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BACKGROUND Intracranial pressure (ICP) and arterial blood pressure (ABP) are related to each other through cerebral autoregulation. Central venous pressure (CVP) is often measured to estimate cardiac filling pressures as an approximate measure for the volume status of a patient. Prior modelling efforts have formalized the functional relationship between CVP, ICP and ABP. However, these models were used to explain short segments of data during controlled experiments and have not yet been used to explain the slowly evolving ICP increase that occurs typically in patients after aneurysmal subarachnoid hemorrhage (SAH). OBJECTIVE To analyze the functional relationship between ICP, ABP and CVP recorded from SAH patients in the first five days after aneurysm. METHODS Two methods were used to elucidate this relationship on the running average of the signals: First, using Spearman correlation coefficients calculated over 30 min segments Second, for each patient, linear state space models of ICP as the output and ABP and CVP as inputs were estimated. RESULTS The mean and variance of the data and the correlation coefficients between ICP-ABP and ICP-CVP vary over time as the patient progresses through their stay in the ICU. On average, after an SAH event, the models show that a) ABP is the bigger driver of changes in ICP than CVP and that increasing ABP leads to reduction in ICP and (b) increasing CVP leads to an increase in ICP. CONCLUSIONS Finding a) agrees with the hypothesis that patients with subarachnoid hemorrhage have defective autoregulation, and b) agrees with the positive correlation observed between central venous pressure and intracranial pressure in the literature.

Background Chronic obstructive pulmonary disease (COPD) patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand‐activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke‐induced AHR activation causes adverse muscle impact. Methods We used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno‐associated virus‐mediated gene transfer). Results Sixteen weeks of tobacco smoke exposure in mice caused muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down‐regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signalling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR‐dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice. Conclusions These results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment, and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.

Climate change may make semiarid grasslands increasingly prone to wildfire. We studied fire seasonality and growing season condition effects on a semiarid grassland in Southern Alberta, Canada. Plots were hand-torched in either fall or spring. Response variables estimated included plant composition and diversity, plant height, aboveground net primary production (ANPP), and forage nitrogen quality. The experiment was replicated over three consecutive growing seasons, and each replicate was monitored for 3 yr thereafter. Drought conditions occurred during two of the six growing seasons. Fall fires appeared to be hotter than spring fires based on a greater fuel mass (standing litter) and exposed the soil surface to a longer period without the benefit of standing litter over winter. Although this grassland is resilient to fire, compared with spring-burned grasslands, the species composition, ANPP, and leaf length of grasses of fall burned communities took a longer time to recover to preburn conditions. Our results suggest that spring-burned grasslands should not be grazed for 1 year post burn to allow time for recovery of ANPP and litter. However, given that ANPP of fall-burned communities also exhibited higher nitrogen concentration that may make the forage more palatable to livestock, and that these communities were more severely impacted, it seems prudent to delay their grazing for more than 1 year to prevent overgrazing. The negative impacts of fire on ANPP may be ameliorated with above-average precipitation in June, which may be forecast during an El Nino year.

The iconic Tasmanian devil (Sarcophilus harrisii) is endangered due to the transmissible cancer Devil Facial Tumour Disease (DFTD), of which there are two genetically independent subtypes (DFT1 and DFT2). While DFT1 and DFT2 can be differentially diagnosed using tumour biopsies, there is an urgent need to develop less-invasive biomarkers that can detect DFTD and distinguish between subtypes. Extracellular vesicles (EVs), the nano-sized membrane-enclosed vesicles present in most biofluids, represent a valuable resource for biomarker discovery. Here, we characterized the proteome of EVs from cultured DFTD cells using data-independent acquisition–mass spectrometry and an in-house spectral library of > 1500 proteins. EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with focal adhesion functions. Furthermore, hallmark proteins of epithelial–mesenchymal transition were enriched in DFT2 EVs relative to DFT1 EVs. These findings were validated in EVs derived from serum samples, revealing that the mesenchymal marker tenascin-C was also enriched in EVs derived from the serum of devils infected with DFT2 relative to those infected with DFT1 and healthy controls. This first EV-based investigation of DFTD increases our understanding of the cancers’ EVs and their possible involvement in DFTD progression, such as metastasis. Finally, we demonstrated the potential of EVs to differentiate between DFT1 and DFT2, highlighting their potential use as less-invasive liquid biopsies for the Tasmanian devil.

Substance use disorders are debilitating disorders with far reaching effects. However, many healthcare providers do not receive sufficient training on how to identify or respond to individuals who ...

Damage control surgery (DCS) is a standardized treatment concept in severe abdominal injury. Despite its evident advantages, DCS bears the risk of substantial morbidity and mortality, due to open abdomen therapy (OAT). Thus, identifying the suitable patients for that approach is of utmost importance. Furthermore, little is known about the use of DCS and the related outcome, especially in blunt abdominal trauma. Patients recorded in the TraumaRegister DGU® from 2008 to 2017, and with an Injury Severity Score (ISS) ≥ 9 and an abdominal injury with an Abbreviated Injury Scale (AIS) score ≥ 3 were included in that registry-based analysis. Patients with DCS and temporary abdominal closure (TAC) were compared with patients who were treated with a laparotomy and primary closure (non-DCS) and those who did receive non-operative management (NOM). Following descriptive analysis, a matched-pairs study was conducted to evaluate differences and outcomes between DCS and non-DCS group. Matching criteria were age, abdominal trauma severity, and hemodynamical instability at the scene. The injury mechanism was predominantly blunt (87.1%). Of the 8226 patients included, 2351 received NOM, 5011 underwent laparotomy and primary abdominal closure (non-DCS), and 864 were managed with DCS. Thus, 785 patient pairs were analysed. The rate of hepatic injuries AIS > 3 differed between the groups (DCS 50.3% vs. non-DCS 18.1%). DCS patients had a higher ISS (p = 0.023), required more significant volumes of fluids, more catecholamines, and transfusions (p

Purpose HMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown. Methods Intracellular distribution of HMGA2 was analyzed in PDAC (n = 106) and peritumoral, non-malignant ducts (n = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells. Results HMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors (p = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei (p = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel (p = 0.004) and venous invasion (p = 0.046). Conclusion HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.

Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) is a significant contributor to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. Prior experimental evidence has suggested cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) as a pathophysiological driver of SAH-SBI. The aim of this study was to investigate the clinical and pathophysiological association between CSF-Hb and SAH-SBI. We prospectively enrolled 47 consecutive patients and collected daily CSF samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between CSF-Hb and SAH-SBI. The diagnostic accuracy of CSF-Hb for SAH-SBI markedly exceeded that of established methods (area under the curve: 0.89 [0.85-0.92]). Temporal LC-MS/MS CSF proteomics demonstrated that erythrolysis accompanied by an adaptive macrophage response are the two dominant biological processes occurring in the CSF space after aneurysm rupture. To further investigate the pathophysiology between CSF-Hb and SAH-SBI, we explored the vasoconstrictive and lipid peroxidation activities of Hb ex-vivo. These experiments revealed critical inflection points overlapping CSF-Hb concentration thresholds in patients with SAH-SBI. Selective Hb depletion and in-solution neutralization by the Hb-scavenger haptoglobin or the heme-scavenger hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb in patient CSF. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

Persons living with spinal cord injury (SCI) are potentially at risk for severe COVID-19 disease given that they often have decreased lung capacity and may lack the ability to effectively evacuate their lungs. Known risk factors for negative outcomes after COVID-19, such as obesity, diabetes, and cardiovascular disease, disproportionally affect people with SCI and raise concerns for the mortality risk among persons with SCI. A rapid systematic review of English, Spanish, Portuguese, and Chinese literature on COVID-19 and SCI was performed using the keywords "spinal cord injury" and "COVID-19." We included studies that provided information on clinical presentation, characteristics, course, and outcomes of COVID-19 disease in SCI. We excluded studies on patients who did not have an SCI before severe acute respiratory syndrome coronavirus-2 infection or did not report clinical information. We included 10 studies in total: nine studies with a total of 171 patients and a survey study of 783 healthcare professionals. Fever (74%), cough (52%), and dyspnea (33%) were the most frequently reported symptoms, and 63% showed abnormalities on X-ray imaging. In the included case series and reports (N = 31), only 1 patient required mechanical ventilation, but 3 patients died (10%). The mortality rate in a large registry study (N = 140) was 19%. Clinical presentation of COVID-19 in SCI patients was similar to the general population, and though adverse events and intensive care unit admission were low, the mortality rate was high (10-19%). No prognostic factors for severe disease or mortality could be identified. Registration (PROSPERO): CRD42020196565.

Background There are no valid recommendations or reliable guidelines available to guide patients how long they should refrain from lifting weights or returning to heavy physical labor after abdominal or hernia surgery. Recent studies found that surgeons’ recommendations not to be evidence-based and might be too restrictive considering data on fascial healing and incisional hernia development. It is likely that this impairs the patient’s quality of life and leads to remarkable socio-economic costs. Hence, we conducted this survey to gather international expert’s opinions on this topic. Materials and methods At the 41st Annual International Congress of the EHS, attending international experts were asked to complete a questionnaire concerning recommendations on given proposals for postoperative refrain from heavy work or lifting after abdominal surgery and also after hernia repairs. Results In total, 127 experts took part in the survey. 83.9% were consultants with a mean experience since specialization of more than 11 years. Two weeks of no heavy physical strain after laparoscopic surgery were considered sufficient by more than 50% of the participants. For laparotomy, more than 50% rated 4 weeks appropriate. For mesh-augmented sublay and IPOM repair of ventral or incisional hernias, more than 50% rated 4 weeks of rest appropriate. For complex hernia repair, 37% rated 4 weeks reasonable. Two weeks after, groin hernia surgery was considered sufficient by more than 50% of the participants. Conclusion Following groin hernia repair (Lichtenstein/endoscopic technique) and laparoscopic operation, the majority agreed on the proposal of 2 weeks refraining from physical strain. Four weeks of no physical strain were considered appropriate by a majority after laparotomy and open incisional hernia repair. However, the results showed substantial variation in the ratings, which indicates uncertainty even in this selected cohort of hernia surgery experts and emphasizes the need for further scientific evaluation. This is particularly remarkable, because a lack of evidence that early postoperative strain leads to higher incisional hernia rates. Trial registration Number DRKS00023887.

Introduction Little is known about the long-term outcome of open abdomen treatment with vacuum-assisted wound closure and mesh-3. Therefore, this study’s purpose is to evaluate this with a particular focus on incisional hernia development and quality of life (QoL). Materials and Methods Fifty-five patients who underwent vacuum-assisted wound closure and mesh-mediated fascial traction at our institution from 2006 to 2013 were prospectively enrolled in this study. After a median follow-up period of 3.8 years, 34 patients attended a follow-up examination, including the SF-36 QoL questionnaire. Results The fascial closure rate was 74% (intention-to-treat) and 89% (per-protocol). Enteroatmospheric fistulae occurred in 1.8%. In-hospital mortality was 16.4%, and during the follow-up period, it was 27.4%. Incisional hernias developed in 35% of the cases. The SF-36 physical role (54.6 ± 41.0 (0-100), P A subgroup analysis revealed that the lower scores for physical role, physical functioning, and physical component summary only existed in the subgroup of incisional hernia patients. In contrast, physical and mental SF-36 scores of patients without incisional hernias did not differ from the normative scores. Conclusions Vacuum-assisted wound closure and mesh-mediated fascial traction seems to result in low complication rates. However, incisional hernias occur in 35%, which are the leading cause of reduced QoL. Measures to further improve this rate, such as prophylactic meshes, have to be evaluated.

The open abdomen (OA) is an established concept for treating severe abdominal diseases. The most frequent reasons for placement of an open abdomen are abdominal sepsis (e.g. from intestinal perforation or anastomotic leakage), severe abdominal organ injury and abdominal compartment syndrome. The pathophysiology is much more complex than the surgeon's eye can see in an OA. The temporary closure of the abdominal wall ensures sufficient drainage of infected ascites, protection of the intestinal loops and conditioning of the abdominal wall in order to be able carry out definitive closure of the abdominal wall at the end of the surgical treatment. Negative peritoneal pressure therapy combined with fascia traction (with or without mesh) is well-established in the management of an open abdomen.

Background Biliary cancer, comprising cholangio- and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation. Methods Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer patients, as well as from healthy individuals, were isolated by sequential two-step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis. Results Two directly tumour-related antigen combinations (AnnV+ CD44v6+ and AnnV+ CD44v6+ CD133+ ) and two combinations related to progenitor cells from the tumour microenvironment (AnnV+ CD133+ gp38+ and AnnV+ EpCAM+ CD133+ gp38+ ) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV+ CD44v6+ EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively. Conclusions EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies.

Purpose Definitive fascial closure is an essential treatment objective after open abdomen treatment and mitigates morbidity and mortality. There is a paucity of evidence on factors that promote or prevent definitive fascial closure. Methods A multi-center multivariable analysis of data from the Open Abdomen Route of the European Hernia Society included all cases between 1 May 2015 and 31 December 2019. Different treatment elements, i.e. the use of a visceral protective layer, negative-pressure wound therapy and dynamic closure techniques, as well as patient characteristics were included in the multivariable analysis. The study was registered in the International Clinical Trials Registry Platform via the German Registry for Clinical Trials (DRK00021719). Results Data were included from 630 patients from eleven surgical departments in six European countries. Indications for OAT were peritonitis (46%), abdominal compartment syndrome (20.5%), burst abdomen (11.3%), abdominal trauma (9%), and other conditions (13.2%). The overall definitive fascial closure rate was 57.5% in the intention-to-treat analysis and 71% in the per-protocol analysis. The multivariable analysis showed a positive correlation of negative-pressure wound therapy (odds ratio: 2.496, p p p = 0.029) and the number of surgical procedures before OAT (odds ratio: 0.740, p = 0.005) with DFC. Conclusion The clinical course and prognosis of open abdomen treatment can significantly be improved by the use of treatment elements such as negative-pressure wound therapy and dynamic closure techniques, which are associated with definitive fascial closure.

Clinical trial. Spinal cord injury (SCI) impacts autonomic function and bowel management. Bowel care is a potential trigger for autonomic dysreflexia (AD; paroxysmal hypertension elicited by sensory stimuli below the level of lesion). AD can be life threatening so strategies to minimise AD are prioritised after SCI. Lidocaine lubricant is recommended during bowel care with the rationale to minimise the sensory stimulus, reducing AD. The objective of this study was to assess whether lidocaine lubricant (Xylocaine 2%) ameliorates AD during at-home bowel care compared with standard lubricant (placebo). Community. Participants (n = 13; age 44.0 ± 3.3 years) with high-level SCI (C3-T4) performed their normal at-home bowel care on two days, each time using a different lubricant, with continuous non-invasive cardiovascular monitoring. Injury to spinal autonomic (sympathetic) nerves was determined from low-frequency systolic arterial pressure (LF SAP) variability. Participants displayed reduced autonomic function (LF SAP 3.02 ± 0.84 mmHg2), suggesting impaired autonomic control. Bowel care duration was increased with lidocaine (79.1 ± 10.0 min) compared to placebo (57.7 ± 6.3 min; p = 0.018). All participants experienced AD on both days, but maximum SAP was higher with lidocaine (214.3 ± 10.5 mmHg) than placebo (196.7 ± 10.0 mmHg; p = 0.046). Overall, SAP was higher for longer with lidocaine (6.5 × 105 ± 0.9 × 105 mmHg • beat) than placebo (4.4 × 105 ± 0.6 × 105 mmHg • beat; p = 0.018) indicating a higher burden of AD. Heart rate and rhythm disturbances were increased during AD, particularly with lidocaine use. At-home bowel care was a potent trigger for AD. Our findings contradict recommendations for lidocaine use during bowel care, suggesting that anaesthetic lubricants impair reflex bowel emptying, resulting in longer care routines with an increased burden of AD.

Neuropsychologia : an international journal in behavioural and cognitive neuroscience 159, 107921 (2021). doi:10.1016/j.neuropsychologia.2021.107921, Published by Elsevier Science, Amsterdam [u.a.]

Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces, and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here, we show that the novel oncogene RASSF1C drives mesenchymal‐to‐amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC‐mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that RASSF1C‐induced amoeboid cells display increased expression of cancer stem‐like markers such as CD133, ALDH1, and Nanog, and are accompanied by higher invasive potential in vitro and in vivo. Further, RASSF1C‐induced amoeboid cells employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C‐driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early‐stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification., Tumour‐suppressor RASSF1A encodes an alternative transcript, RASSF1C, that acts as oncogene in human breast cancer, triggering pro‐invasive cellular features and aggressiveness.

Objectives Sepsis is a life-threatening medical emergency. There is a paucity of information on whether quality improvement approaches reduce the in-hospital sepsis caseload or save lives and decrease the healthcare system and society's cost at the provincial/national levels. This study aimed to assess the outcomes and economic impact of a province-wide quality improvement initiative in Canada. Design Retrospective population-based study with interrupted time series and return on investment analyses. Setting The sepsis cases and deaths averted over time for British Columbia were calculated and compared with the rest of Canada (excluding Quebec and three territories). Patients Aggregate data were obtained from the Canadian Institute for Health Information on risk-adjusted in-hospital sepsis rates and sepsis mortality in acute care sites across Canada. Interventions In 2012, the British Columbia Sepsis Network was formed to reduce sepsis occurrence and mortality through education, knowledge translation, and quality improvement. Measurements and main results A return on investment analysis compared the financial investment for the British Columbia Sepsis Network with the savings from averted sepsis occurrence and mortality. An estimated 981 sepsis cases and 172 deaths were averted in the post-British Columbia Sepsis Network period (2014-2018). The total cost, including the development and implementation of British Columbia Sepsis Network, was $449,962. Net savings due to cases averted after program costs were considered were $50.6 million in 2018. This translates into a return of $112.5 for every dollar invested. Conclusions British Columbia Sepsis Network appears to have averted a greater number of sepsis cases and deaths in British Columbia than the national average and yielded a positive return on investment. Our findings strengthen the policy argument for targeted quality improvement initiatives for sepsis care and provide a model of care for other provinces in Canada and elsewhere globally.

Background: There is no conclusive data on postoperative recommendations after abdominal and hernia surgery, and there is significant variation in the literature on that question. Thus, this study evaluates the status quo of recommendations of postoperative activity restriction after abdominal surgery.Materials and Methods: A national (German) and international survey of general surgeons on postoperative recommendations after abdominal and hernia surgery was pooled and analyzed.Results: A total of 74.6% recommended postoperative reduced activity for 2 weeks or less after laparoscopy. For midline laparotomy, 48.8% considered a reduced activity of 4 weeks or less to be sufficient. A majority from the national survey recommended more than 4 weeks instead (60.2%), whereas only 31.5% from the international survey did so (p = 0.000). In the pooled analysis, 258 of 450 (57.3%) rated 4 weeks or less suitable. However, the recommendations differed significantly between the surveys (4 weeks or less: a national survey, 47.1% vs. international survey, 64.6%; p = 0.000).Conclusion: There was substantial variation in the given recommendations. However, we found no evidence against immediate mobilization, reduced physical activity, and lifting for up to 2 weeks after laparoscopic surgery and for up to 4 weeks after open abdominal surgery and open incisional/ventral hernia repair in uncomplicated and standard cases. There might be individual and socioeconomic benefits to allow patients to return to their whole personal level of activity and work without putting them at risk of complications. Due to lack of evidence, both retrospective and prospective, controlled studies are in need to develop reliable recommendations.

While surgical treatment is preferred for Graves' disease with active forms of GO, there are various concepts for treating inactive forms of GO. The goal of radioiodine therapy is to resolve immunogenic hyperthyroidism by damaging the thyroid cells.The effects of the radioiodine dose on an associated inactive GO remain unclear, however. We conducted a retrospective analysis of 536 patients who received first-time radioiodine therapy to treat Graves' hyperthyroidism. Patients without GO always received 200 Gy of iodine-131. Before the introduction of a differentiated treatment concept, patients with GO also received 200 Gy, while afterwards they received 300 Gy. For further analysis, we formed three patient groups based on GO diagnosis and administered radiation dose and compared their results. The main research question focused on the effect of an increased dose on Graves' orbitopathy. The sub-questions addressed the resolution rate achieved with the higher dose as well as the development of GO in patients who received radioiodine therapy. The results show that GO symptoms were improved after radioiodine treatment in 68.5 % of patients treated with 300 Gy but only in 47.5 % of the patients treated with 200 Gy (p = 0.003). While in the 300 Gy group, hyperthyroidism was resolved in 93.2 % of patients, this was achieved in only 68.8 % of patients in the 200 Gy group (p /= 0.001). Especially with an inactive form of GO profit from their hyperthyroidism being quickly and sufficiently resolved. This is achieved significantly better by administering 300 Gy instead of 200 Gy. For this reason, data analysis supports a differentiated dose concept that provides 300 Gy for patients with GO and 200 Gy for patients without GO. Während eine chirurgische Behandlung bevorzugt wird für Patienten mit Morbus Basedow und aktiven Formen der endokrinen Orbitopathie (EO), existieren verschiedene Konzepte zur Behandlung von Patienten mit Morbus Basedow und inaktiven Formen der EO. Das Schlüsselziel der Radiojodtherapie ist es, die immunogene Hyperthyreose durch Schädigung der Schilddrüsenzellen zu beheben. Die Auswirkungen der Radioioddosis auf eine damit verbundene inaktive EO bleiben jedoch weitestgehend unklar. Es wurde eine retrospektive Analyse an 536 Patienten durchgeführt, die zum ersten Mal eine Radiojodtherapie zur Behandlung des Morbus Basedow erhielten. Patienten ohne EO erhielten immer 200 Gy Jod-131. Vor der Einführung eines differenzierten Behandlungskonzepts, erhielten auch Patienten mit GO 200 Gy, danach erhielten sie 300 Gy. Zur weiteren Analyse, wurden drei Patientengruppen basierend auf dem Vorhandensein einer EO und der verabreichten Strahlendosis gebildet und verglichen. Die Hauptfragestellung konzentrierte sich auf die Wirkung einer erhöhten Dosis auf die EO. Die Nebenfragestellungen adressierte die mit der höheren Dosis assoziierte Therapieerfolgsrate sowie die Neuentwicklung einer EO unter Radiojodtherapie. Es zeigt sich, dass die EO-Symptome nach Radiojodbehandlung bei 68.5 % der mit 300 Gy behandelten Patienten, jedoch nur bei 47.5 % der mit 200 Gy behandelten Patienten verbessert wurde (p = 0.003). Während in der 300 Gy Gruppe die Hyperthyreose bei 93.2 % der Patienten behoben wurde, wurde dies nur bei 68.8 % der Patienten in der 200 Gy-Gruppe erreicht (p 0.001). Vor allem Patienten mit Morbus Basedow und einer begleitenden inaktiven Form der EO profitieren von einem möglichst schnellen und suffizienten Therapieerfolg der Radioiodtherapie hinsichtlich des Behebens der Hyperthyreose. Dies wird durch die Verabreichung von 300 Gy signifikant besser erreicht als mit 200 Gy. Aus diesem Grund unterstützt die Datenanalyse eine differenziertes Dosis-Konzept, das 300 Gy für Patienten bereitstellt mit GO und 200 Gy für Patienten ohne GO.

After non-invasive diagnostic modalities high risk thyroid nodules are investigated with fine needle aspiration cytology in order to find the right surgical strategy for suspected malignancies. Despite the clear recommendation by the European and the American associations (ETA, ATA) its clinical value is doubted and its importance in clinical practice not fully clarified. A multicentric study of 119 patients with differentiated thyroid cancer operated on in 24 surgical departments was conducted. The aim was not only to evaluate the use of FNAC as a diagnostic tool, but also to investigate its diagnostic validity and compare it with that of other, non-invasive diagnostic methods. FNAC was used only in 25 % of malignant thyroid nodules. In these patients sensitivity of FNAC was 60 %. In 40 % with preoperative FNAC, the result had an impact on the surgical approach. 17 % underwent surgery only because of the FNAC result, and 23 % underwent a planned surgical resection with total thyroidectomy and lymphadenectomy on account of the FNAC result. In comparison to non-invasive diagnostics (ultrasonography in conjunction with scintigraphy with Na99mTcO4) FNAC reached the same sensitivity. The results of our study reveal a limited application of preoperative FNAC in diagnosing thyroid nodules as well as a limited conclusiveness in our study population if not performed according to standards. In order to increase the benefits of this diagnostic modality, it seems to be important to perform FNAC according to the guidelines and in a standardized manner. FNAC should always be conducted in combination with ultrasonography. An experienced cytopathologist should be consulted and the Bethesda classification system should be established.EINFüHRUNG: Nach Ausschöpfung der nicht-invasiven Diagnostik werden Schilddrüsenknoten mit hohem Malignitätsrisiko zur weiteren Abklärung einer Feinnadelaspirationszytologie zugeführt. Um durch präzise Diagnosestellung, unnötige Schilddrüsenoperationen zu vermeiden und bei Malignitätsnachweis die leitliniengerechte Operationsstrategie zu planen. Trotz klare europäischer und amerikanischer Leitlinienempfehlungen der klinischer Wert der FNAC Gegenstand der Diskussion und ihre Bedeutung für die klinische Praxis nicht vollständig geklärt. Eine multizentrische Studie mit 119 Patienten in 24 chirurgischen Abteilungen wurde durchgeführt. Jeder Patient mit einem differenzierten Schilddrüsenkarzinom während 2 aufeinanderfolgenden Jahren wurde eingeschlossen. Ziel war es, nicht nur die Verwendung von FNAC als Diagnosewerkzeug zu bewerten, sondern auch seine diagnostische Validität zu untersuchen und mit der anderer nicht-invasiver Diagnoseverfahren zu vergleichen. FNAC wurde nur bei 25 % der malignen Schilddrüsenknoten verwendet. Bei diesen Patienten betrug die Sensitivität von FNAC 60 %. Bei 40 % mit präoperativem FNAC hatte das Ergebnis einen Einfluss auf den chirurgischen Ansatz. 17 % wurden nur aufgrund des FNAC-Ergebnisses operiert, und 23 % wurden aufgrund des FNAC-Ergebnisses einer geplanten chirurgischen Resektion mit totaler Thyreoidektomie und Lymphadenektomie unterzogen. Im Vergleich zur nicht-invasiven Diagnostik (Sonographie in Verbindung mit Szintigraphie mit Na99mTcO4) erreichte FNAC die gleiche Sensitivität. Die Ergebnisse unserer Studie zeigen eine begrenzte Anwendung der präoperativen FNAC bei der Diagnose von Schilddrüsenknoten – entgegen den empfohlenen Richtlinien – sowie eine begrenzte Aussagekraft im untersuchten Studiensetting. Um die Vorteile dieser Diagnosemodalität zu optimieren, scheint es entscheidend zu sein, sie auf standardisierte Weise durchzuführen. FNAC sollte immer in Kombination mit Ultraschall durchgeführt werden, und erfahrene Zytopathologen sollten konsultiert werden, um die Rate falsch-negativer Befunde zu verringern. Darüber hinaus sollte ein standardisiertes Klassifizierungssystem für die zytologische Bewertung differenzierter Schilddrüsenkarzinome implementiert werden, um die Diagnose und die Interpretation der Ergebnisse zu standardisieren.

In March 2020, at the onset of the coronavirus disease 2019 (COVID-19) pandemic in the United States, the Southern California Extracorporeal Membrane Oxygenation (ECMO) Consortium was formed. The consortium included physicians and coordinators from the 4 ECMO centers in San Diego County. Guidelines were created to ensure that ECMO was delivered equitably and in a resource effective manner across the county during the pandemic. A biomedical ethicist reviewed the guidelines to ensure ECMO use would provide maximal community benefit of this limited resource. The San Diego County Health and Human Services Agency further incorporated the guidelines into its plans for the allocation of scarce resources. The consortium held weekly video conferences to review countywide ECMO capacity (including census and staffing), share data, and discuss clinical practices and difficult cases. Equipment exchanges between ECMO centers maximized regional capacity. From March 1 to November 30, 2020, consortium participants placed 97 patients on ECMO. No eligible patients were denied ECMO due to lack of resources or capacity. The Southern California ECMO Consortium may serve as a model for other communities seeking to optimize ECMO resources during the current COVID-19 or future pandemics.

BackgroundCOPD patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke-induced AHR activation causes adverse muscle impact.MethodsWe used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno-associated virus-mediated gene transfer).Results16 weeks tobacco smoke exposure in mice caused: muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down-regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signaling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR-dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice.ConclusionsThese results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.

Objective To evaluate the influence of a visceral protective layer (VPL) on the formation of enteroatmospheric fistulae (EAF) in open abdomen treatment (OAT) for peritonitis. Background EAF formation is a severe complication of OAT. Despite the widespread use of OAT, there are no robust evidence-based recommendations for preventing EAF. Methods A total of 120 peritonitis patients with secondary peritonitis as a result of a perforation of a hollow viscus or anastomotic insufficiency who had undergone OAT were included, and 14 clinical parameters were recorded in prospective OAT databases at 2 tertiary referral centers. For this analysis, patients with a VPL were assigned to the treatment group and those without a VPL to the control group. Propensity Score (PS) matching was performed. Known risk factors in OAT such as malignant disease, mortality, emergency operation, OAT duration, and fascial closure were matching variables. The influence of VPL on EAF formation was statistically evaluated using logistic regression analysis. Results With 34 patients in each group, no notable differences were identified with regard to age, sex, underlying disease, mortality, emergency operation, fascial closure, and OAT duration. Overall, a mortality rate of 22.1% for OAT due to peritonitis was observed. Mean OAT duration was approximately 9 days, and secondary fascial closure was achieved in more than two-thirds of all patients. Fascial traction was used in more than 75% of cases. EAF formation was significantly more frequent in the control group (EAF formation: VPL group 2.9% vs control 26.5%; P = 0.00). In the final regression analysis, the use of VPL resulted in a significant reduction in the risk of EAF formation (odds ratio 0.08; 95% confidence interval 0.01-0.71, P = 0.02), which translates to a relative risk reduction of 89.1%. Conclusion VPL effectively prevents EAF formation during OAT in patients with peritonitis. We recommend the consistent use of VPL as part of a standardized OAT treatment algorithm.

BACKGROUND: The prevalence of adult chronic kidney disease and cardiovascular comorbidities in Canadian Indigenous communities is largely unknown. We conducted a study to document the prevalence of chronic kidney disease and concurrent diabetes mellitus, hypertension and dyslipidemia in a First Nations population in northwest Ontario. METHODS: In this observational study, we used retrospective data collected from regional electronic medical records of 16 170 adults (age ≥ 18 yr) from 26 First Nations communities in northwest Ontario from May 2014 to May 2017. Demographic and laboratory data included age, gender, prescribed medications, estimated glomerular filtration rate, urine albumin:creatinine ratio, low-density lipoprotein cholesterol (LDL-C) level and glycated hemoglobin (HbA(1c)) concentration. We identified patients with diabetes by an HbA(1c) concentration of 6.5% or higher, or the use of a diabetic medication, those with dyslipidemia by an elevated LDL-C level (≥ 2.0 mmol/L) or use of lipid-lowering medication, and those with hypertension by use of antihypertensive medication. RESULTS: Of the 16 170 adults residing in the communities, 5224 unique patients (32.3%) had renal testing (albumin:creatinine ratio and/or estimated glomerular filtration rate). The age-adjusted prevalence of chronic kidney disease was 14.5%, and the prevalence of stage 3–5 chronic kidney disease (estimated glomerular filtration rate < 60 mL/min) was 7.0%. Most patients with chronic kidney disease (1487 [80.0%]) had at least 1 cardiovascular comorbidity. A total of 1332 patients (71.6%) had diabetes, 1313 (70.6%) had dyslipidemia, and 1098 (59.1%) had hypertension; all 3 comorbidities were present in 716 patients (38.5%). INTERPRETATION: We document a high prevalence of advanced chronic kidney disease in this First Nations population, 7.0%, double the rate in the general population. High rates of cardiovascular comorbidities were also common in these patients with chronic kidney disease, which places them at increased risk for cardiovascular disease.

Background: Open abdomen treatment (OAT) is widely accepted to manage severe abdominal conditions such as peritonitis and abdominal compartment syndrome but can be associated with high morbidity and mortality. The main risks in OAT are (1) entero-atmospheric fistula (EAF), (2) failure of primary fascial closure, and (3) incisional hernias. In this study, we assessed the long-term functional outcome after OAT to understand which factors impacted most on quality of life (QoL)/daily living activities and the natural course after OAT.Materials and Methods: After a retrospective analysis of 165 consecutive OAT patients over a period of 10 years (2002–2012) with over 65 clinical parameters that had been performed at our center (1), we initiated a prospective structured follow-up approach. All survivors were invited for a clinical follow-up. Forty complete datasets including clinical and social follow-up with SF-36 scores were available for full analysis.Results: The patients were dominantly male (75%) with a median age of 52 years. Primary fascial closure (PC) was achieved in 9/40 (23%), while in 77% a planned ventral hernia (PVH) approach was followed. A total of 3/4 of the PVH patients underwent a secondary-stage abdominal wall reconstruction (SSR), but 2/3 of these reconstructed patients developed recurrent hernias. Fifty-five percent of the patients with PC developed an incisional hernia, while 20% of all patients developed significant scarring (Vancouver Scar Score >8). Scar pain was described by 15% of the patients as “moderate” [Visual Analog Scale (VAS) 4–6] and by 10% as “severe” (VAS > 7). While hernia presence, PC or PVH, and scarring showed no impact on QoL, male sex and especially EAF formation significantly reduced QoL.Discussion: Despite many advantages, OAT was associated with relevant mortality and morbidity, especially in the early era before the implementation of a structured concept at our center. Follow-up revealed that hernia incidence after OAT and secondary reconstruction were high and that 25% of patients qualifying for a secondary reconstruction either did not want surgery or were unfit. Sex and EAF formation impacted significantly on QoL, which was lower than in the general population. With regard to hernia incidence, new strategies such as prophylactic mesh implantation upon fascial closure should be discussed analogous to other major abdominal procedures.

Extracellular vesicles (EVs) are nano-sized membrane enclosed vesicles that are released by cells. While initially thought to be cellular detritus or particles involved in eliminating waste from cells, EVs have been recognised as important mediators of intercellular communication by transferring their bioactive cargoes. Notably, over the last two decades, a substantial research effort has been undertaken to understand the role of EVs in cancer. It is now understood that tumour derived EVs can transfer their contents to influence metastatic behaviour, as well as establish favourable microenvironments and pre-metastatic niches that support cancer development and progression. EV-mediated intercellular communication in cancer will be of importance to understanding the emerging paradigm which views cancer as the establishment of a new species within the host organism. Here, we provide a concise overview of EVs and the current understanding of their role and application in cancer. In addition, we explore the potential wider role of EVs in the transfer of inherited characteristics and evolutionary biology.

The COVID-19 pandemic has transformed medical care worldwide. General surgery has been affected in elective procedures, yet the implications for emergency surgery are unclear. The current study analyzes the effect of the COVID-19 lockdown in spring 2020 on appendicitis treatment in Germany. Hospitals that provided emergency surgical care during the COVID-19 lockdown were invited to participate. All patients diagnosed with appendicitis during the lockdown period (10 weeks) and, as a comparison group, patients from the same period in 2019 were analyzed. Clinical and laboratory parameters, intraoperative and pathological findings, and postoperative outcomes were analyzed. A total of 1915 appendectomies from 41 surgical departments in Germany were included. Compared to 2019 the number of appendectomies decreased by 13.5% (1.027 to 888, p=0.003) during the first 2020 COVID-19 lockdown. The delay between the onset of symptoms and medical consultation was substantially longer in the COVID-19 risk group and for the elderly. The rate of complicated appendicitis increased (58.2 to 64.4%), while the absolute number of complicated appendicitis decreased from 597 to 569, (p=0.012). The rate of negative appendectomies decreased significantly (6.7 to 4.6%; p=0.012). Overall postoperative morbidity and mortality, however, did not change. The COVID-19 lockdown had significant effects on abdominal emergency surgery in Germany. These seem to result from a stricter selection and a longer waiting time between the onset of symptoms and medical consultation for risk patients. However, the standard of emergency surgical care in Germany was maintained.

Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here we show that the novel oncogene RASSF1C drives mesenchymal to amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that amoeboid cells display the cancer stem cell markers CD133, ALDH1 and the pluripotent marker Nanog; are accompanied by higher invasive potential in vitro and in vivo; and employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification.

A hypothermic avalanche victim underwent, during extracorporeal warming from asystolic arrest, 3-dimensional transesophageal echocardiography. At 33°C core temperature, left ventricular ejection fraction had recovered, whereas myocardial strain still demonstrated significant dysfunction until 36°C. Deformation analysis seems more sensitive than global assessment during myocardial recovery from hypothermic cardiac arrest. (Level of Difficulty: Intermediate.), Graphical abstract

Background Nimodipine is routinely administered in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the effect of nimodipine on oxygen exchange in the lungs is insufficiently explored. Methods The study explored nimodipine medication in artificially ventilated patients with aSAH. The data collection period was divided into nimodipine-dependent (ND) and nimodipine-independent (NID) periods. Values for arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2) were collected and compared between the periods. Patients were divided in those with lung injury (LI), defined as median Horowitz index (PaO2/FiO2) ≤40 kPa (≤300 mmHg), and without and in those with lower respiratory tract infection (LRTI) and without. Results A total of 53 out of 150 patients were artificially ventilated, and in 29 patients, the Horowitz index could be compared between ND and NID periods. A linear mixed model showed that during ND period the Horowitz index was 2.3 kPa (95% CI, 1.0–3.5 kPa, PPP=0.011 and P=0.002, respectively. Conclusions In patients with LI or LRTI in the context of aSAH, pulmonary function may worsen with nimodipine treatment. The drop of 2 to 3 kPa of the Horowitz index in patients with no lung pathology may not outweigh the benefits of nimodipine. However, in individuals with concomitant lung injury, the effect may be clinically relevant.

Introduction: Incisional hernia development after open abdomen therapy (OAT) remains a common complication in the long run. To demonstrate the feasibility, we describe our method of prophylactic onlay mesh implantation with definitive fascial closure after open abdomen therapy (PROMOAT). To display the feasibility of this concept, we evaluated the short-term outcome after absorbable and non-absorbable synthetic mesh implantation as prophylactic onlay.Material and Methods: Ten patients were prospectively enrolled, and prophylactic onlay mesh (long-term absorbable or non-absorbable) was implanted at the definitive fascial closure operation. The cohort was followed up with a special focus on incisional hernia development and complications.Results: OAT duration was 21.0 ± 12.6 days (95% CI: 16.9–25.1). Definitive fascial closure was achieved in all cases. No incisional hernias were present during a follow-up interval of 12.4 ± 10.8 months (range 1–30 months). Two seromas and one infected hematoma occurred. The outcome did not differ between mesh types.Conclusion: The prophylactic onlay mesh implantation of alloplastic, long-term absorbable, or non-absorbable meshes in OAT showed promising results and only a few complications that were of minor concern. Incisional hernias did not occur during follow-up. To validate the feasibility and safety of prophylactic onlay mesh implantation long-term data and large-scaled prospective trials are needed to give recommendations on prophylactic onlay mesh implantation after OAT.

Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide and the third most common cause of cancer-related death. One of the major problems faced by researchers and clinicians in this area is the lack of reliable disease biomarkers, which would allow for an earlier diagnosis, follow-up or prediction of treatment response, among others. In this regard, the “HCC circulome”, defined as the pool of circulating molecules in the bloodstream derived from the primary tumor, represents an appealing target, the so called liquid biopsy. Such molecules encompass circulating tumor proteins, circulating tumor cells (CTCs), extracellular vesicles (EVs), tumor-educated platelets (TEPs), and circulating tumor nucleic acids, namely circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA). In this article, we summarize recent findings highlighting the promising role of liquid biopsies as novel potential biomarkers in HCC, emphasizing on its clinical performance.

Stroke is a major cause of disability and death worldwide. Oxygen and glucose deprivation (OGD) in brain tissue preparations can reproduce several pathological features induced by stroke providing a valuable ex vivo protocol for studying the mechanism of action of neuroprotective agents. Guanosine, an endogenous guanine nucleoside, promotes neuroprotection in vivo and in vitro models of neurotoxicity. We previously showed that guanosine protective effect was mimicked by inhibition of nitric oxide synthases (NOS) activity. This study was designed to investigate the involvement of nitric oxide (NO) in the mechanisms related to the protective role of guanosine in rat hippocampal slices subjected to OGD followed by reoxygenation (OGD/R). Guanosine (100 μM) and the pan-NOS inhibitor, l-NAME (1 mM) afforded protection to hippocampal slices subjected to OGD/R. The presence of NO donors, DETA-NO (800 μM) or SNP (5 μM) increased reactive species production, and abolished the protective effect of guanosine or l-NAME against OGD/R. Guanosine or l-NAME treatment prevented the impaired ATP production, lactate release, and glutamate uptake following OGD/R. The presence of a NO donor also abolished the beneficial effects of guanosine or l-NAME on bioenergetics and glutamate uptake. These results showed, for the first time, that guanosine may regulate cellular bioenergetics in hippocampal slices subjected to OGD/R injury by a mechanism that involves the modulation of NO levels.

Extracellular vesicles (EVs) are important modulators of physiological functions in the central nervous system (CNS). These cell-derived lipid-bilayer encapsulated nanovesicles contain a wide array of cargoes such as proteins, RNA and bioactive lipids—all of which can take part in different functional roles in cell to cell communication. Furthermore, emerging evidence highlights that secreted EVs are highly heterogeneous, differing in their hydrodynamic size as well as EV surface composition. In neurodegenerative disorders EV secretion is dysfunctional in a sense that EVs secreted from diseased cells in the CNS take on additional roles in spreading the disease pathology. This alters the balance of the entire cell communication network. Understanding these pathological mechanisms helps not only to shed light to novel aspects of biological mechanisms of neurodegenerative diseases, it also helps to devise innovative therapeutic strategies, and to develop biomarkers for monitoring disease progression and response to treatments. In this chapter we discuss the role of EVs in normal CNS physiology and in neurodegenerative diseases, by focusing on Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis and prion diseases as examples.

Objective Case series with different clinical presentations indicating central nervous system (CNS) involvement in coronavirus disease 2019 (COVID-19) have been published. Comprehensive work-ups including clinical characteristics, laboratory, electroencephalography (EEG), neuroimaging and cerebrospinal fluid (CSF) findings are needed to understand the mechanisms.DesignWe evaluated 32 consecutive patients with severe SARS-CoV-2 infection treated at a tertiary care centre from March 09 to April 03, 2020 for concomitant severe central nervous system (CNS) symptoms occurring during their critical disease state. Those with CNS disorders were examined in detail regarding clinical characteristics and undergoing additional examinations, e.g. computed tomography (CT), magnetic resonance imaging (MRI), (EEG), (CSF) analysis and autopsy if they had died.ResultsOf 32 critically ill patients with COVID-19 eight (18%) had severe CNS involvement (mean [SD] age, 67.6 [6.8] years; seven men; two patients died). All eight patients had cardiovascular risk factors, most frequently arterial hypertension. Two patients presented with lacunar ischemic stroke and one with status epilepticus in the early phase. As most common presentation, six patients presented with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in three of them with additional subarachnoid haemorrhage and in another two with additional small ischemic lesions. In three patients intracranial vessel wall sequence MRI was performed, for the first time to our knowledge. All cases showed contrast-enhancement of vessel walls in large and middle-sized cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. CSF analysis showed normal cells counts and chemistry. RT-PCRs for SARS-CoV-2 in CSF were all negative, and no intrathecal SARS-CoV-2 specific IgG synthesis was detectable.ConclusionsCNS disorders are common in patients with severe COVID-19. Different mechanisms might be involved. Besides unspecific encephalopathy and encephalitic syndromes, large vessel strokes might occur early after disease onset. In a later phase, microbleeds and microinfarctions indicate potential CNS small vessel disease. MRI vessel wall contrast enhancement suggests cerebral vascular wall pathologies with an inflammatory component. CNS disorders associated with COVID-19 may lead to long-term disabilities aggravating socio-economic damage. The mechanisms have to be investigated urgently in order to develop preventive and therapeutic neuroprotective strategies.

Background In Germany as elsewhere, standardized recommendations are lacking on the avoidance of physical exertion to protect the abdom - inal wall in patients who have recently undergone abdominal surgery. It is unclear how much stress the abdominal wall can withstand and how long the patient should be exempted from work. The goal of this review is to determine whether there are any standardized, evidence-based recommendations for postoperative care from which valid recommendations for Germany can be derived. Methods We systematically searched the literature for evidence-based recommendations on exertion avoidance after abdominal surgery, as well as for information on the extent to which postoperative abdominal wall stress contributes to incisional hernia formation. We then created a questionnaire on recommendation practices and sent it to all of the chiefs of general and visceral surgery services that were listed in the German hospital registry (1078 chiefs of service as of June 2016). Results All 16 of the included studies on postoperative exertion avoidance contained low-level evidence that could only be used to formulate weak recommendations ("can," rather than "should" or "must"). Some 50 000 incisional hernia repair procedures are performed in Germany each year, with a reported incidence of 12.8% in the first two years after surgery. The scientifically documented risk factors for incisional herniation are related to techniques of wound closure, the suture materials used, wound infections, and the patient risk profile. From the biological point of view, the abdominal wall regains full, normal resistance to exertional stress 30 days after a laparotomy with uncomplicated healing. Most incisional hernias (>50%) arise 18 months or more after surgery; they are more common in patients who have avoided exertion for longer periods of time (more than 8 weeks). Our questionnaire was returned by 386 surgical clinics. The responses showed that 78% of recommendations were based on personal experience only. The recommendations varied widely; exertion avoidance was recommended for as long as 6 months. Conclusion The dilemma of a deficient evidence base for postoperative exertion avoidance to protect the abdominal wall should be resolved with the much higher-quality evidence available from hernia research, which concerns the patient population with the biologically least favorable starting conditions. Based on our analysis of the available literature in light of the biomechanical principles of abdominal wall healing, we propose a new set of recommendations on postoperative exertion avoidance after abdominal surgery, with the goal of eliminating excessively protracted exertion avoidance and enabling a timely return to work.

Autonomic dysfunction is common in individuals with spinal cord injury (SCI) and leads to numerous abnormalities, including profound cardiovascular and bowel dysfunction. In those with high-level lesions, bowel management is a common trigger for autonomic dysreflexia (AD; hypertension provoked by sensory stimuli below the injury level). Improving bowel care is integral for enhancing quality of life (QoL). We aimed to describe the relationships between bowel care, AD, and QoL in individuals with SCI. We performed an online community survey of individuals with SCI. Those with injury at or above T7 were considered at risk for AD. Responses were received from 287 individuals with SCI (injury levels C1-sacral and average duration of injury 17.1 ± 12.9 [standard deviation] years). Survey completion rate was 73% (n = 210). Bowel management was a problem for 78%: it interfered with personal relationships (60%) and prevented staying (62%) and working (41%) away from home. The normal bowel care duration was >60 min in 24% and most used digital rectal stimulation (59%); 33% reported bowel incontinence at least monthly. Of those at risk for AD (n = 163), 74% had AD symptoms during bowel care; 32% described palpitations. AD interfered with activities of daily living in 51%. Longer durations of bowel care (p

First Place Award Submission - CA147Category: Clinical ApplicationManagement of obesity after spinal cord injury: a systematic reviewMir Hatef Shojaei1, Mohammad Alavinia1, B. Catharine Craven1,21N...

Purpose This paper describes the development of quality indicators for an external statutory and cross-sectoral quality assurance (QA) procedure in the context of the German health care system for adult patients suffering from schizophrenia, schizotypal and delusional disorders (F20–F29). Methods Indicators were developed by a modified RAND/UCLA Appropriateness Method with 1) the compilation of an indicator register based on a systematic literature search and analyses of health care claims data, 2) the selection of indicators by an expert panel that rated them for relevance and for feasibility regarding implementation. Indicators rated positive for both relevance and feasibility formed the final indicator set. Results 847 indicators were identified by different searches. Out of these, 56 were selected for the indicator register. During the formal consensus process the expert panel recommended another 45 indicators so that a total of 101 indicators needed to be considered by the panel. Of these, 27 indicators rated both relevant and feasible were included in the final set of indicators: this set included 4 indicators addressing structures, 19 indicators addressing processes and 4 indicators addressing outcomes. 17 indicators of the set will be reported by hospitals and 8 by psychiatric outpatient facilities. Two indicators considered to be cross-sectoral will be reported by both sectors. Discussion F20–F29 and its treatment show some specific features which so far have not been addressed by any procedure within the statutory QA program of the German health care system. These features include: Schizophrenia and related disorders a) are potentially chronic conditions, b) are mainly treated in outpatient settings, c) require a multi-professional treatment approach and d) are treated regionally in catchment areas. These specific features in combination with the peculiarities of some legal, political and organizational characteristics of the German health care system and its statutory QA program have strongly influenced the development of indicators. The result was a seemingly “imbalanced” set of indicators with a greater number of indicators for inpatient than for outpatient care despite the fact that clinical reality is otherwise. Conclusions The circumstances of the German health care system that restricted the development of this cross-sectoral QA procedure addressing care for F20–F29 are also most likely to emerge with the development of cross-sectoral QA procedures for other (potentially) chronic conditions that are mainly treated in the outpatient setting by multi-professional teams or by networks of different providers. In order to be able to develop a QA procedure that mirrors the reality of service provision for (potentially) chronic diseases such as F20–F29 we need to explore further current and new data sources, diminish sectoral borders, and implement health care responsibility on the level of catchment areas.

Open abdomen management has become a well-established strategy in the treatment of serious intra-abdominal pathologies. Key objectives are fistula prevention and high fascial closure rates. The current level of evidence on laparostoma is insufficient. This is due to the rareness of laparostomas, the heterogeneity of study cohorts, and broad diversity of techniques. Collecting data in a standardised, multicentre registry is necessary to draw up evidence-based guidelines. In order to improve the level of evidence on laparostomy, CAMIN (surgical working group for military and emergency surgery) of DGAV (German Society for General and Visceral Surgery), initiated the implementation of a laparostomy registry. This registry was established as the Open Abdomen Route by EuraHS (European Registry of Abdominal Wall Hernias). Key objectives include collection of data, quality assurance, standardisation of therapeutic concepts and the development of guidelines. Since 1 May 2015, the registry is available as an online database called Open Abdomen Route of EuraHS (European Registry of Abdominal Wall Hernias). It includes 11 categories for data collection, including three scheduled follow-up examinations. As part of this pilot study, all entries of the first 120 days were analysed, resulting in a review of 82 patients. At 44%, secondary peritonitis was the predominant indication. The mortality rate was 22%. A comparison of methods with and without fascial traction reveals fascial closure rates of 67% and 25%, respectively (intention-to-treat analysis, p

Introduction Hyper- and hypocapnia have known vaso-modulatory effects in the coronary circulation. Oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) detects changes in tissue oxygenation and can provide a comprehensive assessment of the impact of systemic blood gas changes on the myocardium. The purpose of this study was to compare the physiological responses to rapid blood gas changes induced by hyperventilation followed by apnea in comparison to steady-state levels of hypocapnia and hypercapnia in an experimental animal model. Methods Eighteen anaesthetized female swine were used in this study. A blood flow probe was attached to the left descending coronary artery (LAD) after a left-sided thoracotomy. In ten animals a hemodynamically significant LAD stenosis was induced, while eight animals served as controls. In a 3 Tesla MRI, paCO2 was modulated from a pre-set baseline (paO2=100mmHg/paCO2=40mmHg) to 30mmHg and subsequently 50mmHg by minor changes in ventilation rate. Rapid changes in paCO2 were achieved by 60s of hyperventilating (30/min) from baseline followed by an apnea of up to 90 seconds. OS-CMR images, coronary blood flow (CBF) of the LAD and arterial blood gases were recorded at each state. Results Targeting stable hypocapnia of 30mmHg from baseline did not alter CBF or myocardial oxygenation. Subsequent stable hypercapnia (paCO2=50mmHg) increased CBF significantly in control (5±5%, p=0.007) and stenosed (4±6%, p=0.036) animals, and myocardial oxygenation rose in both post-stenotic territories (4.2±6.2%, p=0.036) and in control subjects (6.2±6.2%, p=0.011). Rapid hyperventilation induced a similar degree of hypocapnia (control: paCO2=25±7mmHg, stenosed: 27±3mmHg) and showed a significant decrease of CBF by -34±23% (p=0.012) in healthy animals, and a significant decrease of -10±6% (p=0.010) in stenosed animals. This had no effect on tissue oxygenation. Apnea resulted in a similar paCO2 (control: paCO2=52±9mmHg, stenosed: 47±7mmHg) compared to steady-state blood gas levels, which increased CBF significantly in controls 346±327% (p=0.008) and stenosed 82±110 (p=0.039) animals markedly. By the end of apnea, a rise in tissue oxygenation of 2.9±2.2% was observed in controls (p=0.008), -2.7±5.1 (0.125) was observed in the stenosed group (Figure). Significant difference in myocardial oxygenation responses observed between control and stenosed subject was exclusively observed with apnea (p=0.011). Discussion Rapid hyperventilation followed by apnea results in more pronounced changes in myocardial blood flow than similar steady state deflections in paCO2. Only apnea after hyperventilation induced deoxygenation in the stenotic myocardium, which is in agreement with the concept of hypercapnia induced intercoronary steal, while steady state deviation did not compromise myocardial oxygenation. Similar breathing maneuvers may be seen in the induction phase of anaesthesia, which could potentially be a harbinger of perioperative ischemic myocardial events.

A 13-month-old infant was admitted to hospital approximately 3 weeks after ingestion of a button battery, which was lodged in the esophagus and had caused a tracheoesophageal fistula requiring mechanical ventilation. Since the battery had partially penetrated into the tracheal lumen just above the carina and also was in direct contact with the pulmonary artery, extensive considerations regarding airway and circulatory management were required preoperatively, which are presented and discussed in this case report.

Introduction: Due to high rates of obesity in Canada, weight loss is an important primary care challenge. Recent innovations in strategies include intermittent fasting and low-carbohydrate diets, with limited research in a rural setting. Methods: This prospective 1-year observational study provided patients in Sioux Lookout, Northwestern Ontario with information on fasting and low-carbohydrate diets. Patients were recommended to attend every 3 months for measurements of weight, waist circumference, body mass index (BMI) and blood pressure. Initial and 6-month bloodwork included A1c and Lipids. A survey of health status and diet was administered at 6 months. Results: Of the 94 initial registrants, 36 participants completed 1 year and achieved a 9% weight loss and an 8.6% decrease in BMI and waist circumference. Most participants were female with an average age of 60 years. Clinically insignificant changes in blood pressure and serology were observed. Participants reported few side effects and good compliance with intermittent fasting, averaging 15 h/day, 6 days/week. As in other dietary studies, the dropout rate was high at 62%. Conclusion: This low-resource initiative was successful in assisting self-selected patients at a rural primary care clinic to achieve significant weight loss at 1-year. This approach is practical and is fertile ground for ongoing research.

Herbage minerals affect performance of grazing cattle. We investigated the response of herbage P, K, Ca and Mg contents and Ca/P and K/(Ca + Mg) ratios to long-term stocking rate, continuous vs. discontinued grazing practice, and sampling year. Cattle had been stocked at 2·4 and 4·8 animal unit months ha−1 since 1949. Exclosures were installed in April 1998. Herbage samples were collected near peak herbage mass in 2001, 2003, 2008 and 2012 and analysed for mineral content. Mineral contents were similar between the two stocking rates, but were lower (P

The development of cross-sectoral quality assurance programs usually requires extensive topic identification. Illustrated by the complex processes of care for stroke and transient ischemic attacks (TIAs), a method for comprehensive topic identification is presented. The first step involves a thorough literature search in terms of systematic reviews, health technology assessments, guidelines, studies into healthcare delivery and the use of specific instruments. Routine data as well as epidemiologic studies are used to analyze the reality of service provision. In addition, experts are consulted to gain expertise concerning deficits of care, approaches to quality assurance and experience with existing quality assurance programs. Furthermore individual patient experiences are collected to add the patients' perceptions of care. Because of the limitation on the regulatory scope of Book V of the German Social Code, which, in this case, was necessary, another source of information was the legal framework and its impact on rescue chain, acute treatment and rehabilitation. Existent quality management systems, accreditations and quality assurance programs in prevention, acute treatment and rehabilitation have been searched in order to avoid any overlap with existing measures. After identifying a total of 71 quality targets according to deficits of care, recommendations for care and expert opinions in primary and secondary prevention, rescue chain, acute treatment, rehabilitation and supply of assistive equipment and therapies, respectively, the usability of instruments was tested. These instruments included case documentation, patient surveys and routine data. 14 quality targets proved to be reproducible by these instruments and were included in the recommendations for a cross-sectoral quality assurance program for stroke and TIA.

OBJECTIVES Patients with Hashimoto thyroiditis show structural changes of the thyroid that can be identified by a variety of sonographic criteria. We conducted this study to investigate whether there is a correlation between sonography and antibody activity and to assess the role of sonography in the diagnosis and follow-up of Hashimoto thyroiditis. In addition, we present a new classification system (termed the VESINC system [volume, echogenicity, sonographic texture, pseudonodular hypoechoic infiltration, nodules, and cysts]), which helps improve the clarity of sonographic findings. METHODS The study included 223 consecutive patients with previously diagnosed Hashimoto autoimmune thyroiditis who attended the thyroid clinic of the German Armed Forces Central Hospital in Koblenz for follow-up examinations between 2006 and 2008. Laboratory tests were performed to measure the levels of free triiodothyronine, free thyroxine, thyrotropin, anti-thyroglobulin antibodies (TgAbs), and antithyroid peroxidase antibodies (TPOAbs). Sonography was performed according to a strict protocol. We then assessed whether a correlation existed between antibody activity and the 6 sonographic variables of the VESINC system. RESULTS Hypoechogenicity, heterogeneity, and pseudonodular hypoechoic infiltration were associated with significantly higher TPOAb activity (P < .001). There were no significant correlations between the other sonographic variables examined (cysts, nodules, and volume) or the biometric data with the TPOAb and TgAb levels. In addition, an assessment of TgAb levels did not show significant differences in correlations with any of the sonographic variables. CONCLUSIONS Sonography is a noninvasive diagnostic imaging modality that provides information about the level of inflammatory activity. Markedly decreased echogenicity, heterogeneity, and multifocal pseudoinodular hypoechoic infiltration are indicative of a high level of inflammatory activity. The sonographic classification system presented here (VESINC system) can be a useful tool for comparing sonographic findings in a rapid and objective manner during follow-up of Hashimoto thyroiditis.

Tumor cells shed exosomes, which are released to the blood. Detecting tumor-derived exosomes containing RNA in plasma (liquid biopsy) is currently being investigated for early identification of occult metastases or relapses. Isolation of exosomes is laborious, resulting in low RNA yields. As a more robust (but less sensitive) alternative, the authors examined whether whole blood can be used as well. Tumor samples from nonmetastasized seminoma (n = 5) and colon cancer patients (n = 6) were taken during surgery. Whole-blood samples were taken before and 5-7 d after surgery. A whole genome mRNA microarray screening was performed. Candidate genes were selected based on two criteria: (1) gene expression in the presurgical whole-blood sample/tumor biopsy; and (2) a two-fold decrease in the copy number of candidate genes was expected in the postsurgical whole-blood sample 5-7 d after intervention, relative to the presurgical blood sample. The rationale behind this is the loss of tumor material in the body and the decline in the release of tumor-derived RNA in exosomes. For both tumor entities and for each patient, several hundred candidate genes could be identified. In a group-wise comparison, 20 candidate genes could be identified in the seminoma and 32 in the colon cancer group. These findings indicate that whole blood might be suitable for a liquid biopsy. However, this study identified the short period after surgery (5-7 d) as a possible confounder. The authors plan to add an additional time point several weeks after the operation to discriminate tumor candidate genes from genes induced by the surgery.