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Background: Infections are a major cause of morbidity in burn patients. We aimed to investigate the epidemiology and antibiotic susceptibility of blood stream infections in order to gain a better understanding of their role and burden in our Burn Wound Center. Methods: This retrospective epidemiological investigation analyzed data derived from medical files of patients admitted to our Burn Wound Center having had at least one positive blood culture between 1 January and 31 December 2018. We focused on the prevalence of causative agents in blood stream infections in function of the time after injury and on their drug sensitivity. Results: Among the 363 patients admitted to our Burn Wound Center during the study period, 29 had at least one episode of blood stream infection. Gram-negative organisms accounted for 56,36% of the pathogens in blood stream infections, Gram-positives for 38,17%, and yeasts for 5,45%. Pseudomonas aeruginosa was the most common bacterium (20%), followed by Staphylococcus epidermidis (16.36%), Escherichia coli and Klebsiella pneumoniae (9,09% each). A third of the Gram-negative isolates were multidrug resistant. Gram-positive cocci were isolated from blood cultures at a median of 9 days after the injury, earlier than Gram-negative rods (median 15 days). The main sources of blood stream infections were the burn wounds, followed by infected catheters. Conclusions: Multidrug resistant bacteria must be considered when selecting empirical antibiotic therapy in septic burn patients. In our center, we need to update our antibiotic guidelines, to review the hospital infection control measures and to introduce routine typing technology.

The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMR beta knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMR beta KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders. We thank Dr. Tom Struys, Katrien Wauterickx, and Joke Vanhoof for excellent technical assistance. This work was financially supported by grants from the Research Foundation of Flanders (FWO Vlaanderen, G04441N, G050617N, G0A5716N, and 1106817N), the Interuniversity Attraction Poles (IUAP-P7-39), the Belgian MS-Liga and the Charcot Foundation of Belgium, Methusalem NEURONET, the European FP7 project, HEALTH-F2-2011-278850 (INMiND), and Bijzonder Onderzoeksfonds (BOF)-UHasselt. Hellings, N (reprint author), Hasselt Univ, Biomed Res Inst, Dept Immunol, B-3590 Diepenbeek, Belgium. niels.hellings@uhasselt.be

Study objective The first ever report of vaginal natural orifice transluminal endoscopic surgery (vNOTES) for benign gynaecological was reported in 2012. There has been an exponential uptake of the number of surgeons performing such procedures worldwide with no official guidance to ensure the safe implementation of this technique into gynaecological practice due its recency. The objective of this study is to report an international consensus-based statement to help guide a basis for adopting vNOTES into clinical practice. Study design The consensus-based statement was developed amongst 39 international experts using the Delphi methodology over three successive rounds. Consensus was pre-defined as an agreement of 80% or more by the experts. Consensus sought over eight key concepts pertaining to vNOTES including patient selection, perioperative management, surgical technique, instruments, anatomy, training, registries and trials and definition of the surgical technique. Recommendations from an expert anaesthetist and urogynaecologist were also sought to give a broader perspective with respect to the implementation of vNOTES. Results Fifty nine international surgeons were invited to participate and 39 (66%) agreed to participate based on being involved in a minimum of 20 vNOTES procedures. They were from 13 countries across 5 continents (Europe, North America, South America, Australia and Asia). Participation was 100% on all three rounds. Overall, consensus was reached in 50 of the 56 questions (89%) with the remaining 6 questions where consensus was not reached pertaining to the domain of patient selection. Conclusion An international expert based vNOTES statement is presented here to help guide adoption of vNOTES based on the experience of early adopters. Consensus was achieved on most components of this consensus statement. Given the recency of this technique, until high-level evidence becomes available, this statement provides an appropriate guidance to the safe implementation of vNOTES into gynaecological practice.

Objective To compare adnexectomy by vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) versus laparoscopy. Design Parallel group, 1:1 single-centre single-blinded randomised trial, designed as non-inferiority study with a margin of 15%. Setting Belgian teaching hospital POPULATION: Non-pregnant non-virgin women with an intact uterus and without obliteration of the pouch of Douglas scheduled to undergo removal of an adnexal mass assessed to be benign on ultrasound by IOTA criteria. Methods Randomisation to laparoscopy (control group) or vNOTES (experimental group). Stratification according to adnexal size. Blinding of participants and outcome assessors by sham incisions. Main outcome measures The primary outcome measure was adnexectomy by the allocated technique. Secondary outcomes included duration of surgery, pain scores and analgesics used, quality of life and adverse events. Results We randomly assigned 67 participants (34 to the vNOTES group and 33 to the laparoscopy group). The primary endpoint was always reached in both groups: there were no conversions. We performed a sensitivity analysis for the primary outcome, assuming one conversion in the vNOTES group and no conversions in the laparoscopy group: the one-sided 95% upper limit for the differences in proportions of conversion was estimated as 13%, which is below the predefined non-inferiority margin of 15%. The secondary outcomes demonstrated a shorter duration of surgery, lower pain scores, lower total dose of analgesics and a trend for more adverse events in the vNOTES group. Conclusions vNOTES is non-inferior to laparoscopy for a successful adnexectomy without conversion. vNOTES allowed shorter operating times and less postoperative pain but there was a trend for more adverse events.

Study Objective The Hominis surgical system is a novel robot-assisted system, designed specifically for robotic vaginal natural orifice transluminal endoscopic surgery (RvNOTES). We presented our experience of the first 30 RvNOTES hysterectomies assessing the feasibility and safety of this technology. Design A two-center prospective study. Setting Academic tertiary referral centers. The ethics committees approved the study in both centers. Patients Thirty women with benign indication for hysterectomy. Intervention RvNOTES hysterectomy performed by the Hominis surgical system. Measurements and Main Results The primary outcome of the study was the rate of conversion to open or conventional laparoscopic approaches. Secondary outcomes included intra- and postoperative adverse events, operative time, estimated blood loss, length of hospital stay, and 6-week follow-up assessment. A total of 15 women were enrolled at each site. The median age was 59 years (range: 37–79) and the median body mass index was 25.4 kg/m2 (range: 17.6–40.0). Twenty-four women (80%) had comorbidities. All the procedures were completed successfully without conversion to open abdominal, traditional vaginal, or conventional laparoscopic surgery. No intraoperative complications were observed. Median blood loss and procedure duration were 50 mL (range: 20–400) and 57 minutes (range: 24–88), respectively. Postoperative pain was minimal, with a median visual analog scale of 3 (range: 1–5) for the first 24 hours following surgery. The median hospital stay was 3 days (range: 2–8). According to the treating physicians’ evaluations, the vaginal cuff was fully healed in all patients at the 6-week postoperative follow-up visit. Conclusions This is the first publication of robot-assisted vaginal hysterectomy using the Hominis surgical system. The positive results of this study show this new technology to be a safe and effective tool for vaginal natural orifice transluminal endoscopic surgery, enabling surgeons to operate vaginally with the known advantages of robotic modality.

The development of disease-modifying therapies for Parkinson’s disease is a major challenge which would be facilitated by a better understanding of the pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are key players in Parkinson’s disease, but their relationship remains incompletely resolved. Previous studies investigating the effect of LRRK2 on α-synuclein–induced neurotoxicity and neuroinflammation in preclinical Parkinson’s disease models have reported conflicting results. Here, we aimed to further explore the functional interaction between α-synuclein and LRRK2 and to evaluate the therapeutic potential of targeting physiological LRRK2 levels. We studied the effects of total LRRK2 protein loss as well as pharmacological LRRK2 kinase inhibition in viral vector–mediated α-synuclein–based Parkinson’s disease models developing early- and late-stage neurodegeneration. Surprisingly, total LRRK2 ablation or in-diet treatment with the LRRK2 kinase inhibitor MLi-2 did not significantly modify α-synuclein–induced motor deficits, dopaminergic cell loss, or α-synuclein pathology. Interestingly, we found a significant effect on α-synuclein–induced neuroinflammatory changes in the absence of LRRK2, with a reduced microglial activation and CD4(+) and CD8(+) T cell infiltration. This observed lack of protection against α-synuclein–induced toxicity should be well considered in light of the ongoing therapeutic development of LRRK2 kinase inhibitors for idiopathic Parkinson’s disease. Future studies will be crucial to understand the link between these neuroinflammatory processes and disease progression as well as the role of α-synuclein and LRRK2 in these pathological events. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01007-8.

Trans-vaginal natural orifice transluminal endoscopic surgery (vNOTES) is a recently popularised minimally invasive surgical procedure, aimed at minimising abdominal wall scars and improving pain and patient recovery times. Although vNOTES has been studied in the context of post-operative pain and cosmesis, women’s acceptance of the technique has only been cursorily examined. In this survey-based observational study, we assessed the acceptability of this technique among a cohort of Middle Eastern women. A cohort of 175 Middle Eastern women were surveyed using a 13-item questionnaire at a single gynaecology centre. The survey used was a translated version of a questionnaire from a previous study (1) and comprised open-response, five-point Likert Scale and agree-disagree items. Among 175 Middle Eastern women participated in this study most of them holding neutral view on abdominal and gynaecological procedures via vagina. 47% of participants were unsure regarding the effect of surgery via vagina on their sexual function. Although 61% of the participants showed no preference towards vNOTES over laparoscopic cholecystectomy, more than half of them indicated preference if vNOTES shown to be as effective and safe as laparoscopic cholecystectomy. The gender of the surgeon was shown to have no influence on the perspectives of the majority of participants to undergo vNOTES. vNOTES may hold value for women who have conservative upbringing and/or value cosmesis. This study provides information regarding Middle Eastern women’s perspectives on vNOTES, which may be of considerable clinical use as the popularity of this surgical technique continues to increase.

STUDY OBJECTIVE To evaluate the safety and feasibility of vaginal natural orifice transluminal endoscopic surgery (vNOTES) for benign gynaecological indications. STUDY DESIGN Prospective observational study (Canadian Task Force classification II-3) in a non-university teaching hospital. One thousand consecutive patients (2013-2018) who were eligible for vNOTES approach to benign gynaecological surgery were included. RESULTS Patient data and perioperative outcomes were included for analysis after the vNOTES surgical approach was standardized and made the default route of surgery. Of the 1000 vNOTES cases performed during this study period, hysterectomy (73%) was the most common followed by adnexal surgery (18%) and salpingectomy (4%). The mean age of the patient cohort was 46 yrs of age (22-83) and mean BMI, 26 kg/m2(16.5-52). There was a conversion rate of 0.4% (4 cases), 3 to conventional laparoscopy and 1 to laparotomy. The mean operating time was 42 minutes (14-250 minutes). The total complication rate was 3.9% (39) of which 1% (10) was intraoperative complications and 2.9% (29) were post-operative complications. When the hysterectomy cohort was sub analyzed, the total complication rate was 5.2% in this group (intraoperative 1.4% and post-operative 3.8%) with only a 0.4% complication rate in the non-hysterectomy sub-group. Of the complications in the hysterectomy group there were 9 cystotomies (1.2%). The mean specimen weight for all hysterectomies was 172 g (20-3361 g) with an average operating time of 46 minutes (20-250). CONCLUSION The perioperative outcomes of this large vNOTES case series for benign gynaecological indications is comparable to other vNOTES procedures reported in the literature apart from the risk of cystotomy which is a hysterectomy specific risk. The outcomes are that of a single high-volume surgeon incorporating cases within his respective learning curve of the surgical technique and as such should be interpreted accordingly. Since 2015 the International NOTES Society has initiated a prospective complication database where all vNOTES surgeons are invited to register their cases.

OBJECTIVE The aim of this study was to describe our experience with transvaginal natural orifice transluminal endoscopic surgery (vNOTES) uterosacral ligament suspension (USLS) and to evaluate the learning curve of mastering the skills to operate this procedure. METHODS This is a prospective study of the first 35 vNOTES hysterectomy and USLS surgeries performed between October 2018 and April 2019 at Rambam Health Care Campus (Israel) (n = 26) and Imelda Hospital (Belgium) (n = 9). The primary outcome was surgical time. Secondary outcomes included intraoperative bleeding, length of hospitalization, pain during the first 24 hours postoperative pain, and the need for analgesia, intraoperative, and postoperative adverse events. RESULTS The median age was 55 years (range, 40-81). The median operative time was 113 minutes (range, 89-233). For the procedures performed at Rambam, total operative time decreased from the first 13 to the following 13: from 149 minutes (range, 89-233 minutes) to 103 (89-170) (

Background and objective Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) has been applied massively in the gynecological field in recent years. The aim of the current study is to present the surgical technique of vNOTES omentectomy and to evaluate the feasibility of this procedure. Methods A case series study of the first 5 vNOTES omentectomy procedures performed for surgical staging of suspicious early stage ovarian cancer, at Rambam Health Care Campus (Israel) and Imelda Hospital (Belgium) between November 2018 and August 2019. Sociodemographic and clinical data were retrieved from patients’ electronic charts. Primary points of interest included intra-operative bleeding, length of surgery, length of hospitalization, and surgical complications. Results The median age was 61 years (range 50–72), and the median BMI was 27 kg/m2 (range 23–33). All the operations were carried out to completion through the vaginal GelPOINT, without insertion of an assistant abdominal trocar or conversion to another surgical approach. The median omentectomy time was 45 min (range: 39–52). The median estimated intraoperative blood loss was 150 ml (range: 20–200). The median hospital stay was 2 days (range: 1–3). Conclusions vNOTES is a feasible technique for omentectomy in early stage ovarian cancer, with low rates of complications and improved cosmetic results.

INTRODUCTION Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce. The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients. PATIENTS AND METHODS Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS - PSA-PFS) and cancer specific and overall survival (CSS - OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) - ADT + AAP (N=48) - ADT + docetaxel (N=19). Survival analysis was performed using Kaplan-Meier statistics. RESULTS Median RPFS was 13 months (95% confidence interval [CI]: 9-17) for ADT only, 21 months (95% CI: 19-23) for ADT + AAP and 12 months (95% CI: 11-14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently. CONCLUSION Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice.

Early Access; International audience; A growing world population as well as the need to enhance sustainability and health create challenges for crop breeding. To address these challenges, not only quantitative but also qualitative improvements are needed, especially regarding the macro- and micronutrient composition and content. In this review, we describe different examples of how the nutritional quality of crops and the bioavailability of individual nutrients can be optimised. We focus on increasing protein content, the use of alternative protein crops and improving protein functionality. Furthermore, approaches to enhance the content of vitamins and minerals as well as healthy specialised metabolites and long-chain polyunsaturated fatty acids are considered. In addition, methods to reduce antinutrients and toxins are presented. These approaches could help to decrease the 'hidden hunger' caused by micronutrient deficiencies. Furthermore, a more diverse crop range with improved nutritional profile could help to shift to healthier and more sustainable plant-based diets.

Main Teaching Point: MRI-US fusion-guided transperineal prostate biopsy can help sampling clinically relevant prostate cancer in patients with a history of abdominoperineal resection and is feasible under local anaesthesia and in an outpatient setting. Prostate cancer remains one of the most diagnosed cancers in men worldwide. Prostate biopsy in patients with a history of abdominoperineal resection poses a serious challenge since transrectal ultrasound is not possible. Several techniques have been described with their respective limitations and risks. This report of such a patient aged 75, presents a Magnetic Resonance Imaging-Ultrasound fusion-guided transperineal approach to prostate biopsy which can be performed under local anaesthesia and in an outpatient setting.

Genes associated with endolysosomal function have been recently associated with familial Parkinson's disease and described as risk factors for sporadic cases. This indicates that deficits in this pathway predispose to parkinsonism. To better understand the role of these genes in disease development, rodent models have been created by targeting genes playing a role in endolysosomal function, such as LRRK2, DNAJC6, SYNJ1, VPS35, GBA1, ATP13A2 and TMEM175. Here, we review the latest findings describing parkinsonian features in these animal models secondary to endolysosomal dysfunction. Also, we provide suggestions for further development and application of these animal models to better understand the contribution of endolysosomal dysfunction in Parkinson's disease and provide novel models for testing therapeutic approaches.

We investigated the glucose metabolism in an adeno-associated viral vector based alpha-synuclein rat model for Parkinson's disease (PD) using longitudinal 18F-FDG PET imaging, which resulted in an improved characterization of this animal model. We generated a PD specific pattern (PDSP) based on a multivariate classification approach to differentiate between a PD and control group at a late disease stage, where the neurodegeneration is considered nearly complete. In particular, we applied a principal component analysis prior to classification by a support vector machine (SVM). Moreover, by using a SVM for regression to predict corresponding motor scores, a PD motor pattern (PDMP) was derived as well. The PDSP mainly corresponds to the PDMP and overlaps to a large extent with the human pattern. We were able to quantify disease expression at previous time points by projecting onto the PDSP and PDMP. While a univariate analysis indicated metabolic changes which did not persist through time, both PDSP and PDMP were able to differentiate significantly (p-value

The transvaginal natural orifice transluminal endoscopic surgery (vNOTES) is a new minimally invasive and emerging technique. Feasibility and safety profiles of peritoneal access via transvaginal routes have been demonstrated especially for the adnexal surgery. In order to be reproducible and replicable with a standardized procedure, we propose the step-by-step video description of the vNOTES salpingectomy. The advantages of the vNOTES (low postoperative pain, faster postoperative recovery, scarless surgery) could lead to a promising alternative to conventional laparoscopic salpingectomy/adnexectomy.

Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) is a minimally invasive, scar-free technique that uses a vaginal colpotomy to access the peritoneal cavity. Hysterectomy via vNOTES has shown to be technically feasible and safe, with shorter hospital stay and lower postoperative pain scores. Moreover, vNOTES adds the advantages of endoscopy to those of vaginal surgery and thereby broadens the indications of a conventional vaginal hysterectomy. Virginity has been contraindicated for vNOTES so far, as vaginal accessibility can be severely reduced in virgin women. Therefore, cases of vNOTES hysterectomy in virgin patients have never been reported in the literature. The objective of this study is to assess the technical feasibility and safety of hysterectomy in virgin women. We performed a retrospective analysis of patient files of all vNOTES hysterectomies performed on virgin women in our centre (Imelda Hospital, Bonheiden, Belgium) from July 2016 until June 2020 (N = 9). Despite limited vaginal accessibility, vNOTES hysterectomy was successfully performed in all nine patients, without conversion to laparoscopy or laparotomy and without clinically relevant complications. In this first IDEAL stage 1 study, vaginal NOTES hysterectomy appears to be technically feasible and safe in virgin women.Impact statementWhat is already known on this subject? Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) is an emerging, minimally invasive technique that offers a safe alternative to laparoscopy and open surgery. Besides better cosmetics (scar-free technique), advantages of vNOTES hysterectomy include shorter hospital stay and less postoperative pain compared to laparoscopic hysterectomy. Moreover, vNOTES adds the benefits of endoscopy (visualisation of anatomy) to conventional vaginal hysterectomy. Virginity has been contraindicated for vNOTES so far, because the absence of uterine descent and narrow vagina in virgins is thought to complicate the vaginal approach. Therefore, vNOTES hysterectomy has never been reported in virgin patients.What do the results of this study add? In this study, we are the first to report the feasibility of performing a vNOTES hysterectomy in virgin patients. The results show that, in experienced hands, indications for vNOTES can be broadened and include virgin women.What are the implications of these findings for clinical practice and/or further research? This first report of vNOTES hysterectomy in virgin patients is only a small but important step in the evaluation of safety and efficacy of this emerging technique. Further research is needed to assess reproducibility of the findings and to carefully determine indications and contraindications of vNOTES.

Study Objective: Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is a novel minimal invasive surgical technique allowing a variety of gynecological procedures. The current literature describes improved patient comfort, improved better cosmetic results, and reduced operation time. This is a first study to assess pregnancy outcome after fertility-preserving vNOTES procedures. Design/Participants/Materials/Setting/Methods: We performed a retrospective observational cohort study including 125 patients under 43 years that underwent fertility-preserving vNOTES over a 5-year period (2014–2019). The gynecological surgical procedures included were vNOTES myomectomy, vNOTES salpingectomy for ectopic pregnancy, vNOTES unilateral adnexectomy, and vNOTES cystectomy. A total of 26 pregnancies in 21 cases were observed, with deliveries between 2015 and 2020. Results: Retrospective analysis in this patient group showed that 18 pregnancies were diagnosed within 1 year after vNOTES (85.7%). Mean interval between surgery and pregnancy was 6 months. Fertility treatment was performed in 28.6%. In the 26 observed pregnancies, no vNOTES-related complications were observed and delivery was at term in all cases. Mode of delivery was a vaginal delivery in twenty cases (76.9% of total) of which 2 cases vacuum assisted (7.7%) and a Caesarean section in 6 cases (23.1% of total). Two cases of trial of labor after Caesarean are described after vNOTES surgery, both ended in an uncomplicated vaginal delivery. In case of vaginal delivery, the perineum was intact in 15%, a mediolateral episiotomy was performed in 50 and 35% a grade 1–2 perineal rupture was described. No grade 3–4 perineal ruptures are described. Limitations: A limitation of this study is the retrospective design which does not correct for confounding factors. Further larger multicenter studies are needed to validate these data. Conclusions: This is the first study describing pregnancy outcome after fertility-preserving vNOTES procedures. vNOTES did not affect the mode of delivery or cause pregnancy-related complications. vNOTES did not increase the risk of extensive perineal tears during vaginal delivery. These preliminary data show no adverse events when vNOTES is performed in women of reproductive age. Posterior colpotomy as performed in all vNOTES procedures is by itself not an indication for an elective Caesarean section.

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This is a first feasibility on vaginal natural orifice transluminal endoscopic surgery (vNOTES) in patients with prior hysterectomy. Our aim was to gain initial experience on performing vNOTES surgery on prior hysterectomy cases, whereby the main concern is that pelvic adhesions may impede safe transvaginal access. Between January 2017 and February 2020, a single surgeon (J.B.) performed vNOTES surgery on nine patients with a history of hysterectomy. Conventional laparoscopic instruments were inserted transvaginally through a vNOTES port. No abdominal incisions were made. Patient data and perioperative data were analyzed. Mean operating time was 38 minutes and there were no operative complications. Postoperative pain scores were low. The mean size of the adnexal cysts that were removed was 26 mm. In this study, vNOTES surgery was successfully performed in nine patients with prior hysterectomy. Following the IDEAL principles, it is important to report on our initial findings of this IDEAL stage 1 study. The results warrant further investigation in IDEAL stage 2 studies but do not validate the widespread use of this approach.

Fibroblast activation protein-α (FAP) is a transmembrane peptidase and a surrogate marker for cancer-associated fibroblasts (CAFs). FAP has been linked to worse prognosis and therapy resistance in several cancers. We hypothesised that FAP might have a prognostic 3biomarker potential to stratify patients with high-grade (HG) T1 non-muscle-invasive bladder cancer (NMIBC). We selected 30 patients with HG T1 NMIBC that progressed to ≥T2 disease which were pair-matched based on CUETO progression score variables with 90 patients that did not progress. After revision a final cohort of 86 patients was retained. Slides were stained for FAP, the luminal marker GATA3 and the basal marker CK5. All HG T1 tumour regions of interest (ROIs) within each patient were annotated, analysed and scored using image analysis software. FAP expression in HG T1 ROIs was significantly higher in progressors vs. non-progressors and was prognostic for recurrence-free survival, progression-free survival, cancer-specific survival, and overall survival. FAP expression in HG T1 ROIs remained strongly prognostic for these outcomes in a bivariable model corrected for adequate BCG per FDA definition. Expression of GATA3 and CK5 did not differ between progressors vs. non-progressors, and were not prognostic for these outcomes. FAP might serve as an easily applicable prognostic biomarker to risk-stratify patients with HG T1 NMIBC if these results are prospectively validated in a larger series. ispartof: PLOS ONE vol:16 issue:9 ispartof: location:United States status: published

vNOTES or vaginal Natural Orifice Transluminal Endoscopic surgery is a new paradigm shift in gynaecological surgery. A first paradigm shift from conventional surgery into laparoscopic surgery was firstly observed in the 1980s and 1990s. vNOTES may represent a shift from 90° to parallel surgery. Almost all benign gynaecological operations can be performed via vNOTES. The chapter presents the technique of vNOTES along with results of various benign and mainly malignant cases. In parallel, the clinical approach of endometrial cancer is widely discussed.

OBJECTIVE: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. METHODS: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. RESULTS: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. SIGNIFICANCE: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy. ispartof: EPILEPSIA vol:62 issue:3 pages:659-670 ispartof: location:United States status: published

Hydropower plants (HPPs) are a source of “green” energy but also a threat to migrating fish such as the European eel (Anguilla anguilla) owing to the disruption of river connectivity and the obstruction of downstream migration. The impact of HPP are well-documented in terms of fish survival and damages but there is no available information concerning the condition of surviving and unharmed fish. The aim of this study is to assess the impact of the passage through HPP on the survival, the physiological and health status of adult eels. Two trials were carried with variants of the Kaplan turbine - one of the most common types in Europe. After a deliberate passage through the turbines, we studied direct mortality, external and internal damages, stress and immune biomarkers such as plasma cortisol and glucose levels, alternative complement (ACH50), lysozyme and peroxidase activities, and total immunoglobulin (Ig) content. Our results showed a lower survival and a higher external and internal damages rates in the HPP groups. Glucose levels, ACH50, lysozyme and peroxidase activities and TIgc were also affected by the passage depending on HPP characteristics. Those findings suggest a greater energy expenditure and a disruption in innate immunity due to this passage. HPPs can not only have an impact in terms of direct mortality and injuries but also affect the physiological and health condition of the surviving eels. This impact may explain the delayed mortality observed in telemetric studies and the passage through many HPPs may compromise the ability of adult eels to migrate successfully to the ocean.

ispartof: FUTURE SCIENCE OA vol:6 issue:7 ispartof: location:England status: published

Objectives: Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is an emerging minimally invasive technique in benign gynaecologic surgery whereby surgical access to the peritoneal cavity is achieved through natural orifices, namely through a vaginal colpotomy. Experience in repeat vNOTES cases is limited and so far, repeat vNOTES cases have not been described in the literature. The purpose of this study was to demonstrate the feasibility of vNOTES hysterectomy in women with a history of previous vNOTES adnexal surgery. Design: We performed a retrospective cohort study of the first 11 repeat vNOTES cases in our centre. All vNOTES procedures, primary adnexal surgery as well as repeat vNOTES hysterectomy, were performed by one surgeon (J.B.). Materials, Setting, Methods: Between March 2016 and May 2020, 11 patients underwent a vNOTES hysterectomy after prior vNOTES adnexectomy or cystectomy in Imelda Hospital, Bonheiden, Belgium. Relevant patient characteristics and outcome data were collected after written informed consent. Results: Median age was 49 years (range 44–65) at the moment of the first vNOTES procedure. Two patients had one or more caesarean sections in history, and 2 women were nulliparous. Median interval between primary and repeat vNOTES procedure was 15 months (range 0.8–37 months). All patients underwent a vaginally assisted NOTES hysterectomy (VANH) as repeat vNOTES procedure. Performing a colpotomy and entering the peritoneal cavity after prior vNOTES was technically feasible in all cases. All VANHs were successfully performed. There were 3 minor complications after repeat vNOTES, of which one was anaesthesia-related. The 2 complications associated with the surgical procedure were both cystitis. In one of these 2 patients, there were high post-void residues, which were easily managed by bladder training. There were no conversions to laparoscopy or laparotomy, neither serious nor life-threatening complications. No ureteric, bladder, or intestinal injuries have occurred. Limitations: The retrospective design and small sample size are the main limitations of this study. Moreover, the follow-up period of the most recently operated patients was too short to draw conclusions on long-term outcomes, including sexual function. Conclusions: In all patients in this case series, vNOTES hysterectomy after prior vNOTES adnexal surgery was successfully performed. Large-scale prospective trials with long-term follow-up are needed to evaluate the safety and feasibility of multiple consecutive vNOTES procedures in 1 patient.

Background Despite being the most frequent renal fusion anomaly, tumors arising from horseshoe kidneys (HSKs) are extremely rare and management guidance is lacking. Objective To evaluate the perioperative, oncological, and functional outcomes of surgically treated HSK tumors. Design, setting, and participants A retrospective, multicenter cohort study of 43 HSK tumors in 40 patients was conducted, and technical description of the surgical approach has been provided. Surgical procedure Surgical resection of renal tumors arising from HSKs was performed either via open surgery or via minimally invasive surgery (MIS). Measurements We analyzed patient and tumor characteristics as well as surgical technique, and functional and oncological outcomes. Results and limitations Eight patients were treated by MIS and 32 by open surgery. One patient (2.5%) experienced an intraoperative complication and 13 patients (32.5%) experienced postoperative complications, of which three (7.5%) were Clavien-Dindo ≥3 complications. Surgical margins were positive in two tumors (4.7%). The most frequent histology was clear-cell renal cell carcinoma (46.5%). The median follow-up was 51 (interquartile range [IQR] 17–73) mo. The 5-yr overall, cancer-specific, and recurrence-free survival rates were 81.2%, 86.8%, and 83.1%, respectively. The percent decreases in estimated glomerular filtration rate at discharge and the last follow-up were 15% (IQR 4–26%) and 17% (IQR 1–31%), respectively. Limitations include the cohort's retrospective nature, heterogeneity, and small sample size. Conclusions Surgical management of tumors in HSKs can be approached via both open surgery and MIS, with maximal preservation of functional renal parenchyma. In this cohort, rates of complications, positive surgical margins, and renal functional decrease were acceptable, considering the anatomical complexity of these kidneys and tumors. These tumors display great variation in histological subtypes. Meticulous presurgical planning, taking advantage of advanced imaging techniques, can aid in achieving good outcomes. Patient summary We evaluated the surgical management of renal tumors in horseshoe kidneys, which are very rare. Although these procedures are highly complex, outcomes are acceptable. Modern imaging techniques are often required in presurgical planning.

Study Objective To evaluate the outcome of hysterectomy through vaginal natural orifice transluminal endoscopic surgery (vNOTES) in cases with a large uterus. Design A retrospective cohort study. Setting Belgian teaching hospital. Patients Women who underwent a vNOTES hysterectomy from March 2015 to March 2020 for benign gynecologic disease with a uterine weight of 280 g or more on pathologic examination (N = 114). Interventions All women underwent vaginally assisted NOTES hysterectomy. We performed a retrospective analysis of baseline patient characteristics and clinical outcomes. Measurements and Main Results The mean age was 50 ± 3.5 years. Twenty-two (19%) patients were obese (body mass index ≥30 kg/m2), and 4 (3.5%) were morbidly obese (body mass index ≥40 kg/m2). Thirty-five (31%) patients were nulliparous, and 15 (13%) women had 1 or more cesarean sections in their medical history. Uterine weight varied from 281 g to 3361 g, with a mean weight of 559 ± 425 g. Mean surgical time was 63 ± 34 minutes. Surgical time was positively associated with uterine size. There were 4 complications: 3 bleeding complications in the first 24 hours after surgery and 1 minor late complication. Conversion to laparotomy for specimen extraction was performed in 1 case (conversion rate 0.9%). There were no conversions to laparoscopy. No ureteric, bladder, or intestinal injuries occurred in this case series, and there were neither life-threatening complications nor intensive care unit admissions. Conclusion The vNOTES technique can offer a safe and effective alternative to laparoscopy or laparotomy in cases with a large to very large uterus, even if the patient has a history of cesarean section, obesity, or nulliparity. In 99% of all women in this study, hysterectomy was successfully performed through vNOTES without conversion. By making use of the advantages of endoscopic surgery, vNOTES might broaden the indications of vaginal hysterectomy. Randomized controlled trials are needed to evaluate whether vaginally assisted NOTES hysterectomy is superior to laparoscopic or abdominal hysterectomy in large uteri cases.

Parkinson’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver. Electronic supplementary material The online version of this article (10.1007/s00401-020-02145-7) contains supplementary material, which is available to authorized users.

The multiple hit hypothesis for Parkinson's disease (PD) suggests that an interaction between multiple (genetic and/or environmental) risk factors is needed to trigger the pathology. Leucine-Rich Repeat Kinase 2 (LRRK2) is an interesting protein to study in this context and is the focus of this review. More than 15 years of intensive research have identified several cellular pathways in which LRRK2 is involved, yet its exact physiological role or contribution to PD is not completely understood. Pathogenic mutations in LRRK2 are the most common genetic cause of PD but most likely require additional triggers to develop PD, as suggested by the reduced penetrance of the LRRK2 G2019S mutation. LRRK2 expression is high in immune cells such as monocytes, neutrophils, or dendritic cells, compared to neurons or glial cells and evidence for a role of LRRK2 in the immune system is emerging. This has led to the hypothesis that an inflammatory trigger is needed for pathogenic LRRK2 mutations to induce a PD phenotype. In this review, we will discuss the link between LRRK2 and inflammation and how this could play an active role in PD etiology. ispartof: Frontiers In Neuroscience vol:14 ispartof: location:Switzerland status: published

Depending on how the future will unfold, today’s progress in biotechnology research has greater or lesser potential to be the basis of subsequent innovation. Tracking progress against indicators for different future scenarios will help to focus, emphasize, or de-emphasize discovery research in a timely manner and to maximize the chance for successful innovation. In this paper, we show how learning scenarios with a 2050 time horizon help to recognize the implications of political and societal developments on the innovation potential of ongoing biotechnological research. We also propose a model to further increase open innovation between academia and the biotechnology value chain to help fundamental research explore discovery fields that have a greater chance to be valuable for applied research., Highlights Identifying most relevant social, economic, and technological trends can help us understand in which direction future worlds could develop. Extrapolating long-term impact of current developments on the way we live may open avenues of biotechnology discovery research that would provide the starting basis for research and innovation addressing future needs. Maximizing innovation output in biotechnology requires a continuous cross-stakeholder interaction to timely share know–how obtained from discovery research in formats tailored to stakeholder use requirements

OBJECTIVE: To compare hysterectomy by transvaginal natural orifice transluminal endoscopic surgery (vNOTES) versus total laparoscopic hysterectomy (TLH) as a day-care procedure. DESIGN: Parallel group, 1:1 randomised single-centre single-blinded trial, designed as a non-inferiority study with a margin of 15%. SETTING: Belgian teaching hospital. POPULATION: Women aged 18-70 years scheduled to undergo hysterectomy for benign indications. METHODS: Randomisation to TLH (control group) or vNOTES (experimental group). Stratification according to uterine volume. Blinding of participants and outcome assessors. MAIN OUTCOME MEASURES: The primary outcome was hysterectomy by the allocated technique. We measured the proportion of women leaving within 12 hours after hysterectomy and the length of hospital stay as secondary outcomes. RESULTS: We randomly assigned 70 women to vNOTES (n = 35) or TLH (n = 35). The primary endpoint was always reached in both groups: there were no conversions. We performed a sensitivity analysis for the primary outcome, assuming one conversion in the vNOTES group and no conversions in the TLH group: the one-sided 95% upper limit for the differences in proportions of conversion was estimated as 7.5%, which is below the predefined non-inferiority margin. More women left the hospital within 12 hours after surgery after vNOTES: 77 versus 43%, difference 34% (95% CI 13-56%), P = 0.007. The hospital stay was shorter after vNOTES: 0.8 versus 1.3 days, mean difference -0.5 days, (95% CI -0.98 to -0.02), P = 0.004. CONCLUSIONS: vNOTES is non-inferior to TLH for successfully performing hysterectomy without conversion. Compared with TLH, vNOTES may allow more women to be treated in a day-care setting. TWEETABLE ABSTRACT: RCT: vNOTES is just as good as laparoscopy for successful hysterectomy without conversion but allows more day-care surgery. ispartof: BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY vol:126 issue:1 pages:105-113 ispartof: location:England status: published

Study Objective We aimed to report an update of the systematic review and meta-analysis published in 2016, comparing hysterectomy by vaginal natural orifice transluminal endoscopic surgery (vNOTES) to the laparoscopic approach for benign indications. Design This was a systematic review and meta-analysis. We searched MEDLINE, EMBASE, CENTRAL and additional sources and aimed to retrieve randomised controlled trials (RCTs), controlled clinical trials (CCTs) and prospective/retrospective cohort studies in human subjects that allowed direct comparison of vNOTES to laparoscopy. Primary outcome was the proportion of women successfully treated with the intended approach to perform hysterectomy without conversion to any other technique. Setting N/A. Patients or Participants We included studies in the adult female population, undergoing removal of the uterus for benign gynecological disease. Studies on interventions for genital prolapse or gynecological malignancy were excluded. Interventions N/A. Measurements and Main Results Our search yielded one RCT and five retrospective cohort trials. Pooled analysis of two subgroups showed that, compared to conventional laparoscopy, vNOTES is equally effective to successfully remove the uterus in individuals meeting the inclusion criteria. vNOTES had significantly lower values for operation time, length of stay and estimated blood loss. There was no significant difference in intra-operative and post-operative complications, readmission, pain scores at 24 hours post-operative and change in haemoglobin on day 1 post-operative. Conclusion The available randomised and observational data show that vNOTES hysterectomy is an effective and safe novel technique for women eligible for endoscopic surgery.

The molecular first hyperpolarizability (β) of bacteriorhodopsin was measured over a broad spectral range (800–1300 nm) by means of a spectral hyper-Rayleigh scattering setup. We observed that two-photon fluorescence introduced a systematic error toward overestimating the β value. Spectrally resolved hyper-Rayleigh scattering allowed us to quantify and correct for this effect, resulting in a drop to about one-half of the β value reported in the literature. Moreover, we determined the dispersion of β over the wavelength range between 800 and 1300 nm. Applications such as second harmonic generation (SHG) imaging rely on accurate molecular first hyperpolarizability values, along with information about resonance effects and wavelength-dependent photodamage. With new and more accurate measurement setups, it will be possible to gain more insight into the nonlinear optical response of bacteriorhodopsin.

This study aims to demonstrate the feasibility of a frugal approach to an endoscopic hysterectomy: the iHysterectomy. An iPhone with endoscope-i adaptor and a portable light source were used instead of a laparoscopic camera, video processor, monitor and light source. A vaginally assisted natural orifice transluminal endoscopic surgery (NOTES) hysterectomy (VANH) was performed by Poor Man9s NOTES technique using a self-constructed glove port and standard reusable instruments. Ten iHysterectomies were successfully performed by a single surgeon (JBa). No conversion to a laparoscopic tower, standard multi incision laparoscopy, or laparotomy was necessary. Mean operation time was 52 min (40–75); mean serum haemoglobin drop was 0.8 g/dL (0.2–2.1). There were no operative complications, and postoperative pain scores were low. The iHysterectomy technique enables surgeons to perform a minimally invasive hysterectomy in a low-resource setting without the need to invest in a laparoscopic tower. The investment required for endoscopic hardware is a fraction of that for conventional laparoscopy or robotic surgery. This is an Idea Development Exploration Assessment Long-term (IDEAL) stage 1 study: iHysterectomy is a novel approach requiring further validation. This is the first report on the use of an iPhone to perform a hysterectomy or any other major operation.

WOS: 000504278000001, PubMed: 31921659, Purpose: To develop a prospective non-muscle-invasive bladder cancer (NMIBC) data registry by generating NMIBC-specific electronic case report forms (eCRFs) in our institution's electronic patient file system, and to report on the development and implementation of a prospective multicentric registry. Methods: Templates for data collection, including clinical outcome parameters and quality indicators, were developed in InfoPath (TM) as an eCRF and were incorporated in our hospital's electronic patient file system. Quality parameters for managing NMIBC patients that were identified by comprehensive literature review were included in the eCRFs. Three separate eCRFs were developed for the management of NMIBC patients: surgery report, bladder instillation form, and multidisciplinary team form. Results: In August 2013, we started a Flemish prospective clinical and pathological data registry for all patients undergoing transurethral resection of bladder tumor (TURBT) for NMIBC in four participating hospitals, three of which continued using this to date. Three more hospitals started enrolling in 2017, 2018, and 2019, respectively. Written reports of the registered clinical actions are automatically generated within the electronic medical file. When urologists complete these eCRFs, an automated ready-to-send letter to the general practitioner is generated. Up till May 2019, 2,756 TURBTs in 2,419 patients are included in the dataset. Currently, we are recruiting over 600 TURBTs every year. Conclusions: Easy-to-use eCRFs were developed and included in the electronic patient file system. This registration tool was implemented in 7 hospitals, 6 of which are still using it today. The register harvests important clinical data, while performing routine clinical practice. The data will be used to analyze real-life data of NMIBC patients, to challenge the existing guidelines, to create novel risk stratification tools, and to develop, monitor and validate quality parameters for NMIBC management.

Objective: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. Methods: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. Results: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. Significance: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Adult hippocampal neurogenesis plays a critical role in a wide spectrum of hippocampus-dependent functions. Brain pathologies that involve the hippocampus like epilepsy, stroke, and traumatic brain injury, are commonly associated with cognitive impairments and mood disorders. These insults can affect neural stem cells and the subsequent neurogenic cascade in the hippocampus, resulting in the induction of aberrant neurogenesis, which is thought to compromise hippocampal network function, thereby hampering hippocampus-dependent behavior. We here summarize recent preclinical literature on hippocampal insult-induced changes in neurogenesis and based on that, we propose that normalizing aberrant neurogenesis post-insult may help to prevent or rescue behavioral deficits which could help develop novel therapeutic strategies.

Rat models based on viral vector-mediated overexpression of α-synuclein are regarded as highly valuable models that closely mimic cardinal features of human Parkinson's disease (PD) such as L-DOPA-dependent motor impairment, dopaminergic neurodegeneration and α-synuclein inclusions. To date, the downstream effects of dopaminergic cell loss on brain glucose metabolism, including the neuroinflammation component, have not been phenotyped in detail for this model. Cerebral glucose metabolism was monitored throughout different stages of the disease using in vivo 2-[18F]-fluoro-2-deoxy- d -glucose ([18F]FDG) positron emission tomography (PET) and was combined with in vitro [18F]DPA-714 autoradiography to assess concomitant inflammation. Rats were unilaterally injected with recombinant adeno-associated viral vector serotype 2/7 (rAAV2/7) encoding either A53T α-synuclein or eGFP. Brain [18F]FDG microPET was performed at baseline, 1, 2, 3, 4, 6, and 9 weeks post-surgery, in combination with behavioral tests. As a second experiment, [18F]DPA-714 autoradiography was executed across the same timeline. Voxel-based analysis of relative [18F]FDG uptake showed a dynamic pattern of PD-related metabolic changes throughout the disease progression (weeks 2–9). Glucose hypermetabolism covering a large bilateral area reaching from the insular, motor- and somatosensory cortex to the striatum was observed at week 2. At week 4, hypermetabolism presented in a cluster covering the ipsilateral nigra-thalamic region, whereas hypometabolism was noted in the ipsilateral striatum at week 6. Elevated [18F]FDG uptake was seen in a cluster extending across the contralateral striatum, motor- and somatosensory cortex at week 9. Increased [18F]FDG in the region of the substantia nigra was associated with increased [18F]DPA-714 binding, and correlated significantly with motor symptoms. These findings point to disease-associated metabolic and neuroinflammatory changes taking place in the primary area of dopaminergic neurodegeneration but also closely interconnected motor and somatosensory brain regions.

Innate immune activation and chronic neuroinflammation are characteristic features of many neurodegenerative diseases including Parkinson´s disease (PD) and may contribute to the pathophysiology of the disease. The discovery of misfolded alpha-synuclein (αSYN) protein aggregates, which amplify in a ?prion-like? fashion, has led us to consider that pathogenic αSYN might be hijacking the activation and mobilization mechanism of the peripheral immune system to reach and disseminate within the CNS. Furthermore, our lab and other groups have recently shown that αSYN can adopt distinct fibril conformations or ?strains? with varying levels of pathogenic impact. Therefore, the aim of this study was to assess the impact of peripheral inflammation on αSYN spreading in order to better understand the participation of the immune system in the progression of PD. The results presented here show that intraperitoneal LPS injection prior to systemic intravenous recombinant administration of two different αSYN pathogenic strains (fibrils or ribbons) in wild type mice, induces an increase in brain resident microglia and promotes the recruitment of leukocytes toward the brain and the spinal cord. Our findings show for the first time that αSYN can be internalized by LPS-primed inflammatory monocytes, which in turn favors the dissemination from the periphery toward the brain and spinal cord. Further, we found a differential recruitment of CD4+ and CD8+ T cells after LPS priming and subsequent administration of the αSYN ribbons strain. Together, these data argue for a role of the peripheral immune system in αSYN pathology. Fil: Peralta Ramos, Javier María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Bousset, Luc. Institut François Jacob; Francia Fil: Melki, Ronald. Institut François Jacob; Francia Fil: Baekelandt, Veerle. Katholikie Universiteit Leuven; Bélgica Fil: Van der Perren, Anke. Katholikie Universiteit Leuven; Bélgica

Aggregation of alpha-synuclein (α-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson's disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, α-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an α-SYN-based rat model for PD using chemogenetics. To do this, we expressed excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) combined with mutant A53T α-SYN, using two different recombinant adeno-associated viral (rAAV) vectors (serotypes 2/7 and 2/8) in rat substantia nigra (SN) and investigated the effect on motor behavior, synapses and neuropathology. We found that chronic neuromodulation aggravates motor deficits induced by α-SYN, without altering dopaminergic neurodegeneration. In addition, neuronal activation led to changes in post-translational modification and subcellular localization of α-SYN, linking neuronal activity to the pathophysiological role of α-SYN in PD. This work was supported by the FWO Flanders (Projects G.0927.14, G080517 N, PhD fellowship to Teresa Torre-Muruzabal and postdoctoral fellowship to Anke Van der Perren), the KU Leuven (OT/14/120, C14/18/102), the ERA-NET JPco-fuND 2015 SYNACTION, and the Medical Foundation Queen Elisabeth.

Background/Objective Pancreatic Cancer Disease Impact (PACADI) score measures the impact of pancreatic cancer (PC) on important health dimensions, selected by patients. The aim of this single center study was to test the psychometric performance of the Pancreatic Cancer Disease Impact (PACADI) score. Methods Patients with suspected pancreatic cancer (PC) completed PACADI, the EuroQol-5D (EQ-5D index) and Edmonton Symptom Assessment System (ESAS) in this longitudinal observational study. Measures were compared across patients with PC (n = 210), other malignant lesions (OML) (n = 109) and non-malignant lesions (NML) (n = 41). Associations, test-retest and internal consistency reliability, longitudinal changes, sensitivity to change and prediction of mortality during the first year were examined in patients with PC. Results The three measures discriminated between PC and OML. The PACADI score correlated strongly at baseline (n = 199)/after three months (n = 85) with the EQ-5D index and ESAS “sense of well-being” (0.64 and 0.66/0.73 and 0.69, p

The phenylpropanoid cis-cinnamic acid stimulates the overall growth of different plant species. The trans-isomer is inactive when used at equimolar concentrations., Agrochemicals provide vast potential to improve plant productivity, because they are easy to implement at low cost while not being restricted by species barriers as compared with breeding strategies. Despite the general interest, only a few compounds with growth-promoting activity have been described so far. Here, we add cis-cinnamic acid (c-CA) to the small portfolio of existing plant growth stimulators. When applied at low micromolar concentrations to Arabidopsis roots, c-CA stimulates both cell division and cell expansion in leaves. Our data support a model explaining the increase in shoot biomass as the consequence of a larger root system, which allows the plant to explore larger areas for resources. The requirement of the cis-configuration for the growth-promoting activity of CA was validated by implementing stable structural analogs of both cis- and trans-CA in this study. In a complementary approach, we used specific light conditions to prevent cis/trans-isomerization of CA during the experiment. In both cases, the cis-form stimulated plant growth, whereas the trans-form was inactive. Based on these data, we conclude that c-CA is an appealing lead compound representing a novel class of growth-promoting agrochemicals. Unraveling the underlying molecular mechanism could lead to the development of innovative strategies for boosting plant biomass.