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Objectives The ICEpop Capability Measure for Adults (ICECAP-A) assesses 5 capabilities (stability, attachment, autonomy, achievement, and enjoyment) that are important to one’s quality of life and might be an important addition to generic health questionnaires currently used in economic evaluations. This study aimed to develop a Dutch tariff of the Dutch translation of the ICECAP-A. Methods The methods used are similar to those used in the development of the UK tariff. A profile case best–worst scaling task was presented to 1002 participants from the general Dutch population. A scale-adjusted latent class analysis was performed to test for preferences of ICECAP-A capabilities and scale heterogeneity. Results A 3-preference class 2-scale class model with worst choice as scale predictor was considered optimal and was used to calculate the resulting tariff. Results indicated that the capabilities stability, attachment, and enjoyment were considered more important aspects of quality of life than autonomy and achievement. Additionally, improving capabilities from low to moderate levels had a larger effect on quality of life than improving capabilities that were already at a higher level. Conclusions The ICECAP-A tariffs found in this study could be used in economic evaluations of healthcare interventions in The Netherlands.

Background At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict coronavirus disease 2019 (COVID-19) illness. However, the results are not conclusive, as critical illness can drastically alter a patient’s microbiome through multiple confounders. Methods To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multicenter, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate, and severe COVID-19 (n = 322 participants). Results In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. Conclusions In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.

OBJECTIVE: Many individuals with an eating disorder do not receive appropriate care. Low-threshold interventions could help bridge this treatment gap. The study aim was to evaluate the effectiveness of Featback, a fully automated online self-help intervention, online expert-patient support and their combination. METHOD: A randomized controlled trial with a 12-month follow-up period was conducted. Participants aged 16 or older with at least mild eating disorder symptoms were randomized to four conditions: (1) Featback, a fully automated online self-help intervention, (2) chat or email support from a recovered expert patient, (3) Featback with expert-patient support and (4) a waiting list control condition. The intervention period was 8 weeks and there was a total of six online assessments. The main outcome constituted reduction of eating disorder symptoms over time. RESULTS: Three hundred fifty five participants, of whom 43% had never received eating disorder treatment, were randomized. The three active interventions were superior to a waitlist in reducing eating disorder symptoms (d = -0.38), with no significant difference in effectiveness between the three interventions. Participants in conditions with expert-patient support were more satisfied with the intervention. DISCUSSION: Internet-based self-help, expert-patient support and their combination were effective in reducing eating disorder symptoms compared to a waiting list control condition. Guidance improved satisfaction with the internet intervention but not its effectiveness. Low-threshold interventions such as Featback and expert-patient support can reduce eating disorder symptoms and reach the large group of underserved individuals, complementing existing forms of eating disorder treatment. PUBLIC SIGNIFICANCE STATEMENT: Individuals with eating-related problems who received (1) a fully automated internet-based intervention, (2) chat and e-mail support by a recovered individual or (3) their combination, experienced stronger reductions in eating disorder symptoms than those who received (4) usual care. Such brief and easy-access interventions play an important role in reaching individuals who are currently not reached by other forms of treatment. ispartof: INTERNATIONAL JOURNAL OF EATING DISORDERS vol:55 issue:10 pages:1361-1373 ispartof: location:United States status: published

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (

The successive cancer plans mobilize health professionals by emphasizing personalized medicine that is accessible to all. This individualization of therapeutic care, along with major innovations in therapeutic tools, leads to the chronicization of certain cancers. A new situation that requires support for people affected by the disease during their treatment and also after in order to preserve autonomy, continuity and quality of life.

Objectives Cardiac support systems are being used increasingly more due to the growing prevalence of heart failure and cardiogenic shock. Reducing cardiac afterload, intracardiac pressure, and flow support are important factors. Extracorporeal membrane oxygenation (ECMO) and intracardiac microaxial pump systems (Impella) as non-permanent MCS (mechanical circulatory support) are being used increasingly. Methods We reviewed the recent literature and developed an international European registry for non-permanent MCS. Results Life-threatening conditions that are observed preoperatively often include reduced left ventricular function, systemic hypoperfusion, myocardial infarction, acute and chronic heart failure, myocarditis, and valve vitia. Postoperative complications that are commonly observed include severe systemic inflammatory response, ischemia-reperfusion injury, trauma-related disorders, which ultimately may lead to low cardiac output (CO) syndrome and organ dysfunctions, which necessitates a prolonged ICU stay. Choosing the appropriate device for support is critical. The management strategies and complications differ by system. The “heart-team” approach is inevitably needed.However despite previous efforts to elucidate these topics, it remains largely unclear which patients benefit from certain systems, when is the right time to initiate (MCS), which support system is appropriate, what is the optimal level and type of support, which therapeutic additive and supportive strategies should be considered and ultimately, what are the future prospects and therapeutic developments. Conclusion The European cardiac surgical register ImCarS has been established as an IIT with the overall aim to evaluate data received from the daily clinical practice in cardiac surgery. Interested colleagues are cordially invited to join the register. Clinical registration number: DRKS00024560. Positive Ethics Vote: AZ 246/20 Faculty of Medicine, Justus-Liebig-University-Gießen.

Objective: The primary aim was assessing the cost-effectiveness of an internet-based self-help program, expert-patient support, and the combination of both compared to a care-as-usual condition. Method: An economic evaluation from a societal perspective was conducted alongside a randomized controlled trial. Participants aged 16 or older with at least mild eating disorder symptoms were randomly assigned to four conditions: (1) Featback, an online unguided self-help program, (2) chat or e-mail support from a recovered expert patient, (3) Featback with expert-patient support, and (4) care-as-usual. After a baseline assessment and intervention period of 8 weeks, five online assessments were conducted over 12 months of follow-up. The main result constituted cost-utility acceptability curves with quality-of-life adjusted life years (QALYs) and societal costs over the entire study duration. Results: No significant differences between the conditions were found regarding QALYs, health care costs and societal costs. Nonsignificant differences in QALYs were in favor of the Featback conditions and the lowest societal costs per participant were observed in the Featback only condition (euro16,741) while the highest costs were seen in the care-as-usual condition (euro 28,479). The Featback only condition had the highest probability of being efficient compared to the alternatives for all acceptable willingness-to-pay values. Discussion: Featback, an internet-based unguided self-help intervention, was likely to be efficient compared to Featback with guidance from an expert patient, guidance alone and a care-as-usual condition. Results suggest that scalable interventions such as Featback may reduce health care costs and help individuals with eating disorders that are currently not reached by other forms of treatment. Public significance statement Internet-based interventions for eating disorders might reach individuals in society who currently do not receive appropriate treatment at low costs. Featback, an online automated self-help program for eating disorders, was found to improve quality of life slightly while reducing costs for society, compared to a do-nothing approach. Consequently, implementing internet-based interventions such as Featback likely benefits both individuals suffering from an eating disorder and society as a whole.

Background Concurrent extrahepatic autoimmune disorders (CEHAID) are frequently observed in autoimmune hepatitis (AIH). It is not clear whether there is any prognostic significance of CEHAID on AIH. The aim of this study was to examine the prognostic impact of CEHAID and the correlation with the disease severity of AIH. Methods This study included 65 hospitalized subjects who fulfilled the accepted criteria for AIH during an 8-year period (2009–2016). All records were manually screened for presence of associated autoimmune diseases. Disease severity of AIH was assessed by liver laboratory tests including the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT) and liver histology. Results Among the enrolled patients, 52 (80%) were female (median age 61 years, IQR 45–75). Fifty-six (86.2%) were classified as type-1 AIH. In 26 (40%) patients at least one additional extrahepatic autoimmune disease was diagnosed. Thirty-four subjects were referred to our hospital because of acute presentation of AIH (supposed by an acute elevation of hepatic enzymes) for subsequent liver biopsy resulting in initial diagnosis of AIH. This group was stratified into 3 subgroups: (A) AIH alone (n = 14); (B) overlap with primary biliary cirrhosis (PBC) / primary sclerosing cholangitis (PSC) (n = 11); and (C) with CEHAID (n = 9). AST/ALT ratio was the lowest in subgroup C (median 0.64, IQR 0.51–0.94; P = 0.023), compared to subgroup A (median 0.91, IQR 0.66–1.10) and subgroup B (median 1.10, IQR 0.89–1.36). Patients with AIH alone showed a trend to the highest grade of fibrosis (mean 2.3; 95% CI: 1.5–3.0) with no statistical significance compared to subjects with CEHAID (lowest grade of fibrosis; mean 1.5; 95% CI: 0.2–2.8; P = 0.380) whereas the ongoing inflammation was comparable. Conclusions AST/ALT ratio and extent of fibrosis were lower in subjects with AIH and CEHAID, compared to subjects with only AIH. Therefore, the occurrence of CEHAID might be a predictor for lower disease severity of newly diagnosed acute onset AIH, possibly caused by an earlier diagnosis or different modes of damage.

Increased activation of sympathetic nervous system contributes to congestive heart failure (CHF) progression, and inhibition of sympathetic overactivation by beta-blockers is successful in CHF patients. Similarly, caloric restriction (CR) reduces sympathetic activity but mediates additional effects. Here, we compared the cardiac effects of CR (− 40% kcal, 3 months) with beta-blocker therapy (BB), diuretic medication (DF) or control diet in 18-months-old Wistar rats. We continuously recorded blood pressure, heart rate, body temperature and activity with telemetric devices and analysed cardiac function, activated signalling cascades and markers of apoptosis and mitochondrial biogenesis. During our study, left ventricular (LV) systolic function improved markedly (CR), mildly (BB) or even deteriorated (DF; control). Diastolic function was preserved by CR and BB but impaired by DF. CR reduced blood pressure identical to DF and BB and heart rate identical to BB. Plasma noradrenaline was decreased by CR and BB but increased by DF. Only CR reduced LV oxidative damage and apoptosis, induced AMPK and Akt phosphorylation and increased mitochondrial biogenesis. Thus, additive to the reduction of sympathetic activity, CR achieves protective effects on mitochondria and improves LV function and ROS damage in aged hearts. CR mechanisms may provide additional therapeutic targets compared to traditional CHF therapy.

The aim was to evaluate the remineralization potential as well as the extent of protection against renewed demineralization of enamel by hydroxyapatite-containing toothpaste (Karex) in comparison to fluoride-containing (Elmex) and fluoride- and hydroxyapatite-free toothpaste (Ajona) as control.Fifty-seven enamel samples were obtained from 19 human teeth. Five demarcated surfaces were created on each tooth (S0-S4). Four of the surfaces (S1-S4) were exposed to lactic acid (pH 3) for 8 h (demineralization). S0 was left untreated as control. S1 was solely treated with acid. After demineralization, S2 was exposed to Karex for 2 min, of which 15 s were brushing. S3 was treated with Elmex and S4 with Ajona, accordingly. Then, the samples were evaluated using a scanning electron microscope and ImageJ image analysis software to determine the percentage of demineralization. Afterwards, S2-S4 were again exposed to lactic acid for 2 h, and subjected to pixel analysis another time. Data were statistically analysed using ANOVA with post-hoc Scheffé test and the Kurskal-Wallis test.The surfaces treated with Elmex showed the lowest percentage of demineralization (mean 5.01 ± 0.98%) (p 0.01). Thus, Elmex remineralized more effectively compared to Ajona (8.89 ± 1.41%) and Karex (9.85 ± 1.63%) (p 0.01). Furthermore, Elmex showed the lowest percentage of demineralized enamel after new demineralization (median 6.29%), followed by Ajona (11.92%) and Karex (13.46%) (p 0.001).In terms of remineralization and protection against renewed demineralization, a hydroxyapatite-containing toothpaste (Karex) appears to be inferior to a fluoride-containing toothpaste (Elmex) and a fluoride- and hydroxyapatite-free toothpaste (Ajona). Hence, the recommendation to use Karex to protect against demineralization should be critically questioned.

Background House dust mites (HDMs) are among the most important allergen sources containing many different allergenic molecules. Analysis of patients from a double-blind, placebo-controlled allergen-specific immunotherapy (AIT) study indicated that patients may benefit from AIT to different extents depending on their molecular sensitization profiles. Objective Our aim was to investigate in a real-life setting whether stratification of patients with HDM allergy according to molecular analysis may enhance AIT success. Methods Serum and nasal secretion samples from patients with HDM allergy (n = 24) (at baseline, 7, 15, 33, and 52 weeks) who had received 1 year of treatment with a well-defined subcutaneous AIT form (Alutard SQ 510) were tested for IgE and IgG reactivity to 15 microarrayed HDM allergen molecules with ImmunoCAP Immuno-solid-phase Allergen Chip technology. IgG subclass levels to allergens and peptides were determined by ELISA, and IgG blocking was assessed by basophil activation. In vitro parameters were related to reduction of symptoms determined by combined symptom medication score and visual analog scale score. Results Alutard SQ 510 induced protective IgG mainly against Dermatophagoides pteronyssinus (Der p) 1 and Der p 2 and to a lesser extent to Der p 23, but not to the other important allergens such as Der p 5, Der p 7, and Der p 21, showing better clinical efficacy in patients sensitized only to Der p 1 and/or Der p 2 as compared with patients having additional IgE specificities. Conclusion Stratification of patients with HDM allergy according to molecular sensitization profiles and molecular monitoring of AIT-induced IgG responses may enhance the success of AIT.

Background Exercise intolerance is a cardinal symptom in right (RV) and left ventricular (LV) failure. The underlying skeletal muscle contributes to increased morbidity in patients. Here, we compared skeletal muscle sarcopenia in a novel two‐stage model of RV failure to an established model of LV failure. Methods Pulmonary artery banding (PAB) or aortic banding (AOB) was performed in weanling rats, inducing a transition from compensated cardiac hypertrophy (after 7 weeks) to heart failure (after 22–26 weeks). Cardiac function was characterized by echocardiography. Skeletal muscle catabolic/anabolic balance and energy metabolism were analysed by histological and biochemical methods, real‐time PCR, and western blot. Results Two clearly distinguishable stages of left or right heart disease with a comparable severity were reached. However, skeletal muscle impairment was significantly more pronounced in LV failure. While the compensatory stage resulted only in minor changes, soleus and gastrocnemius muscle of AOB rats at the decompensated stage demonstrated reduced weight and fibre diameter, higher proteasome activity and expression of the muscle‐specific ubiquitin E3 ligases muscle‐specific RING finger 1 and atrogin‐1, increased expression of the atrophy marker myostatin, increased autophagy activation, and impaired mitochondrial function and respiratory chain gene expression. Soleus and gastrocnemius muscle of PAB rats did not show significant changes in muscle weight and proteasome or autophagy activation, but mitochondrial function was mildly impaired as well. The diaphragm did not demonstrate differences in any model or disease stage except for myostatin expression, which was altered at the decompensated stage in both models. Plasma interleukin (IL)‐6 and angiotensin II were strongly increased at the decompensated stage (AOB > > PAB). Soleus and gastrocnemius muscle itself demonstrated an increase in IL‐6 expression independent from blood‐derived cytokines only in AOB animals. In vitro experiments in rat skeletal muscle cells suggested a direct impact of IL‐6 and angiotensin II on distinctive atrophic changes. Conclusions Manifold skeletal muscle alterations are more pronounced in LV failure compared with RV failure despite a similar ventricular impairment. Most of the catabolic changes were observed in soleus or gastrocnemius muscle rather than in the constantly active diaphragm. Mitochondrial dysfunction and up‐regulation of myostatin were identified as the earliest signs of skeletal muscle impairment.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome. Fil: Hillert, Alicia. No especifíca; Fil: Anikster, Yair. No especifíca; Fil: Belanger Quintana, Amaya. No especifíca; Fil: Burlina, Alberto. No especifíca; Fil: Burton, Barbara K.. No especifíca; Fil: Carducci, Carla. No especifíca; Fil: Chiesa, Ana Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Christodoulou, John. No especifíca; Fil: Dordevic, Maja. No especifíca; Fil: Desviat, Lourdes R.. No especifíca; Fil: Eliyahu, Aviva. No especifíca; Fil: Evers, Roeland A.F.. No especifíca; Fil: Fajkusova, Lena. No especifíca; Fil: Feillet, Francois. No especifíca; Fil: Bonfim Freitas, Pedro E.. No especifíca; Fil: Gizewska, María. No especifíca; Fil: Gundorova, Polina. No especifíca; Fil: Karall, Daniela. No especifíca; Fil: Kneller, Katya. No especifíca; Fil: Kutsev, Sergey I.. No especifíca; Fil: Leuzzi, Vincenzo. No especifíca; Fil: Levy, Harvey L.. No especifíca; Fil: Lichter Koneck, Uta. No especifíca; Fil: Muntau, Ania C.. No especifíca; Fil: Namour, Fares. No especifíca; Fil: Oltarzewsk, Mariusz. No especifíca; Fil: Paras, Andrea. No especifíca; Fil: Perez, Belén. No especifíca; Fil: Polak, Emil. No especifíca; Fil: Polyakov, Alexander V.. No especifíca; Fil: Porta, Francesco. No especifíca; Fil: Rohrbach, Marianne. No especifíca; Fil: Scholl Bürgi, Sabine. No especifíca; Fil: Spécola, Norma. No especifíca; Fil: Stojiljkovic, Maja. No especifíca; Fil: Shen, Nan. No especifíca; Fil: Santana da Silva, Luiz C.. No especifíca; Fil: Skouma, Anastasia. No especifíca; Fil: van Spronsen, Francjan. No especifíca; Fil: Stoppioni, Vera. No especifíca; Fil: Thöny, Beat. No especifíca; Fil: Trefz, Friedrich K.. No especifíca; Fil: Vockley, Jerry. No especifíca; Fil: Yu, Youngguo. No especifíca; Fil: Zschocke, Johannes. No especifíca; Fil: Hoffmann, Georg F.. No especifíca; Fil: Garbade, Sven F.. No especifíca; Fil: Blau, Nenad. No especifíca

Tanycytes are highly specialized ependymal cells that line the bottom and the lateral walls of the third ventricle. In contact with the cerebrospinal fluid through their cell bodies, they send processes into the arcuate nucleus, the ventromedial nucleus, and the dorsomedial nucleus of the hypothalamus. In the present work, we combined transgenic and immunohistochemical approaches to investigate the neuroanatomical associations between tanycytes and neural cells present in the hypothalamic parenchyma, in particular in the arcuate nucleus. The specific expression of tdTomato in tanycytes first allowed the observation of peculiar subcellular protrusions along tanycyte processes and at their endfeet such as spines, swelling, en passant boutons, boutons, or claws. Interestingly, these protrusions contact different neural cells in the brain parenchyma including blood vessels and neurons, and in particular NPY and POMC neurons in the arcuate nucleus. Using both fluorescent and electron microscopy, we finally observed that these tanycyte protrusions contain ribosomes, mitochondria, diverse vesicles, and transporters, suggesting dense tanycyte/neuron and tanycyte/blood vessel communications. Altogether, our results lay the neuroanatomical basis for tanycyte/neural cell interactions, which will be useful to further understand cell‐to‐cell communications involved in the regulation of neuroendocrine functions., Using TAT‐Cre‐mediated transduction of tdTomato in tanycytes, this study morphologically describes peculiar protrusions along tanycyte processes. Combining tdTomato filling, fluorescence immunohistochemistry and electron microscopy, the authors show in 3D reconstructions the diverse tanycyte partners as well as the subcellular organelles and transporters present in tanycyte protrusions. 3V, third ventricle; ER, endoplasmic reticulum; MVB, multivesicular bodies.

MS-assisted lipidomic tissue analysis is a valuable tool to assess sphingolipid metabolism dysfunction in disease. These analyses can reveal potential pharmacological targets or direct mechanistic studies to better understand the molecular underpinnings and influence of sphingolipid metabolism alterations on disease etiology. But procuring sufficient human tissues for adequately powered studies can be challenging. Therefore, biorepositories, which hold large collections of cryopreserved human tissues, are an ideal retrospective source of specimens. However, this resource has been vastly underutilized by lipid biologists, as the components of OCT compound used in cryopreservation are incompatible with MS analyses. Here, we report results indicating that OCT compound also interferes with protein quantification assays, and that the presence of OCT compound impacts the quantification of extracted sphingolipids by LC-ESI-MS/MS. We developed and validated a simple and inexpensive method that removes OCT compound from OCT compound-embedded tissues. Our results indicate that removal of OCT compound from cryopreserved tissues does not significantly affect the accuracy of sphingolipid measurements with LC-ESI-MS/MS. We used the validated method to analyze sphingolipid alterations in tumors compared with normal adjacent uninvolved lung tissues from individuals with lung cancer and to determine the long-term stability of sphingolipids in OCT compound-cryopreserved normal lung tissues. We show that lung cancer tumors have significantly altered sphingolipid profiles and that sphingolipids are stable for up to 16 years in OCT compound-cryopreserved normal lung tissues. This validated sphingolipidomic OCT compound-removal protocol should be a valuable addition to the lipid biologist's toolbox.

Kann das neue Coronavirus SARS-CoV‑2 okulares Geweben infizieren und damit neben dem Kontaktrisiko ein Infektionsrisiko durch das Gewebe darstellen, ist die Frage, die die Augenheilkunde seit Beginn der Infektion beschaftigt. Um einen bestimmten Gewebetyp zu infizieren, muss jedes Virus seinen bestimmten Rezeptor und manchmal auch Korezeptoren oder andere Proteine vorfinden. Ziel dieser Ubersichtsarbeit war es, mithilfe der aktuellen, zuganglichen Literatur (Stand 28.05.2020) den aktuellen Forschungsstatus zusammenzufassen und wiederzugeben. Zum Zeitpunkt der Recherche waren eindeutig ACE2 als Rezeptor und TMPRSS2 als notwendige Protease identifiziert, um die Infektion einer humanen Zelle mit SARS-CoV‑2 zu ermoglichen. Im Auge werden sowohl ACE2 als auch TMPRSS2 exprimiert, wenn auch teilweise sehr schwach und unterschiedlich schwach in verschiedenen Geweben. Beachtenswert ist, dass mit verschiedenen Methoden sehr unterschiedliche Ergebnisse erzielt wurden. Hierfur kommen mehrere Grunde infrage: zum einen die Methode der Detektion bzw. der Konservierung des Gewebes, zum anderen die moglicherweise unterschiedliche Expression der getesteten Gewebeproben, des Weiteren ein moglicherweise rascher Rezeptorexpressionsverlusts post mortem. Eine Infektion des Auges erscheint daher moglich, woruber auch schon in diversen Publikationen berichtet wurde. Welche Virusmenge bzw. welche Rezeptorexpression notwendig ist, um eine Infektion zu ermoglichen, ist ungeklart. Aufgrund der geringeren ACE2- und TMPRSS2-Expression ist das Auge – nach aktuellem Wissenstand – aber nicht als Hochrisikogewebe anzusehen. Trotzdem sind entsprechende Schutzmasnahmen sowohl fur das medizinische Personal als auch fur die Patienten notwendig. Bei Hornhauttransplantation ist eine Infektion des Spendergewebes mit SARS-Cov‑2 auszuschliesen.

Objectives The current systematic review (SR) was undertaken to identify and summarise the published literature reporting on the clinical and economic value of automated in-hospital pharmacy services with a primary focus on systems supporting the dispensing of medicines. Methods Literature searches were conducted in MEDLINE, Embase and the Cochrane Library on 17 December 2017 to identify English-language publications investigating any automated dispensing systems (ADSs) in the inpatient setting to include central pharmacy and ward-based systems. Results 4320 publications were screened by title and abstract and 45 of 175 full publications screened were included. Grey literature searching identified an additional three publications. Therefore, 48 publications relating to ADSs were eligible for inclusion. Although a relatively large evidence base was identified as part of the current SR, the eligible studies were inconsistent in terms of their design and the format of reporting of outcomes. The studies demonstrate that both pharmacy and ward-based ADSs offer benefits over traditional manual dispensing methods in terms of clinical and economic outcomes. The primary benefits following implementation of an ADS include reductions in medication errors, medication administration time and costs. Studies examining optimisation/inventory management strategies/refill programmes for these systems suggest that optimal implementation of the ADS is required to ensure that clinical success and economic benefits are maximised. Conclusions The published evidence suggests positive impacts of ADS and should encourage hospitals to invest in automation, with a global strategy to improve the reliability and the efficiency of the medication process. However, one of the key findings of the current SR is the need for further data from adequately powered studies reporting clinically relevant outcomes which would allow for robust, evidence-based recommendations on the return on investment of the technologies. These studies would probably contribute to a larger adoption of these technologies by European hospitals.

Albrecht von Graefe (1828–1870) is the founder of this archive (1854) and the founder of modern ophthalmology. In 2020, the anniversary of his death will be observed for the 150th time. The “German Ophthalmological Society” (DOG), also a Graefe foundation (1857), has therefore proclaimed a “Graefe year.” In Berlin, his hometown, several Graefe-monuments exist. Ophthalmology owes Albrecht von Graefe numerous first discoveries such as excavation of the optic disc in glaucoma (1855), iridectomy in glaucoma (1857), or central artery occlusion (1859). But his after-effects are not only based on his clinical and scientific merits but also on his extraordinary, fascinating personality, which can be characterized by his spirit of internationality, friendship, self-criticism, love of truth, and modesty. Graefe became a myth not only because of his early death but also because he had apart from great successes, to accept human misfortunes at the same time. Albrecht von Graefe can be regarded as the conscience of ophthalmology in Germany.

Background: There is growing interest both in testing IgE in nasal secretions (NS) and in molecular diagnosis of seasonal allergic rhinitis (SAR). Yet, the reliability of nasal IgE detection with the newest molecular assays has never been assessed in a large cohort of pollen allergic patients. Objective: To investigate with microarray technology and compare the repertoires of specific IgE (sIgE) antibodies in NS and sera of a large population of children and adults with SAR. Methods: Nasal secretions were collected with an absorbent device (Merocel 2000��, Medtronic) and a minimal dilution procedure from 90 children and 71 adults with SAR. Total IgE (tIgE) (ImmunoCAP, Thermo Fisher Scientific (TFS)) and sIgE antibodies against 112 allergen molecules (ISAC-112, TFS) were measured in NS and serum. Results: Nasal sIgE was detectable in 68.3% of the patients. The detected nasal sIgE antibodies recognized airborne (88%), vegetable (10%), and animal food or other (

Tubular ATP release is regulated by mechanosensation of fluid shear stress (FSS). Polycystin-1/polycystin-2 (PC1/PC2) functions as a mechanosensory complex in the kidney. Extracellular ATP is implicated in polycystic kidney disease (PKD), where PC1/PC2 is dysfunctional. This study aims to provide new insights into the ATP signaling under physiological conditions and PKD. Microfluidics, pharmacologic inhibition, and loss-of-function approaches were combined to assess the ATP release in mouse distal convoluted tubule 15 (mDCT15) cells. Kidney-specific Pkd1 knockout mice (iKsp-Pkd1(-/-)) and zebrafish pkd2 morphants (pkd2-MO) were as models for PKD. FSS-exposed mDCT15 cells displayed increased ATP release. Pannexin-1 inhibition and knockout decreased FSS-modulated ATP release. In iKsp-Pkd1(-/-) mice, elevated renal pannexin-1 mRNA expression and urinary ATP were observed. In Pkd1(-/-) mDCT15 cells, elevated ATP release was observed upon the FSS mechanosensation. In these cells, increased pannexin-1 mRNA expression was observed. Importantly, pannexin-1 inhibition in pkd2-MO decreased the renal cyst growth. Our results demonstrate that pannexin-1 channels mediate ATP release into the tubular lumen due to pro-urinary flow. We present pannexin-1 as novel therapeutic target to prevent the renal cyst growth in PKD.

Mutations in the FKBP14 gene encoding FKBP22 (FK506 Binding Protein 22 kDa) cause kyphoscoliotic Ehlers-Danlos Syndrome (kEDS). The first clinical report showed that a lack of FKBP22 protein due to mutations causing nonsense-mediated decay of the mRNA leads to a wide spectrum of clinical phenotypes including progressive kyphoscoliosis, joint hypermobility, hypotonia, hyperelastic skin, hearing loss and aortic rupture. Our previous work showed that these phenotypic features could be correlated with the functions of FKBP22, which preferentially binds to type III, VI and X collagens, but not to type I, II or V collagens. We also showed that FKBP22 catalyzed the folding of type III collagen through its prolyl isomerase activity and acted as a molecular chaperone for type III collagen. Recently, a novel missense mutation Met48Lys in FKBP22 was identified in a patient with kEDS. In this report, we expand the list of substrates of FKBP22 and also demonstrate that the Met48Lys mutation diminishes the activities of FKBP22, indicating that pathology can arise from absence of FKBP22, or partial loss of its function.

Case series Patients: 7 Final Diagnosis: COVID-19 disease Symptoms: Fever • dypspnea Medication: Standard of care Clinical Procedure: C-reactive protein apheresis Specialty: Immunology • Infectious Diseases Objective: Unusual clinical course Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced pneumonia is a disease with high mortality and, still, no effective treatment. Excessively elevated C-reactive protein (CRP) plasma levels inversely correlate with prognosis. As CRP, via complement and macrophage activation, can cause organ damage in COVID-19, we have recently introduced selective CRP apheresis as a potentially effective treatment. Now, we report on the first patients with severe SARS-CoV-2-induced pneumonia treated within the “C-reactive protein Apheresis in COVID” (CACOV) registry. Case Reports: Seven sequential hospitalized patients with documented COVID-19, strongly elevated CRP plasma levels, and respiratory failure were treated by selective CRP apheresis in addition to standard therapy after having given their informed consent for inclusion in the CACOV registry. We performed 2-8 CRP apheresis sessions via either peripheral or central venous access depending on clinical course and CRP plasma levels. CRP apheresis, in COVID-19, reduced CRP plasma levels by approximately 50–90%, and it was thus highly effective, feasible, and safe. Despite severe radiological lung involvement in all our patients, only 2 patients finally required intubation, and none required extracorporeal membrane oxygenation (ECMO). All 7 patients were discharged from our 2 hospitals in good clinical condition. Conclusions: Selective CRP apheresis, starting early after patient admission, may be an effective treatment of SARS-CoV-2-induced pneumonia. SARS-COV-2 can cause organ damage and multiple organ failure predominantly by an excessive CRP-mediated autoimmune response of the ancient innate immune system. Further registry data and randomized trials are needed.

Macular corneal dystrophy is a rare inherited disease of the cornea leading to deposits mainly in the stroma. Affected patients suffer from progressive loss of visual acuity which should be treated with penetrating keratoplasty. This is the first case report describing the clinical and histopathological findings of corneal tissue after failed phototherapeutic keratectomy (PTK) in a patient with macular corneal dystrophy.A 32-year-old man presented with visual impairment, blurred vision and increasing glare sensitivity in both eyes in 2014. All symptoms had existed for several years and had recently increased sharply. A corneal dystrophy was diagnosed and penetrating keratoplasty was recommended but the patient was hesitant to undergo surgery. In 2018, in contrast to current guidelines, a PTK was performed in both eyes in Turkey for unknown reasons. In May 2019, he presented again in our clinic. Best corrected visual acuity was markedly reduced in both eyes. Slit-lamp examination revealed multiple dense, poorly circumscribed grey-white patchy changes in the stroma accompanied by corneal opacity in both eyes. In February 2020, the patient decided to have penetrating keratoplasty performed at the University Eye Hospital in Tübingen. The explanted cornea was stained for acid mucopolysaccharides (AMP) and periodic acid-Schiff staining (PAS). The histopathological examination revealed destruction of Bowman's layer and a subepithelial fibrosis band due to the PTK previously performed. The AMP staining demonstrated blue deposits typical of macular corneal dystrophy, mainly in the stroma but also in the endothelium. Interestingly, the acidic mucopolysaccharides were found increased in the PTK-induced subepithelial fibrosis band. The postoperative course after keratoplasty was favourable with a significant increase in visual acuity and a clear graft.This report presents the first case of a histologically evident exacerbation of macular corneal dystrophy after PTK and emphasizes the relevance of thorough pre-interventional diagnosis and patient selection to consider other therapeutic approaches, such as penetrating keratoplasty.

Background and ObjectiveThe spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody–associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG‐IgG titers in children with MOGAD in correlation with clinical presentation and disease course.MethodsIn this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG–positive.ResultsOne hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG–negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG–negative.DiscussionIn this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG–negative, are shown to have a significantly reduced relapse risk.

Background The Dermatophagoides pteronyssinus molecule Der p 23 is a major allergen whose clinical relevance has been shown in cross‐sectional studies. We longitudinally analysed the trajectory of Der p 23‐specific IgE antibody (sIgE) levels throughout childhood and youth, their early‐life determinants and their clinical relevance for allergic rhinitis and asthma. Methods We obtained sera and clinical data of 191 participants of the German Multicentre Allergy Study, a prospective birth cohort. Serum samples from birth to 20 years of age with sIgE reactivity to Der p 23 in a customised semiquantitative microarray were newly analysed with a singleplex quantitative assay. Early mite exposure was assessed by measuring the average content of Der p 1 in house dust at 6 and 18 months. Results Der p 23‐sIgE levels were detected at least once in 97/191 participants (51%). Prevalence of Der p 23 sensitisation and mean sIgE levels increased until age 10 years, plateaued until age 13 years and were lowest at age 20 years. Asthma, allergic rhinitis (AR) and atopic dermatitis (AD) were more prevalent in Der p 23‐sensitised children, including those with monomolecular but persistent sensitisation (11/97, 11%). A higher exposure to mites in infancy and occurrence of AD before 5 years of age preceded the onset of Der p 23 sensitisation, which in turn preceded a higher incidence of asthma. Conclusions Der p 23 sensitisation peaks in late childhood and then decreases. It is preceded by early mite exposure and AD. Asthma and AR can occur in patients persistently sensitised to Der p 23 as the only mite allergen, suggesting the inclusion of molecular testing of Der p 23‐sIgE for subjects with clinical suspicion of HDM allergy but without sIgE to other major D.pt. allergens.

Background The economic costs of mental disorders for society are huge. Internet-based interventions are often coined as cost-effective alternatives to usual care, but the evidence is mixed. Objective The aim was to review the literature on the cost-effectiveness of internet interventions for mental disorders compared with usual care and to provide an estimate of the monetary benefits of such interventions compared with usual care. Methods A systematic review and meta-analysis of randomized controlled trials was conducted, which included participants with symptoms of mental disorders; investigated a telephone- or internet-based intervention; included a control condition in the form of treatment as usual, psychological placebo, waiting list control, or bibliotherapy; reported outcomes on both quality of life and costs; and included articles published in English. Electronic databases such as PubMed (including MEDLINE), Embase, Emcare, PsycINFO, Web of Science, and the Cochrane Library were used. Data on risk of bias, quality of the economic evaluation, quality-adjusted life years, and costs were extracted from the included studies, and the incremental net benefit was calculated and pooled. Results The search yielded 6226 abstracts, and 37 studies with 14,946 participants were included. The quality of economic evaluations of the included studies was rated as moderate, and the risk of bias was high. A random-effects approach was maintained. Analyses suggested internet interventions were slightly more effective than usual care in terms of quality-adjusted life years gain (Hedges g=0.052, 95% CI 0.010-0.094; P=.02) and equally expensive (Hedges g=0.002, 95% CI −0.080 to 0.84; P=.96). The pooled incremental net benefit was US $255 (95% CI US $91 to US $419; P=.002), favoring internet interventions over usual care. The perspective of the economic evaluation and targeted mental disorder moderated the results. Conclusions The findings indicate that the cost-effectiveness of internet interventions for mental disorders compared with a care-as-usual approach is likely, but generalizability to new studies is poor given the substantial heterogeneity. This is the first study in the field of mental health to pool cost-effectiveness outcomes in an aggregate data meta-analysis. Trial Registration PROSPERO CRD42019141659; https://tinyurl.com/3cu99b34

The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.

In modern 3D microscopy, holding and orienting arbitrary biological objects with optical forces instead of using coverslips and gel cylinders is still a vision. Although optical trapping forces are strong enough and related photodamage is acceptable, the precise (re-) orientation of large specimen with multiple optical traps is difficult, since they grab blindly at the object and often slip off. Here, we present an approach to localize and track regions with increased refractive index using several holographic optical traps with a single camera in an off-focus position. We estimate the 3D grabbing positions around several trapping foci in parallel through analysis of the beam deformations, which are continuously measured by defocused camera images of cellular structures inside cell clusters. Although non-blind optical trapping is still a vision, this is an important step towards fully computer-controlled orientation and feature-optimized laser scanning of sub-mm sized biological specimen for future 3D light microscopy., Optical manipulation of large objects is challenging as optical trap positions are blindly chosen. Here, the authors present off-focus interferometric tracking, which localises optimal grabbing positions with increased refractive index, by analysing the beam deformations of several holographic optical traps.

According to the WHO Malaria Report 2019 a total of 229 million people fall ill with malaria each year and two thirds of deaths involve children under 5 years of age.To review the fundus changes in the context of malaria and the importance of ophthalmoscopy in the diagnosis.Summary of changes in cerebral malaria visible on fundus examination, possible underlying pathomechanisms and the value of ophthalmoscopy in practice.Retinal findings in malaria include white or gray staining of the retina (retinal whitening), color change of retinal vessels (orange or white staining), hemorrhages often with a white center, such as Roth's spot and papilledema.The retinal changes in malaria are specific and may help to differentiate malaria from other causes of coma and fever. Smartphone-based fundus photography and artificial intelligence could support malaria diagnostics particularly in resource-poor regions.HINTERGRUND: Laut WHO Malaria Report 2019 erkranken jährlich 229 Mio. Menschen an Malaria. Zwei Drittel der Todesfälle betreffen Kinder unter 5 Jahren.Überblick über die Fundusveränderungen im Rahmen der okulären Veränderungen bei Malaria, den Stellenwert der ophthalmologischen Diagnostik und die Bedeutung der Fundoskopie bei der Diagnose.Zusammenfassende Darstellung der fundoskopisch sichtbaren Veränderungen bei zerebraler Malaria, möglicher zugrunde liegender Pathomechanismen sowie der Stellenwert der Fundoskopie in der Praxis.Bei Malaria im Fundusbild erkennbar sind eine Weiß- bzw. Graufärbung der Retina („retinal whitening“), Farbveränderung retinaler Gefäße (Orange- oder Weißfärbung), Hämorrhagien, oft mit weißem Zentrum ähnlich den Roth-Flecken sowie ein Papillenödem.Die retinalen Veränderungen bei Malaria sind charakteristisch und können helfen, Malaria von anderen Ursachen von Koma und Fieber abzugrenzen. Smartphone-basierte Fundusfotografie und künstliche Intelligenz könnten in ressourcenarmen Regionen zur Diagnose beitragen.

Malaria is a complex parasitic disease, caused by Plasmodium spp. More than a century after the discovery of malaria parasites, this disease continues to pose a global public health problem and the pathogenesis of the severe forms of malaria remains incompletely understood. Extracellular vesicles (EVs), including exosomes and microvesicles, have been increasingly researched in the field of malaria in a bid to fill these knowledge gaps. EVs released from Plasmodium-infected red blood cells and other host cells during malaria infection are now believed to play key roles in disease pathogenesis and are suggested as vital components of the biology of Plasmodium spp. Malaria-derived EVs have been identified as potential disease biomarkers and therapeutic tools. In this review, key findings of malaria EV studies over the last 20 years are summarized and critically analysed. Outstanding areas of research into EV biology are identified. Unexplored EV research foci for the future that will contribute to consolidating the potential for EVs as agents in malaria prevention and control are proposed.

Purpose The ICEpop CAPability measure for Adults (ICECAP-A) assesses five capabilities that are important to one’s well-being. The instrument might be an important addition to generic health questionnaires when evaluating quality of life extending beyond health. This study aimed to conduct a psychometric assessment of the Dutch translation of the ICECAP-A. Methods Construct validity of the instrument was assessed in two ways. First, by measuring correlations with the EQ-5D-5L questionnaire and a measure of self-efficacy and, second, by investigating the ability to distinguish between groups known to differ on the construct the ICECAP-A means to capture. Additionally, test–retest reliability was evaluated. Results In total, 1002 participants representative of the general Dutch population completed an online survey. For test–retest reliability, 252 participants completed the same questionnaire 2 weeks later. The ICECAP-A indicated moderate to strong correlations with the EQ-5D-5L and a strong correlation with self-efficacy. Furthermore, it was capable of differentiating known groups. Moreover, results indicated adequate test–retest reliability with an intraclass correlation coefficient of 0.79. Conclusion In summary, results suggest adequate test–retest reliability and construct validity and indicate that the ICECAP-A might be of added value, especially when considering areas outside of the traditional health intervention model.

Objectives The National Early Warning Score, Modified Early Warning Score, and quick Sepsis-related Organ Failure Assessment can predict clinical deterioration. These scores exhibit only moderate performance and are often evaluated using aggregated measures over time. A simulated prospective validation strategy that assesses multiple predictions per patient-day would provide the best pragmatic evaluation. We developed a deep recurrent neural network deterioration model and conducted a simulated prospective evaluation. Design Retrospective cohort study. Setting Four hospitals in Pennsylvania. Patients Inpatient adults discharged between July 1, 2017, and June 30, 2019. Interventions None. Measurements and main results We trained a deep recurrent neural network and logistic regression model using data from electronic health records to predict hourly the 24-hour composite outcome of transfer to ICU or death. We analyzed 146,446 hospitalizations with 16.75 million patient-hours. The hourly event rate was 1.6% (12,842 transfers or deaths, corresponding to 260,295 patient-hours within the predictive horizon). On a hold-out dataset, the deep recurrent neural network achieved an area under the precision-recall curve of 0.042 (95% CI, 0.04-0.043), comparable with logistic regression model (0.043; 95% CI 0.041 to 0.045), and outperformed National Early Warning Score (0.034; 95% CI, 0.032-0.035), Modified Early Warning Score (0.028; 95% CI, 0.027- 0.03), and quick Sepsis-related Organ Failure Assessment (0.021; 95% CI, 0.021-0.022). For a fixed sensitivity of 50%, the deep recurrent neural network achieved a positive predictive value of 3.4% (95% CI, 3.4-3.5) and outperformed logistic regression model (3.1%; 95% CI 3.1-3.2), National Early Warning Score (2.0%; 95% CI, 2.0-2.0), Modified Early Warning Score (1.5%; 95% CI, 1.5-1.5), and quick Sepsis-related Organ Failure Assessment (1.5%; 95% CI, 1.5-1.5). Conclusions Commonly used early warning scores for clinical decompensation, along with a logistic regression model and a deep recurrent neural network model, show very poor performance characteristics when assessed using a simulated prospective validation. None of these models may be suitable for real-time deployment.

Preliminary investigations of human corneal tissues from coronavirus disease 2019 (COVID-19) cadaveric donors indicated that no severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is present. Current eye banking guidelines do not recommend any type of routine testing for SARS-CoV‑2 RNA in post-mortem donor tissue. This is partly based on factors that can influence the test results of the reverse transcription polymerase chain reaction (RT-PCR).Die ersten Untersuchungen von humanen Hornhäuten von COVID‑19(Coronavirus Disease 2019/Coronaviruserkrankung 2019)-Spendern legen nahe, dass keine SARS-CoV-2(„severe acute respiratory syndrome-coronavirus-2“/schweres akutes respiratorisches Syndrom-Coronavirus-2)-RNA vorhanden ist. Derzeit wird nicht empfohlen, eine routinemäßige Testung von postmortalen Spendergeweben auf SARS-CoV-2-RNA durchzuführen. Dies begründet sich u. a. in den Faktoren, die das RT-PCR („reverse transcription polymerase chain reaction“/Reverse-Transkriptase-Polymerasekettenreaktion) Testergebnis beeinflussen können.

Die ersten Untersuchungen von humanen Hornhäuten von COVID‑19(Coronavirus Disease 2019/Coronaviruserkrankung 2019)-Spendern legen nahe, dass keine SARS-CoV-2(„severe acute respiratory syndrome-coronavirus-2“/schweres akutes respiratorisches Syndrom-Coronavirus-2)-RNA vorhanden ist. Derzeit wird nicht empfohlen, eine routinemäßige Testung von postmortalen Spendergeweben auf SARS-CoV-2-RNA durchzuführen. Dies begründet sich u. a. in den Faktoren, die das RT-PCR („reverse transcription polymerase chain reaction“/Reverse-Transkriptase-Polymerasekettenreaktion) Testergebnis beeinflussen können.

Genome‐scale high‐throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population‐based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal‐dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co‐occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal‐dominant disorders, enabling the estimation of variant‐filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co‐occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co‐occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.

Purpose The purported affective impact of virtual reality (VR) and active video gaming (AVG) systems is a key marketing strategy underlying their use in stroke rehabilitation, yet little is known as to how affective constructs are measured or linked to intervention outcomes. The purpose of this scoping review is to 1) explore how motivation, enjoyment, engagement, immersion and presence are measured or described in VR/AVG interventions for patients with stroke; 2) identify directional relationships between these constructs; and 3) evaluate their impact on motor learning outcomes. Methods A literature search was undertaken of VR/AVG interventional studies for adults post-stroke published in Medline, PEDro and CINAHL databases between 2007 and 2017. Following screening, reviewers used an iterative charting framework to extract data about construct measurement and description. A numerical and thematic analytical approach adhered to established scoping review guidelines. Results One hundred fifty-five studies were included in the review. Although the majority (89%; N = 138) of studies described at least one of the five constructs within their text, construct measurement took place in only 32% (N = 50) of studies. The most frequently described construct was motivation (79%, N = 123) while the most frequently measured construct was enjoyment (27%, N = 42). A summative content analysis of the 50 studies in which a construct was measured revealed that constructs were described either as a rationale for the use of VR/AVGs in rehabilitation (76%, N = 38) or as an explanation for intervention results (56%, N = 29). 38 (76%) of the studies proposed relational links between two or more constructs and/or between any construct and motor learning. No study used statistical analyses to examine these links. Conclusions Results indicate a clear discrepancy between the theoretical importance of affective constructs within VR/AVG interventions and actual construct measurement. Standardized terminology and outcome measures are required to better understand how enjoyment, engagement, motivation, immersion and presence contribute individually or in interaction to VR/AVG intervention effectiveness. Electronic supplementary material The online version of this article (10.1186/s12984-019-0546-4) contains supplementary material, which is available to authorized users.

Background We report the first histopathologically proven occurrence of a retrocorneal membrane after Descemet’s membrane endothelial keratoplasty. Case presentation A white Caucasian 76-year-old woman received penetrating keratoplasty on her right eye 2 years after Descemet’s membrane endothelial keratoplasty surgery with combined cataract extraction and intraocular lens implantation for Fuchs’ endothelial corneal dystrophy due to an allograft rejection with ensuing graft failure. Her preoperative vision was counting fingers (20/2000) caused by immunological debris, corneal edema, and secondary membrane formation. Her postoperative vision at 3 months was 20/125. The histopathological evaluation showed a membranous structure overlying the denuded Descemet membrane. Conclusions We report a case of a histopathologically proven retrocorneal membrane after Descemet’s membrane endothelial keratoplasty surgery.

BackgroundGray-scale, B-mode ultrasound (US) imaging is part of the standard clinical procedure for evaluating thyroid nodules (TNs). It is limited by its instrument- and operator-dependence and inter-observer variability. In addition, the accepted high-risk B-mode US TN features are more specific for detecting classic papillary thyroid cancer rather than the follicular variant of papillary thyroid cancer or follicular thyroid cancer. Quantitative ultrasound (QUS) is a technique that can non-invasively assess properties of tissue microarchitecture by exploiting information contained in raw ultrasonic radiofrequency (RF) echo signals that is discarded in conventional B-mode imaging. QUS provides quantitative parameter-value estimates that are a function of the properties of US scatterers and microarchitecture of the tissue. The purpose of this preliminary study was to assess the performance of QUS parameters in evaluating benign and malignant thyroid nodules.MethodsPatients from the Thyroid Health Center at the Boston Medical Center were recruited to participate. B-mode and RF data were acquired and analyzed in 225 TNs (24 malignant and 201 benign) from 208 patients. These data were acquired either before (167 nodules) or after (58 nodules) subjects underwent fine-needle biopsy (FNB). The performance of a combination of QUS parameters (CQP) was assessed and compared with the performance of B-mode risk-stratification systems.ResultsCQP produced an ROC AUC value of 0.857 ± 0.033 compared to a value of 0.887 ± 0.033 (p=0.327) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.880 ± 0.041 (p=0.367) for the American Thyroid Association (ATA) risk-stratification system. Furthermore, using a CQP threshold of 0.263 would further reduce the number of unnecessary FNBs in 44% of TNs without missing any malignant TNs. When CQP used in combination with ACR TI-RADS, a potential additional reduction of 49 to 66% in unnecessary FNBs was demonstrated.ConclusionThis preliminary study suggests that QUS may provide a method to classify TNs when used by itself or when combined with a conventional gray-scale US risk-stratification system and can potentially reduce the need to biopsy TNs.

Alzheimer’s disease (AD) is the most common form of dementia. It is associated with the impairment of memory and other cognitive functions that are mainly caused by progressive defects in cholinergic and glutamatergic signaling in the central nervous system. Inhibitors of acetylcholinesterase (AChE) and ionotropic glutamate receptors of the N-methyl- d -aspartate (NMDA) receptor family are currently approved as AD therapeutics. We previously showed using a cell-based assay of NMDA receptor-mediated glutamate-induced excitotoxicity that bis-γ-carbolinium conjugates are useful NMDA receptor blockers. However, these compounds also act as subnanomolar AChE inhibitors, which may cause serious anticholinergic side effects when applied in vivo. Here, we evaluated new structures containing γ-carbolines linked to phenothiazine via a propionyl spacer. These compounds were superior to the previously characterized bis-γ-carbolinium conjugates because they blocked NMDA receptors without requiring a quaternary pyridine N-atom and inhibited AChE with moderate IC50 values of 0.54–5.3 µM. In addition, these new compounds displayed considerable selectivity for the inhibition of butyrylcholinesterase (BChE; IC50 = 0.008–0.041 µM), which may be favorable for AD treatment. Inhibitory activities towards the NMDA receptors and AChE were in the same micromolar range, which may be beneficial for equal dosing against multiple targets in AD patients.