Courtenay, France

Efficacy and Safety of KBP-336 in Obese Individuals with Osteoarthritis

Pulmonary Vein Isolation with the Single Shot Endoscopic Ultra-Compliant PFA Balloon for the Treatment of AF

This is a prospective, single-arm First-in-Human study to demonstrate the safety and effectiveness of the CardioFocus OptiShot Pulsed Field Ablation System for catheter ablation of atrial fibrillation (AF). Patients with symptomatic paroxysmal AF who are undergoing first-time pulmonary vein isolation will be considered for the study. Patients will be followed for one year after the initial ablation procedure.

The Role of Sugars in Fat Accumulation in the Liver

1. INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease, it affects approximately one-quarter of the global population and the incidence of the disease is still rising (doi: 10.1210/endrev/bnz009). The occurrence of NAFLD is tightly associated with the obesity, insulin resistance and/or type 2 diabetes (doi: 10.7759/cureus.20776). Some authors even consider NAFLD to be hepatic manifestation of metabolic syndrome or even the precursor of metabolic syndrome development (doi: 10.1016/j.dld.2014.09.020). The growing incidence of NAFLD has been attributed to sedentary life-style, energy intake inadequate to energy expenditure and also to increased intake of simple carbohydrates (added sugars), and specifically, increased intake of fructose (both as a part of sucrose molecule and also, especially in the United States (US), as a component of high-fructose corn syrup (HFCS)). Over the last decades, a number of papers have been presented which have shown a link between increased consumption of added sugars (especially of fructose) and the obesity and insulin resistance pandemic (doi: 10.1097/MOL.0b013e3283613bca, doi: 10.1007/s00394-018-1711-4, doi: 10.1016/j.nut.2013.08.014). However, recent meta-analyses have not supported the role of increased added sugar or fructose intake in development of obesity, insulin resistance, metabolic syndrome and type 2 diabetes (doi: 10.1017/S0954422414000067, doi: 10.1007/s00394-016-1345-3). They rather suggest that the added sugars are detrimental if associated with inadequately increased energy intake. It was even suggested that increased fructose/added sugars consumption may be a marker of unhealthy life-style. On the other hand, not so many data are available with respect to the role of added sugars and, specifically, fructose, in the development of fatty liver. This may be due to the fact that the metabolism of glucose and fructose metabolism in the liver is fundamentally different (doi: 10.1016/j.jada.2010.06.008, doi: 10.3390/nu9091026, doi: 10.1016/j.clnu.2020.12.022). Contrary to glucose, which is largely metabolized by extrahepatic tissues, most of fructose is directly uptaken and metabolized by the liver. Moreover, phosphorylation of fructose to fructose-1-phosphate catalyzed by fructokinase/ketohexokinase is not under any feedback control and results in uncontrolled production of trioso-3-phosphates. These can enter gluconeogenesis pathway and be further used to replete glycogen (in state of glycogen depletion) but they can also provide a substrate for de novo lipogenesis (DNL) and, at the same time, inhibit fatty acid oxidation. Fructose seems to be also a potent activator of carbohydrate-responsive element-binding protein (ChREBP) regulatory pathway that together with sterol regulatory element-binding protein (SREBP) promotes DNL in the liver. Importantly, in spite of the fact that fatty acids released from adiposse tissue are the major source of the liver fat, the contribution of DNL to liver fat accumulation significantly increases specifically in patients with NAFLD (doi: 10.1172/JCI23621, doi: 10.1053/j.gastro.2013.11.049). Studies looking at the effect of fructose consumption on hepatic fat content (HFC) have not reach a clear conclusion. In healthy subjects, fructose administration under isocaloric conditions does not seem to have any impact on HFC (doi: 10.1093/ajcn/84.6.1374, doi: 10.1093/ajcn/nqz271). Fat accumulated in the livers of healthy subjects only when exposed to a hypercaloric high-fructose diet (doi: 10.3945/ajcn.2008.27336). On the contrary, abdominally obese men accumulated more fat in the liver even on an isocaloric high-fructose diet (doi: 10.1111/joim.12632). Interestingly, in the study comparing a high-glucose and high-fructose diet under both iso- and hypercaloric conditions, overweight men accumulated liver fat in the liver only under hypercaloric conditions but no difference in the effect on HFC was found between glucose and fructose (doi: 10.1053/j.gastro.2013.07.012). 2. PILOT DATA Glucose and fructose can have different effects in the accumulation of fat in the liver which we have demonstrated in our studies of acute changes of HFC after nutrient administration (doi: 10.1093/ajcn/nqy386, doi: 10.26402/jpp.2021.1.05). In these studies we developed and introduced a functional test that allowed us to monitor acute changes in hepatic fat after a challenge with high-fat and/or simple carbohydrate load. In the test, the 150 g of fat is administered to subjects at the beginning of experiment, whereas carbohydrates (50 g of fructose or glucose) are administered every 2 hours to efficiently suppress the lipolysis in adipose tissue as documented by suppression of non-esterified fatty acids (NEFA) concentration (doi: 10.1093/ajcn/nqy386). In this way we can limit the impact of fatty acids from the adipose tissue on accumulation of hepatic fat and the resulting changes should be explained by contribution of dietary fat or DNL. Importantly, in this model we have shown that 6 hours after consumption of 150 g of fat (cream), HFC increases in both healthy non-obese subjects with normal fat content (doi: 10.1093/ajcn/nqy386) and also in non-obese subjects with hepatosteatosis (doi: 10.26402/jpp.2021.1.05). Liver fat increases also when fructose is co-administered with fat. On the contrary, glucose co-administration with fat prevents such an increase in HFC (doi: 10.1093/ajcn/nqy386, doi: 10.26402/jpp.2021.1.05). 3. THE RATIONALE OF THE PROJECT The added sugars represent more than 12% of daily energy intake. Their role in accumulation of liver fat has been studied so far with pure glucose or pure fructose. However, in real life people do not consume pure glucose or fructose, they consume fructose together with glucose both as a part of sucrose or in high-fructose corn syrup. It is not entirely clear how the hepatic fat content will respond to the mixture of both sugars. The question how concurrent consumption of both hexoses affect the accumulation of fat in the liver may be of great practical significance and answering this question might greatly contribute to the modification of dietary recommendations for NAFLD treatment. Importantly, as we were unable to demonstrate the difference between the response of HFC to glucose and fructose administration in non-obese non-diabetic subjects (doi: 10.26402/jpp.2021.1.05), it would be preferable to study the acute effects of these three sugars on HFC after their co-administration with high-fat load. The number of studies clearly documented adverse effects of excessive fructose consumption on metabolic health. On the other hand, if fructose does harm human health, it would be important to know whether fructose restriction has an effect on HFC. Indeed, fructose restriction led to a significant reduction in liver fat after 9 days in obese children (doi: 10.1053/j.gastro.2017.05.043) and after 6 weeks in obese individuals (doi: 10.1093/ajcn/nqaa332). Based on our previous results, it can be hypothesized that eliminating fructose from the diet and replacing it by starch or glucose should effectively suppress hepatic fat content even in a few days. 4. HYPOTHESES Two principal hypotheses will be tested: - The increase of hepatic fat content after high-fat load is blunted by glucose but not fructose neither sucrose (Part A of the project). - The short-term (7 days) dietary fructose restriction results in a decrease of hepatic fat content (Part B of the project) 5. EXPERIMENTAL DESIGN Part A The design of this part of the study will be the same as that in our previous studies (doi: 10.1093/ajcn/nqy386, doi: 10.26402/jpp.2021.1.05) except that only two measurements of hepatic fat content (HFC) by magnetic resonance spectroscopy (MRS) will be carried out during each experiment. The three examinations lasting approximately 8 hours will be carried out in each subject in the study. First, hepatic fat content (HFC) will be measured using MRS (30-45 mins). The cannula will be then inserted into the antecubital vein and the first blood draw will be carried out. The subjects will then receive 460 ml of cream (high fat load - 150g of fat in total) with fruit tea sweetened with 50 g of one of the sugars (glucose/fructose/sucrose). Two and four hours later they will receive again fruit tea sweetened with the same sugar as at time 0 h. The blood for biochemical analyses will be then taken at 0.5, 1, 2 (before tea), 2.5, 3, 4 (before tea), 4.5, 5 and 6 hours. During the day, the subjects will not receive any food and they will be allowed to drink only water or fruit tea. The measurement of hepatic fat content will be repeated at time 6 hours. During magnetic resonance (MR) examination the volume of visceral fat will be also measured and body composition will be determined. The order of examinations will be randomized and they will be carried out in at least two-week intervals. Subjects: Two groups of male volunteers will be studied in this part of the project - 15 nonobese subjects (Body Mass Index (BMI) < 30 kg/m2) and 15 obese subjects (BMI ˃ 30 kg/m2). The subjects will be 18 - 70 years old and groups will be age-matched. Based on our previous studies with healthy male subjects the number of 13 subjects in one group should be sufficient to detect 10 ± 10% increment in HFC after the fat load at α = 0.05 (two-tailed paired t-test) and β = 0.10. The slightly higher number per group covers the risks associated with the exclusion or withdrawal of some subjects during the study. The exclusion criteria for both groups will be diabetes mellitus (fasting glucose above 7 mmol/l, 2-hour glucose after oGTT ˃ 11.1 mmol/l, or antidiabetic treatment) or other serious illnesses (cardiovascular disease, cancer, etc.), alcohol consumption ˃ 30 g/day, fructose intolerance, use of drugs affecting lipid metabolism and intolerance of MR examination (claustrophobia, metal implants, etc.). Before the entry into the study, subjects will sign the informed consents with participation in the study and genetic tests and before each experiment they will sign the informed consent with MR examination. Part B Subjects selected for this part of the study will first complete a detailed three-day dietary record allowing us to quantify their fructose consumption among other things. They will then be instructed in detail how to change their diet to eliminate fructose and receive these recommendations also in writing. On the first day of the seven-day dietary intervention, they will have fasting blood drawn and then the hepatic fat content will be measured by MRS. After that they will receive a package of glucose and selected foods without fructose to supplement their diet. For seven days they then will adhere to the diet without fructose and keep the detailed dietary record. On the last day of the intervention, they will have fasting blood drawn and HFC measured by MRS again (after 168 hours exactly). Subjects: Fifteen subjects 18 to 70 years old will be included in the study. Similarly as in Part A, such a number of subjects is slightly higher than 13 - a number sufficient to detect 10 ± 10% decrease in HFC at α = 0.05 (two-tailed paired t-test) and β = 0.10. To be included, the hepatic fat content in the subjects must be higher than 6.2% and less than 16.5% which corresponds to steatosis grade 2 (doi: 10.1007/s10334-011-0264-9). The participants of Part A of the study meeting this criterion can be also included in Part B. The exclusion criteria will be the same as in Part A. Before the entry into the study, subjects will sign the informed consents with participation in the study and genetic tests and before each experiment they will sign the informed consent with MR examination. 6. METHODS MR spectroscopy (MRS). Standard single voxel spectroscopy sequence with breath holding (3 Tesla VIDA Siemens magnetic resonance (MR) system equipped with multi-channel surface body coil) will be used to measure hepatic fat content (HFC). MR images in three anatomical orientations will be used to set the volume of interest of 40x30x25 mm. The correction of signal intensities to T2 relaxation will be done. To get information about lipid profile of the liver triglycerides (TG) the MRS spectra will be analyzed as described earlier (doi: 10.3390/metabo11090625.). HISTO MR imaging (MRI). Proton Density Fat Fraction (PDFF) imaging will be measured by HISTO Siemens protocol approved by Food and Drug Administration (FDA). It includes spectroscopic, Dixon and multiecho Dixon sequences. Data evaluation. MR spectra will be evaluated using the LCModel (doi: 10.1002/nbm.698) and percentage of HFC assessed by MRS will be calculated according to Longo (doi: 10.1002/jmri.1880050311). Visceral fat content measurement by MR imaging. The content of visceral fat will be measured by turbo spin echo sequence before or after PDFF measurement. To evaluate the volume of visceral and subcutaneous fat software written in MATLAB will be used. To reduce the impact of the operator, visceral fat areas will be evaluated by two independent experts. Body composition. The body composition during the screening will be determined using InBody. Biochemical analysis. The blood will be collected into tubes containing all necessary inhibitors, immediately placed on the ice and centrifuged to collect plasma within 15 min. Glucose, triglyceride (TG), non-esterified fatty acids (NEFA), insulin, and β-hydroxybutyrate will be measured in all the samples obtained in the study. All the necessary biochemical, Radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) methods for determination of these parameters are currently in use in the laboratories of applicants. Lipidomics. The VLDL will be isolated by ultracentrifugation, and the analysis of fatty acid profile of VLDL-triglycerides and plasma free fatty acids will be carried out by liquid chromatography - mass spectrometry (LC-MS) in Metabolomics department of Institute of Physiology, Czech Academy of Sciences (paid service). Genetics. The polymorphisms of genes (PNPLA, TM6SF2, and others) known to affect accumulation of liver fat will be determined. Statistics. Statistical data analysis and correlations will be performed with PRISM 9.1 or JMP software. 7. TIME SCHEDULE OF THE PROJECT 2024: Part A: Preparation of study protocols, search and screening of subjects, start of the study examinations in first subjects - approximately 20 whole-day examinations will be carried out of 90 examinations total (3 examinations per each of 30 subjects). The number of subjects that can be studied is limited by the availability of MR tomograph for research studies (1 day a week) and complexity of examinations. Basic biochemical analyses will be carried out continuously but all the samples from each subject (30 total) will be stored at -80°C and analyzed simultaneously. Part B: Preparation of study protocols and dietary records that can be used for quantification of fructose consumption. Search and screening of subjects. 2025: Part A: Screening of subjects, study examinations - min. 30 whole-day examinations will be carried out. Continuation of biochemical analyses. Part B: Screening of subjects (subjects with hepatosteatosis studied in Part A can be also included in Part B). Dietary intervention experiments (approx. n=20) in approx. 10 subjects (1 subject a week can be intervened, including MR examination and overnight isolation of VLDL on the first and the last day of intervention). Biochemical analyses. 2026: Part A: Screening of subjects, study examinations - min. 30 whole-day examinations will be carried out. Continuation of biochemical analyses. Start of intensive data analysis. Part B: Screening of subjects. Dietary intervention experiments (n = 10) in remaining subjects on the first and the last day of intervention. Biochemical analyses. Specialized biochemical analyses (for example, ELISA for fibroblast rowth factor 19 (FGF-19), selected hepatokines or other proteins that can be involved in regulation of de novo lipogenesis) and lipidomic analysis of fatty acid profile in free fatty acid (FFA) pool and TG in VLDL. Analysis of the data and publication of results. 2027: Part A: Study examinations in remaining subjects - max. 10 whole-day examinations will be carried out. Continuation of routine biochemical analyses. Specialized biochemical analyses (see above). Analysis of the data and publication of results. Part B: Final analysis of the data and publication of results. 8. ANTICIPATED RESULTS This project will provide new insights into the mechanisms by which simple carbohydrates affect the accumulation of liver fat. Of particular importance will be comparison the role of fructose and glucose (which are intensively studied but not used by population) and that of sucrose, the sugar generally used to sweeten by the whole population. Moreover, the experiment with fructose restriction from the diet should determine whether such an intervention can be useful for treatment of hepatosteatosis. On the whole, both parts of the projects should provide the results that can be implemented in practical dietary recommendations and improve the strategies for management of NAFLD.

A Stepped Wedge Cluster Randomised Trial of Video Versus Direct Laryngoscopy for Intubation of Newborn Infants

INTRODUCTION Many newborn infants have difficulty breathing after birth. Some of these babies have a tube inserted into their "windpipe" (trachea) - an endotracheal tube (ETT) - through which they are given breathing support (ventilation). When clinicians attempt to intubate (insert an ETT), they use an instrument called a laryngoscope to view the airway in order to identify the entrance to the trachea (larynx). Standard laryngoscopes have a "blade" (which, despite its name, is not sharp) with a light at the tip. Doctors insert the blade into the baby's mouth to view the larynx. Traditionally, clinicians used a standard laryngoscope to look directly into the baby's mouth to view the larynx (direct laryngoscopy, DL). When clinicians attempt to intubate newborns with DL, less than half of first attempts are successful. Also adverse effects - such as falls in the blood oxygen levels (fall in oxygen saturation (SpO2), or "desaturation"), slowing down of the heart rate (bradycardia), oral trauma - are relatively common. In recent years, video laryngoscopes (VL) have been developed. In addition to a light, VL have a video camera at the tip of the blade. This camera acquires a view of the larynx and displays it on a screen that the clinician views when attempting intubation (indirect laryngoscopy). In a randomised study performed at the National Maternity Hospital, Dublin, Ireland, more infants were successfully intubated at the first attempt when clinicians used VL compared to DL [79/107 (74%) versus 48/107 (45%), P<0.001]. While this study was large enough to show that VL resulted infants being successfully intubated at the first attempt in one hospital, it couldn't give information about how it might work in a range of hospitals, and it wasn't large enough to see what effect VL had on adverse events. There is a large difference in cost between a standard laryngoscope (approx. €300) and a video laryngoscope (approx. €21,000). This is a matter of concern for all hospitals, particularly in settings where resources are more limited. The investigators aim to assess whether VL compared to DL results in more infants being intubated at the first attempt without physiological instability. STUDY DESIGN A recent single centre study reported that that more newborn infants were successfully intubated at the first attempt when VL was used to indirectly view the airway compared to DL. This study was not large enough to determine the effect of VL on adverse effects that are seen commonly (e.g. desaturation) or more rarely (e.g. bradycardia, receipt of chest compressions or adrenaline, oral trauma) during intubation attempts. For the current study, the investigators chose a stepped-wedge cluster randomised controlled design, where the participating centre, rather than the individual infant, will be the unit of randomisation. This design has been found appropriate to test the effects of an intervention that encompasses a behavioural aspect and to implement interventions while studying them at the same time. In this study, all centres will begin in the "control group"; where clinicians will routinely attempt intubation with DL, as is their usual practice. At specified intervals, centres will be randomly assigned to cross over to the "intervention group", where clinicians will routinely attempt intubation with VL. All participating centers will have included patients in both arms by the end of the study. SAMPLE SIZE ESTIMATION To determine the intra-cluster correlation (that means the correlation between two observations from the same centre), the investigators used the dataset of the MONITOR trial that included infants from 7 delivery rooms worldwide. In this trial, the intra-cluster correlation for intubation in the delivery room was reported as 0.1. This complete stepped-wedge cluster-randomized design includes 21 time periods (including the baseline) and 20 centres that will be including patients, with each randomised to a unique sequence. Each time period lasts a fortnight. Each time period, 1 centre will switch their treatment from DL to VL. With all centres including 2 patients each time period, 42 patients will be included per centre which will provide a total sample size of 840 patients. Assuming a control proportion of 0.4, this sample will achieve 90% power (0.9091) to detect a treatment proportion of 0.55, assuming a conservative ICC of 0.05. The power is not very sensitive to ICC values up to 0.1 (power of >90% to detect difference 40% versus 56%). The test statistic used is the two-sided Wald Z-Test. TREATMENT OF SUBJECTS DIRECT LARYNGOSCOPY (DL, control period) At the start of the study, clinicians at participating centres will attempt intubation using a standard laryngoscope to perform DL as is their normal practice. VIDEO LARYNGOSCOPY (VL, intervention period) For each centre, a lot will be drawn which indicates the month in which endotracheal intubation will be routinely attempted with VL rather than DL. In the month before the switch, centres will be provided with a C-MAC VL by the manufacturers, Karl Storz-Endoskop (Tuttlingen, Germany). The system will be provided on loan for the duration of the study and will consist of an 8" high-definition monitor with connecting cable and reusable straight Miller type blades size 0 and size 1. The equipment will be demonstrated by representatives from Karl Storz, and clinicians who intubate babies at participating hospitals will be encouraged to practice with the equipment on mannequins. We will have an virtual meeting with each centre in the week before they are due to switch to review the protocol, data collection and to answer any queries that they may have. All other procedures in the delivery room and NICU will be performed according to international and local guidelines. All other aspects of the approach to intubation at the participating centre are at the discretion of the local clinicians and should remain the same for the duration of the study; e.g.: - The drugs used before intubation attempts (e.g. opiate, atropine, curare-like drug) - The route by which intubation is usually attempted (i.e. oral or nasal) - Whether they use a stylet is routinely used - Whether supplemental oxygen is given during attempts

A Prospective Observational Study of Video Laryngoscopy Versus Direct Laryngoscopy for Insertion of a Thin Endotracheal Catheter for Surfactant Administration in Newborn Infants

Many newborn infants have breathing difficulty after birth, particularly when they are born prematurely. Many of these infants are supported with nasal continuous positive airway pressure (NCPAP). Some of the infants deteriorate despite treatment with NCPAP and have a thin catheter inserted into their trachea for the administration of surfactant, which is then immediately removed (often referred to as "less-invasive surfactant administration" or LISA). Insertion of a thin catheter is usually performed by doctors who are experienced at intubation (i.e. inserting endotracheal tubes, ETTs). They look directly into the the infants mouth using a standard laryngoscope to identify the opening of the airway (i.e. perform direct laryngoscopy). More recently video laryngoscopes have been developed. These devices display a magnified image of the airway on a screen that can be viewed indirectly by the doctor attempting to insert the ETT or thin catheter, and also by others. A single centre study reported that more infants were successfully intubated at the first attempt when doctors performed indirect video laryngoscopy compared to direct laryngoscopy. It is possible to independently verify when a doctor has correctly inserted and ETT, for example by detecting carbon dioxide coming out of the tube or seeing condensation in the tube during exhalation, or by hearing breath sounds by listening to the chest during positive pressure inflations. It is not possible to independently verify whether a doctor has correctly inserted a thin catheter under direct laryngoscopy, by these or other means. The standard (and to date only) way of confirming that a thin catheter has been correctly inserted is to rely on the report of the operator. Video laryngoscopy, in contrast, allows the independent verification of the tip of a thin catheter by one or more people observing the screen. The investigators are performing NEU-VODE, a stepped wedge cluster randomised study of the introduction of video laryngoscopy versus direct laryngoscopy for the intubation of newborn infants. Alongside this study, the investigators are performing a study of infants who have a thin endotracheal catheter inserted under video laryngoscopy versus direct laryngoscopy. As it is not possible to measure the outcome of successful insertion of the thin catheter equally in both groups, this is a prospective observational cohort study. The investigators will record information on infants who have a thin catheter inserted into the trachea for the purpose of surfactant administration at centres participating in the NEU-VODE study. The type of laryngoscope used for thin catheter insertion attempts will not be mandated; instead, the investigators will compare the information of groups within the cohort who have their first attempt made using the video laryngoscope to the group who have their first attempt made with direct laryngoscopy.

Strength-Endurance Circuit Training in Parkinson's Disease

CART123 T Cells in Relapsed or Refractory CD123+ Hematologic Malignancies: a Dose Escalation Phase I Trial

This is an open-label, single arm study on up to 18 adult subjects with refractory or relapsed CD123+ AML, MDS, ALL or BPDCN. Following lymphodepleting conditioning regimen, the subjects will receive a single dose of autologous CAR123 T lymphocytes supplied by the sponsor´s manufacturing facility. CART123 dose will be increased in three predefined steps using the accelerated Bayesian optimal interval (BOIN) design in order to establish recommended CART123 dose for further study, which will be either Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD), whichever is reached first. Alternative dosing schedule will be adopted in case of dose limitation due to insufficient CART123 expansion during IMP manufacture. Due to concern for potentially prolonged or irreversible hematologic toxicity of CART123, all patients recruited in the study must be eligible for hematopoietic stem cell transplantation (HSCT) and have a donor of allogeneic hematopoietic stem cells identified and cleared by the transplant center. Decision to perform HSCT will be made on a case-by-case basis.

Biodegradable Stents in Liver Transplant RecipIents for Treatment of Biliary Anastomotic Strictures

Liver transplantation (LT) is nowadays a standard treatment method of end-stage liver disease, primary liver cancer and acute liver failure. Biliary complications (BCs) following liver transplantation are the leading source of morbidity and liver graft failure and are associated with up to 10% mortality rate. The incidence of BCs remains high, being reported in 10-25% in cadaveric donors (DDLT) and in more than 30% in living donor liver transplantations (LDLT), despite improved both preoperative and postoperative care and enhanced surgical technique. Anastomotic biliary strictures (ABS) are together with bile leaks the most common biliary complication occurring any time after LT, but being primarily found within the first year LT. The incidence ranges between 5-15% in DDLT and 13-36% in LDLT. Anastomotic strictures are typically present at the site of anastomosis, tend to be short, single and constitute up to 86% of all biliary strictures. The clinical presentation can differ from patients being asymptomatic to some presenting with symptoms of biliary obstruction (jaundice, fever, chills, nausea, abdominal pain). The clinical picture can resemble also other conditions and it is important to differentiate biliary complication (BC) from other similarly presenting entities such as acute rejection, hepatic artery thrombosis, recurrence of primary sclerosing cholangitis or acute hepatitis). The gold standard for diagnosis of BCs is MRCP with reported sensitivity and specificity of up to 95%. The first line therapy of BCs is endoscopic retrograde cholangiopancreatography (ERCP), in case of failure or altered anatomy percutaneous approach may be indicated. If both methods fail surgery is required. ERCP is an invasive endoscopic technique used primarily for therapy of pancreatobiliary tract. It is associated with risk of complications such as acute pancreatitis, bleeding, acute cholangitis or in rare cases perforation. There are two standard approaches in the treatment of anastomotic biliary strictures, similarly to the treatment of other benign strictures of the bile duct. First, the use of multiple plastic stents (MPS) requiring their repeated endoscopic exchanges may be employed. Alternatively, a single self-expandable metal stent is placed for a longer period of time. The endoscopic therapy of anastomotic strictures using multiple plastic stents typically requires multiple stent exchanges, starting with placing a single stent and adding multiple stents during further sessions. The sessions are scheduled every 1 to 3 months. The resolution of the anastomotic stricture is usually achieved in 12months, exposing the patient typically to 3-4 ERCP procedures. MPS technique was firstly described and put in practice in a single center study by Costamagna et al. with clinical success rate in 89%. After that many other studies have been published regarding this topic, including a meta-analysis, where the resolution rate of strictures were reported in 94%-100%. Finally in 2017 by Koksa et al. was reported a review demonstrating that in patients with more than 12 months of stenting, with higher total number of stents and number of stents inserted per session, a higher resolution rate and a lower recurrence rate were showed. Alternative option for the endoscopic treatment of ABS is the use of a single fully covered self-expandable metal stent (FC-SEMS), in studies showing similar rates of ABS resolution compared to MPS method with the advantage of not repeating ERCP to place multiple stents, although with higher risk of migration. The use of endoscopically inserted biodegradable stents is a novel technique with a potential to overcome some downsides of standard treatment with MPS and FC-SEMS. Biodegradable stents are made of different synthetic polymers or their co-polymers. First use of biodegradable stents in the GI tract was described in the setting of an esophageal stricture in 1996 and was later used in small intestine and colon for benign strictures. In the pancreatobiliary tract biodegradable stents have begun to be used in the recent years, mostly for benign biliary strictures such as those caused by chronic pancreatitis and in postoperative cystic duct leaks. Most of the reported experience comes from percutaneously inserted stents. The experience with endoscopic insertion of biodegradable stents is very limited and the data about use of biodegradable stents in liver transplant recipients are extremely scarce. A systematic review on the use of biodegradable stents in biliary tract by Siiki at al. reviewed studies from 1997 to 2017. This review included 12 animal and 7 human studies. In human studies biodegradable stents were inserted in 4 studies percutaneously and in 3 studies endoscopically. The main indications were benign biliary strictures, postoperative cystic duct leaks, leaks from hepaticojejunal anastomosis, strictures of hepaticojejunal anastomosis, bilioenteric anastomosis strictures or chronic pancreatitis. In all studies stents made out of polydioxanone with time of degradation between 3-6 months were used. The studies proved good feasibility and safety of BDS in both animal and human setting and demonstrated their successful use in the treatment of benign biliary strictures and cystic bile duct leaks. In the first and biggest study with the endoscopic use of biodegradable stents in humans in treatment of cystic duct leaks and benign biliary strictures (BBS), the overall clinical success rate in treatment of BBS was noted in 83% with no secondary hyperplastic strictures. Surprisingly quite high rate of acute cholangitis occurred, in 23% after 90 days, although all cases were mild. In another recent systematic review and metanalysis by Almeida et al. biodegradable stents were compared to multiples plastic stent implantation in benign biliary strictures. In total 9 studies met the inclusion criteria and were analyzed. Biodegradable stent group (BDBS) consisted of one retrospective and two prospective cohort studies, where stents were deployed both endoscopically and percutaneously with a minimal follow up of 20,8 months. In contrast the MPS group consisted of one randomized control trial comparing the use of multiple plastic stents to FCSEMS for different types of benign biliary strictures, and 5 cohort studies from which were 4 retrospective and one was prospective with a minimal follow up of 78,4 months. The overall success rate to achieve long-term stricture resolution was 83% for the BDBS group and 84% for the MPS group. The average number of interventions in the MPS group was 3 in contrast to 1 in the BDBS group (per case). In a majority of cases the stents were placed percutaneously and only one cohort study included endoscopically released BDBS (13 patients). The treatment-related complication rate was reported for acute cholangitis, acute pancreatitis, stent migration and abdominal pain and was 24,1%, 0,7 %, 1,5 %, 0, 8% for BDBS and 6,1%, 2,7%, 6,8% and 6,8 % for MPS. An observational single center study by Dopazo et al. reported 20 adult and pediatric patients where BDS were used for benign biliary strictures after liver transplantation using a transhepatic approach. The overall feasibility was 100%, the overall clinical success including both anastomotic and nonastomotic strictures was 75%. The clinical success was higher in anastomotic strictures (81,25%). Only one case of acute pancreatitis was observed. Based on the available evidence, BDS have shown promising results with good stent patency, feasibility, efficacy and safety profile. Therefore, BDS may represent a novel treatment modality and an alternative to current techniques in the management of biliary anastomotic strictures with a reduced number of ERCPs. However, prospective comparative data are needed. The investigators aim to compare the use of biodegradable stents with the multiple stenting technique using plastic stents for the treatment of biliary anastomotic strictures and to demonstrate the non-inferiority of biodegradable stents, as well as the safety profile and technical feasibility.

Cavo-Tricuspid Isthmus Block Durability After Pulsed Electric Field Ablation

Background Cavo-tricuspid isthmus (CTI) ablation is commonly performed as a concomitant procedure in patients undergoing pulmonary vein isolation (PVI) or more extensive left atrial ablations for the treatment of atrial fibrillation (AF). While the acute and long-term resumption of conduction in the CTI after radiofrequency ablation has already been investigated, the acute durability of the CTI block created by pulsed-electric field (PEF) energy has not been systematically evaluated. Study population A prospective, multicentric randomized study conducted at high-volume centre with the routine use of intracardiac echocardiography (ICE). A total of 150 consecutive patients with paroxysmal AF undergoing PVI by PEF energy with documented typical atrial flutter or patients with persistent AF in whom catheter ablation of CTI is planned as a part of a complex procedure will be enrolled in the study. Methods Procedures will be performed under general anaesthesia (GA) or deep analgo-sedation and on uninterrupted anticoagulation. One decapolar catheter will be introduced into the coronary sinus (CS). A duodecapolar catheter will be placed in the right atrium around the tricuspid annulus. A single transseptal puncture will be performed under ICE guidance. After obtaining the left atrial (LA) access, the Faradrive sheath will be redrawn into the right atrium. Patient presenting with AF or other atrial arrhythmias at the beginning of the procedure will be cardioverted. Prior to initiating pulsed field ablation (PFA) on the CTI, sublingual nitrates will be administered in the form of two sprays of nitroglycerin at a dose of 0.30 mg per spray. The CTI ablation will be performed during regular atrial pacing from the proximal CS at a cycle length of 600 ms. Sequential applications of PEF energy will be delivered in an overlapping fashion from the tricuspid annulus to the inferior cava vein under ICE guidance. Patients will be randomized in a 1:1 ratio based on the configuration of the catheter used to achieve CTI block (basket vs. flower). In both groups, three applications will be deployed at each spot. If acute block is not achievable using the randomized configuration, patients will be ablated using the other configuration and any additional lesions per operator discretion to achieve acute block. After demonstrating the bidirectional CTI block with standard pacing maneuvers (differential pacing from duodecapolar catheter and proximal CS), the surface electrocardiogram (ECG) will be analyzed across all 12 leads to evaluate for the presence of ST segment elevation. The left atrial procedure will be then performed during regular atrial pacing from the proximal CS. An eventual conduction recovery over the CTI and the corresponding time since the last ablation on the CTI will be recorded. Dormant conduction over the CTI will be assessed using an I.V. bolus of 12-18 mg of adenosine during continuous atrial pacing immediately after the confirmation of the CTI block and at the end of the procedure. The total waiting time and number of PEF applications on the CTI will be documented. At the end of the procedure, additional PEF applications per operator discretion on the CTI will be delivered if needed. Sample size While no clear data on comparison of different Farapulse configurations on CTI are available, with 150 patients in the trial at a given expected acute success rate of 85 % in basket configuration given our clinical experience and a noninferiority design, a noninferiority margin of 15% at a power level of 82% can be tested. Plasmatic biomarkers Venous blood samples for the assessment of plasma biomarkers (free hemoglobin [fHb], lactate dehydrogenase [LDH], total bilirubin, and haptoglobin) will be collected at two time points: before the procedure (T1) and after CTI isolation before LA ablation (T2). Clinical implications 1. Achieving CTI block at the beginning of the catheter ablation of AF may provide sufficient waiting time to verify the durability of the block on TCI and thus enhance the long-term clinical effect of the procedure. 2. An absence of adenosine-induced CTI reconnection immediately after the CTI block could predict the durability of block at the end of the procedure and obviate the need for prolonged waiting period. 3. The use of the flower configuration to achieve CTI block could be associated with a non-inferior acute success rate and lower incidence of hemolysis.

A Study to Evaluate Efficacy and Safety of AMZ001 for the Treatment of Knee Osteoarthritis Symptoms

This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week trial of a formulation of AMZ001 once daily versus placebo once daily. Participants will be evaluated for osteoarthritis by X-ray images of the knees and one knee will be selected for treatment as the target knee. The study gel will be applied directly to that knee throughout the 6 weeks of the study.