[Asymptomatic SARS-CoV-2 Infection and "in situ split" Liver Resection with Fatal Outcome - A Case Report]. / SARS-CoV-2-Infektion und "In-situ-Split"-Leberresektion mit tödlichem Verlauf.

We report the perioperative course of a 47-year-old patient who underwent a two-stage liver resection for bilobar metastatic colorectal carcinoma. The respiratory asymptomatic patient was tested positive for SARS-CoV-2 by PCR detection one day before the second surgical procedure. Postoperatively, the patient suffered cardiovascular arrest on postoperative day 8 and died despite immediately initiated resuscitative measures. With an initial clinical suspicion of vascular liver failure, postmortem pathologic examination revealed the underlying cause of death to be COVID-19-related myocarditis with acute right heart failure. Individual multidisciplinary risk assessment should be considered very critically when deviating from the "7-week rule" because the benefit is difficult to objectify, even in oncologic patients.

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

[Difficult Airway Management in Thoracic Anaesthesia]. / Atemwegsmanagement ­ der schwierige Atemweg beim thoraxchirurgischen Patienten.

Difficult airway management in thoracic anesthesia has rarely been addressed in current guidelines. However, difficult airway management may be a challenge in thoracic anaesthesia: Achieving lung separation and collapse in combination of potentially distorted upper airway anatomy (difficult upper airway), the presence of subglottic pathologies (difficult lower airway) and the need for one-lung ventilation (difficult lung separation). This review will focus on identification of patients at risk, recommendations and algorithms for the airway management in the anticipated and unexpected difficult in-/extubation, and choice of devices for lung separation in this context.

Understanding and preventing type 1 diabetes through the unique working model of TrialNet.

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.

Modulation of 7 T fMRI Signal in the Cerebellar Cortex and Nuclei During Acquisition, Extinction, and Reacquisition of Conditioned Eyeblink Responses.

Classical delay eyeblink conditioning is likely the most commonly used paradigm to study cerebellar learning. As yet, few studies have focused on extinction and savings of conditioned eyeblink responses (CRs). Saving effects, which are reflected in a reacquisition after extinction that is faster than the initial acquisition, suggest that learned associations are at least partly preserved during extinction. In this study, we tested the hypothesis that acquisition-related plasticity is nihilated during extinction in the cerebellar cortex, but retained in the cerebellar nuclei, allowing for faster reacquisition. Changes of 7 T functional magnetic resonance imaging (fMRI) signals were investigated in the cerebellar cortex and nuclei of young and healthy human subjects. Main effects of acquisition, extinction, and reacquisition against rest were calculated in conditioned stimulus-only trials. First-level ß values were determined for a spherical region of interest (ROI) around the acquisition peak voxel in lobule VI, and dentate and interposed nuclei ipsilateral to the unconditioned stimulus. In the cerebellar cortex and nuclei, fMRI signals were significantly lower in extinction compared to acquisition and reacquisition, but not significantly different between acquisition and reacquisition. These findings are consistent with the theory of bidirectional learning in both the cerebellar cortex and nuclei. It cannot explain, however, why conditioned responses reappear almost immediately in reacquisition following extinction. Although the present data do not exclude that part of the initial memory remains in the cerebellum in extinction, future studies should also explore changes in extracerebellar regions as a potential substrate of saving effects. Hum Brain Mapp 38:3957-3974, 2017. © 2017 Wiley Periodicals, Inc.

Uncoupling protein 2 deficiency reduces proliferative capacity of murine pancreatic stellate cells.

BACKGROUND: Uncoupling protein 2 (UCP2) has been suggested to inhibit mitochondrial production of reactive oxygen species (ROS) by decreasing the mitochondrial membrane potential. Experimental acute pancreatitis is associated with increased UCP2 expression, whereas UCP2 deficiency retards regeneration of aged mice from acute pancreatitis. Here, we have addressed biological and molecular functions of UCP2 in pancreatic stellate cells (PSCs), which are involved in pancreatic wound repair and fibrogenesis. METHODS: PSCs were isolated from 12 months old (aged) UCP2-/- mice and animals of the wild-type (WT) strain C57BL/6. Proliferation and cell death were assessed by employing trypan blue staining and a 5-bromo-2'-deoxyuridine incorporation assay. Intracellular fat droplets were visualized by oil red O staining. Levels of mRNA were determined by RT-PCR, while protein expression was analyzed by immunoblotting and immunofluorescence analysis. Intracellular ROS levels were measured with 2', 7'-dichlorofluorescin diacetate. Expression of senescence-associated beta-galactosidase (SA beta-Gal) was used as a surrogate marker of cellular senescence. RESULTS: PSCs derived from UCP2-/- mice proliferated at a lower rate than cells from WT mice. In agreement with this observation, the UCP2 inhibitor genipin displayed dose-dependent inhibitory effects on WT PSC growth. Interestingly, ROS levels in PSCs did not differ between the two strains, and PSCs derived from UCP2-/- mice did not senesce faster than those from corresponding WT cells. PSCs from UCP2-/- mice and WT animals were also indistinguishable with respect to the activation-dependent loss of intracellular fat droplets, expression of the activation marker alpha-smooth muscle actin, type I collagen and the autocrine/paracrine mediators interleukin-6 and transforming growth factor-beta1. CONCLUSIONS: A reduced proliferative capacity of PSC from aged UCP2-/- mice may contribute to the retarded regeneration after acute pancreatitis. Apart from their slower growth, PSC of UCP2-/- mice displayed no functional abnormalities. The antifibrotic potential of UCP2 inhibitors deserves further attention.

Sum Rules of Charm CP Asymmetries beyond the SU(3)_{F} Limit.

We find new sum rules between direct CP asymmetries in D meson decays with coefficients that can be determined from a global fit to branching ratio data. Our sum rules eliminate the penguin topologies P and PA, which cannot be determined from branching ratios. In this way, we can make predictions about direct CP asymmetries in the standard model without ad hoc assumptions on the sizes of penguin diagrams. We consistently include first-order SU(3)_{F} breaking in the topological amplitudes extracted from the branching ratios. By confronting our sum rules with future precise data from LHCb and Belle II, one will identify or constrain new-physics contributions to P or PA. The first sum rule correlates the CP asymmetries a_{CP}^{dir} in D^{0}→K^{+}K^{-}, D^{0}→π^{+}π^{-}, and D^{0}→π^{0}π^{0}. We study the region of the a_{CP}^{dir}(D^{0}→π^{+}π^{-})-a_{CP}^{dir}(D^{0}→π^{0}π^{0}) plane allowed by current data and find that our sum rule excludes more than half of the allowed region at 95% C.L. Our second sum rule correlates the direct CP asymmetries in D^{+}→K[over ¯]^{0}K^{+}, D_{s}^{+}→K^{0}π^{+}, and D_{s}^{+}→K^{+}π^{0}.

Molecular heterogeneity in histomorphologic subtypes of lung adeno carcinoma represents a challenge for treatment decision.

Lung cancer is the leading cause in cancer related death, with non-small cell lung cancer (NSCLC) being the most frequent subtype. The importance of NSCLC is reflected by the various targeted therapy options especially for NSCLC adenocarcinomas (lung adeno carcinoma (LUAD)) as well as a set of options for immune therapies. However, despite these therapy advances, the majority of patients do not show a long-term response to either targeted therapy or immune checkpoint inhibition. One reason for treatment failure appears to be the NSCLC tumor heterogeneity. NSCLC heterogeneity might lead to an insufficient molecular characterization of a given sample due to the limited tumor material used for pathological assessment as the majority of analyses is performed on small biopsies. To get a more detailed insight into the tumor heterogeneity of NSCLC LUAD, especially in the light of its different histomorphological growth patterns, we analysed isolated NSCLC growth pattern areas and the corresponding entire tumor samples of a cohort of 31 NSLCS LUAD patients and compared their mutational landscape and their expression profiles. While significant differences of complex biomarkers, like tumor mutational burden (TMB) or microsatellite instability (MSI), were not detected between the five growth patterns -lepidic, papillary, micropapillary, acinar, and solid- we observed various subclonal mutations and copy number variants. Moreover, RNASeq analysis revealed growth pattern specific expression profiles affecting cellular processes like apoptosis, metastasis and proliferation. Taken together, our data provide novel insights into the tumor heterogeneity of LUAD required to overcome tumor heterogeneity related therapy resistance.

Droplet Motion Driven by Liquid Dielectrophoresis in the Low-Frequency Range.

Electrohydrodynamic wetting manipulation plays a major role in modern microfluidic technologies such as lab-on-a-chip applications and digital microfluidics. Liquid dielectrophoresis (LDEP) is a common driving mechanism, which induces hydrodynamic motion in liquids by the application of nonhomogeneous electrical fields. Among strategies to analyze droplet movement, systematic research on the influence of different frequencies under AC voltage is missing. In this paper, we therefore present a first study covering the motion characteristics of LDEP-driven droplets of the dielectric liquids ethylene glycol and glycerol carbonate in the driving voltage frequency range from 50 Hz to 1600 Hz. A correlation between the switching speed of LDEP-actuated droplets in a planar electrode configuration and the frequency of the applied voltage is shown. Hereby, motion times of different-sized droplets could be reduced by up to a factor of 5.3. A possible excitation of the droplets within their range of eigenfrequencies is investigated using numerical calculations. The featured fluidic device is designed using larger-sized electrodes rather than typical finger or strip electrodes, which are commonly employed in LDEP devices. The influence of the electrode shape is considered simulatively by studying the electric field gradients.

Most discriminative stimuli for functional cell type clustering.

Identifying cell types and understanding their functional properties is crucial for unraveling the mechanisms underlying perception and cognition. In the retina, functional types can be identified by carefully selected stimuli, but this requires expert domain knowledge and biases the procedure towards previously known cell types. In the visual cortex, it is still unknown what functional types exist and how to identify them. Thus, for unbiased identification of the functional cell types in retina and visual cortex, new approaches are needed. Here we propose an optimization-based clustering approach using deep predictive models to obtain functional clusters of neurons using Most Discriminative Stimuli (MDS). Our approach alternates between stimulus optimization with cluster reassignment akin to an expectation-maximization algorithm. The algorithm recovers functional clusters in mouse retina, marmoset retina and macaque visual area V4. This demonstrates that our approach can successfully find discriminative stimuli across species, stages of the visual system and recording techniques. The resulting most discriminative stimuli can be used to assign functional cell types fast and on the fly, without the need to train complex predictive models or show a large natural scene dataset, paving the way for experiments that were previously limited by experimental time. Crucially, MDS are interpretable: they visualize the distinctive stimulus patterns that most unambiguously identify a specific type of neuron.

Cdkn1a is a key mediator of rat pancreatic stellate cell senescence.

BACKGROUND/OBJECTIVES: Completion of pancreatic wound healing requires termination of pancreatic stellate cell (PSC) activation to prevent fibrosis. Besides induction of apoptosis and return to a quiescent phenotype, senescence of PSC followed by immune cell-mediated cytolysis represents a potential mechanism. Here, we have studied if the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21/Waf1), expression of which is increased in senescent rat PSC, plays a causative role in the senescence process. METHODS: Senescence was induced by doxorubicin treatment. The functions of Cdkn1a were analyzed using two approaches, treatment of primary rat PSC with siRNA and tetracycline-regulated overexpression of Cdkn1a in immortalized rat cells. Expression of senescence-associated ß-galactosidase (SA ß-Gal) was used as a surrogate marker of senescence. RESULTS: The knockdown of Cdkn1a significantly attenuated the growth-inhibitory effect of doxorubicin and strongly diminished the portion of SA ß-Gal-positive cells. Overexpression of Cdkn1a enhanced both the antiproliferative effect of doxorubicin and induction of senescence. In primary PSC, doxorubicin treatment was associated with increased expression of interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-9, while expression of the activation marker α-smooth muscle actin (α-SMA), p53, Cdk1 and Rad54 was diminished. The application of Cdkn1a siRNA specifically antagonized the effects of doxorubicin on the expression of p53, Cdk1 and Rad54 but not IL-6 and α-SMA, while MMP-9 expression and also activity were even enhanced. CONCLUSIONS: Cdkn1a plays a direct role in the process of rat PSC senescence. Additional Cdkn1a-independent pathways may contribute to the partial maintenance of a gene expression profile typical of senescent PSC.

Evaluation of a preservative-free, cross-linked sodium hyaluronate-based solution, Lacri +®, in dogs with dry eye: a pilot trial.

BACKGROUND: The purpose of this pilot trial was to evaluate the efficacy and benefits of a preservative-free cross-linked sodium hyaluronate solution (Lacri +®, MP Labo, France) in 19 privately-owned dogs with dry eye. The animals were administered 2 drops of the tested product in each affected eye, twice a day (BID) for 30 days. Improvement in the global ocular clinical score (sum of the individual scores for conjunctivitis, ocular discharge, eye irritation, and corneal opacity/pigmentation/vascularization, each rated from 0 to 3) was defined as the primary outcome. Besides an improvement in each individual ocular score, tear film quality (Tear Break Up Time, TBUT), dogs' and owners' quality of life (QoL), as well as an increase in tear production (Schirmer Tear Test-1, STT1), were considered secondary outcomes. These criteria were assessed on D0, D0 + 15 days, and D0 + 30 days. Finally, a qualitative evaluation of clinical improvement was requested from the owners on D0 + 2, + 15 & + 30 days and from the investigators during the follow-up. RESULTS: The global clinical ocular score as well as the individual conjunctival and irritation scores improved significantly (p < 0.0001) during the pilot trial. The average reduction of the global score reached 30% on D0 + 15 days and 55% on D0 + 30 days compared to D0. Ocular discharge was significantly lower (p = 0.0002) on D0 + 30 days compared to baseline; however corneal opacity did not show any significant changes from D0 to the end of the follow-up period. The quantitative tear production was increased at D + 30 (p < 0.0001), with a significant improvement as soon as 2 weeks in, with around 30% and 60% of dogs presenting an STT1 value above 10 on D0 + 15 days and on D0 + 30 days, respectively. The QoL score was significantly improved compared to D0 at all time points (p < 0.0001). After 2 days of treatment, 39% of the owners rated the efficacy as "good". The efficacy of the tested product was considered "Good" or "Very Good" by the investigators in 78% and 93% of the cases, on D0 + 15 days and D0 + 30 days, respectively. The tolerance of this preservative-free formulation was good, with only rare and transient minor local reactions, realated to administration rather than the product itself.

Senescence determines the fate of activated rat pancreatic stellate cells.

In chronic pancreatitis (CP), persistent activation of pancreatic stellate cells (PSC) converts wound healing into a pathological process resulting in organ fibrosis. Here, we have analysed senescence as a novel mechanism involved in the termination of PSC activation and tissue repair. PSC senescence was first studied in vitro by establishing long-term cultures and by applying chemical triggers, using senescence-associated ß-Galactosidase (SA ß-Gal) as a surrogate marker. Subsequently, susceptibility of PSC to immune cell-mediated cytolysis was investigated employing cocultures. Using the model of dibutyltin dichloride-induced CP in rats, appearance of senescent cells was monitored by immunohistochemistry and immunofluorescence, and correlated with the progression of tissue damage and repair, immune cell infiltration and fibrosis. The results indicated that long-term culture and exposure of PSC to stressors (doxorubicin, H(2) O(2) and staurosporine) induced senescence. Senescent PSC highly expressed CDKN1A/p21, mdm2 and interleukin (IL)-6, but displayed low levels of α-smooth muscle actin. Senescence increased the susceptibility of PSC to cytolysis. In CP, the number of senescent cells correlated with the severity of inflammation and the extension of fibrosis. Areas staining positive for SA ß-Gal overlapped with regions of fibrosis and dense infiltrates of immune cells. Furthermore, a close physical proximity of immune cells and activated PSC was observed. We conclude that inflammation, PSC activation and cellular senescence are timely coupled processes which take place in the same microenvironment of the inflamed pancreas. Lymphocytes may play a dual-specific role in pancreatic fibrogenesis, triggering both the initiation of wound healing by activating PSC, and its completion by killing senescent stellate cells.

Effect of cold acclimatization on exercise economy in the cold.

We sought to determine if cold acclimatized men display higher economy (i.e. lower oxygen consumption at a given workload) during graded cycle ergometry in the cold (5°C). After completing a familiarization trial 1 week prior, five cold weather athletes (CWA) and eight physically active men (NON) underwent graded exercise tests to volitional fatigue in 5°C. The protocol always started at 60 W and increased by 20 W each minute. Oxygen consumption (VO(2)), respiration rate (RR), tidal volume (TV), and respiratory exchange ratio (RER) were determined via open circuit spirometry. Individuals were matched for body size and minutes of weekly physical activity. Repeated measures analyses of variance were conducted across time (workload) and cold acclimatization was entered as a between subjects factor. VO(2) peak was not different between groups but CWA had lower VO(2) at 60 and 240 W. CWA also had lower RR at 180 and 260 W as well as lower RER at 240 and 260 W. At submaximal workloads, cold acclimatized men have higher exercise economy than non-acclimatized men. This could have implications for those who work in this context.

Active reconfiguration of cytoplasmic lipid droplets governs migration of nutrient-limited phytoplankton.

Nutrient availability, along with light and temperature, drives marine primary production. The ability to migrate vertically, a critical trait of motile phytoplankton, allows species to optimize nutrient uptake, storage, and growth. However, this traditional view discounts the possibility that migration in nutrient-limited waters may be actively modulated by the emergence of energy-storing organelles. Here, we report that bloom-forming raphidophytes harness energy-storing cytoplasmic lipid droplets (LDs) to biomechanically regulate vertical migration in nutrient-limited settings. LDs grow and translocate directionally within the cytoplasm, steering strain-specific shifts in the speed, trajectory, and stability of swimming cells. Nutrient reincorporation restores their swimming traits, mediated by an active reconfiguration of LD size and coordinates. A mathematical model of cell mechanics establishes the mechanistic coupling between intracellular changes and emergent migratory behavior. Amenable to the associated photophysiology, LD-governed behavioral shift highlights an exquisite microbial strategy toward niche expansion and resource optimization in nutrient-limited oceans.

Body height among adult male and female Swiss Health Survey participants in 2017: Trends by birth years and associations with self-reported health status and life satisfaction.

The increase in adult height for 150 years is linked to overall improvements in nutrition, hygiene, and living standards. Height is positively associated with general health and success on various levels (e.g. quality of life, earnings or happiness). The aim of this study was to investigate whether different subgroups show different trends across birth cohorts. We wanted to know whether taller individuals considered themselves as healthier and their quality of life as better than shorter individuals. We included 19,435 participants from the Swiss population-based Health Survey 2017. GAM were used to assess nonlinear associations between height and birth year. Multinomial logistic regression was used to predict probabilities of self-rated health in relation to height. The increase in average height slows down from the 1970s birth cohorts. Participants with parents from Central/Northern/Western Europe (men 177.9 cm, women: 165.1 cm) or Eastern Europe (men 178.7 cm, women: 165.7 cm) were taller than participants with parents from South America (men 174.3 cm, women: 161. cm) and Asia (men 173.2 cm, women: 160.1 cm). Participants with tertiary education were taller than participants from education levels (mean difference men: 4.5 cm, women: 5.0 cm). Height was positively associated with self-declared aspects of health and life satisfaction. These results support the conclusion that body height as a co-factor of health aspects should be considered in public health research. Although adult body height can no longer be influenced, nutritional status and thus also healthy growth can be influenced in childhood by public health programs, by eliminating social inequalities, and by strengthen healthy living conditions.

Two Facets of Emotion Dysregulation Are Core Symptomatic Domains in Adult ADHD: Results from the SR-WRAADDS, a Broad Symptom Self-Report Questionnaire.

OBJECTIVES: Emotional dysregulation (ED) in adult ADHD is frequent but definition and tools for its evaluation are not consensual. Our aim was to determine the core ADHD symptomatic domains via the Self-Reported Wender-Reimherr Adult Attention Deficit Disorder Scale (SR-WRAADDS) following its validation in a large clinical sample of adults with ADHD and controls. METHOD: Three hundred sixty-nine adult patients with ADHD and 251 healthy participants completed the SR-WRAADDS and questionnaires about ADHD, depression, and ED. We analyzed the psychometric properties of the SR-WRAADDS and a factor analysis yielded symptomatic domains. RESULTS: The SR-WRAADDS has good reliability. The 30 symptoms were best organized in a four-factor solution: attention/disorganization, hyperactivity/restlessness, impulsivity/emotional outbursts, and emotional lability. CONCLUSIONS: The symptomatic structure of the SR-WRAADDS includes two distinct dimensions related to ED: "impulsivity/emotional outbursts" and "emotional lability." The SR-WRAADDS is a reliable and clinically useful tool that assesses all ADHD symptom domains, including facets of ED.

Association between Intraoperative Blood Transfusion, Regional Anesthesia and Outcome after Pediatric Tumor Surgery for Nephroblastoma.

BACKGROUND: Recent data suggest that anesthesiologic interventions-e.g., the choice of the anesthetic regimen or the administration of blood products-might play a major role in determining outcome after tumor surgery. In contrast to adult patients, only limited data are available regarding the potential association of anesthesia and outcome in pediatric cancer patients. METHODS: A retrospective multicenter study assessing data from pediatric patients (0-18 years of age) undergoing surgery for nephroblastoma between 2004 and 2018 was conducted at three academic centers in Europe. Overall and recurrence-free survival were the primary outcomes of the study and were evaluated for a potential impact of intraoperative administration of erythrocyte concentrates, the use of regional anesthesia and the choice of the anesthetic regimen. The length of stay on the intensive care unit, the time to hospital discharge after surgery and blood neutrophil-to-lymphocyte ratio were defined as secondary outcomes. RESULTS: In total, data from 65 patients were analyzed. Intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival (hazard ratio (HR) 7.59, 95% confidence interval (CI) 1.36-42.2, p = 0.004), whereas overall survival (HR 5.37, 95% CI 0.42-68.4, p = 0.124) was not affected. The use of regional anesthesia and the choice of anesthetic used for maintenance of anesthesia did not demonstrate an effect on the primary outcomes. It was, however, associated with fewer ICU transfers, a shortened time to discharge and a decreased postoperative neutrophil-to-lymphocyte ratio. CONCLUSIONS: The current study provides the first evidence for a possible association between blood transfusion as well as anesthesiologic interventions and outcome after pediatric cancer surgery.