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Background Increasing incidence rates of cutaneous melanoma (CM) observed during the last five decades in white populations are largely attributed to increased exposure to solar ultraviolet radiation (UVR), often expressed as population attributable fraction (PAF). Thus, many CMs could be prevented by reducing UVR exposure. The aim of this study was to estimate the PAF of CM attributable to UVR exposure and demographic changes in Denmark and Saarland/Germany for the period 1943 to 2036. Material and methods CM incidence data (ICD-10, C43) for Denmark (1943–2016) and the German Federal State of Saarland (1972–2016) were retrieved from the NORDCAN database and from the Saarland Cancer Registry. The number of CMs attributable to UVR exposure was calculated by comparing contemporary or predicted CM incidence rates with CM rates in Denmark during the years 1943–1946. Results In Denmark, the proportion of CM cases attributable to UVR exposure increased from around 20% in 1947–1951 to 96% in 2012–2016; in the Federal State of Saarland, it increased from 50% in 1972–1976 to 90% in 2012–2016. Until 2032–2036, the PAF is expected to rise in Denmark to 97% and in the Saarland to 92%. The demographic influence, on the other hand, is rather small. Conclusions More than 90% of all CM in Germany and Denmark are attributable to UVR exposure, and in principle, preventable. These findings underline the need for primary prevention strategies, aiming to increase the awareness of melanoma and its risk factors and to promote behavioural changes that decrease sun exposure.

Kinder haben Anspruch auf eine bestmogliche medizinische Versorgung. Zunehmende Versorgungsengpasse durch fehlendes Behandlungskapazitaten fuhren zu einer Gefahrdung dieses Anspruchs und zunehmenden Abmeldung der Kinderkliniken von der Rettungsleitstelle. Ziel dieser Studie ist die Darstellung der stationaren Kindernotfallversorgung am Beispiel einer Grosstadt und der Notwendigkeit sog. Akutbelegungen als primarer Endpunkt mangelnder Versorgungskapazitaten. Retrospektive Analyse der uber den Zeitraum vom 01.01.2015 bis 31.12.2019 erhobenen Krankenhauseinweisungen von Kindern

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent type of non-melanoma skin cancer. Its incidence has been rising in recent years, with the highest rate reported in Switzerland compared to other countries in Europe. While the majority of cSCC cases are low-grade tumors with an excellent prognosis following surgical excision, a minority of cSCC lesions (approximately 5% of patients) progress to locally advanced cSCC (lacSCC) or distant metastatic disease (mcSCC), both of which have an unfavorable prognosis. Recent evidence from studies with checkpoint immunotherapy has changed the systemic treatment landscape for lacSCC and mcSCC patients. While both programmed death-1 (PD-1) receptor inhibitors cemiplimab and pembrolizumab are approved by the FDA, cemiplimab is the only approved systemic therapy for the treatment of nonresectable advanced cSCC in the EU and was recently also approved in Switzerland. Based on the latest evidence from randomized clinical trials, national consensus recommendations for the systemic treatment of advanced cSCC have been defined. For classification and optimal management of patients with lacSCC or mcSCC, an interdisciplinary tumor board discussion should be mandatory. Difficult-to-treat advanced cSCC patients should be referred to and treated by specialized centers. These Swiss recommendations provide guidance for the management of patients aged ≥18 years with lacSCC or mcSCC, specifically systemic therapy with a PD-1 inhibitor in the first-line setting. These up-to-date recommendations will also help Swiss physicians in their decision-making and address treatment variability in Swiss clinical practice. Keywords: cSCC, locally advanced, metastatic, systemic treatment, immunotherapy, cemiplimab

Patients with cancer, in particular patients with hematologic malignancies, are at increased risk for critical illness upon COVID-19. We here assessed antibody as well as CD4+ and CD8+ T-cell responses in unexposed and SARS-CoV-2–infected patients with cancer to characterize SARS-CoV-2 immunity and to identify immunologic parameters contributing to COVID-19 outcome. Unexposed patients with hematologic malignancies presented with reduced prevalence of preexisting SARS-CoV-2 cross-reactive CD4+ T-cell responses and signs of T-cell exhaustion compared with patients with solid tumors and healthy volunteers. Whereas SARS-CoV-2 antibody responses did not differ between patients with COVID-19 and cancer and healthy volunteers, intensity, expandability, and diversity of SARS-CoV-2 T-cell responses were profoundly reduced in patients with cancer, and the latter associated with a severe course of COVID-19. This identifies impaired SARS-CoV-2 T-cell immunity as a potential determinant for dismal outcome of COVID-19 in patients with cancer. Significance: This first comprehensive analysis of SARS-CoV-2 immune responses in patients with cancer reports on the potential implications of impaired SARS-CoV-2 T-cell responses for understanding pathophysiology and predicting severity of COVID-19, which in turn might allow for the development of therapeutic measures and vaccines for this vulnerable patient population. See related commentary by Salomé and Horowitz, p. 1877. This article is highlighted in the In This Issue feature, p. 1861

A 59-year-old male patient who suffered from a systemically metastasized, large extrascleral uveal melanoma recurrence of the left eye presented with active hemorrhage from the tumor. He had undergone proton beam irradiation for an epithelioid ciliary body melanoma 4 years before presentation and was lost to follow-up. Magnetic resonance angiography showed vascularization of the lesion via the ophthalmic and maxillary artery. Selective transarterial embolization of the tumor was conducted with polyvinyl alcohol microparticles followed by coiling of the supplying arteries. The bleeding stopped after 2 days and the tumor started to become necrotic. As tumor removal was the primary wish of the patient at this point in time, exenteration was carried out a week later without significant blood loss, intraoperative or postoperative complications. Socket healing was adequate, and the patient reported improved quality of life. He refused systemic palliative treatment and died 3 months after the intervention.

Checkpoint inhibitors have improved survival of metastatic melanoma. However, reliable biomarkers to predict response are still needed. Immunoglobulin G (IgG) antibody subclasses reflect immunocompetence in individuals and are known to be involved in essential functions in our immune system. This prospective study evaluated the association between serum IgG with its subclasses IgG1, IgG2, IgG3, and IgG4 and antitumor response according to RECIST 1.1. Serum samples from 49 patients were prospectively collected before the start of treatment with a checkpoint inhibitor. We observed a statistically significant association of baseline IgG2 with response to therapy (P=0.011). After defining optimal cutpoints, we found significant associations between total IgG (>9.66 g/L, P=0.038), IgG1 (>6.22 g/L, P=0.025), IgG2 (>2.42 g/L, P=0.019), and IgG3 (>0.21 g/L, P=0.034) with progression-free survival. Prolonged overall survival was associated with elevated IgG2 (>2.42 g/L, P=0.043). Together, these findings define total IgG and subclasses as predictors of clinical successful checkpoint inhibition in metastatic melanoma patients.

Cancer vaccination aims at inducing an adaptive immune response against tumor-derived antigens. In this study, we utilize recombinant human adenovirus serotype 5 (rAd5) and recombinant lymphocytic choriomeningitis virus (rLCMV)-based vectors expressing the melanocyte differentiation antigen gp100. In contrast to single or homologous vaccination, a heterologous prime boost vaccination starting with a rAd5-gp100 prime immunization followed by a rLCMV-gp100 boost injection induces a high magnitude of polyfunctional gp100-specific CD8+ T cells. Our data indicate that an optimal T cell induction is dependent on the order and interval of the vaccinations. A prophylactic prime boost vaccination with rAd5- and rLCMV-gp100 protects mice from a B16.F10 melanoma challenge. In the therapeutic setting, combination of the vaccination with low-dose cyclophosphamide showed a synergistic effect and significantly delayed tumor growth. Our findings suggest that heterologous viral vector prime boost immunizations can mediate tumor control in a mouse melanoma model., Graphical Abstract, Virus-based vectors expressing a melanocyte differentiation antigen were used for a heterologous prime boost vaccination. Adeno prime immunization followed by a LCMV boost injection induced antigen-specific CD8+ T cells. Our findings suggest that heterologous viral vector prime boost immunizations can mediate tumor control in a mouse melanoma model.

Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4–22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations. GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment. In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050). The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.

Die ständige Vorhaltung und Verfügbarkeit eines Schockraums zur Versorgung von kritisch kranken und schwer verletzten Patienten ist eine wesentliche und für die transsektorale Notfallversorgung wichtige klinische Ressource. In diesem Artikel sollen die derzeitigen Entwicklungen der Schockraumbereitstellung in Deutschland aufgezeigt werden.

Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing–remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses.

Background Checkpoint inhibitors (CIs) are highly effective but can induce severe immune-related adverse events (irAEs), which cannot be predicted. We investigated whether human leukocyte antigen (HLA) genes predispose to developing of irAEs during therapy and thus hold a predictive role. Methods We established a prospective observational single-centre study and collected data from patients with either metastatic non–small cell lung cancer (NSCLC) or metastatic melanoma, who were treated with anti–PD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyte–associated protein 4) or both CIs combined. Data include irAEs and ranges from 15th July 2016 until 10th May 2018. In addition, we performed HLA typing via next generation sequencing. Results We enrolled 102 patients (median [range] age, 68 [62–74] years) with metastatic cancer in our study who received CI therapy. Of these patients, 59 (58%) developed one or more irAEs, among which pruritus (n = 32 (54%)) and rash (n = 24 (41%)) had the highest rates. We did not find evidence for a single HLA gene being associated with all irAEs (all P > .05). When assessing each irAE individually, we found a significant association between HLA-DRB1*11:01 and pruritus (OR = 4.53, X21,95 = 9.45, P

Objective To characterize the clinical presentation, advanced imaging features, and outcome of orbital disease in a referral population of dogs and cats that underwent computed tomography (CT) or magnetic resonance imaging (MRI). Animals studied Client-owned animals. Procedures Animals referred for orbital disease undergoing ophthalmic examination and either head MRI or CT were included. Demographic and imaging features were compared between animals diagnosed with inflammatory disease and neoplastic disease using Mann-Whitney U and Fischer's exact tests. Results Ninety-seven animals (81 dogs and 16 cats) were included. Eighty-four and 13 patients underwent CT and MRI scanning, respectively. Inflammatory orbital disease was more frequently detected than neoplasia in dogs (59% vs. 41%) and cats (62% vs. 39%). Orbital cellulitis was the most common diagnosis in dogs (36/81, 44.4%) and cats (8/16, 80%). A foreign body was suspected in 36.1% of dogs with orbital cellulitis but only 3 were retrieved during orbitotomy. Multi-drug resistant bacteria were identified in 3 samples and influenced treatment plans. The most common neoplasms were sarcoma (10/30) and carcinoma (7/30) in dogs and lymphoma in cats (3/6). Imaging findings of osteolysis (p = 0.0002) and intracranial extension (p = 0.0001) were significantly associated with neoplasia in dogs. In contrast, osteolysis extension was present in cats with both inflammatory (7/10) and neoplastic (6/6) orbital disease. Conclusions Inflammatory disease, particularly orbital cellulitis, was more common than neoplasia in dogs and cats with orbital disease in our population. We recommend including bacterial culture and susceptibility as part of the diagnostic work up when orbital cellulitis is suspected.

Supplemental Digital Content is available in the text, Background: A declining selenium (Se) status constitutes a characteristic of critical illness and may affect disease course and survival. The dynamics of trauma-induced changes in biomarkers of Se status are poorly characterized, and an association with multiple organ failure (MOF) and mortality can be hypothesized. It was the aim of this study to investigate Se and selenoprotein P (SELENOP) concentrations in major trauma patients during the early posttraumatic period. Patients and Methods: Twenty-four patients after major trauma (ISS ≥16) were included at our level one trauma center. Se supplementation ever during the 90-day observation period was defined as an exclusion criterion. Serum samples were drawn within less than 60 min after trauma, and after 6 h, 12 h, 24 h, 48 h, and 72 h. Serum Se was analyzed by X-ray fluorescence and SELENOP concentrations by ELISA. The data were correlated to clinical parameters, occurrence of MOF defined by MOF and APACHE II score, lung injury defined by Horowitz index and clinical outcome (90-days survival). Results: Serum Se and SELENOP concentrations of the trauma patients were significantly below the average of healthy European subjects (mean ±SD; Se, 41.2±8.1 vs. 84.7±23.3 μg/L, P

Ein 73-jahriger Patient erlitt mehrere Hundebissverletzungen an linker Hand und Unterarm, die im erstversorgenden Krankenhaus konservativ mit Wundnahtstreifen und Verbanden versorgt wurden. Zur weiteren Behandlung wurde der Patient an den Hausarzt verwiesen, der 2 Tage spater eine Eiterentleerung unter den Wundnahtstreifen vorfand. Am 3. Tag wurde der Patient in ein anderes Krankenhaus eingewiesen, in dem bei Aufnahme eine operative Versorgung mit Debridement, Anlage von Vakuumverbanden und konsekutiver Lappenplastik erfolgte. Ein Jahr nach dem Hundebiss zeigten sich bei Untersuchung stechende Schmerzen an der Bissstelle mit Ausstrahlung in den Daumen uber dem Karpometakarpalgelenk, Anasthesie am Handrucken, Gefuhllosigkeit am Daumen ulnar, eingeschranktes Bewegungsausmas in Handgelenk und Daumen. Es ergab sich der Verdacht auf eine Neurombildung. Im darauffolgenden Schlichtungsverfahren bemangelte der Patient die Erstversorgung, bei der die Bisswunden nicht gesaubert, nur mit Wundnahtstreifen verschlossen und kein Antibiotikum gegeben worden seien, weshalb es seiner Meinung nach zu einer umfangreichen Infektion mit operativen Behandlungen und bleibenden Beschwerden gekommen sei. Das Gutachten der Schlichtungsstelle stellte eine ungenugende klinische Befunderhebung bei der Erstuntersuchung sowie eine fehlerhafte Wundversorgung fest, durch die es u. a. zu Bewegungseinschrankungen aller Finger der linken Hand kam.

Peptide mimicry breaks the heart Myocarditis, a prolonged chronic inflammation of heart muscle, can eventually progress to inflammatory cardiomyopathy, a serious condition associated with heart failure. Activated T helper (T H ) cells that recognize myosin heavy chain 6–derived peptides are thought to play a central role in this pathogenesis. Using a mouse model of myocarditis, Gil-Cruz et al. found that cardiac myosin–reactive T H cells are initially primed by myosin-peptide mimics derived from commensal Bacteroides species in the gut (see the Perspective by Epelman). Unlike heathy controls, human myocarditis patients also showed detectable immune reactivity to both Bacteroides and cardiac myosin antigens. Treatment with antibiotics dampened inflammatory responses and prevented lethal heart disease. Science , this issue p. 881 ; see also p. 806

Purpose: PD-(L)1–blocking antibodies have clinical activity in metastatic non–small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. Experimental Design: Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade. Results: We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10–2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction. Conclusions: We identified an association of the KIR3DS1 allelic variant with response to PD-1–targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1–targeted immunotherapy.

Several studies proposed a loss of neural structures (such as hair cells or neurons within the spiral ganglion) in Menière’s disease (MD). It has been shown that VIIth and VIIIth cranial nerves are enlarged within MD patients compared to normal controls. We now aimed to investigate potential differences in these two nerves in patients with MD. Etiology of endolymphatic hydrops, central pathological hallmark of MD, includes genetic predisposition, autoimmune processes, viral infections, cellular apoptosis and oxidative stress. We evaluated morphometric properties (long and short diameter, cross-sectional area) of the VIIth and VIIIth cranial nerves passing from the cerebellopontine angle to the inner ear modiolus, acquired on a clinical 3T magnetic resonance imaging scanner. 71 patients with MD were included, 53 of whom clinically showed a unilateral affection. Our data showed no differences in nerve morphometry between the clinically non-affected and the clinically affected side in patients with clinically unilateral MD. There was also no correlation to duration of symptoms, in contrast to previously demonstrated correlations between clinical features and the extent of endolymphatic hydrops. A disease process starting before the onset of clinical symptoms could be a potential explanation.

Immune checkpoint inhibitors (ICIs) that target the programmed death 1 receptor (anti–programmed cell death 1 [PD-1] therapy) have ushered in a new era of cancer therapy. However, their application has been curtailed by serious immune-related adverse events (irAEs), such as colitis, pneumonitis, and myocarditis, that remain largely unpredictable. Although the use of tumor mutational burden (TMB) as a biomarker for expected therapy response has been advocated,1 a similar parameter for irAEs is lacking. In an attempt to fill this clinically relevant knowledge gap, we investigated the association between irAEs reported during anti–PD-1 therapy and TMB by comparing large-scale surveillance data of irAEs with the median TMB across multiple cancer types. Methods We retrieved postmarketing data of adverse events from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from July 1, 2014, to March 31, 2019. According to the ethics committee policy of the EKOS (Ethikkommission Ostschweiz, Switzerland), this study was exempt from ethical review because all analyzed datasets are deidentified and publicly available. We considered only reports for which the anti–PD-1 agents nivolumab or pembrolizumab were the suspected cause of adverse events. Anti–PD-1 and anti-cytotoxic T-lymphocyte–associated protein 4 combination treatment was excluded. Closely related indications were aggregated to unified terms; for example, “malignant melanoma” was aggregated to “melanoma.” To limit our analysis to irAEs, we filtered terms to match broadly accepted diagnoses that were outlined in peer-reviewed irAE management guidelines. The median TMB in tumor tissue was obtained from previously published comprehensive genomic profiling.2,3 Lastly, we only considered cancers for which there were at least 100 cases of adverse events during anti–PD-1 therapy reported in FAERS. To assess the risk of a patient developing any irAE, we estimated reporting odds ratios (RORs) by comparing the odds of reporting these irAEs rather than others for the anti–PD-1 agents with the odds for all other drugs in the database, which represents standard practice for quantitative analyses of data in FAERS and similar databases.4 Results Our search strategy identified a total of 47 304 adverse events (AEs) in 16 397 patients reported as treated with anti–PD-1 monotherapy for 19 different cancer types. Of these patients, 3661 had at least 1 irAE (22.3%; 95% CI, 21.7-23.0). The comparator group comprised 16 411 749 AE reports from 5 160 064 patients. Our analysis revealed a significant positive correlation between the ROR of reporting an irAE during anti–PD-1 therapy and the corresponding TMB across multiple cancer types, with a higher ROR of irAE associated with a higher median number of coding somatic mutations per megabase of DNA (Figure; Pearson correlation coefficient R = 0.704; P

Cancer patients, in particular patients with hematological malignancies, are at increased risk for critical illness upon COVID-19. We here assessed antibody as well as CD4+ and CD8+ T cell responses in unexposed and SARS-CoV-2-infected cancer patients to characterize SARS-CoV‑2 immunity and to identify immunological parameters contributing to COVID-19 outcome. Unexposed patients with hematological malignancies presented with reduced prevalence of pre-existing SARS-CoV-2 cross-reactive CD4+ T cell responses and signs of T cell exhaustion when compared to solid tumor patients and healthy volunteers. Whereas SARS-CoV-2 antibody responses did not differ between COVID-19 cancer patients and healthy volunteers, intensity, expandability, and diversity of SARS-CoV-2 T cell responses were profoundly reduced in cancer patients, and the latter associated with a severe course of COVID-19. This identifies impaired SARS-CoV-2 T cell immunity as determinant for dismal outcome of COVID-19 in cancer patients.

Complications affecting the lung are hallmarks of severe coronavirus disease 2019 (COVID-19). While there is evidence for autoimmunity in severe COVID-19, the exact mechanisms remain unknown. Here, we established a prospective observational cohort to study lung specific autoantibodies (auto-Abs). Incubation of plasma from severe COVID-19 patients with healthy human lung tissue revealed the presence of IgA antibodies binding to surfactant-producing pneumocytes. Enzyme-linked immunosorbent assays (ELISA) and protein pull-downs using porcine surfactant confirmed the presence of auto-Abs binding to surfactant proteins in severe COVID-19 patients. Mass spectrometry and ELISAs with recombinant proteins identified IgA auto-Abs that target human surfactant proteins B and C. In line with these findings, lungs of deceased COVID-19 patients showed reduced pulmonary surfactant. Our data suggest that IgA-driven autoimmunity against surfactant may result in disease progression of COVID-19.

Objectives Cutaneous melanoma (CM) and keratinocyte cancer (KC) cause considerable morbidity and mortality. We analysed long-term trends of CM and KC in different white populations. Material and methods Age-standardised (European Standard Population 2013) incidence and mortality rates (ASIR, ASMR) of CM were extracted from cancer registries in Denmark, New Zealand and the US SEER-Database. ASIRs of KC were sourced from registries of the German federal states Saarland and Schleswig–Holstein, and from Scotland. Age-period-cohort models were used to project melanoma incidence trends. Results In Denmark between 1943 and 2016, melanoma ASIR increased from 1.1 to 46.5 in males, and from 1.0 to 48.5 in females, estimated to reach 60.0 and 73.1 in males and females by 2036. Melanoma mortality in Denmark (1951–2016) increased from 1.4 to 6.7 (males) and 1.2 to 3.7 (females). In New Zealand between 1948 and 2016, ASIR increased from 2.7 to 81.0 (males) and from 3.8 to 54.7 (females), slight declines are estimated by 2036 for both genders. Melanoma mortality increased six-fold in New Zealand males between 1950 and 2016; smaller increases were observed in females. We observed three- to four-fold increases in melanoma incidence in US whites, predicted to rise to 56.1 and 36.2 in males and females until 2036. Melanoma mortality also increased among US whites between 1970 and 2017, female melanoma mortality remained stable. Similar trends are shown for KC. Conclusions In white populations, incidence of CM and KC significantly increased. CM incidence continues to rise in the short term but is predicted to decline in future.

BackgroundCheckpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.MethodsMGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB–IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.ResultsPretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, pConclusionsHigh pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.

Key Points Question How stable are the conclusions of phase 3 randomized clinical trials of immune checkpoint inhibitors in oncology? Findings This cross-sectional study of 45 randomized clinical trials calculated the survival-inferred fragility index and found that many oncologic trials assessing immune checkpoint inhibitors have a low survival-inferred fragility index, often less than a small fraction of the sample size and less than the number of patients censored soon after randomization. Meaning These results challenge the robustness of many phase 3 randomized clinical trials of immune checkpoint inhibitors in oncology and address the uncertainty regarding their potential clinical benefit., Importance In science and medical research, extreme and dichotomous conclusions may be drawn based on whether the P value falls above or below the threshold. The fragility index (ie, the minimum number of changes from nonevents to events resulting in loss of statistical significance) captures the vulnerability of statistics in trials with binary outcomes. There are a growing number of clinical trials of immune checkpoint inhibitors (ICIs), as well as expanding eligibility for patients to receive them. The robustness of survival outcomes in randomized clinical trials (RCTs) should be evaluated using the fragility index extended to time-to-event data. Objective To calculate the fragility of survival data in RCTs evaluating ICIs. Design, Setting, and Participants In this cross-sectional study, data on phase 3 prospective RCTs investigating ICIs included in PubMed from inception until January 1, 2020, were extracted. Two- or three-group studies reporting results for overall survival were eligible for the survival-inferred fragility index (SIFI) calculation, which is the minimum number of reassignments of the best survivors from the interventional group to the control group resulting in loss of significance (defined as P, This cross-sectional study calculates the fragility of survival data in randomized clinical trials evaluating immune checkpoint inhibitors.

BackgroundWhile the pathogenesis of coronavirus disease 2019 (COVID-19) is becoming increasingly clear, there is little data on IgA response, the first line of bronchial immune defense.ObjectiveTo determine, whether COVID-19 is associated with a vigorous total IgA response and whether IgA autoantibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome (APS), our approach focused on antiphospholipid antibodies (aPL).Materials and methodsIn this retrospective cohort study we compared clinical data and aPL from 64 patients with COVID-19 from three independent centers (two in Switzerland, one in Liechtenstein). Samples were collected from April 9, 2020 to May 1, 2020. Total IgA and aPL were measured with FDA-approved commercially available clinical diagnostic kits.ResultsClinical records of the 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID, n=26 [41%]), a discovery cohort with severe illness (sdCOVD, n=14 [22%]) and a confirmation cohort with severe illness (scCOVID, n=24 [38%]). Severe illness was significantly associated with increased total IgA (sdCOVID, P=0.01; scCOVID, PPP=0.003; scCOVID, PPConclusionsHigher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response triggered in the bronchial mucosa induces systemic autoimmunity.

Characterize ocular adverse events (oAEs) caused by immune checkpoint inhibitors (ICIs).Retrospective analysis of 41,674 cancer patients in the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database receiving anti-PD-1/PD-L1, anti-CTLA-4, or anti-PD-1+ anti-CTLA-4 combination. Reporting odds ratio (ROR) was used to approximate oAE rate across regimens and indications.The most common indications were lung cancer (27.3%) and melanoma (22.7%); 76.3% received anti-PD-1/PD-L1 monotherapy. 1,268 patients (3.0%) reported oAEs, namely vision disorders (30.8%), uveitis (15.1%), and retinal, lacrimal, and optic nerve disorders (10.7%, 9.0%, 8.4%). Melanoma showed the highest proportion of uveitis (117/9,471 cases; 1.2%). Addition of anti-CTLA-4 to anti-PD-1 increased the ROR of uveitis from 4.77 (95% CI 3.83-5.94) to 17.1 (95% CI 12.9-22.7). Among anti-PD-1/PD-L1 cases, uveitis was differentially reported in melanoma (ROR 14.7, 95% CI 10.7-20.2) compared with lung cancer (ROR 2.67, 95% CI 1.68-4.23).ICI-induced oAEs are rare, and uveitis is significantly associated with melanoma and anti-PD-1+ anti-CTLA-4 combination.

Background Because insufficient data are available, the overall number of patients treated in German emergency departments can only be estimated. It is evident, however, that case numbers have been rising steadily in recent years, and that a lack of capacity is now leading with increasing freuqency to forced centralized allocation of patients by the emergency medical services (EMS) to emergency departments that are, officially, temporarily "closed". Methods Trends in patient allocation of this type in greater Munich, Germany, over the years 2013-2019 were analyzed for the first time on the basis of data from 904 997 cases treated by the emergency rescue services. Results From 2014 to 2019, the number of forced centralized patient allocations rose approximately by a factor of nine, from 70 to 634 per 100 000 persons per year. In the same period, the overall number of cases treated by the emergency rescue services rose by 14.5%. Peak values for forced centralized allocations were reached in the first quarter of each calendar year (2015: 1579, 2017: 2435, 2018: 3161, 2019: 3990). Of all medical specialties, internal medicine was the most heavily affected (more than 59% of the total). Especially in the years 2017-2019, the free availability of internal medicine declined in hospitals participating in the common greater Munich reporting system. Conclusion The reasons for the sharp rise in forced centralized allocations are unclear. This observed trend seems likely to persist over the coming years, in view of the current staff shortage, the aging population, and diminishing hospital capacities. The relevant decision-makers must collaborate to create emergency plans that will prevent care bottlenecks so that patients will not be endangered.

Die Morbiditat und Mortalitat polytraumatisierter Patienten wird wesentlich durch das Ausmas der posttraumatischen Inflammationsreaktion beeinflusst. In einer genomweiten mRNA-Microarray-Analyse konnte ein funktionelles Netzwerk an Genen, darunter die Matrixmetalloproteinase MMP‑9 und ihr Inhibitor TIMP‑1 (Tissue Inhibitor of Matrix Metalloproteinase‑1) identifiziert werden, welches in Abhangigkeit der klinischen Parameter „Massentransfusion (MT)“ sowie „Schadel-Hirn-Trauma (SHT)“ signifikant unterschiedlich exprimiert war. Ziel der vorliegenden Arbeit war es nun, die Serumkonzentrationen von TIMP‑1 und MMP‑9 in Abhangigkeit dieser klinischen Variablen in der fruhen posttraumatischen Phase zu untersuchen. In diese prospektive Studie wurden Patienten (≥18 Jahre) mit einem „Injury Severity Score“ (ISS) ≥ 16 Punkte eingeschlossen. Die Unterteilung des Kollektivs erfolgte anhand der klinischen Parameter MT (≥ 10EK/24 h) und SHT (CCT-positiv). Die Bestimmung der Serumkonzentrationen (0 h, 6 h, 12 h, 24 h, 48 h, 72 h) erfolgte mittels ELISA („Enzyme-linked Immunosorbent Assay“). Massentransfundierte Patienten (n = 21; 50 ± 15,7 Jahre; ISS 39 ± 12,8 Punkte) zeigten eine insgesamt signifikant erhohte TIMP‑1-Konzentration (p = 0,003) sowie signifikant hohere TIMP‑1-Level nach 12–72 h. SHT-Patienten (n = 28; 44 ± 19 Jahre; ISS 42 ± 10 Punkte) zeigten signifikant hohere MMP‑9-Konzentrationen im posttraumatischen Verlauf (p = 0,049). Polytraumatisierte Patienten, die massentransfundiert wurden, wiesen signifikant hohere TIMP‑1-Konzentrationen auf als Nichtmassentransfundierte. Dies scheint Ausdruck einer massiv uberschiesenden Inflammationsreaktion zu sein und stellt so einen wesentlichen Faktor bei der Pathogenese der schweren posttraumatischen Immundysfunktion dieses Kollektivs dar. Der signifikante MMP‑9-Anstieg bei begleitendem SHT spiegelt die zentrale Rolle der Matrixmetalloproteinase in der Pathophysiologie des SHT wider.

Due to its antibacterial actions, silver sulfadiazine is widely used as a topical agent in the treatment of wounds, including burns. Widespread or prolonged topical application of silver sulfadiazine dressings can lead to argyria including systemic symptoms due to the resorption of silver. Here, we report a patient experiencing localized argyria due to sunlight exposure after topical use of silver sulfadiazine cream on his face.

Objective To determine free and total cortisol serum concentrations in the first 24 h after trauma and to evaluate the influence of traumatic brain injury (TBI) on their dynamics. Methods This prospective cohort study enrolled patients who had experienced multiple trauma and were admitted to a level 1 trauma centre. The patients were divided in two groups based on the presence of TBI according to clinical and radiological findings. Blood was collected initially as well as at 12 h and 24 h after the traumatic injury. Total cortisol, corticosteroid binding globulin (CBG) and free cortisol levels were determined. Results The study analysed data from 49 patients (36 males and 13 females) with a mean ± SD age of 45.0 ± 16.0 years. Of these, 36 presented with TBI and 13 had multiple injuries without TBI. Patients with TBI showed significantly lower concentrations of total cortisol and free cortisol compared with patients without TBI. Repeated measures analysis revealed different concentration dynamics in patients with TBI, with no increase in cortisol after trauma. Conclusion Multiple trauma patients with TBI are at risk of acute impaired cortisol secretion and show an attenuated stress response as early as 12 h after injury.

More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI.This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9-15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT.Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931-0·995) and an NPV of 0·996 (0·987-0·999). In three (1%) of 1959 patients, the CT scan was positive when the test was negative.These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted.Banyan Biomarkers and US Army Medical Research and Materiel Command.

Response to immune checkpoint inhibitors depends on tumor intrinsic properties and also on host factors in the tumour microenvironment including the presence of immune cells (IC). We hypothesized that nivolumab efficacy varies across different metastatic sites. We retrospectively analyzed computed tomography scans of patients with metastatic non-small cell lung carcinoma (NSCLC) receiving nivolumab. RECIST 1.1 criteria were applied to assess the overall response rate (ORR) and organ-specific response rate (OSRR). We analyzed 52 patients including 44% females, 58% adenocarcinoma and 8% never smokers. Involved organs had target-lesions in the lung (42%), liver (25%), lymph nodes (56%) and soft tissue (13%) and non-target lesions in the bones (23%). ORR and disease control rate (DCR) were 20% and 45%, respectively. Median overall survival, progression-free survival and duration of response were 11.9, 2.3 and 10.3 months. OSRR and organ-specific DCR (OSDCR) were 28% and 90% in lymph nodes, 8% and 54 in the liver, and 9% and 55% in lung metastases. Nine out of 12 patients with bone metastases had progressive lesions. The cumulative incidence probability of organ-specific progression at 6 months was 14% in lymph nodes, 42% in the liver, 36% in lung metastases and 26% in the primary tumor, 29% in soft tissue and 33% in adrenal metastases. In conclusion, the efficacy of immunotherapy is dependent on the metastatic location. Treatment appears more active in lymph nodes compared to other organ sites such as liver, adrenals and bone. Future strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.

BACKGROUND Superior canal dehiscence syndrome (SCDS) is a relatively rare neurotological disorder that is characterized by a heterogeneous clinical picture. Recently, vestibular evoked myogenic potential (VEMP) measurementwas established for the diagnosis of SCDS. In the present study, a case series of patients with SCDS were analyzed, with a focus on VEMP. METHODS Four patients with SCDS were prospectively examined with ocular VEMP (oVEMP) and cervical VEMP (cVEMP). The clinical features and the standard audiovestibular test battery results are summarized and analyzed. The diagnostic accuracy of VEMP testing is evaluated. RESULTS The increased oVEMP amplitudes had a specificity of 100% in this patient population. All patients had normal caloric function and head impulse testing. The Tullio sign was observed in two patients. Three patients had autophony. The airbone gap was not greater than 10 dB in any of the patients. Two patients had marked fremitus nystagmus. All patients had a bony dehiscence of the superior semicircular canal on computed tomography imaging. CONCLUSION The subjective and clinical features in this case series of SCDS patients were heterogeneous. However, objective oVEMP testing had the highest diagnostic value. Furthermore, we describe a new diagnostic clinical sign: fremitus nystagmus.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) frequently entails complications that bear similarities to autoimmune diseases. To date, there are little data on possible immunoglobulin (Ig) A-mediated autoimmune responses. Here, we aim to determine whether COVID-19 is associated with a vigorous total IgA response and whether IgA antibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome, our approach focused on antiphospholipid antibodies (aPL). METHODS: In this retrospective cohort study, clinical data and aPL from 64 patients with COVID-19 were compared from 3 independent tertiary hospitals (1 in Liechtenstein, 2 in Switzerland). Samples were collected from 9 April to 1 May 2020. RESULTS: Clinical records of 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID; 41%), a discovery cohort with severe illness (sdCOVID; 22%) and a confirmation cohort with severe illness (scCOVID; 38%). Total IgA, IgG, and aPL were measured with clinical diagnostic kits. Severe illness was significantly associated with increased total IgA (sdCOVID, P = .01; scCOVID, P < .001), but not total IgG. Among aPL, both cohorts with severe illness significantly correlated with elevated anticardiolipin IgA (sdCOVID and scCOVID, P < .001), anticardiolipin IgM (sdCOVID, P = .003; scCOVID, P< .001), and anti-beta 2 glycoprotein-1 IgA (sdCOVID and scCOVID, P< .001). Systemic lupus erythematosus was excluded from all patients as a potential confounder. CONCLUSIONS: Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA response, possibly triggered in the bronchial mucosa, induces systemic autoimmunity.

Immunotherapy with the programmed death receptor-1 (PD-1) antibody nivolumab has changed the field of metastatic non-small cell lung cancer (NSCLC) treatment. Nivolumab shows better outcome compared to standard second line chemotherapy, but reliable prognostic markers are lacking. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation and associated with worse overall survival (OS) in several tumor types, but have not been analysed extensively in lung cancer in the era of immunotherapy.Patients with metastatic NSCLC treated with nivolumab were enrolled. Pre-treatment NLR and PLR were calculated by division of neutrophils and platelets by lymphocytes measured in peripheral blood. Cox regression analyses were conducted to study the prognostic role of NLR and PLR on OS and progression free survival (PFS). Logistic regression was used to study the association of NLR and PLR. The combined impact of NLR and other known prognostic factors was explored with multivariable regression.Fifty-two patients were included. Elevated NLR was associated with worse OS (HR for log(NLR)=3.64, 95% CI 1.78-7.46, p0.001) and lower response rates (OR for log(NLR)=0.17, 95% CI 0.04-0.68, p=0.013). There was no significant association with PFS (HR for log(NLR)=1.46, 95% CI=0.91-2.34, p=0.114). The AUC for the prediction of 10-month survival using log(NLR) was 0.738, the AUC for the prediction of response to nivolumab was 0.776. Relationships with PLR were similar. NLR and PLR didn't correlate with other known prognostic factors (i.e histology, tobacco use, ECOG performance status,) in our cohort. Inclusion of NLR in multivariable models with these other factors significantly improved the prediction of OS.Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors.

To establish an optimized ultralow-dose digital pulsed fluoroscopy (FP) protocol for upper gastrointestinal tract examinations and to investigate the radiation dose and image quality. An Alderson-Rando-Phantom with 60 thermoluminescent dosimeters was used for dose measurements to systematically evaluate the dose–area product (DAP) and organ doses of the optimized FP protocol with the following acquisition parameters: 86.7 kV; 77 mA; 0.9 mm3, automatic image noise and contrast adaption. Subjective image quality, depiction of contrast agent and image noise (5-point Likert scale; 5 = excellent) were assessed in 41 patients, who underwent contrast-enhanced FP with the aforementioned optimized protocol by two radiologists in consensus. A conventional digital radiograph (DR) acquisition protocol served as the reference standard for radiation dose and image quality analyses. Phantom measurements revealed a general dose reduction of approximately 96% per image for the FP protocol as compared to the DR standard. DAP could be reduced by 97%. Significant dose reductions were also found for organ doses, both in the direct and scattered radiation beam with negligible orbital (FP 5.6 × 10−3 vs. DR 0.11; p = 0.02) and gonadal dose exposure (female FP 2.4 × 10−3 vs. DR 0.05; male FP 8 × 10−4 vs. DR 0.03; p ≤ 0.0004). FP provided diagnostic image quality in all patients, although reading scores were significantly lower for all evaluated parameters as compared to the DR standard (p

Loss of neural structures (such as hair cells or neurones within the spiral ganglion) has been proposed to be involved in Meniere’s disease (MD) (Spoendlin et al. Acta oto-laryngologica Supplementum 499:1–21, 1; Merchant et al. Eur Arch Oto-Rhino-Laryngol Off J Eur Feder Oto-Rhino-Laryngol Soc (EUFOS) Affil German Soc Oto-Rhino-Laryngol Head Neck Surg 252(2):63–75, 2; Tsuji et al. Ann Otol Rhinol Laryngol Suppl 81:26–31, 3; Kariya, Otol Neurotol Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol 28(8):1063–1068, 4; Megerian Laryngoscope 115(9):1525–1535, 5) but this has yet to be confirmed. Therefore, the aim of this study was to investigate morphometric changes of VIIth and VIIIth cranial nerve in MD. MD is characterized by episodic vertigo, tinnitus, fluctuating hearing loss, and aural fullness. The exact pathophysiological mechanisms involved such as viral infections, autoimmune processes, genetic predisposition, cellular apoptosis, and oxidative stress are still not clear. Using a T2-weighted 3D-GE “constructive interference in steady state” (CISS) 3T magnetic resonance imaging (MRI) sequence, we evaluated the properties of the VIIth and VIIIth cranial nerves as they passed from the cerebellopontine angle to the inner ear modiolus. 21 patients with MD were examined along with 39 normal controls. Bidirectional nerve diameters and cross-sectional areas (CSA) were measured in a transverse plane. The comparison of study and control group showed statistically significant (P

Background. Patients after polytrauma regularly suffer from posttraumatic immune system destabilization, which closely influences the further clinical development. Increasing age has recently been identified as an isolated risk factor for an adverse outcome after major trauma. Higher rates and intensity of acute inflammation following severe injury suggest that deregulated inflammation may contribute to these higher rates of posttraumatic morbidity and mortality in older adults. MMP-9 and TIMP-1 have been found to play a major role in posttraumatic immune disorder in a previous genome-wide mRNA analysis. Objective. The aim of this study was to evaluate the differences in serum protein dynamics in older and younger polytraumatized adults. Methods. Blood samples were drawn immediately within 90 minutes after trauma and subsequently after 6, 12, 24, 48, and 72 h. Serum levels of TIMP-1 and MMP-9 were quantified using ELISA. Age groups were divided according to a cutoff of 60 years. Results. 60 polytrauma patients (ISS>16) were included (n=49; ≥60 years, n=11). Serum TIMP-1 and MMP-9 levels showed a highly significant serum dynamic in young and old polytrauma patients (p<0.001). Patients≥60 years showed significantly higher overall TIMP-1 levels (p=0.008). TIMP-1 levels showed a significant maximum after 72 h in the older study population. MMP-9 levels were nonsignificantly higher during the whole observational period in older polytrauma patients when compared to younger patients. Conclusion. The posttraumatic immune response is characterized by significantly higher TIMP-1 levels in older polytrauma patients. This significant association between TIMP-1 levels and patients’ age indicates a more extensive immune dysregulation following major trauma in older adults.

Objectives The sensitivity of molecular and serological methods for COVID-19 testing in an epidemiological setting is not well described. The aim of the study was to determine the frequency of negative RT-PCR results at first clinical presentation as well as negative serological results after a follow-up of at least 3 weeks. Methods Among all patients seen for suspected COVID-19 in Liechtenstein (n=1921), we included initially RT-PCR positive index patients (n=85) as well as initially RT-PCR negative (n=66) for follow-up with SARS-CoV-2 antibody testing. Antibodies were detected with seven different commercially available immunoassays. Frequencies of negative RT-PCR and serology results in individuals with COVID-19 were determined and compared to those observed in a validation cohort of Swiss patients (n=211). Results Among COVID-19 patients in Liechtenstein, false-negative RT-PCR at initial presentation was seen in 18% (12/66), whereas negative serology in COVID-19 patients was 4% (3/85). The validation cohort showed similar frequencies: 2/66 (3%) for negative serology, and 16/155 (10%) for false negative RT-PCR. COVID-19 patients with negative follow-up serology tended to have a longer disease duration (p=0.05) and more clinical symptoms than other patients with COVID-19 (p Conclusions RT-PCR at initial presentation in patients with suspected COVID-19 can miss infected patients. Antibody titers of SARS-CoV-2 assays are linked to the number of disease symptoms and the duration of disease. One in 25 patients with RT-PCR-positive COVID-19 does not develop antibodies detectable with frequently employed and commercially available immunoassays.

S100B is may complement the diagnostic tool set for mild TBI. Under certain circumstances the S100B measurement can replace a traditional CT imaging scan in suspected TBI. During longer hospitalization, S100B levels can provide insights regarding patient progression and outcome. Increased S100B concentration does not conclusively prove cerebral damage, but a physiological concentration in adult patients admitted with TBI does rule out cerebral damage with sufficient certainty. In an adult patient with a Glasgow Coma score of at least 14, presenting within 6 hours of head injury, guidelines suggest that an S100B level below 0.1 microgram/liter can prevent the need for a head CT scan.

Traumatic brain injury represents a major economic and sociologic burden. The use of clinical risk factors to prospectively stratify patients into cohorts of injury severity is valuable. The most commonly used risk scoring systems are the Glasgow Coma Scale (GCS) and the Full Outline of UnResponsiveness (FOUR) score. In addition, neuroimaging risk stratification tools include the Marshall scale and the Rotterdam scale, which also are prospective determinants of injury severity. Beyond the initial damage, avoidance of secondary brain injury is critical, including the prevention of hypoxia, hypotension, and hypothermia, which can also be included in outcome predictors. Other predictors of poor outcomes may include elevated biomarkers, such as S-100βprotein, CSFα-synuclein, and NSE. Finally, there are outcome prediction models for patients with traumatic brain injury that sum many of the above described factors. These include the CRASH model that incorporates GCS, age, pupils, extracranial injury, country, and CT findings, and the IMPACT model of pupils, GCS motor response, age, CT imaging hypotension, hypoxemia, hemoglobin, and glucose levels. This chapter reviews the data supporting the use of these various risk stratification tools.