Virchows Archiv European Journal of Pathology

Machine learning approaches for pathologic diagnosis Abstract Machine learning techniques, especially deep learning techniques such as convolutional neural networks, have been successfully applied to general image recognitions since their overwhelming performance at the 2012 ImageNet Large Scale Visual Recognition Challenge. Recently, such techniques have also been applied to various medical, including histopathological, images to assist the process of medical diagnosis. In some cases, deep learning–based algorithms have already outperformed experienced pathologists for recognition of histopathological images. However, pathological images differ from general images in some aspects, and thus, machine learning of histopathological images requires specialized learning methods. Moreover, many pathologists are skeptical about the ability of deep learning technology to accurately recognize histopathological images because what the learned neural network recognizes is often indecipherable to humans. In this review, we first introduce various applications incorporating machine learning developed to assist the process of pathologic diagnosis, and then describe machine learning problems related to histopathological image analysis, and review potential ways to solve these problems.

CD39 downregulation in chronic intervillositis of unknown etiology Abstract Chronic intervillositis of unknown etiology (CIUE) is a rare placental lesion associated with infiltration of mononuclear inflammatory cells into the intervillous space, poor perinatal outcomes (intrauterine fetal demise or fetal growth restriction), and high rates of recurrence. CD39 is the ectonucleotidase that protects tissues from inflammatory stress and cell injury, which is localized on the surface of villi in normal placentas; however, its expression and role in CIUE are unknown. The aims of this retrospective study were to determine the expression of CD39 in CIUE and its significance in pregnancy outcomes. We compared the number of CD68- and CD3-positive cells, CD39 expression, and complement 4d (C4d) and fibrin deposition in placental tissues from patients with CIUE (n = 22) and gestational age-matched controls (n = 20), and between CIUE pregnancies with poor and good outcomes. The numbers of CD68- or CD3-positive cells were significantly higher (P < 0.0001), whereas CD39 expression on the surface of villi and endothelial cells of the stem villi was significantly lower in the CIUE group than that in controls (45% vs. 95%, P < 0.0001 and 77% vs. 96%, P < 0.001, respectively). C4d and fibrin deposition were also significantly increased in CIUE compared with those of controls. Furthermore, CD39 downregulation and the number of CD68 cells were strongly associated with poor pregnancy outcomes (P < 0.01 and P < 0.05, respectively), but other histological parameters (CD3, C4d, and fibrin) did not show this association. Our study suggests that CD39 downregulation is a useful marker of CIUE and is associated with poor pregnancy outcomes in patients with CIUE.

Two cases of phenotypic switch of primary cutaneous T cell lymphoma after treatment with an aggressive course and review of the literature Abstract A "phenotypic switch" (PS) is a well-known phenomenon that occurs in hematopoietic neoplasms, often after treatment. However, in cutaneous T cell lymphoma (CTCL), this event has rarely been reported, and thus, very little is known about its relevance to disease prognosis. We report two cases of patients that were diagnosed with a CD4+ mycosis fungoides with positive T cell receptor gene rearrangement studies. Both patients originally responded to treatment, but subsequently, their CTCL came back with a different phenotype of a CD4− CTCL. Gene rearrangement studies were performed on the second occurrence in order to prove that this was the same lymphoma. Both patients died from their CTCL. Additionally, we collected seven cases of primary CTCL from the literature with tissue samples from before and after treatment with molecular studies confirming these neoplasms contained the same T cell clone, providing evidence of a true PS. This too revealed a poor prognosis in the majority of these cases. CTCL should be worked up to determine whether a PS has occurred after therapy since it could confuse management of patients and appears to portend a poor prognosis.

Identification of a novel PRR15L-RSPO2 fusion transcript in a sigmoid colon cancer derived from superficially serrated adenoma Abstract Superficially serrated adenoma (SuSA) is a recently proposed subtype of colorectal serrated lesion. We here report a sigmoid colon cancer derived from SuSA, which exhibited aggressive clinical behavior. Endoscopically, the tumor appeared as a superficial elevated lesion with a large nodule. Histological examination of the surgically resected material showed tubular adenocarcinoma associated with SuSA. Although tumor invasion was limited to the submucosal layer, lymph node and extranodal metastases were detected. The patient subsequently developed peritoneal metastases and died 15 months after surgery. Molecular analyses identified a KRASmutation and a novel PRR15L-RSPO2 fusion, which retains the entire coding region of RSPO2, in both SuSA and adenocarcinoma components. The present study demonstrates the malignant potential of SuSA and expands the spectrum of RSPO fusions in colorectal neoplasms.

Immunohistochemical expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in prostate cancer: correlation with grade groups (WHO 2016) and ERG and PTEN status Abstract The role of DNA MMR genes in prostate cancer (PrCa) is controversial, as genetic alterations leading to microsatellite instability are incompletely defined in these tumors. ERG rearrangements and PTEN loss are concomitant events in PrCa. The aim of this study has been to analyze the immunohistochemical (IHC) expression of MSH2, MSH6, MLH1, PMS2, ERG, and PTEN and their potential association with the grade group (GG) grading system (WHO 2016) and PSA recurrence in a series of 200 PrCa (PSMAR-Biobank, Barcelona, Spain). MSH2, MLH1, PMS2, and PTEN losses were documented in 8%, 5%, 2%, and 36.5%, respectively. ERG expression was found in 48%. MSH6 showed an increase of expression with respect to basal levels in 42.1% of the cases. A statistical association between MSH6 overexpression and GG5 was found (p = 0.0281). ERG-wild-type cases were associated with single MSH2 loss (p = 0.024), and MSH2 and/or MLH1 loss (p = 0.019). The percentage of cases with PTEN loss was 20.5% (8/39) in GG1, 37.6% (53/141) of clustered GG2 to 4, and 60% (12/20) of GG5 (chi-square test, p = 0.01). Thus, PTEN expression loss was statistically more frequent in the upper-grade tumors. PMS2 loss was an infrequent event, but it was statistically associated with shorter time to PSA recurrence (p = 0.011). These results suggest the existence of an alternative non-ERG pathway associated with MSH2 or MLH1 expression loss. MSH6 overexpression could be a marker of aggressiveness in PrCa. The IHC assessment of DNA MMR proteins, ERG and PTEN, could identify different altered PrCa pathways, which could aid patient stratification.

Pathologist second opinion significantly alters clinical management of pT1 endoscopically resected colorectal cancer Abstract We retrospectively collected a series of 82 endoscopically removed early colorectal cancers. Histological specimens were revised by two gastrointestinal pathologists, performing a re-evaluation of all risk factors for lymph node metastasis. The comparison between second opinion and first pathological report revealed that lymphovascular invasion and tumor grading showed a lower level of concordance than other parameters. Our results demonstrated that second opinion modified risk assessment in about 10% of cases. It was mainly due to a lack in reporting of some parameters at the first diagnosis and a different evaluation in second opinion for updated guidelines. Considering the subgroup of patients with modified risk assessment, clinical data revealed that tumors, re-classified as low risk, did not develop lymph node metastasis that, conversely, occurred in patients identified as high risk by second opinion. In conclusion, second opinion significantly alters risk perception of endoscopically removed early colorectal carcinomas representing a valuable tool for their appropriate clinical management.

Recent advances in invasive adenocarcinoma of the cervix Abstract Endocervical adenocarcinomas (ECAs) are currently classified according to the 2014 World Health Organization (WHO) system, which is predominantly based on descriptive morphologic characteristics, considers factors bearing minimal etiological, clinical, or therapeutic relevance, and lacks sufficient reproducibility. The 2017 International Endocervical Adenocarcinoma Criteria and Classification (IECC) system was developed by a group of international collaborators to address these limitations. The IECC system separates ECAs into two major groups—those that are human papillomavirus-associated (HPVA) and those that are non-HPV-associated (NHPVA)—based on morphology (linked to etiology) alone, precluding the need for an expensive panel of immunohistochemical markers for most cases. The major types of HPVA ECA include the usual (with villoglandular and micropapillary architectural variants) and mucinous types (not otherwise specified [NOS], intestinal, signet-ring, and invasive stratified mucin-producing carcinoma). Invasive adenocarcinoma NOS is morphologically uninformative, yet considered part of this group when HPV positive. NHPVA ECAs include gastric, clear cell, endometrioid, and mesonephric types. The IECC system is supported by demographic and clinical features (HPVA ECAs develop in younger patients, are smaller, and are diagnosed at an earlier stage), p16/HPV status (almost all HPVA ECAs are p16 and/or HPV positive), prognostic parameters (NHPVA ECAs more often have lymphovascular invasion, lymph node metastases, and are Silva pattern C), and survival data (NHPVA ECAs are associated with worse survival). A move from the morphology-based WHO system to the IECC system will likely provide clinicians with an improved means to diagnose and classify ECAs, and ultimately, to better personalize treatment for these patients.

Constitutional abnormality of nuclear membrane proteins in small cell lung carcinoma Abstract Nuclear membrane proteins reportedly play important roles in maintaining nuclear structures and coordinating cell activities. Studying profiles of nuclear membrane proteins may help us evaluate the biological and/or clinical nature of malignant tumors. Using immunohistochemistry with antibodies for emerin, lamin A/C, lamin B, and LAP2, we examined 105 lung cancer tissues from 33 small cell lung carcinomas (SCLCs) and 72 non-SCLCs (34 adenocarcinomas, 30 squamous cell carcinomas, and 8 large cell carcinomas). Emerin had negative or local/weak positivity in 79% of SCLCs and 1% of non-SCLCs, and lamin A/C had similar positivity in 91% of SCLCs and 3% of non-SCLCs. LAP2's expression was similar between SCLCs and non-SCLCs. RT-PCR analyses for these four nuclear membrane proteins over 7 cell lines showed that mRNA of emerin and lamin A/C were distinctly downregulated in the SCLC cell lines, supporting the immunohistochemical results. In conclusion, we suggest that downregulation of the nuclear membrane proteins emerin and lamin A/C is characteristic of SCLC cells, and this constitutional abnormality of the nuclear membrane may be related to the biological and/or clinical nature of SCLC. In addition, knowing the nuclear protein profile in SCLC cells may contribute to our understanding of nuclear fragility known as the crush artifact in pulmonary biopsy specimens.

Follicular dendritic cells display microvesicle-associated LMP1 in reactive germinal centers of EBV+ classic Hodgkin lymphoma Abstract Expression of the latent membrane protein-1 (LMP1) of Epstein-Barr virus (EBV) was investigated in 153 cases of EBV+ classic Hodgkin lymphoma (cHL); 120 cases were pediatric patients (< 14 years of age) from Iraq, and 33 cases were adult patients from Italy. We describe for the first time the presence of LMP1 protein in EBV-encoded RNA (EBER)-negative follicular dendritic cells (FDCs) of reactive germinal centers (GC) associated with EBV+ cHL. Presence of LMP1+ GCs was independent of geographic region and age of patients. Variable numbers of reactive GCs were present in 22.2% of cases (34 of 153), whereas LMP1 staining of FDCs was present in about a third of cases (10 of 34) with reactive GC. Most cases with LMP1+ GC were mixed-cellularity (MC) subtype, but some nodular sclerosis (NS) was also present. GC cells with LMP1+ FDCs were surrounded by numerous EBV-infected cells which were positive for EBER, LMP1, and CD30. Double immunolocalization analysis revealed that LMP1 was associated with CD63, an exosomal marker, and with CD21. The possibility is discussed that peri-follicular EBV-infected cells release LMP1 protein, perhaps through exosomes, and that the protein is then captured by FDCs and is presented to EBER-negative GC B cells.

Spread through air spaces (STAS) is a predictor of poor outcome in atypical carcinoids of the lung Abstract Spread through air spaces (STAS) have been recently recognized as a prognostic factor for adenocarcinoma and squamous cell carcinoma of the lung. Pulmonary neuroendocrine neoplasms (NENs) include tumors with different morphology and a heterogeneous clinical behavior. Among atypical carcinoids (ACs), new prognostic factors able to refine prognosis are needed. In the present study, a retrospective series of 91 surgically resected ACs was investigated, in parallel with 191 control cases of typical carcinoids (TCs) and of high-grade small- and large-cell neuroendocrine carcinomas, to assess the presence and potential prognostic role of STAS. STAS was defined by the presence of neoplastic nests or single cells in air spaces beyond the tumor edge. Clinicopathological parameters and survival were correlated by univariate and multivariate analyses. STAS was identified in 48% of ACs (44/91) compared to 20.5% of TCs and 71–88% of high-grade large- and small-cell carcinomas in the control group. In the carcinoid group, presence of STAS was significantly correlated with unfavorable parameters, such as high tumor stage, positive nodal status, high Ki-67 index, presence of angioinvasion, and with adverse disease outcome, shorter overall survival, and time to progression. In conclusion, the presence of STAS is an additional relevant adverse prognostic factor in pulmonary AC that currently has the most unpredictable outcome and the most controversial treatment strategy.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Cognitive Therapy and Research

Profiles of Emotion Regulation in Young People Accessing Youth Mental Health and Drug Treatment Abstract Deficits regulating emotions are a core process underlying both substance use and mental health disorders. Research has focused on identifying one-to-one associations between individual emotion regulation (ER) strategies and mental health symptoms. Consequently, little is known about how patterns of ER relate to a broad range of psychopathology, in treatment seeking young people. Latent class analysis was used to examine patterns of ER strategies and their relationship with symptoms of depression, anxiety, eating disorders, substance use and borderline personality disorder, in a sample of young treatment seekers. Participants were young people (N = 306, M = 20.8 years) accessing youth advocacy and support or mental health services in Australia. Participants recalled an emotionally-arousing event experienced when on their own and indicated their use of 14 possible ER responses in an online questionnaire. Symptoms of mental health and substance use were measured. The LCA identified three distinct classes of ER responses: Ruminators/avoiders (n = 76), active regulators (n = 81), and low regulators (n = 129). The ruminators/avoiders endorsed the most severe symptom picture across all disorders except alcohol use. Within this cohort, distinct patterns of ER responding had unique relationships with symptoms of psychopathology. The deleterious impact of heightened maladaptive ER strategies (rumination and avoidance) in the absence of adaptive strategies was highlighted.

Feasibility and Impact of a Guided Symptom Exposure Augmented Cognitive Behavior Therapy Protocol to Prevent Symptoms of Pharmacologically Induced Depression: A Pilot Study Abstract Depression is the leading cause of disability and a major cause of morbidity worldwide, with societal costs now upwards of 1 trillion dollars across the globe. Hence, extending current efforts to augment prevention outcomes is consistent with global public health interests. Although many prevention programs have been developed and have demonstrated efficacy, studies have yet to demonstrate that CBT is effective in preventing symptoms in populations at risk for developing depression induced by pharmacological substances. Using a randomized, controlled design, this pilot study reports on the feasibility and preliminary effects of a novel, guided symptom exposure augmented cognitive behavioral prevention intervention (GSE-CBT) in a sample diagnosed with Hepatitis C at risk for developing medication induced depression. Results demonstrated that the guided symptom exposure augmented CBT (GSE-CBT) was feasible in this population and was delivered with high integrity. Although not statistically different, we observed a pattern of lower depression levels in the GSE-CBT group versus those in the control group throughout. This pilot study demonstrates that a psychosocial prevention intervention is feasible for use in patients at risk for developing pharmacologically induced depression and that a guided symptom exposure augmented CBT protocol has the potential to prevent symptoms of depression that develop as a side effect to taking these medications. Results are preliminary and future studies should use larger samples and test the intervention in other populations.

Early Versus Later Improvements in Dialectical Behavior Therapy Skills Use and Treatment Outcome in Eating Disorders Abstract Dialectical behavior therapy (DBT) has demonstrated initial efficacy for the treatment of eating disorders (EDs). However, no study has examined potential processes that may contribute to observed improvements in DBT for EDs. The present study sought to investigate changes in DBT skills use throughout treatment as a predictor of symptom change in a DBT-based partial hospital program (PHP) for adults with EDs. Adults [n = 135; M(SD) age = 25.08 (7.88)] with EDs completed self-report measures at treatment admission, one-month post-admission, and discharge from PHP. DBT skills use, as measured by the DBT Ways of Coping Checklist, increased by 12.65% from admission to one-month post-admission and increased by 24.10% from admission to discharge. Early (admission to month 1) and later (month 1 to discharge) improvements in DBT skills use predicted greater improvements in ED, depressive, and emotion dysregulation symptoms from treatment admission to discharge. Notably, early versus later change in skills use was a stronger predictor of outcome. Results are consistent with the theoretical model of DBT and add to a growing literature on DBT for EDs.

Different Patterns of Attention Bias in Worry and Rumination Abstract In two studies with college student participants, we explored the ways in which worry and rumination may be similar or distinct. Towards that end, as part of our research, we developed new laboratory measures of worry and rumination. In Study 1, we examined how the new lab instruments we developed differentiate worry versus rumination and initiation versus termination. We did so by comparing them with two other measurement methods of worry and rumination, ecological momentary assessment and questionnaires. We found that the laboratory measures were reasonably able to differentiate worry from rumination, but not initiation from termination. In Study 2, we further examined the relationship between attentional biases to threat/danger and loss/failure (using the dot probe task) and both worry and rumination to explore the nature of distinctions between worry and rumination. We found different patterns of attentional bias associated with worry and rumination. Worry was associated with bias away from threat. In contrast, rumination was associated with bias toward loss/failure. The results of the two studies suggest that there are some meaningful differences between worry and rumination. The implications of the current findings are discussed.

#Sad: Twitter Content Predicts Changes in Cognitive Vulnerability and Depressive Symptoms Abstract Research shows that social media networks can affect both the physical and mental health of its users. We hypothesized that social media would also be associated with cognitive vulnerability to depression. To test this hypothesis, we used a 3-month pre-post prospective longitudinal design with a sample of undergraduates (n = 105). Results showed that participants who had tweets with a "past focus" (as determined by LIWC software) were more likely to exhibit increases in cognitive vulnerability and depressive symptoms than participants who did not have tweets with a past focus. Increases in cognitive vulnerability were associated with increases in depressive symptoms. However, the effect of Twitter content on future depressive symptoms was not accounted for by increases in cognitive vulnerability. Rather, one's past focus Twitter content had an effect on future depressive symptoms that was independent of its effect on future cognitive vulnerability levels. These results provide further support for the plasticity of cognitive vulnerability in early adulthood as well as corroborate emerging evidence for the association between social media and mental health risk factors.

Symptom-Specific Threat Perception Mediates the Relationship Between Obsessive Beliefs and OCD Symptoms Abstract Cognitive theories of obsessive compulsive disorder (OCD) propose that obsessive beliefs bias individuals' perception of OC-relevant threats, which in turn maintain OCD symptoms. However, no prior research has directly tested this mediational model in a clinical sample. The current study bridges this gap in the literature. Sixty adults with OCD completed a diagnostic interview, self-report questionnaires and a threat perception task. More specifically, participants rated the perceived threat associated with (a) OC-specific stimuli (e.g., toilet) that matched their most interfering symptom dimension (e.g., contamination) and (b) generally negative terms (e.g., pain). Results supported hypotheses, in that the threat associated with OC-specific—but not generally negative—terms significantly mediated the relationship between obsessive beliefs and the severity of participants' most interfering OCD symptom dimension. Findings underscore the importance of targeting inflated perceptions of OC-specific threats in the treatment of OCD. Limitations and future directions are discussed.

Does Modification of Implicit Associations Regarding Contamination Affect Approach Behavior and Attentional Bias? Abstract Individuals with contamination concerns show aberrant interpretational and attentional processes. Yet, it is unclear whether threat-related associations play a causal role in anxiety symptoms and attentional bias. The objective of our study was to investigate if training implicit associations affects stress reactivity and attention in the context of contamination concerns. In a double-blind randomized design, we used a modified Implicit Associations Task (IAT) to train associations between contamination and danger in a non-clinical sample (N = 121). Dependent measures were a brief-IAT to assess changes in associations, contamination-related behavior approach tasks, and a spatial cueing task to measure attentional bias. Results show that training successfully modified implicit associations. However, there were no transfer effects on approach behavior or attention. Findings suggest that the modified IAT is a useful task for training implicit associations, but that transfer to other domains (attention and behavior) is limited. Limitations and future implications are discussed.

How Do I Say This? An Experimental Comparison of the Effects of Partner Feedback Styles on Reassurance Seeking Behaviour Abstract Interventions for reassurance seeking (RS) in obsessive–compulsive disorder typically include reducing accommodation by asking partners to not provide reassurance, which may decrease RS but increase distress and be perceived as unhelpful. Alternatively, having partners provide support to encourage coping may be effective and associated with greater perceived helpfulness and lower negative affect. This experiment tested hypotheses that compared with no reassurance, supportive feedback would be associated with higher ratings of intervention helpfulness, fewer requests for reassurance, and lower ratings of RS urges and negative affect. Participants completed a threat-inducing kitchen task while observed by a partner, and afterwards sought reassurance to make a decision about safety. Partners' feedback was manipulated such that half (n = 51) provided typical accommodation reduction-focused feedback and half (n = 51) provided support-focused feedback. Results suggest that individuals who received support-focused feedback versus accommodation reduction-focused feedback rated their partner's feedback as significantly more helpful (d = 1.22). There was also a small-to-moderate effect size and trend suggesting that support was associated with less RS (d = 0.33). Overall, support provision may be associated with less RS behaviour and greater perceived helpfulness, and holds promise as an alternative intervention technique to strict accommodation reduction for problematic RS.

Intergenerational Transfer of Early Maladaptive Schemas in Mother–Daughter Dyads, and the Role of Parenting Abstract Expanding limited research on the origins of early maladaptive schemas, this study investigated relations between parental (mother) schemas and parenting styles with child (adult daughter) schemas using cross-sectional methodology. One hundred women (aged 18–88) participated in the study and 39 matched mother–daughter dyads were analysed. The Young Schema Questionnaire, Depression Anxiety and Stress Scale, Parental Bonding Instrument and Parental Authority Questionnaire were used to assess individual schemas, parenting styles from the daughters' perspective, and depression as a mood-state control variable. Mother schemas predicted a range of daughter schemas. There was also evidence of direct transference ('selective internalisation') of some schemas between mothers and daughters. Daughter schemas were associated with parenting styles. In particular, high authoritative parenting predicted lower levels of daughter schemas and high overprotective parenting predicted higher levels of daughter schemas. There was no firm evidence that authoritative parenting mediated the relationship between mother and daughter schemas in this domain. The major limitations of this study are the cross-sectional design and relatively small sample. In conclusion, mother maladaptive schemas and style of parenting predict daughter schemas. The results provide support for interpersonal, intergenerational influences on schema development. In highlighting the possible intergenerational sources of maladaptive core beliefs, this research may open new avenues of therapist–client dialogue.

Effects of Mindfulness-Based Cognitive Therapy on a Behavioural Measure of Rumination in Patients with Chronic, Treatment-Resistant Depression Abstract It has been found that Mindfulness-based cognitive therapy (MBCT) reduces rumination in remitted and currently depressed patients. However, less is known about the effects of MBCT on rumination in chronically and treatment-resistant depressed patients. Typically, questionnaires are used to assess rumination, but this introduces the risk of response and recall biases. A recent systematic review (van der Velden et al. Clinical Psychology Review 37:26–39, 2015) proposes to also include behavioural measures. A behavioural measure that has previously been used to assess rumination in dysphoric students is the breathing focus task (BFT). The first aim of this research was to investigate whether the BFT can be used in chronically, treatment-resistant depressed patients to measure rumination. We therefore administered the BFT in patients with chronic, treatment-resistant depression (n = 73) and compared them with never-depressed controls (n = 106). Patients reported significantly more negative thought intrusions and subsequent sad mood. Secondly we tested in a randomized-controlled trial whether MBCT in combination with treatment-as-usual (MBCT + TAU, n = 26) compared with TAU (n = 36) reduces rumination assessed with the BFT in chronically, treatment-resistant depressed patients. Negative thought intrusions significantly decreased in the MBCT + TAU condition, compared with TAU. The results show that MBCT reduces rumination assessed with the BFT in chronically, treatment-resistant depressed patients.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Molecular Neuroscience

Correction to: PACAP/PAC1 Regulation of Inflammation via Catecholaminergic Neurons in a Model of Multiple Sclerosis The original version of this article unfortunately contained mistakes. The captured article title and corresponding author were incorrect.

Distribution and Functional Implication of Secretin in Multiple Brain Regions Abstract Secretin is a polypeptide hormone initially identified for its gastrointestinal functions. However, emerging evidences show wide distribution of secretin and secretin receptor across various brain regions from cerebral cortex, hippocampus, hypothalamus to cerebellum. In this mini review, we will firstly describe the region-specific expression pattern of secretin and secretin receptor in the brain, followed by a summary of central physiological and neurological functions mediated by secretin. Using genetic manipulation and pharmaceutical approaches, one can elucidate the role of secretin in mediating various neurological functions from simple behaviors, such as water and food intake, to more complex functions including emotion, motor, and learning or memory. At last, current weakness and future perspectives of secretin in the central nervous system will be discussed, aiming to provide the potency of using secretin or its analog for treating various neurological disorders.

Effects of PACAP on Dry Eye Symptoms, and Possible Use for Therapeutic Application Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 27- or 38-amino acid neuropeptide, which belongs to the vasoactive intestinal polypeptide/glucagon/secretin family of peptides. PACAP and its three receptor subtypes are expressed in neural tissues and in the eye, including the retina, cornea, and lacrimal gland. PACAP is known to exert pleiotropic effects on the central nervous system and in eye tissues where it plays important roles in protecting against dry eye. This review provides an overview of current knowledge regarding dry eye symptoms in aged animals and humans and the protective effects, mechanisms of action. In addition, we also refer to the development of a new preventive/therapeutic method by PACAP of dry eye patients.

Adipose Tissue Expression of PACAP, VIP, and Their Receptors in Response to Cold Stress Abstract Obesity arises from disrupted energy balance and is caused by chronically higher energy intake compared to expenditure via basal metabolic rate, exercise, and thermogenesis. The brown adipose tissue (BAT), the primary thermogenic organ, has received considerable attention as a potential therapeutic target due to its ability to burn lipids in the production of heat. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been identified as a key regulator of the physiological stress response both centrally and peripherally. While PACAP has been shown to increase thermogenesis by acting at the hypothalamus to increase sympathetic output to BAT, a peripheral role for PACAP-activated thermogenesis has not been studied. We identified PACAP receptor (PAC1, VPAC1/2) expression for the first time in murine BAT and confirmed their expression in white adipose tissues. PAC1 receptor expression was significantly altered in all three adipose tissues studied in response to 3.5-week cold acclimation, with expression patterns differing by depot type. In primary cell culture, VPAC1 was increased in differentiated compared to non-differentiated brown adipocytes, and the same trend was observed for the PACAP-specific receptor PAC1 in gonadal white fat primary cultures. The primary PAC1R mRNA splice variant in interscapular BAT was determined as isoform 2 by RNA-Seq. These results show that PACAP receptors are present in adipose tissues and may have important functional roles in adipocyte differentiation, lipid metabolism, or adipose sensitization to sympathetic signaling in response to thermogenic stimuli.

PACAP Attenuates Optic Nerve Crush-Induced Retinal Ganglion Cell Apoptosis Via Activation of the CREB-Bcl-2 Pathway Abstract Retinal ganglion cell (RGC) apoptosis is considered an important pathological hallmark of glaucoma. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with potent neuroprotective properties. In our previous study, we found that the expression of PACAP and its high-affinity receptor PACAP receptor type 1 (PAC1R) increased markedly after optic nerve crush (ONC), and occurred mainly in the ganglion cell layer of the retina. This suggests that the upregulation of PACAP may play a vital role in inhibiting RGC death after ONC. Therefore, in the present study, we investigate the specific effects and underlying mechanism of PACAP in RGC death after ONC. Vehicle (physiological saline) or PACAP (1 nM to 200 nM) solution was injected into the vitreous body. Seven days later, the retinas were harvested, and the surviving RGCs were retrogradely labeled with Fluoro-Gold (FG; Fluorochrome) at different concentrations of PACAP. Immunofluorescence double staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were used to observe the effects of PACAP on RGC apoptosis. Our results showed that PACAP treatment inhibited caspase-3-mediated RGC apoptosis, promoted the phosphorylation of cAMP response element binding protein (CREB), up-regulated the expression of B-cell lymphoma 2 (Bcl-2), and ultimately improved RGC survival. These results suggest that PACAP may prevent RGC apoptosis after ONC via activation of CREB-mediated Bcl-2 transcription. The study thus contributes to a basic understanding of the mechanism by which PACAP decreased RGC apoptosis and provides a theoretical basis for future clinical application of PACAP in the treatment of glaucoma.

PACAP38-Mediated Bladder Afferent Nerve Activity Hyperexcitability and Ca 2+ Activity in Urothelial Cells from Mice Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate PAC1 receptor (Adcyap1r1) have tissue-specific distributions in the lower urinary tract (LUT). The afferent limb of the micturition reflex is often compromised following bladder injury, disease, and inflammatory conditions. We have previously demonstrated that PACAP signaling contributes to increased voiding frequency and decreased bladder capacity with cystitis. Thus, the present studies investigated the sensory components (e.g., urothelial cells, bladder afferent nerves) of the urinary bladder that may underlie the pathophysiology of aberrant PACAP activation. We utilized bladder-pelvic nerve preparations and urothelial sheet preparations to characterize PACAP-induced bladder afferent nerve discharge with distention and PACAP-induced Ca2+ activity, respectively. We determined that PACAP38 (100 nM) significantly (p ≤ 0.01) increased bladder afferent nerve activity with distention that was blocked with a PAC1/VPAC2 receptor antagonist PACAP6-38 (300 nM). PACAP38 (100 nM) also increased Ca2+activity in urothelial cells over that observed in control preparations. Taken together, these results establish a role for PACAP signaling in bladder sensory components (e.g., urothelial cells, bladder afferent nerves) that may ultimately facilitate increased voiding frequency.

Vasoactive Intestinal Peptide Decreases β-Amyloid Accumulation and Prevents Brain Atrophy in the 5xFAD Mouse Model of Alzheimer's Disease Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular deposits of fibrillary β-amyloid (Aβ) plaques in the brain that initiate an inflammatory process resulting in neurodegeneration. The neuronal loss associated with AD results in gross atrophy of affected regions causing a progressive loss of cognitive ability and memory function, ultimately leading to dementia. Growing evidence suggests that vasoactive intestinal peptide (VIP) could be beneficial for various neurodegenerative diseases, including AD. The study investigated the effects of VIP on 5xFAD, a transgenic mouse model of AD. Toward this aim, we used 20 5xFAD mice in two groups (n = 10 each), VIP-treated (25 ng/kg i.p. injection, three times per week) and saline-treated (the drug's vehicle) following the same administration regimen. Treatment started at 1 month of age and ended 2 months later. After 2 months of treatment, the mice were euthanized, their brains dissected out, and immunohistochemically stained for Aβ40 and Aβ42 on serial sections. Then, plaque analysis and stereological morphometric analysis were performed in different brain regions. Chronic VIP administration in 5xFAD mice significantly decreased the levels of Aβ40 and Aβ42 plaques in the subiculum compared to the saline treated 5xFAD mice. VIP treatment also significantly decreased Aβ40 and Aβ42 plaques in cortical areas and significantly increased the hippocampus/cerebrum and corpus callosum/cerebrum ratio but not the cerebral cortex/cerebrum ratio. In summary, we found that chronic administration of VIP significantly decreased Aβ plaques and preserved against atrophy for related brain regions in 5xFAD AD mice.

Altered Notch Signaling in Developing Molar Teeth of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)-Deficient Mice Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with neuroprotective and neurotrophic effects. This suggests its influence on the development of teeth, which are, similarly to the nervous system, ectoderm and neural crest derivatives. Our earlier studies have shown morphological differences between wild-type (WT) and PACAP-deficient mice, with upregulated sonic hedgehog (SHH) signaling in the lack of PACAP. Notch signaling is a key element of proper tooth development by regulating apoptosis and cell proliferation. In this study, our main goal was to evaluate the possible effects of PACAP on Notch signaling pathway. Immunohistochemical staining was performed of Notch receptors (Notch1, 2, 3, 4), their ligands [delta-like protein (DLL)1, 3, 4, Jagged1, 2], and intracellular target molecules [CSL (CBF1 humans/Su (H) Drosophila/LAG1 Caenorhabditis elegans transcription factor); TACE (TNF-α converting enzyme), NUMB] in molar teeth of 5-day-old WT, and homozygous and heterozygous PACAP-deficient mice. We measured immunopositivity in the enamel-producing ameloblasts and dentin-producing odontoblasts. Notch2 receptor and DLL1 expression were elevated in ameloblasts of PACAP-deficient mice compared to those in WT ones. The expression of CSL showed similar results both in the ameloblasts and odontoblasts. Jagged1 ligand expression was elevated in the odontoblasts of homozygous PACAP-deficient mice compared to WT mice. Other Notch pathway elements did not show significant differences between the genotype groups. The lack of PACAP leads to upregulation of Notch pathway elements in the odontoblast and ameloblast cells. The underlying molecular mechanisms are yet to be elucidated; however, we propose SHH-dependent and independent processes. We hypothesize that this compensatory upregulation of Notch signaling by the lack of PACAP could represent a salvage pathway in PACAP-deficient animals.

Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy Abstract Members of the neurotrophin family and in particular brain-derived neurotrophic factor (BDNF) regulate the response to rapid- and slow-acting chemical antidepressants and voluntary exercise. Recent work suggests that rapid-acting antidepressants that modulate N-methyl-D-aspartate receptor (NMDA-R) signaling (e.g., ketamine and GLYX-13) require expression of VGF (non-acronymic), the BDNF-inducible secreted neuronal protein and peptide precursor, for efficacy. In addition, the VGF-derived C-terminal peptide TLQP-62 (named by its 4 N-terminal amino acids and length) has antidepressant efficacy following icv or intra-hippocampal administration, in the forced swim test (FST). Similar to ketamine, the rapid antidepressant actions of TLQP-62 require BDNF expression, mTOR activation (rapamycin-sensitive), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation (NBQX-sensitive) and are associated with GluR1 insertion. We review recent findings that identify a rapidly induced autoregulatory feedback loop, which likely plays a critical role in sustained efficacy of rapid-acting antidepressants, depression-like behavior, and cognition, and requires VGF, its C-terminal peptide TLQP-62, BDNF/TrkB signaling, the mTOR pathway, and AMPA receptor activation and insertion.

Retinoprotective Effects of TAT-Bound Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Polypeptide Abstract Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) belong to the same peptide family and exert a variety of biological functions. Both PACAP and VIP have protective effects in several tissues. While PACAP is known to be a stronger retinoprotective peptide, VIP has very potent anti-inflammatory effects. The need for a non-invasive therapeutic approach has emerged and PACAP has been shown to be retinoprotective when administered in the form of eye drops as well. The cell penetrating peptide TAT is composed of 11 amino acids and tagging of TAT at the C-terminus of neuropeptides PACAP/VIP can enhance the traversing ability of the peptides through the biological barriers. We hypothesized that TAT-bound PACAP and VIP could be more effective in exerting retinoprotective effects when given in eye drops, by increasing the traversing efficacy and enhancing the activation of the PAC1 receptor. Rats were subjected to bilateral carotid artery occlusion (BCCAO), and retinas were processed for histological analysis 14 days later. The efficiency of the TAT-bound peptides to reach the retina was assessed as well as their cAMP increasing ability. Our present study provides evidence, for the first time, that topically administered PACAP and VIP derivatives (PACAP-TAT and VIP-TAT) attenuate ischemic retinal degeneration via the PAC1 receptor presumably due to a multifactorial protective mechanism.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Der Urologe

Das Belegarztwesen in Deutschland: Ende einer sektorenverbindenden Versorgungsform? Zusammenfassung Im klassischen Belegarztsystem ist für Patientinnen und Patienten in idealtypischer Weise die konservative und operative Versorgung sektorenübergreifend garantiert. Neutrale Gutachter bestätigen seit Jahren den ressourcenschonenden Umgang mit dem Aufgrund des demographischen Wandels zunehmenden Leistungsbedarfs im medizinischen Alltag. Dennoch wird diese Versorgungsform durch deren fehlende Unterstützung zunehmend durch „belegarztersetzende" Strukturen verdrängt. Nur durch eine Rückbesinnung auf diese bis zur Mitte des letzten Jahrhunderts führenden sektorenauflösende Versorgungsform und eine entsprechenden gesetzgeberischen Maßnahme zur Rettung wird das Belegarztwesen überleben.

Endoskopisches Management anteriorer Harnröhrenstrikturen mittels direkter visueller interner Urethrotomie mit Mitomycin C und intermittierendem Selbstkatheterismus

Verordnungsregresse

Prospektive Analyse der Ergebnisse und Komplikationen des künstlichen Schließmuskels (AMS 800) nach vorheriger Mundschleimhautplastik

Wenn der Staatsanwalt zweimal klingelt … Zusammenfassung Die Einführung der sog. Antikorruptionstatbestände §§ 299a, b StGB im Jahr 2016 und stetig steigende Fallzahlen v. a. beim Abrechnungsbetrug (§ 263 StGB) rücken das Strafrecht immer mehr in den Fokus von Ärzten und Industrie. Der Aufsatz fasst zunächst die wichtigsten Straftatbestände und die aktuellen Entwicklungen der Strafverfolgung im Gesundheitswesen zusammen. Sodann wird dargestellt, wie es zu strafrechtlichen Ermittlungsverfahren kommen kann und warum im Prinzip jederzeit gegen jeden ermittelt werden kann, wenn in einer Strafanzeige von dritter Seite Verdachtsmomente auch nur behauptet werden. Weiter wird erklärt, wie Ermittlungsverfahren im Einzelnen ablaufen und wie man sich dabei als Beschuldigter verhalten sollte. Anhand von 3 Fallstudien aus der Praxis (Aktienbeteiligung an einem Unternehmen der Gesundheitsbranche, separate Rabattgewährungen, Anwendungsbeobachtungen) wird strafbares von nichtstrafbarem Handeln abgegrenzt. Als Ergebnis wird aufgezeigt, dass letztlich v. a. die strikte Einhaltung der Compliance-Vorgaben und ein besonnenes, gezieltes Verteidigungsverhalten im Falle eines Ermittlungsverfahrens effektiv vor Strafbarkeit schützen.

Molekulares Tumorboard – Nierenzellkarzinom Zusammenfassung Die Einführung molekularer zielgerichteter Substanzen hat die Therapie des metastasierten Nierenzellkarzinoms grundlegend verändert. Eine erste Welle der Entwicklung basiert auf dem verbesserten Verständnis der Tumorbiologie seit der Entdeckung der Bedeutung des VHL-Gens für die Progression, was den Weg für Therapieoptionen geebnet hat, die v. a. die Neoangiogenese hemmen. Relevant sind hier die Überexpression proangiogener und proliferationsfördernder Faktoren (VEGF, „vascular endothelial growth factor"; PDGF; „platelet derived growth factor") sowie eine Überaktivierung des PI3K- (Phosphatidylinositol-3-Kinase‑)Akt-Signalwegs: Zielstruktur ist hierbei das „mammalian target of rapamycin" (mTOR-)Molekül, das an der Regulation zellproliferativer Prozesse beteiligt ist. Vor allem die VEGF-, PDGF- und mTOR-Signale bzw. Signalwege sind zentrale Angriffspunkte aktueller zielgerichteter Substanzen. Eine zweite Welle ist in der Entwicklung von Therapieansätzen mit der zielgerichteten Aktivierung und Modulation des Immunsystems zu sehen, die die „Immuntherapie" wieder in den Fokus des Interesses gerückt hat. Zentrale Entwicklung ist die Anwendung von Immun-Checkpoint-Inhibitoren, mit deren Hilfe eine (Re‑)Aktivierung der zellulären Abwehr und hier v. a. von T‑Zellen erfolgt, was per se das Potenzial einer zytoreduktiven Therapie durch Abtöten der Tumorzellen in sich birgt. Auch, wenn sich die Prognose durch die rasante Entwicklung der letzten Jahre signifikant verbesserte, bleibt die Behandlung anspruchsvoll, da die meisten Patienten einen Progress erleben müssen und ein Langzeitüberleben in nur etwa 20 % der Fälle erreicht werden kann, da eben auch ein Teil der Patienten primär refraktär ist oder nicht anspricht.

Nachsorge des nicht muskelinvasiven Harnblasenkarzinoms Zusammenfassung Die Tumornachsorge des NMIBC („non-muscle invasive bladder cancer") ist eine Abwägung zwischen der Belastung durch die Diagnostik sowie dem Risiko für Rezidiv und insbesondere Progress. Die Einteilung in Hoch‑, Intermediär- und Niedrigrisikotumoren ermöglicht eine risikoadaptierte Tumornachsorge. Durch die Verwendung von Risikokalkulatoren lässt sich das individuelle Rezidiv- und Progressionsrisiko abschätzen. Die Nachsorge basiert v. a. auf der Zystoskopie, welche bei Hoch- und Intermediärrisikotumoren lebenslang, bei Low-risk-Tumoren bis zum 5. tumorfreien Jahr durchgeführt werden soll. Die Zytologie besitzt hohe Sensitivität und Spezifität für High-grade-Tumoren und wird in der Nachsorge dieser empfohlen. Aufgrund der unzureichenden Evidenz kann bisher kein kommerziell erhältlicher Urinmarker in der Nachsorge empfohlen werden. Für die Abklärung synchroner und metachroner Tumoren des oberen Harntrakts wird die CT(Computertomographie)-, alternativ die MR(Magnetresonanz)-Urographie empfohlen.

Vertragsärztliche Ermächtigung – ein Segen! Zugleich ein Fluch?

Internetnutzung nach Prostatakrebs Zusammenfassung Hintergrund und Ziel Das Internet bietet zahlreiche Informationen über das Prostatakarzinom (PCa). Inwieweit PCa-Langzeitüberlebende das Internet nutzen, den gefundenen Informationen vertrauen und von welchen Parametern dies abhängig ist, wurde in vorliegender Studie untersucht. Material und Methoden Auf Basis der nationalen Datenbank „Familiäres Prostatakarzinom" wurden Langzeitüberlebende 2017 hinsichtlich ihrer Internetnutzung befragt und die Assoziation zu soziodemographischen (Befragungsalter, Kinder, Partnerschaft, Schulbildung) und krankheitsbezogenen Parametern (Zeit seit Diagnose, PCa-Familienanamnese, Progress) mittels multipler logistischer Regression analysiert. Ergebnisse In die Analyse gingen 4636 PCa-Langzeitüberlebende (Alter: M = 76,9 ± 6,6 Jahre) mit einem durchschnittlichen Follow-up von 14,0 Jahren ein. 62,1 % der PCa-Langzeitüberlebenden nutzten das Internet. Unter den Nichtnutzern hatten 23,5 % starke Bedenken, bei den Nutzern nur 2,8 %. 47,2 % der Nutzer suchten nach PCa-Informationen, davon gaben 18,0 % Schwierigkeiten an. Mehr als die Hälfte fand die Informationen zum PCa unpassend. Niedrigeres Alter, kürzere Zeit seit Diagnose, Progress und häufigere Internetnutzung waren mit PCa-bezogener Informationssuche assoziiert. Nur ein Drittel vertraute den Informationen voll. Dieses Vertrauen war mit einem hohen Alter, höherer Schulbildung und häufiger Informationssuche assoziiert. Viele gaben an, v. a. ihrem Urologen zu vertrauen. Diskussion Zwei Drittel der PCa-Langzeitüberlebenden nutzt das Internet. Bei der PCa-Informationssuche bestehen Schwierigkeiten, passende und vertrauenswürdige Informationen zu finden. Urologen sollten daher mit Internetangeboten vertraut sein, um Patienten beraten und internetbezogene Informationen empfehlen zu können.

Verzahnung ambulanter und stationärer Urologie: „Hand-in-Hand" oder „aus einer Hand"? Ein Vorschlag

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Neurological Sciences

Ictal dancing-like semiology in frontal lobe epilepsy

Peculiar EEG signatures, ictal drinking and long-term follow-up in anti-LGI1 encephalitis

G327E mutation in SCN9A gene causes idiopathic focal epilepsy with Rolandic spikes: a case report of twin sisters Abstract The voltage-gated sodium channel NaV1.7, encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in epileptogenesis. Previous studies have identified an increasing number of SCN9A mutations in patients with variable epilepsy phenotypes. Phenotypes of SCN9A mutations include febrile seizures (FS), genetic epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS), which pose challenges in clinical treatment. Here, we identified a heterozygous SCN9A mutation (c.980G > A chr2:167149868 p.G327E) from two twin sisters with Rolandic epilepsy by whole-exome sequencing. The patient became seizure free with a combination of levetiracetam and clonazepam. Identification of this mutation is also helpful for advancing our understanding of the role of SCN9A in epilepsy and provides deeper insights for SCN9Amutations associated with broad clinical spectrum of seizures.

Reply to: "Diagnostic test accuracy of the Montreal Cognitive Assessment in the detection of post-stroke cognitive impairment under different stages and cutoffs: a systematic review and meta-analysis"

Autoimmune autonomic ganglionopathy associated with monoclonal gammopathy of undetermined significance: a case report

Lack of inter-muscular coherence of axial muscles in Pisa syndrome Abstract Background Pisa syndrome is a lateral deviation of the trunk described in Parkinson's disease (PD). Its etiology is still unknown; advanced muscular signal analysis techniques, such as inter-muscular coherence, could help clarifying its pathophysiology and suggest therapeutic strategies. Methods Fourteen idiopathic PD subjects with a lateral deviation of the trunk of at least 10° were included. Electromyographic (EMG) signal was recorded from bilateral thoracic, and lumbar para-spinal and obliqui externi muscles. The synchronization between EMG right and left side signals was quantified using the magnitude-squared coherence function. Results In our sample, coherence (range 0–1) did not exceed 0.3, which indicates a lack of intra-muscular coherence. Conclusion This finding is suggestive of a defective muscular fine-tuning, which has been associated with bradykinesia. These data support the hypothesis of PS as a clinical sign of bradykinesia, impacting on therapeutic and rehabilitative options.

Uremia presented as acute cranial neuropathy

Desensitization of two young patients with infantile-onset Pompe disease and severe reactions to alglucosidase alfa Abstract Pompe disease is a metabolic myopathy, due to deficiency of alpha glucosidase, with a wide clinical spectrum. Enzyme replacement therapy is the only available treatment to improve morbidity and mortality, especially in infantile-onset form. However, some patients experience infusion-associated reactions, which may restrict their access to this treatment. We report on two patients (respectively 12 and 3 months old) with infantile-onset Pompe disease and severe cardiomyopathy, that presented with severe reactions during infusion of enzyme replacement therapy and were successfully desensitized with a new individualized protocol. Our protocol, using microdilution and a premedication with antihistamines, corticosteroids, and tranexamic acid, seems safe and effective and it may allow the continuation of therapy in Pompe patients resulting in the reduction of morbidity and mortality related to this disease.

Report on a child with neurofibromatosis type 2 and unilateral moyamoya: further evidence of cerebral vasculopathy in NF2

Cancer and motor neuron disease—causal or coincidental? Two contrasting cases Abstract Introduction Motor neuron disease (MND) can occur in patients with cancer, but there is minimal evidence that this is more than by chance. We contrast two cases of motor neuronopathies occurring in the context of systemic malignancy and argue that in one case the cause was most likely paraneoplastic, while in the other it was not. Case 1 A 61-year-old woman developed progressive walking difficulties over 9 months with weakness and stiffness in her legs. EMG showed fibrillations and positive sharp waves in multiple lower limb muscles bilaterally, with neurogenic units and a reduced recruitment pattern. An invasive ductal carcinoma of the breast was identified and she continued to deteriorate neurologically with worsening mobility, upper limb spasticity and fasciculations. She died approximately 26 months after symptom onset. Case 2 A 57-year-old woman developed weight loss and weakness of her right arm without any sensory symptoms. At presentation, she had wasting and fasciculations in her right upper limb muscles, with normal reflexes, normal left upper limb and lower limb examination. Over the following week, she developed left upper limb weakness and fasciculations, brisk knee reflexes, and flexor plantar responses. Her EMG showed upper and lower limb denervation. She was found to have anti-Hu and anti-CV2 antibodies present in serum. A PET-CT showed active uptake in lymph nodes in the right hilum. Biopsy confirmed a small cell lung cancer. She had chemoradiation therapy and the tumour went into remission. She has remained well on follow-up 24 months later, regaining weight and strength after her chemotherapy. She continues to be monitored for cancer recurrence, but thus far appears to be in remission. Conclusion In cases with rapidly progressive MND, particularly of upper limb onset, consideration should be given to testing anti-neuronal antibodies and searching for an occult tumour.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Trauma and Emergency Surgery

Prevalence and patterns of maxillofacial trauma: a retrospective descriptive study Abstract Introduction We aimed to describe the prevalence and pattern of maxillofacial trauma in Qatar. Methods This is a retrospective study of trauma registry data at Hamad General Hospital during the period from January 2011 to December 2014. The study included all traumatic maxillofacial patients who underwent CT scan and were admitted during the study period. Results A total of 1187 patients with maxillofacial injuries were included in the study and 18.5% of all trauma admissions were related to maxillofacial injuries. Young age and males were predominantly affected. Mechanisms of injury were mainly traffic-related and fall. Orbital injuries were the commonest followed by maxillary injuries. The median and range face abbreviated injury score (AIS) was 2 [1–3] with 66% had a score of 2. Maxillofacial fractures were frequently associated with traumatic brain injuries. One out of five patients was managed with surgery and had median length of stays in ICU and hospital 5 and 7 days, respectively. Overall, in-hospital mortality was 8.3%. Mortality in isolated maxillofacial was low (0.3%) in comparison to 15% in polytrauma patients (p = 0.001). Multivariable regression analysis showed that Injury Severity Score, face AIS and Glasgow Coma Scale were predictors of mortality with age-adjusted odd ratio of 1.15, 2.48 and 0.82; respectively. Conclusions Maxillofacial trauma requiring admission is not uncommon in our trauma center and mostly it is mild to moderate in severity. Associated injuries are present in most of the maxillofacial injured patients and further diagnostic investigations should be part of the assessment in maxillofacial injuries.

Blunt aortic injuries in the new era: radiologic findings and polytrauma risk assessment dictates management strategy Abstract Purpose Blunt aortic injuries (BAI) have historically been considered an indication for emergent surgical intervention. Nevertheless, the observation that the outcome of the concomitant traumatic injuries has a major impact on prognosis and the rise of thoracic endovascular aortic repair (TEVAR) as an effective therapy for BAI have significantly changed in recent years the treatment algorithm of this condition. Our objective was to identify findings associated with the aortic injury which would be the best predictor of prognosis, with the objective of guiding the decision-making process for selecting the optimal timing of aortic repair. Methods We reviewed blunt aortic injuries from 3 Level I Trauma Centers from July 2008 to December 2016. We analyzed overall and BAI-related 30-day mortality in relation to: hemodynamics, timing of treatment, TEVAR vs open repair, and aortic injury grade as defined by the Society for Vascular Surgery. Based on computed tomographic angiography (CT scan) imaging, we selected the radiologic aortic findings most indicative of high mortality risk, which we defined as "Radiographic Severe Injury" (RSI): (1) total/partial aortic transection, (2) active contrast extravasation, or (3) the association of 2 of more of the following: contained contrast extravasation > 10 mm, periaortic hematoma, and/or mediastinal hematoma with thickness > 10 mm, or significant left pleural effusion. Results Of a total of 76 consecutive patients, 50 (66%) underwent immediate repair, 24 (31%) delayed aortic repair, and 2 (3%) died prior to repair. 58 patients (76%) had TEVAR, while 16 (24%) had open repair. Overall mortality was 18% and BAI-related mortality was 13%. In BAI-related mortalities, 70% of patients had RSI. Patients with high risk of overall mortality had hypotension and tachycardia (SBP < 100, HR ≥ 100), high ISS, and required vasopressors. Factors only associated with BAI-related mortality included RSI. Conclusion CT scan findings suggestive of RSI are predictive of mortality associated with BAI. Radiologic assessment of the severity of the aortic injury with characterization for the presence of RSI may represent the key factors to determine the optimal timing of treatment of the aortic injury and guide the overall treatment strategy. Level of evidence IV.

Long-term mortality and quality of life after trauma: an ancillary study from the prospective multicenter trial FROG-ICU Abstract Introduction The long-term outcomes of intensive care unit (ICU) patients are known to be worse than those of the general population, but they are poorly known in severe trauma patients. We conducted an ancillary examination of the FROG-ICU study to identify risk factors and biomarkers associated with the poorer long-term outcomes and mortality in trauma ICU patients. Methods Mortality, quality of life (QoL) and stress level scores were obtained 1 year after discharge from ICU. Blood samples were collected at ICU admission and discharge for measurement of inflammatory and cardiovascular biomarkers. Results ICU trauma patients had a significantly lower 1-year mortality than non-trauma patients (7% vs. 23%, p < 0.001), but had worse stress levels scores (19 vs. 13, p = 0.041). No difference was found regarding physical and mental QoL scores (33 vs. 31, p = 0.19 and 30 vs. 28, p = 0.42). Patients with better QoL scores had lower tracheotomy rates (11% vs. 30%, p = 0.01). Worse stress level scores are associated with poor QoL scores and vice versa. Some study biomarkers were significantly higher in those ICU trauma patients who had worse QoL scores at 1 year after discharge. Discussion Our study suggests that quality of life 1 year after an ICU stay is poor and is similar in both trauma and non-trauma patients, but ICU trauma patients are at greater risk of developing post-traumatic stress disorder-related symptoms. Tracheotomy and high levels of inflammatory biomarkers could be associated with impaired quality of life.

Reappraising the need for a control CT in mild head injury patients on anticoagulation Abstract Background Head injury is a frequent reason for admission to the emergency department. In parallel, there is a growing use of anticoagulants in an increasingly aging population, which renders this particular group of trauma patients more frequent. In several countries, including Portugal, a 24-h surveillance period followed by repetition of head computed tomography (CT) is the standard procedure for these patients. However, these recommendations have not been based on studies of prevalence of intracranial hemorrhages in control head CTs, namely in this group of anticoagulated patients. This study intends to evaluate the prevalence of de novo intracranial hemorrhages in control head CTs in anticoagulated patients. Method An observational study was carried out, which included patients admitted to Hospital de Braga between June 2017 and January 2018, victims of head injury and on anticoagulation therapy, whose admission head CT excluded intracranial hemorrhage. Results We collected a total of 201 patients, with a mean age of 81.6 years, and 57.5% of them were prescribed warfarin; 181 of these patients repeated the head CT 24 h later. Of these 181 patients, 3 (1.66%) exhibited intracranial hemorrhage in control CT, without surgical indication. All patients were followed up 1 month after the trauma, and there was no readmission requiring hospitalization, surgery or death. Conclusions In conclusion, de novo intracranial hemorrhage in control head CT of anticoagulated patients is rare. We propose that these patients may be discharged if the admission CT does not reveal intracranial hemorrhage, providing that they are accompanied by a caregiver and informed about red flags.

Spectral analysis of heart rate variability for trauma outcome prediction: an analysis of 210 ICU multiple trauma patients Abstract Purpose This study aimed to test and compare short-term spectral HRV indices with most used trauma scorings in outcome prediction of multiple trauma, and then to explore the efficacy of their combined application. Methods A prospective study was conducted for patients with blunt multiple trauma admitted to an emergency intensive care unit (ICU) between January 2016 and December 2017. Short-term spectral HRV indices on admission were measured, including normalized low-frequency power (nLF), normalized high-frequency power (nHF), and the nLF/nHF ratio. Injury severity score (ISS), new injury severity score (NISS), and revised trauma score (RTS) were evaluated for each patient, as well as probability of survival (Ps) by trauma and injury severity score (TRISS) model. The primary outcome was 30-day mortality and secondary outcomes were incidence of multiple organ dysfunction syndrome (MODS) and length of ICU stay. Results Two hundred and ten patients were recruited. The nLF/nHF ratio, RTS, and Ps(TRISS) were independent predictors of 30-day mortality, while nLF/nHF, NISS and RTS were independent predictors of MODS. The area under the receiver operating characteristic (ROC) curve (AUC) of nLF/nHF for 30-day mortality prediction was 0.924, comparable to RTS (0.951) and Ps(TRISS) (0.892). AUC of nLF/nHF-RTS combination was 0.979, significantly greater than that of each alone. Combination of nLF/nHF and Ps(TRISS) showed an increased AUC (0.984) compared to each of them. The nLF/nHF ratio presented a similar AUC (0.826) to NISS (0.818) or RTS (0.850) for MODS prediction. AUC of nLF/nHF-RTS combination was 0.884, significantly greater than that of nLF/nHF. Combination of nLF/nHF and NISS showed a greater AUC (0.868) than each alone. The nLF/nHF ratio, NISS, RTS, and Ps(TRISS) were correlated with length of ICU stay for survivors, with correlation coefficients 0.476, 0.617, − 0.588, and − 0.539. Conclusions These findings suggest that the short-term spectral analysis of HRV might be a potential early tool to assess injury severity and predict outcome of multiple trauma. Combination of nLF/nHF and conventional trauma scores can provide more accuracy in outcome prediction of multiple trauma.

Emergency room as primary point of access in the German healthcare system Abstract Background The importance of emergency rooms (ERs) as everyday healthcare suppliers is growing. Due to increasing patient flows, hospitals are forced to raise physicians' and caregivers' headcount continuously to meet the new demand of patients seeing the ER as primary point of contact in non-emergency situations. Patients from various cultural and educational backgrounds approach the ER for different reasons. Detailed understanding of these reasons and their roots is key to be able to offer guidance for patients as well as planning and staffing of hospitals in the future. Aim This study examines motivation for the entrance to the medical system via the ER in Germany via an anonymized patient survey. Evaluation in regard to socioeconomic and medical reasons is taken into account. Materials and methods Over the course of 210 h in the ER, a total of 235 patients were interviewed in the surgical emergency room of Klinikum rechts der Isar in the year 2016. Focus was set on standard cases to allow for facilitated comparability. Heavily injured patients were excluded from the study. Results The main reasons for patients entering the ER were immediate help (45.9%) and treatment by a specialist (35.4%). Furthermore, the location/good accessibility (47.9%) and prior positive experience with the emergency room (20.7%) were decisive reasons for choosing the hospital over the outpatient sector. Analysis of demands of patients in relation to their migration background and their religious confession showed no significant difference between groups. Conclusion Younger patients tend to more often access the ER instead of an outpatient clinic or doctor in private practice. As a survey suits the less urgent patients, our research describes this population in detail. The need for better information of patients regarding treatment options becomes apparent. The study's outcomes aim to teach physicians as well as operators how to influence resource management in the healthcare system by meaningful information of patients. Further research may evaluate long-term results of information measures.

Blunt cerebrovascular injury: incidence and long-term follow-up Abstract Purpose Blunt cerebrovascular injuries (BCVI), which can result in ischemic stroke, are identified in 1–2% of all blunt trauma patients. Computed tomography angiography (CTA) scanning has improved and is the diagnostic modality of choice in BCVI suspected patients. Data about long-term functional outcomes and the incidence of ischemic stroke after BCVI are limited. The aim of this study was to determine BCVI incidence in relation to imaging modality improvements and to determine long-term functional outcomes. Methods All consecutive trauma patients from 2007 to 2016 with BCVI were identified from the level 1 trauma center prospective trauma database. Three periods were identified where CTA diagnostic modalities for trauma patients were improved. Long-term functional outcomes using the EuroQol six-dimensional (EQ-6D™) were determined. Results Seventy-one BCVI patients were identified among the 12.122 (0.59%) blunt trauma patients. In the first period BCVI incidence among the overall study cohort, polytrauma, basilar skull fracture and cervical trauma subgroups was found to be 0.3%, 0.9%, 1.2%, 4.6%, respectively, which more than doubled towards the third period (0.8, 2.4, 1.9 and 8.5% respectively). Ischemic stroke as a result of BCVI was found in 20 patients (28%). In-hospital stroke rate was lower in patients receiving antiplatelet therapy (p < 0.01). Six in-hospital deaths were BCVI related. Long-term follow-up (follow-up rate of 83%) demonstrated lower functional outcomes compared to Dutch reference populations (p < 0.01). Ischemic stroke was identified as a major cause of functional impairment at long-term follow-up. Conclusions Improved CTA diagnostic modalities have increased BCVI incidence. Furthermore, BCVI patients reported significant functional impairment at long-term follow-up. Antiplatelet therapy showed a significant effect on in-hospital stroke rate reduction.

Reply to: Wanted: Automated objective proficiency assessment metrics for the FAST exam (and other POCUS studies)

Ankle ultrasound for detecting anterior talofibular ligament tear using operative finding as reference standard: a systematic review and meta-analysis Abstract Purpose To evaluate the diagnostic accuracy of ankle ultrasound for detection of anterior talofibular ligament (ATFL) tear with a reference standard of operative finding. Methods A computerized search of PubMed and EMBASE databases was performed to identify relevant original articles on ankle ultrasound for ATFL tear. The pooled proportions of the diagnostic accuracy estimates were assessed using random-effects modeling. We also assessed pooled proportions of the diagnostic accuracy according to injury stage (acute or chronic) and severity of injury (complete or partial). Heterogeneity among studies was determined using the inconsistency index (I2). Meta-regression analyses were performed to evaluate the potential sources of heterogeneity. Results Ten studies were included. The pooled proportion of the diagnostic accuracy of ankle ultrasound for ATFL was 0.95 (95% confidence interval [CI] 0.88–0.98). In subgroup analysis, the pooled proportion of the diagnostic accuracy of ankle ultrasound for acute ATFL tear was 0.92 (95% CI 0.85–0.95). The pooled proportion of the diagnostic accuracy of ankle ultrasound for chronic ATFL tear was 0.96 (95% CI 0.84–0.99). The pooled proportions of the diagnostic accuracy for complete and partial ATFL tear were 0.82 (95% CI 0.72–0.89) and 0.88 (95% CI 0.70–0.96), respectively. In the meta-regression analyses, the inclusion of pediatric patients was only significantly different (p = 0.007). Conclusions Ankle ultrasound may be a useful diagnostic modality in the detection of ATFL tear in adults and children, regardless of injury stage and severity. For correct diagnosis of ATFL tear, a high-frequency ultrasound probe and sufficient experience of the examiner are mandatory.

Diagnostic performance of thromboelastometry in trauma-induced coagulopathy: a comparison between two level I trauma centres using two different devices Abstract Purpose The implementation of a ROTEM®-based algorithm requires reliable thresholds to mirror a prothrombin time (PT) ratio > 1.2 and/or a fibrinogen concentration < 1.5 g l−1. Our goal was to compare the diagnostic performances of two devices (ROTEM® Sigma and Delta, IL Werfen, Munich, Germany) in two level-I trauma centres for the diagnostic of post-traumatic coagulopathy. Methods We conducted a retrospective analysis of two registries across two periods of time: from September 2014 to December 2015 in Lyon-Sud university trauma centre and from April 2016 to January 2018 in the Grenoble Alps Trauma Centre. Accuracies of EXTEM and FIBTEM assays to detect patients with coagulation disorders were tested for each device using receiver operating characteristic (ROC) analyses. Results Within the study period, 74 trauma patients in the Grenoble cohort and 75 trauma patients in the Lyon cohort had concomitant ROTEM® and standard coagulation testing on admission. No statistically significant difference was found between the two ROC curves for FIBTEM amplitude at 5 min (A5), FIBTEM maximum clot firmness, EXTEM clotting time (CT) and EXTEM A5 for ROTEM® Sigma and Delta to diagnose post-traumatic coagulation disorders. The best threshold for FIBTEM A5 to predict low fibrinogen concentration was 7 mm for each device. EXTEM CT thresholds to diagnose PT ratio > 1.2 were 78 s and 74 s for ROTEM® Sigma and Delta, respectively. Conclusions These results suggest that ROTEM®-based algorithms may be transposed from one trauma centre to another independently of the setting and the ROTEM® device in use.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com