu beobachten. Die arztliche Approbationsordnung erwahnt Rechtsfragen der arztlichen Berufsausubung als Unterrichtsgegenstand. Eine verbindliche Regelung uber den Umfang und Inhalt medizinrechtlichen Unterrichts existiert nicht. Der Nationale Lernzielkatalog fur Mediziner (NLKM) greift diese Problematik auf und beschreibt Lernziele, welche die ethischen und rechtlichen Kenntnisse, Fahigkeiten und Fertigkeiten definieren, die Medizinstudierenden im Verlauf ihres Studiums vermittelt werden sollen. Der NKLM entfaltet jedoch gegenuber den medizinischen Fakultaten keine Bindungswirkung. Erstmals wurden Studierende im praktischen Jahr (PJ) an 18 medizinischen Fakultaten mittels eines standardisierten Fragebogens nach ihrer Einschatzung der Bedeutung des Medizinrechts insgesamt und auch zu medizinrechtlichen Einzelthemen befragt. Von den befragten Studierenden sah die ganz grose Mehrheit die Vermittlung von Rechtskenntnissen als sehr wichtig bzw. als auserordentlich wichtig an. Uberwiegend wurde die Etablierung einer eigenstandigen Lehrveranstaltung zum Medizinrecht mit einer Verankerung in der arztlichen Approbationsordnung fur sinnvoll erachtet. Die Relevanz einzelner Themen wurde unterschiedlich beurteilt. So wurden u. a. die Themen Aufklarung und Einwilligung, Rechtsfragen bei Verdacht auf Kindesmisshandlung, Verhalten bei einem Behandlungsfehlervorwurf, arztliche Schweigepflicht und Dokumentationspflichten des Arztes als relevant eingestuft. Als weniger wichtig werden z. B. gesehen: Rechtsfragen der Komplementarmedizin, der Reproduktionsmedizin, ethisch-religios-weltanschauliche Konflikte, einschlieslich Sterbehilfe, oder die Rolle von Ethikkommissionen. Die Studierenden zeigen sich gegenuber Fragen des Medizinrechts grundsatzlich offen und sehen die Relevanz zahlreicher konkreter Rechtsfragen. Dies sollte bei der weiteren Diskussion zum NKLM, aber auch von den medizinischen Fakultaten und den in der Lehre Tatigen starker berucksichtigt werden. Sinnvoll erscheint die Bereitstellung eines Lehrbeauftragten fur Medizinrecht.

The agenesis of one or both upper thyroid horns (UTH) cannot be considered rare with an incidence ranging between 0.8–9.4%. Studies so far have mostly described frequencies, yet surveys on its morphology and traumatology are missing. It is unknown to what extent this anatomical variant impacts the overall symmetry of the larynx. For the trauma reconstruction after cervical trauma this knowledge is required as an asymmetric larynx can show a different fracture pattern. In this investigation, larynxes with unilateral (n = 21)/bilateral (n = 5) agenesis of the upper thyroid horn(s) and a control group with regular larynxes (n = 23) were juxtaposed. Various measurements were taken after μ-CT scanning. In total 10 distances/angles for the thyroid cartilage and 8 for the cricoid cartilage were compared. Using intra-individual and matched pair comparisons the symmetry was assessed. The results of this investigation showed significant differences in the intra-individual and pairwise comparison for the opening angle and the length of the thyroid alae although the lateral inclination of the thyroid alae showed no significant difference. Combining these three parameters into one symmetry score, the comparison was not significant. This research demonstrates that neither unilateral nor bilateral agenesis of the UTH is related to a structural disbalance of the larynx. Thus, different fracture patterns or vulnerabilities are not to be expected.

Der Schadel stellt haufig das Ziel interpersoneller Gewalt dar und weist infolge von schweren (todlichen) Unfallen nicht selten Verletzungen auf. Bestimmte Frakturmuster des Gehirnschadels lassen sich unter rekonstruktiven Gesichtspunkten interpretieren. Publikationen hierzu thematisieren diesbezuglich jedoch eher Frakturen des Schadeldachs als jene der Schadelbasis. Ein aktueller Sektionsfall, bei dem es durch ein disloziertes Mandibulakopfchen zu einer Lochfraktur der Schadelbasis gekommen war, gab Anlass zu einer retrospektiven Auswertung von Obduktionsfallen aus den Instituten fur Rechtsmedizin in Frankfurt am Main, Giesen und Homburg (Saar) in einem Zehnjahreszeitraum. Daruber hinaus erfolgte eine Literaturrecherche uber die Metadatenbank PubMed. Im Auswertungszeitraum von 2009 bis 2018 wurden in den genannten rechtsmedizinischen Instituten 10.733 gerichtliche Obduktionen durchgefuhrt. Es fanden sich lediglich 2 Falle von Lochfrakturen der Schadelbasis, bei denen jeweils das intakte Unterkieferkopfchen im Sinne einer zentralen Kiefergelenkluxation in die mittlere Schadelgrube eingedrungen war. Bei beiden Verstorbenen war ein Sturzgeschehen ursachlich, die Lochfraktur, fur sich betrachtet, jedoch nicht todesursachlich. Die Literaturrecherche erbrachte mehrere klinische Fallberichte, systematisch aufgearbeitete Fallserien und Ubersichtsarbeiten sowie eine rechtsmedizinische Kasuistik. Als Hauptursache der superioren bzw. zentralen Kiefergelenkluxationen werden Verkehrsunfalle angesehen. Die in der klinischen Fachliteratur beschriebenen, mit dieser Fraktur einhergehenden typischen Symptome (Malokklusion mit einem unilateral offenen und kontralateralen Kreuzbiss, fixierte Mandibulastellung) konnen postmortal durch Rigor mortis und Dunsung der Gesichtsweichteile uberlagert werden und fallen somit bei der auseren Leichenschau ggf. nicht auf. Bei dieser besonderen Lochfraktur der Schadelbasis handelt es sich um eine auserst seltene Verletzung, die – analog zur Schadelbasisringfraktur – als Sonderform einer Biegungsfraktur der Schadelbasis betrachtet werden kann. Ihr Auftreten lasst rekonstruktive Aussagen zum Unfall- bzw. Tatgeschehen zu. Als Verletzungsmechanismus ist die Fortleitung einer von vorn unten auf das Kinn einwirkenden stumpfen Gewalteinwirkung anzusehen.

When people judge the duration of stimuli, judgments are influenced by the physical size of these stimuli. Specifically, people tend to judge the duration of large stimuli longer than the duration of small stimuli. However, some authors (Bottini & Casasanto, 2010; Ma, Yang, & Zhang, 2012) have reported that even implicit size can affect duration estimates. The present study extends the results of these studies. Specifically, we examined whether the imagined size of objects would also influence duration estimates. In each trial, participants reproduced the duration of an animal word. During the presentation of the word, they were asked to imagine the word's referent. The animals employed in all experiments varied in size. In Experiment 1, participants were instructed to imagine the animals in a fixed context. Reproduced duration increased not only with the numbers of letters of the animal word (i.e., physical size) but also with the size of the word's referent (i.e., implicit size of the animal). Experiments 2 and 3 examined whether the effect of size would increase when the size of the animals was made more salient. The results of all experiments showed that reproduced duration increases with implicit stimulus size. In addition, Experiments 2 and 3 provide some evidence that the imagined size effect becomes more pronounced when the participant's attention is drawn to the size differences among the imagined animals. It is argued that the implicit size effect is mediated by mental imagery that operates on pre-existing space-time associations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background Trisomy 21 is the most common human chromosomal abnormality. Its manifestation includes intellectual impairment and more or less typical anatomical malformations and functional deficiencies that can cause sudden or unexpected deaths. Typical medicolegal questions at autopsy are related to medical malpractice, improper care, neglect, or abuse, and, depending on the cause of death, whether the death might have been avoidable. The aim of this study was to examine whether the causes of death in individuals with trisomy 21 were linked to the known health risks for this condition and to consider how these deaths might have been prevented. Material and methods A retrospective study was performed at the Institutes for Legal Medicine in Giessen and Frankfurt am Main, Hesse, Germany. All records for forensic autopsy cases within a 20-year period from 1998 to 2017 were reviewed for the diagnosis trisomy 21”, respectively, “Down’s syndrome”. Results Twenty-three cases complied with the inclusion criteria trisomy 21 and autopsy. The age of the deceased ranged from 23 days to 61 years. Infectious diseases, mainly respiratory, were the leading cause of death, followed by accidental deaths. Conclusion The medicolegal relevance of the known health risks in Down’s syndrome could be illustrated by the autopsy findings and the results of the additional examinations. The known high susceptibility to infections, with an increased risk of a rapid course and lethal outcome, in individuals with Down’s syndrome could be confirmed in our study. A sound knowledge of the risks and abnormalities associated with trisomy 21 are helpful in medicolegal assessments, particularly, in relation to medical malpractice charges.

Eicosanoids are lipid-mediator molecules with key roles in inflammatory skin diseases, such as psoriasis. Eicosanoids are released close to the source of inflammation, where they elicit local pleiotropic effects and dysregulations. Monitoring inflammatory mediators directly in skin lesions could provide new insights and therapeutic possibilities. Here, we analyzed dermal interstitial fluid samples obtained by dermal open-flow microperfusion in a rat model of skin inflammation. We developed a solid-phase extraction ultra-HPLC/MS/MS method to reliably and precisely analyze small-volume samples and quantified 11 eicosanoids [thromboxane B(2), prostaglandin (PG) E(2), PGD(2), PGF(2α), leukotriene B(4), 15-HETE, 12-HETE, 5-HETE, 12-hydroxyeicosapentaenoic acid, 13-HODE, and 17-hydroxydocosahexaenoic acid]. Our method achieved a median intraday precision of approximately 5% and interday precision of approximately 8%. All calibration curves showed excellent linearity between 0.01 and 50 ng/ml (R(2) > 0.980). In the rat model, eicosanoids were significantly increased in imiquimod-treated inflamed skin sites compared with untreated control sites. Oral treatment with an anti-inflammatory glucocorticoid decreased eicosanoid concentrations. These results show that a combination of tissue-specific sampling with LC/MS analytics is well suited for analyzing small sample volumes from minimally invasive sampling methods such as open-flow microperfusion or microdialysis to study local inflammation and the effect of treatments in skin diseases.

Zusammenfassung Misshandlung und sexueller Missbrauch von Kindern hinterlassen u.a. physische Verletzungen. Diese können bei zeitnaher Dokumentation entscheidend sein für eine Beweisführung u.a. vor Gericht. Dabei werden körperliche Untersuchungen von verschiedenen Institutionen in Auftrag gegeben (Jugendamt, Polizei, Staatsanwaltschaft, Gericht) und es werden Gewaltformen unterschieden: stumpfe Gewalt (z.B. Schläge), thermische Gewalt (z.B. Verbrennen durch eine Zigarette), scharfe Gewalt (z.B. durch ein Messer). Hinzu kommen spezielle Formen der Kindesmisshandlung: u.a. das Schütteltrauma-Syndrom und das Münchhausen-Syndrom by proxy.

Die Untersuchung der Ossifikation des Schildknorpels ist nicht nur in Form von anatomischer und morphologischer Grundlagenforschung, sondern auch fur rechtsmedizinische Uberlegungen von Belang. Ziel war es, einen Geschlechts- und Alterspolymorphismus mittels Mikro-Computertomographie (µCT) nachzuweisen. An 53 autoptisch asservierten Kehlkopfpraparaten wurde eine mikrocomputertomographische Bildgebung durchgefuhrt. Die µCT eignet sich durch ihre hohe raumliche Auflosung und das nichtdestruktive Erschaffen dreidimensionaler Volumendatensatze zur quantitativen Analytik von Knochenstrukturparametern und zur Visualisierung von Unterschieden und Veranderungen der trabekularen Knochenstruktur. Dabei wurden u. a. Parameter bestimmt wie z. B. die Knochendichte, das Knochen- und Gesamtvolumen und ein eigens entwickelter Score fur die Art der Verknocherung. Sowohl ein Alters- als auch ein Geschlechtspolymorphismus konnten nachgewiesen werden. Die mannlichen und die alteren Schildknorpel sind deutlich starker trabekular und vollstandiger verknochert und weisen ein groseres Knochen- und Gesamtvolumen auf als die jungeren und die weiblichen Schildknorpel. Damit lasst sich ein Nutzen fur die Rechtsmedizin aufzeigen, mit dem Schildknorpel als Pradiktor fur das Geschlecht und das Alter eines Knochen- bzw. Leichenfundes.

Introduction The estimation of age-at-death of unidentified cadavers is a central aspect of the identification process. With increasing age, the incidence of glomerulosclerosis and the thickness of the carotid wall have been observed to also increase. This correlation has been demonstrated in various international histological studies. The aim of our study was to assess whether these correlations also apply to a Western European population. Methodology In this retrospective observational study, kidney and common carotid artery samples from 216 cases autopsied at the Institute of Legal Medicine at the Justus-Liebig University in Giessen, Germany, were examined. Only cases with available tissue samples from both body sides were included. Exclusion criteria were poor sample quality and an age younger than 21 years. After histological processing, the tissue samples were assessed and digitally evaluated. Regression and classification analyses were used to investigate the correlation between age-at-death and intima-media thickness and age-at-death and the incidence of renal glomerular sclerosis. Results Of the 216 autopsy cases, 183 were included for evaluation. Analysis of the carotid artery segments showed a strong correlation (Pearson correlation coefficient r = 0.887) between the intima-media-complex thickness and chronological age. Classification of the glomerulosclerotic incidence showed a correlation of 37.7–43.1% with the predicted age group. Discussion Both the intima-media thickness and the proportion of sclerotic glomeruli can be used to estimate age in Western European cadavers. On the basis of these results, both methods are suited to supplement other already established methods for age-at-death estimation in the identification of an unknown cadaver.

Objective: To implement OFM-recirculation and OFM-suction capable of direct and absolute in-vivo quantification of albumin in the ISF of pigs. Approach: OFM-recirculation and OFM-suction were used to collect ISF in-vivo in pigs and lymph was collected from the same pigs after OFM sampling. Blood was collected before and after OFM sampling, plasma was isolated and mean albumin plasma concentrations per pig were used to yield albumin ISF-to-plasma ratios. We characterized the quality of the collected undiluted ISF via (1) stable albumin ISF-to-plasma ratio in OFM-recirculation and in OFM-suction samples, (2) comparison of albumin ISF-to-plasma ratios from OFM-recirculation and OFM-suction and (3) comparison of normalized albumin concentrations in the ISF and lymph. Main results: Both advanced OFM methods were successfully implemented and albumin was quantified from the collected ISF samples. OFM-recirculation reached stable albumin ISF-to-plasma ratios after 20 recirculation cycles. Absolute ISF albumin concentrations were 11.2 mg ml−1 (OFM-recirculation) and 14.2 mg ml−1 (OFM-suction). Albumin ISF-to-plasma ratios were 0.39 ± 0.04 (OFM -recirculation) and 0.47 ± 0.1 (OFM-suction). Significance: Knowledge of the ISF protein content is of major importance when assessing PK/PD effects, especially of highly protein bound drugs. Up to now, only blood albumin values have been available to determine the degree of protein binding in several tissues. OFM-recirculation and OFM-suction allow direct, absolute quantification of albumin in ISF for the first time and enable investigation of the degree of protein binding of a drug directly in its target tissue.

The treatment of macular diseases requires frequent monitoring by optical coherence tomography (OCT). Home monitoring would reduce the burden of frequent clinical visits and increase therapy adherence. In a pilot study with 47 patients having different macular diseases we tested a proprietary self-examination low-cost full-field OCT (SELFF-OCT). For comparison, scans with a standard clinical spectral domain OCT were taken. Data was graded by a reading center. Patients were able to successfully acquire images that were clinically gradable for 85% of the included eyes. The sensitivity and specificity for an anti-VEGF treatment decision based on the SELFF-OCT was 0.94 and 0.95, respectively.

Purpose New lasers with a continuous wave power exceeding 15 W are currently investigated for retinal therapies, promising highly localized effects at and close to the Retinal Pigment Epithelium (RPE). The goal of this work is to evaluate mechanisms and thresholds for RPE cell damage by means of pulse durations up to 50 µs. Methods A diode laser with a wavelength of 514 nm, a power of 15 W, and adjustable pulse durations between 2 µs and 50 µs was used. Porcine RPE-choroidal explants (ex vivo) and chinchilla bastard rabbits (in vivo) were irradiated to determine threshold radiant exposures for RPE damage \({\bar H_{Cell}}\) by calcein vitality staining and fluorescence angiography, respectively. Thresholds for microbubble formation (MBF) \({\bar H_{MBF}}\) were evaluated by time-resolved optoacoustics. Exemplary histologies support the findings. Results \({\bar H_{{{MBF}}}}\) is significantly higher than \({\bar H_{Cell}}\) at pulse durations ≥ 5 µs (P < 0.05) ex vivo, while at 2 µs, no statistically significant difference was found. The ratios between \({\bar H_{{{MBF}}}}\) and \({\bar H_{Cell}}\) increase with pulse duration from 1.07 to 1.48 ex vivo and 1.1 to 1.6 in vivo, for 5.2 and 50 µs. Conclusions Cellular damage with and without MBF related disintegration are both present and very likely to play a role for pulse durations ≥ 5 µs. With the lower µs pulses, selective RPE disruption might be possible, while higher values allow achieving spatially limited thermal effects without MBF. However, both modi require a very accurate real-time dosing control in order to avoid extended retinal disintegration in this power range.

Burn injuries initiate numerous processes such as heat shock response, inflammation and tissue regeneration. Reliable burn models are needed to elucidate the exact sequence of local events to be able to better predict when local inflammation triggers systemic inflammatory processes. In contrast to other ex vivo skin culture approaches, we used fresh abdominal skin explants to introduce contact burn injuries. Histological and ultrastructural analyses confirmed a partial-thickness burn pathology. Gene expression patterns and cytokine production profiles of key mediators of the local inflammation, heat shock response, and tissue regeneration were analyzed for 24 h after burn injury. We found significantly increased expression of factors involved in tissue regeneration and inflammation soon after burn injury. To investigate purely inflammation-mediated reactions we injected lipopolysaccharide into the dermis. In comparison to burn injury, lipopolysaccharide injection initiated an inflammatory response while expression patterns of heat shock and tissue regeneration genes were unaffected for the duration of the experiment. This novel ex vivo human skin model is suitable to study the local, early responses to skin injuries such as burns while maintaining an intact overall tissue structure and it gives valuable insights into local mechanisms at the very beginning of the wound healing process after burn injuries.

Traditionally, cutaneous drug delivery is studied by skin accumulation or skin permeation, while alternative techniques may enable the interactions between the drug and the skin to be studied in more detail. Time-resolved skin profiling for pharmacokinetic monitoring of two Janus Kinase (JAK) inhibitors, tofacitinib and LEO 37319A, was performed using dermal open-flow microperfusion (dOFM) for sampling of perfusate in an ex vivo and in vivo setup in pig skin. Additionally, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed to investigate depth-resolved skin distributions at defined time points ex vivo in human skin. By dOFM, higher skin concentrations were observed for tofacitinib compared to LEO 37319A, which was supported by the lower molecular weight, higher solubility, lipophilicity, and degree of protein binding. Using MALDI-MSI, the two compounds were observed to show different skin distributions, which was interpreted to be caused by the difference in the ability of the two molecules to interact with the skin compartments. In conclusion, the techniques assessed time- and depth-resolved skin concentrations and were able to show differences in the pharmacokinetic profiles of two JAK inhibitors. Thus, evidence shows that the two techniques can be used as complementary methods to support decision making in drug development.

In April 2020, the QUality Assessment and REProducibility for Instruments and Images in Light Microscopy (QUAREP-LiMi) initiative was formed. This initiative comprises imaging scientists from academia and industry who share a common interest in achieving a better understanding of the performance and limitations of microscopes and improved quality control (QC) in light microscopy. The ultimate goal of the QUAREP-LiMi initiative is to establish a set of common QC standards, guidelines, metadata models, and tools, including detailed protocols, with the ultimate aim of improving reproducible advances in scientific research. This White Paper 1) summarizes the major obstacles identified in the field that motivated the launch of the QUAREP-LiMi initiative; 2) identifies the urgent need to address these obstacles in a grassroots manner, through a community of stakeholders including, researchers, imaging scientists, bioimage analysts, bioimage informatics developers, corporate partners, funding agencies, standards organizations, scientific publishers, and observers of such; 3) outlines the current actions of the QUAREP-LiMi initiative, and 4) proposes future steps that can be taken to improve the dissemination and acceptance of the proposed guidelines to manage QC. To summarize, the principal goal of the QUAREP-LiMi initiative is to improve the overall quality and reproducibility of light microscope image data by introducing broadly accepted standard practices and accurately captured image data metrics., Comment: 17 pages, 3 figures, shortened abstract, Co-Lead Authors: Glyn Nelson and Ulrike Boehm, Corresponding author: Roland Nitschke

To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement. Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7–33-fold higher than the dISF concentrations. Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

Purpose Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study. Methods Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products. Results The overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject’s skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability. Conclusions Inter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability.

The identification of unknown bodies is the fulfilment of a moral obligation towards the deceased, serves to maintain legal security within a society, and gives families the certainty they need to mourn. Taking into account respective local conditions, the aim should always be to achieve a secure and quick identification. To achieve this goal, a functioning cooperation between investigating authorities and forensic sciences is essential. The main objective of this study was to clarify the potential role of tattoos in the identification process of unknown deceased persons in the state of Jalisco, Mexico. Post-mortem data of 2045 bodies from the Instituto Jaliscience de Ciencias Forenses in Guadalajara were evaluated. Of the deceased 46% were tattooed (male: 47%, female: 39%), with 29% of all bodies (male: 29%, female: 26%) showing tattoos at body locations usually visible in everyday life (i.e. head and neck, forearms and hands). The male bodies were most frequently tattooed on the shoulders and upper arms, followed by the forearms and hands and the torso. Female bodies mostly showed tattoos on the forearms and hands, followed by the torso and legs. Taking local tattooing habits into account, the authors developed a classification for tattoo motives. With decreasing frequency, the following keywords could be assigned to the motives: letters and/or numbers, human, symbol (other), plant, symbol (religious), animal, object, tribal/ornament/geometry, fantasy/demon/comic, other. Results of the study indicate the great importance of tattoos as a possible mean of identification in Jalisco, Mexico – either as a stand-alone identification method, as a complementary tool or for planning and prioritizing subsequent investigations. Die Identifizierung unbekannter Verstorbener stellt die Erfüllung einer moralischen Verpflichtung gegenüber dem Verstorbenen dar, dient der Wahrung der Rechtssicherheit innerhalb einer Gesellschaft und gibt Familien Gewissheit, um Abschied nehmen zu können. Hauptziel der vorgestellten Studie war es, die mögliche Rolle von Tätowierungen im Identifizierungsprozess unbekannter Verstorbener unter den aktuell herrschenden Bedingungen im mexikanischen Bundesstaat Jalisco zu klären. Hierfür wurden postmortale Daten von 2045 Verstorbenen aus dem Instituto Jaliscience de Ciencias Forenses in Guadalajara ausgewertet. Von den Verstorbenen waren 46 % tätowiert (männlich: 47 %, weiblich: 39 %), wobei 29 % aller Verstorbenen (männlich: 29 %, weiblich: 26 %) Tätowierungen an im Alltag üblicherweise sichtbaren Körperlokalisationen (Kopf, Hals, Unterarme, Hände) aufwiesen. Männliche Verstorbene waren am häufigsten an den Schultern und Oberarmen, Unterarmen und Händen und am Rumpf tätowiert. Die weiblichen Verstorbenen wiesen zumeist Tätowierungen an den Unterarmen und Händen, am Rumpf und den Beinen auf. Unter Berücksichtigung der lokalen Tätowiergewohnheiten entwickelten die Autoren eine Klassifizierung für Tätowiermotive. Mit abnehmender Häufigkeit konnten den Motiven folgende Schlüsselwörter zugeordnet werden: Buchstaben und/oder Zahlen, human, Symbol (andere), Pflanze, Symbol (religiös), Tier, Objekt, Tribal/Ornament/Geometrie, Fantasie/Dämon/Comic, andere. Die Ergebnisse der Studie deuten auf eine große Bedeutung von Tätowierungen als mögliches Mittel zur Identifizierung im Bundesstaat Jalisco, Mexiko, hin – als eigenständige Identifizierungsmethode, als ergänzendes Werkzeug oder zur Planung und Priorisierung nachfolgender Untersuchungen.

Die vorliegende Arbeit nimmt den Rahmen für den Transformationsprozess, in dem sich gegenwärtig die österreichische Schulaufsicht befindet, in den Blick indem sie - Herausforderungen für die Aufgaben und die Rolle der Schulaufsicht, die durch gesellschaftliche Veränderungsprozesse und veränderte bildungspolitische Vorgaben entstanden sind, skizziert - aus einem kurzen historischen Überblick heraus schulaufsichtliche Spannungsfelder identifiziert, die durch die gegenwärtige Reform der Schulaufsicht aufgelöst (oder zumindest abgeschwächt) werden sollen - die aktuellen Rahmenbedingungen für schulaufsichtliche Tätigkeit (Schulautonomie und die Einführung der externen Schulevaluation) darstellt. Auf dieser Grundlage, werden Perspektiven für die Entwicklung der Schulaufsicht in der Rolle als - Vermittlerin und Verantwortungsträgerin hinsichtlich der Implementierung von Reformvorhaben, - professionelle Unterstützerin bzw. Beraterin (im Kontext der Rechenschaftslegung eigenverantwortlicher Schulen und der in Österreich erst neu zu definierenden Arbeitsbeziehungen zur externen Schulevaluation) und - strategische Führungskraft, die in supervidierender Form Schulleitungen einer Bildungsregion führt, vorgeschlagen. Diese Perspektiven verstehen sich als ein Beitrag zur Diskussion, wie künftig Schulqualitätsmanager/innen ihre Rolle als Schulaufsichtsorgane entwickeln können. In Zeiten tiefgreifender Veränderungen, die auch eine beträchtliche Unsicherheit im Rollenbild ausgelöst haben, werden damit konkrete Vorschläge zur Entwicklung einer stabilen Rolle von Schulaufsichtspersonen vorgelegt.

The goal of this study was to investigate the usefulness of various photographic techniques in visualizing previous tattoos under cover-up tattoos. Ten volunteers with 11 known cover-up tattoos were examined using different photographic techniques: A Canon EOS 6D full-frame digital single-lens reflex camera used in conjunction with a SB600 off-camera flash system and an extension cord; and a Leica M8 digital imaging system camera in conjunction with two different infrared filters (715 nm and 850 nm) and a Metz CL-45 handle-mount flash. A Lumatec Superlite 400 forensic light source was used along with the Canon EOS 6D as a third system. The best results for black cover-up tattoos were achieved with the full-frame digital single-lens reflex camera in conjunction with the off-camera flash system and, for colored cover-up tattoos, with IR-photography at a wavelength of 850 nm. The Lumatec Superlite 400 light source did not provide better results for conventional photography than those obtained with flash lighting. In nine out of eleven cover-up tattoos, the previous tattoos could, at least, be partially visualized. The quality of the visualization depended on the color, pattern, density, and quality of the cover-up tattoo as well as on the photographic technique. None of the examined photographic techniques could satisfactorily image the previous tattoo if the cover-up tattoo was large and black, especially not if it was densely inked. Depending on the color of the cover-up tattoo, a full-frame digital single-lens reflex camera in conjunction with a SB600 off-camera flash system (for black cover-ups) or infrared photography with flash lighting and an 850 nm filter (for colored cover-ups) proved to be the best of the investigated techniques to visualize a previous tattoo under a cover-up tattoo.

Purpose To image, track and map the nerve fiber distribution in excised rabbit corneas over the entire stromal thickness using micro-optical coherence tomography (µOCT) to develop a screening tool for early peripheral neuropathy. Methods Excised rabbit corneas were consecutively imaged by a custom-designed µOCT prototype and a commercial laser scanning fluorescence confocal microscope. The µOCT images with a field of view of approximately 1 × 1 mm were recorded with axial and transverse resolutions of approximately 1 µm and approximately 4 µm, respectively. In the volumetric µOCT image data, network maps of hyper-reflective, branched structures traversing different stromal compartments were segmented using semiautomatic image processing algorithms. Furthermore, the same corneas received βIII-tubulin antibody immunostaining before digital confocal microscopy, and a comparison between µOCT image data and immunohistochemistry analysis was performed to validate the nerval origin of the tracked network structures. Results Semiautomatic tracing of the nerves with a high range of different thicknesses was possible through the whole corneal volumes, creating a skeleton of the traced nerves. There was a good conformity between the hyper-reflective structures in the µOCT data and the stained nerval structures in the immunohistochemistry data. Conclusions This article demonstrates nerval imaging and tracking as well as a spatial correlation between µOCT and a fluorescence corneal nerve standard for larger nerves throughout the full thickness of the cornea ex vivo. Translational relevance Owing to its advantageous properties, µOCT may become useful as a noncontact method for assessing nerval structures in humans to screen for early peripheral neuropathy.

Background: Optical coherence tomography (OCT) is indispensable for studying the progression of age-related macular degeneration (AMD), since it can show quantitatively morphological changes of the retina. However, current OCT devices can only be used in clinical settings and do not provide functional[for full text, please go to the a.m. URL], 7th International Symposium on AMD: Age-related Macular Degeneration - Understanding Pathogenetic Mechanisms of Disease