Cannabichromene Induces Neuronal Differentiation in NSC-34 Cells: Insights from Transcriptomic Analysis.

Phytocannabinoids, with their variety of beneficial effects, represent a valid group of substances that could be employed as neurogenesis-enhancers or neuronal differentiation inducers. We focused our attention on the neuronal-related potential of cannabichromene (CBC) when administered to undifferentiated NSC-34 for 24 h. Transcriptomic analysis showed an upregulation of several neuronal markers, such as Neurod1 and Tubb3, as well as indicators of neuronal differentiation process progression, such as Pax6. An in-depth investigation of the processes involved in neuronal differentiation indicates positive cytoskeleton remodeling by upregulation of Cfl2 and Tubg1, and active differentiation-targeted transcriptional program, suggested by Phox2b and Hes1. After 48 h of treatment, the markers previously examined in the transcriptomic analysis are still overexpressed, like Ache and Hes1, indicating that the differentiation process is still in progress. The lack of GFAP protein suggests that no astroglial differentiation is taking place, and it is reasonable to indicate the neuronal one as the ongoing one. These results indicate CBC as a potential neuronal differentiation inducer for NSC-34 cells.

State of the Art and Future of Stem Cell Therapy in Ischemic Stroke: Why Don't We Focus on Their Administration?

Stroke is one of the leading causes of death and disability worldwide, so there is an urgent need to find a therapy for the tragic outcomes of this cerebrovascular disease. Stem cells appeared to be a good solution for many conditions, so different experiments were made to establish stem cells as a feasible therapy for stroke. The aim of this review is to analyze the state of the art of stem cell therapy for stroke and if the route of administration could represent a valid adjusting point for ameliorating the therapy's outcome. To obtain this, we searched the scientific literature of the last 10 years for relevant in vitro and in vivo evidence regarding stem cells' potential in stroke therapy. In vitro evidence points to hypoxia, among the preconditioning strategies, as the most used and probably efficient method to enhance cells qualities, while in vivo results raise the question if it is the type of cells or how they are administrated which can make the difference in terms of efficiency. Unfortunately, despite the number of clinical trials, only a few were successfully concluded, demonstrating how urgent the necessity is to translate pre-clinical results into clinics. Since any type of stem cell seems suitable for therapy, the chosen route of administration corresponds to different engraftment rates, distribution and efficiency in terms of the beneficial effects of stem cells. Intravenous administration was widely used for delivering stem cells into the human body, but recently intranasal administration has given promising results in vivo. It allows stem cells to efficiently reach the brain that was precluded to intravenous administration, so it is worth further investigation.

Reducing Carbapenem-Resistant Enterobacteriaceae Using the Targeted Solution Tool: A Quality Improvement Project.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) is a worldwide urgent health problem. Hand hygiene (HH) is an effective intervention to reduce the spread of CRE. LOCAL PROBLEM: In 2017, an increase in the rate of health care-associated (HA) CRE colonization was observed in a large multiorgan transplant center in Italy. This study aimed to reduce the HA-CRE colonization rates by improving HH compliance. METHODS: A pre-/post-intervention project was conducted from November 2017 through December 2020. INTERVENTIONS: The DMAIC (Define, Measure, Analyze, Improve, and Control) framework was used to implement the HH Targeted Solution Tool (TST). RESULTS: Hand hygiene compliance increased from 49% to 76.9% after the Improve phase ( P = .0001), and to 81.9% after the second Control phase ( P = .0001). The rate of HA-CRE decreased from 24.9% to 5.6% ( P = .0001). CONCLUSIONS: Using the DMAIC framework to implement the TST can result in significant improvements in HH compliance and HA-CRE colonization rates.

Cannabidiol Promotes Neuronal Differentiation Using Akt and Erk Pathways Triggered by Cb1 Signaling.

Recently, the scientific community has started to focus on the neurogenic potential of cannabinoids. The phytocompound cannabidiol (CBD) shows different mechanism of signaling on cannabinoid receptor 1 (CB1), depending on its concentration. In this study, we investigated if CBD may induce in vitro neuronal differentiation after treatment at 5 µM and 10 µM. For this purpose, we decided to use the spinal cord × neuroblastoma hybrid cell line (NSC-34) because of its proliferative and undifferentiated state. The messenger RNAs (mRNAs) expression profiles were tested using high-throughput sequencing technology and Western blot assay was used to determine the number of main proteins in different pathways. Interestingly, the treatment shows different genes associated with neurodifferentiation statistically significant, such as Rbfox3, Tubb3, Pax6 and Eno2. The CB1 signaling pathway is responsible for neuronal differentiation at 10 µM, as suggested by the presence of p-ERK and p-AKT, but not at 5 µM. A new correlation between CBD, neurodifferentiation and retinoic acid receptor-related orphan receptors (RORs) has been observed.

Cannabinerol and NSC-34 Transcriptomic Analysis: Is the Dose Who Makes Neuronal Differentiation?

Cannabis sativa L. proved to be a source of several phytocompounds able to help patients facing different diseases. Moreover, these phytocompounds can help ameliorate general conditions and control certain unpleasant effects of diseases. Some cannabinoids, however, provided more benefits applicable to settings other than palliative care. Using the NSC-34 cell line, we evaluated the barely known phytocompound named cannabinerol (CBNR) at different doses, in order to understand its unique characteristics and the ones shared with other cannabinoids. The transcriptomic analysis suggests a possible ongoing neuronal differentiation, principally due to the activation of cannabinoid receptor 1 (CB1), to which the phosphorylation of serine-threonine protein kinase (Akt) followed, especially between 20 and 7.5 µM. The increase of Neurod1 and Map2 genes at 7.5 µM, accompanied by a decrease of Vim, as well as the increase of Syp at all the other doses, point toward the initiation of differentiation signals. Our preliminary results indicate CBNR as a promising candidate to be added to the list of cannabinoids with neuronal differentiation-enhancer properties. However, further studies are needed to confirm this initial insight.

The Role of Hypoxia in Improving the Therapeutic Potential of Mesenchymal Stromal Cells. A Comparative Study From Healthy Lung and Congenital Pulmonary Airway Malformations in Infants.

Mesenchymal stromal cells (MSCs) play an important role in the field of regenerative medicine thanks to their immunomodulatory properties and their ability to secrete paracrine factors. The use of MSCs has also been tested in children with congenital lung diseases inducing fibrosis and a decrease in lung function. Congenital malformations of the pulmonary airways (CPAM) are the most frequently encountered lung lesion that results from defects in early development of airways. Despite the beneficial properties of MSCs, interventions aimed at improving the outcome of cell therapy are needed. Hypoxia may be an approach aimed to ameliorate the therapeutic potential of MSCs. In this regard, we evaluated the transcriptomic profile of MSCs collected from pediatric patients with CPAM, analyzing similarities and differences between healthy tissue (MSCs-lung) and cystic tissue (MSCs-CPAM) both in normoxia and in cells preconditioned with hypoxia (0.2%) for 24 h. Study results showed that hypoxia induces cell cycle activation, increasing in such a way the cell proliferation ability, and enhancing cell anaerobic metabolism in both MSCs-lung and MSCs-CPAM-lung. Additionally, hypoxia downregulated several pro-apoptotic genes preserving MSCs from apoptosis and, at the same time, improving their viability in both comparisons. Finally, data obtained indicates that hypoxia leads to a greater expression of genes involved in the regulation of the cytoskeleton in MSCs-lung than MSCs-CPAM.

Laparoscopic giant hiatal hernia repair with absorbable mesh.

Background: The best operative approach to large hiatal hernias still remains controversial between suture cruroplasty and prosthetic hiatal herniorrhaphy. This study aims at analysing results from a single institution in Italy in terms of subjective and objective outcomes. Methods: Retrospectively collected data of all patients that underwent laparoscopic hiatal hernia repair since 2011 were considered. Sixty-five patients were included overall; 17 of them fit the criteria of large hiatal hernia. Follow-up (FU) was assessed by visit, questionnaires and X-ray imaging. Results: No major complications occurred in the post-operative course. No patient was lost during the FU period. Out of all the patients included, 13 agreed to have an X-ray with water-soluble contrast. The questionnaires showed a 76.5% rate of satisfaction (13 patients), and the recurrence rate demonstrated by radiology was 29.4% (five patients). There were no major mesh-related complications. Conclusion: The best operative approach for large hiatal hernias remains far from standardised: There is a lack of evidence on the use of a mesh for this kind of surgery as well as substantial controversy over the definition of what a giant hiatal hernia is. Nevertheless, the results from this study and the main studies in the literature seem to be encouraging in improving giant hiatal hernia repair outcomes.

Will Cannabigerol Trigger Neuroregeneration after a Spinal Cord Injury? An In Vitro Answer from NSC-34 Scratch-Injured Cells Transcriptome.

Spinal cord injury affects the lives of millions of people around the world, often causing disability and, in unfortunate circumstances, death. Rehabilitation can partly improve outcomes and only a small percentage of patients, typically the least injured, can hope to return to normal living conditions. Cannabis sativa is gaining more and more interest in recent years, even though its beneficial properties have been known for thousands of years. Cannabigerol (CBG), extracted from C. sativa, is defined as the "mother of all cannabinoids" and its properties range from anti-inflammatory to antioxidant and neuroprotection. Using NSC-34 cells to model spinal cord injury in vitro, our work evaluated the properties of CBG treatments in motor neuron regeneration. While pre-treatment can modulate oxidative stress and increase antioxidant enzyme genes, such as Tnx1, decreasing Nos1 post-treatment seems to induce regeneration genes by triggering different pathways, such as Gap43 via p53 acetylation by Ep300 and Ddit3 and Xbp1 via Bdnf signaling, along with cytoskeletal remodeling signaling genes Nrp1 and Map1b. Our results indicate CBG as a phytocompound worth further investigation in the field of neuronal regeneration.

Aducanumab and Its Effects on Tau Pathology: Is This the Turning Point of Amyloid Hypothesis?

Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people around the world. The two main pathological mechanisms underlying the disease are beta-amyloid (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of Tau proteins in the brain. Their reduction has been associated with slowing of cognitive decline and disease progression. Several antibodies aimed to target Aß or Tau in order to represent hope for millions of patients, but only a small number managed to be selected to participate in clinical trials. Aducanumab is a monoclonal antibody recently approved by the Food and Drug Administration (FDA), which, targeting (Aß) oligomers and fibrils, was able to reduce Aß accumulation and slow the progression of cognitive impairment. It was also claimed to have an effect on the second hallmark of AD, decreasing the level of phospho-Tau evaluated in cerebrospinal fluid (CSF) and by positron emission tomography (PET). This evidence may represent a turning point in the development of AD-efficient drugs.

SARS-CoV-2 Exposed Mesenchymal Stromal Cell from Congenital Pulmonary Airway Malformations: Transcriptomic Analysis and the Expression of Immunomodulatory Genes.

The inflammatory response plays a central role in the complications of congenital pulmonary airway malformations (CPAM) and severe coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the transcriptional changes induced by SARS-CoV-2 exposure in pediatric MSCs derived from pediatric lung (MSCs-lung) and CPAM tissues (MSCs-CPAM) in order to elucidate potential pathways involved in SARS-CoV-2 infection in a condition of exacerbated inflammatory response. MSCs-lung and MSCs-CPAM do not express angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TRMPSS2). SARS-CoV-2 appears to be unable to replicate in MSCs-CPAM and MSCs-lung. MSCs-lung and MSCs-CPAM maintained the expression of stemness markers MSCs-lung show an inflammatory response (IL6, IL1B, CXCL8, and CXCL10), and the activation of Notch3 non-canonical pathway; this route appears silent in MSCs-CPAM, and cytokine genes expression is reduced. Decreased value of p21 in MSCs-lung suggested no cell cycle block, and cells did not undergo apoptosis. MSCs-lung appears to increase genes associated with immunomodulatory function but could contribute to inflammation, while MSCs-CPAM keeps stable or reduce the immunomodulatory receptors expression, but they also reduce their cytokines expression. These data indicated that, independently from their perilesional or cystic origin, the MSCs populations already present in a patient affected with CPAM are not permissive for SARS-CoV-2 entry, and they will not spread the disease in case of infection. Moreover, these MSCs will not undergo apoptosis when they come in contact with SARS-CoV-2; on the contrary, they maintain their staminality profile.

Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration?

The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting. Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell. Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases. The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.

Ginger, a Possible Candidate for the Treatment of Dementias?

As the human life expectancy increases, age-linked diseases have become more and more frequent. The worldwide increment of dementia cases demands medical solutions, but the current available drugs do not meet all the expectations. Recently the attention of the scientific community was attracted by natural compounds, used in ancient medicine, known for their beneficial effects and high tolerability. This review is focused on Ginger (Zingiber officinale) and explore its properties against Alzheimer's Disease and Vascular Dementia, two of the most common and devastating forms of dementia. This work resumes the beneficial effects of Ginger compounds, tested in computational in vitro and in vivo models of Alzheimer's Disease and Vascular Dementia, along with some human tests. All these evidences suggest a potential role of the compounds of ginger not only in the treatment of the disease, but also in its prevention.

Transcriptomic Analysis of HCN-2 Cells Suggests Connection among Oxidative Stress, Senescence, and Neuron Death after SARS-CoV-2 Infection.

According to the neurological symptoms of SARS-CoV-2 infection, it is known that the nervous system is influenced by the virus. We used pediatric human cerebral cortical cell line HCN-2 as a neuronal model of SARS-CoV-2 infection, and, through transcriptomic analysis, our aim was to evaluate the effect of SARS-CoV-2 in this type of cells. Transcriptome analyses revealed impairment in TXN gene, resulting in deregulation of its antioxidant functions, as well as a decrease in the DNA-repairing mechanism, as indicated by the decrease in KAT5. Western blot analyses of SOD1 and iNOS confirmed the impairment of reduction mechanisms and an increase in oxidative stress. Upregulation of CDKN2A and a decrease in CDK4 and CDK6 point to the blocking of the cell cycle that, according to the deregulation of repairing mechanism, has apoptosis as the outcome. A high level of proapoptotic gene PMAIP1 is indeed coherent with neuronal death, as also supported by increased levels of caspase 3. The upregulation of cell-cycle-blocking genes and apoptosis suggests a sufferance state of neurons after SARS-CoV-2 infection, followed by their inevitable death, which can explain the neurological symptoms reported. Further analyses are required to deeply explain the mechanisms and find potential treatments to protect neurons from oxidative stress and prevent their death.

Laparoscopic adrenalectomy for giant adrenal tumours: Technical considerations and surgical outcome.

BACKGROUND: Giant adrenal tumours are tumours with size ≥6 cm. These are rare cancer associated with malignancy in 25% of cases. PATIENTS AND METHODS: A retrospective review was conducted on the medical records of patients admitted to our high-volume centre of Careggi University Hospital with a giant adrenal tumour and submitted to adrenalectomy between January 2008 and December 2018. The group of patients who underwent to laparoscopic adrenalectomy was compared with a group of patients that was submitted to open adrenalectomy. RESULTS: In the past 10 years, we performed about 245 adrenalectomies for benign and malignant adrenal tumours. Fifty (20.4%) of these were giant tumours. The medium size was 9.9 cm (7-22 cm). The mean age was 57 years (21-81 years). Thirty-four (68%) of these cancers were laparoscopically removed and 16 (32%) with an open approach. The surgical outcomes in these patients were optimal if compared to the group of patients submitted to open approach in terms of good pain control, hospital stay, mean operative time and bloodless. No difference was observed about post-operative complications in the two groups. The follow-up after 30 months for malignant tumours did not show local recurrences. CONCLUSION: Our results pinpoint the advantages of performing a laparoscopic adrenalectomy for giant adrenal tumours. The tumour size is only a predictive parameter of possible malignancy, and the laparoscopic approach is a safe and feasible method in terms of surgical and oncological, only if performed by expert surgeons and in high-volume centres.

Perioperative outcomes of robotic and laparoscopic adrenalectomy: a large international multicenter experience.

BACKGROUND: The aim of the study was to describe the surgical outcomes of a retrospective series of consecutive patients treated with laparoscopic and robotic approach for adrenal masses in two tertiary referral centers. METHODS: We retrospectively gathered data of 477 patients submitted to adrenalectomy performed at two Institutions from March 2008 to February 2018 by six highly experienced surgeons. We excluded from the analysis 43 patients that had an open approach for tumors or for anesthetic contraindications to minimally invasive surgery (MIS). Patients were selected for surgery after a radiologic and an endocrinology work up. Preoperative, perioperative and postoperative data were recorded. RESULTS: Overall, 477 patients were included in the study. The robotic and the laparoscopic group included 110 and 367 patients, respectively. The preoperative characteristics were similar in both groups except for ASA score with a median (IQR) of 3 and 2 in the robotic and in the laparoscopic group, respectively (p = 0.03). Tumor size of adrenal tumors treated robotically (4, IQR 2.6-6 cm) was significantly larger than those treated laparoscopically (3, IQR 2.3-4.1 cm) (p = 0.01). The intraoperative complication rates were similar between robotic and laparoscopic groups (6.3% and 6%, respectively). The postoperative complication rate was 5.4% for robotic group and similarly 3.5% for laparoscopic adrenalectomy strategy. We analyzed the tumor ≥ 6 cm, with 29 patients in the robotic group and 43 in the laparoscopic one, with an overall complication rate of 19.5%. At multivariable analyses tumor size (OR 1.287; CI 1.128-1.468; p < 0.001) was the only independent predictor of overall complication. CONCLUSION: Adrenal tumors can be safely treated either by robotic or laparoscopic strategy. MIS seems to be feasible also in larger adrenal masses (≥ 6 cm). Tumor size represents the only predictive factors for overall complication.

Turmeric (Curcuma longa L.) food supplements and hepatotoxicity: an integrated evaluation approach.

INTRODUCTION: Turmeric is the common name for the rhizome of Curcuma longa L. In the recent years, food supplements containing turmeric have been marketed and widely used by an increasing number of consumers. Spontaneous reports of suspected adverse reactions to food supplements are collected within the Phytovigilance system. METHODS: An ad hoc multidisciplinary group investigated the suspected cases of hepatotoxicity reported to the Italian Phytovigilance system associated with the assumption of turmeric food supplements with the methodology specific to pharmacovigilance as well as for the evaluation of the quality and safety of food supplements. RESULTS: A cluster of 28 spontaneous reports of acute hepatitis, mostly with cholestasis, associated with turmeric products were sent to the Italian Phytovigilance system in the first six months of 2019. In all cases, except one, the causality assessment was at least possible. The suspected products were collected and analysed for the presence of drugs, heavy metals, aflatoxins, pesticides, synthetic dyes and pyrrolizidine alkaloids. CONCLUSION: On the basis of the results of all the activities performed by multidisciplinary group, regulatory intervention was taken. This study highlights the importance of developing an integrated evaluation approach for the evaluation of the adverse effects associated with the use of food supplements.

Chevrel technique for ventral incisional hernia. Is it still an effective procedure?

BACKGROUND: Incisional hernia still represents the most frequent late complication of abdominal surgery. After a direct repair, in literature is reported a recurrence rate ranging from 31 to 49%, meanwhile after a prosthetic repair such values were much lower, with a recurrence rate up to 10%. The sites of prosthetic placement in the abdominal wall are premusculo-aponeurotic (onlay, or Chevrel technique), retromuscular-prefascial and preperitoneal (Rives technique, Stoppa technique), whereas intraperitoneal insertion can be done with open or laparoscopic surgery. The aim of this study was to evaluate the immediate and late postoperative results in patients treated with a Chevrel technique for ventral incisional hernia. METHODS: A retrospective review was conducted on the medical records of patients undergoing ventral hernia repair between January 2008 and December 2018 at the Emergency Surgery Unit of the Careggi University Hospital in Florence. RESULTS: Between January 2008 and December 2018 at the Emergency Surgery Unit of the Careggi University Hospital in Florence, 461 patients (245 male, 216 female) with a mean age of 61,52 years were submitted to ventral incisional hernia repair with a Chevrel technique. The mean operatory time was 95.29 min (±50.48) and in 72 patients (15.61%) human fibrin glue was vaporized under the mesh using a spray device. Mean postoperative hospital stay was 5 days and all drain tubes were removed after 7.1 days as mean (±4.3). No intraoperative mortality nor postoperative mortality was reported. In our experience the Chevrel technique for ventral incisional hernia show a recurrence rate (3.2%). Parietal complications observed were seroma in 7.1% of patients, hematoma in 4.7%, localized skin necrosis in 5.2%, surgical site infection in 6.7%, data comparable with the results reported in the other studies. CONCLUSIONS: Most of the objections to the Chevrel procedure focus on the parietal complications and risk of infection. Chevrel procedure cannot be considered an obsolete intervention, in our series, results were very satisfactory in both immediate and late follow-up; moreover this technique is safe and easy to perform.

Germline Mutation in KIF1Bß Gene Associated with Loss of Heterozygosity: Usefulness of Next-Generation Sequencing in the Genetic Screening of Patients with Pheochromocytoma.

The genetic approach of pheochromocytomas and paragangliomas has changed in the last two decades. Nowadays, we know that more than 40% of patients have a germline mutation in one of the susceptibility genes identified to date. Our aim is to underline how genetic diagnosis by next-generation sequencing (NGS) can improve the management of patients affected by pheochromocytomas and paragangliomas in our routine diagnostic screening. We reported a case presentation and next-generation sequencing analysis supported by in silico studies and evaluation of mitochondrial status in KIF1Bß tissue. A 46-year-old male affected by a left secreting pheochromocytoma underwent surgery in 2017. After surgery, the normetanephrine levels decreased very slowly and a suspected abdominal lymph node was detected. We found a novel germline KIF1Bß gene mutation, c.4052C > T, p. Pro1351Leu associated with tumor loss of heterozygosity, and resulted likely-pathogenetic by in silico studies. This mutation was also associated with an increased number of mitochondria through the electron microscopy compared with wild-type tissues as suggestive for mitochondria neoformation compensatory to the mitochondrial autophagic figures observed. Our results underline the usefulness of next-generation sequencing in the presence of multiple tumor predisposition genes and how, at the same time, its use may result challenging for the clinicians. To date, performing the genetic analysis according to the latest Consensus Statement is mandatory in patients affected by PHEO/PGL.

The Italian National Registry for minimally invasive pancreatic surgery: an initiative of the Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS).

The value of minimally invasive pancreatic surgery (MIPS) is still uncertain, despite the growing number of publications, including reviews and meta-analyses, and the quick diffusion of these procedures worldwide. The Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS) was created under the auspices of three Scientific Societies: Associazione Italiana Studio Pancreas (AISP), Associazione Italiana Chirurgia Epato-Bilio-Pancreatica (AICEP, former IT-IHPBA), and Società Italiana di Chirurgia Endoscopica (SICE). The main aim of IGoMIPS is to develop and implement a national registry for MIPS. IGoMIPS was founded on February 22, 2019 in Pisa. The IGoMIPS registry became operational in September 2019, following approval by the Ethic Committees of founding Institutions, inscription into the Registry of Patient Registries (RoPR), and a wrap-up meeting held in Bologna during the Annual Congress of the Italian Surgical Society. During this meeting IGoMIPS members approved that the Italian Registry will provide data to the European Registry, while retaining the right to analyze and publish Italian data. An audience survey was also conducted to obtain information on perceived value and current implementation of MIPS in founding Institutions. MIPS is performed in 94.7% of IGoMIPS centers, including pancreaticoduodenectomy in 42.1%. Robotic assistance was employed in 52.6% of Institutions. The annual volume of MIPS was 6-10 cases in 38.9% of the centers, 11-20 cases in 16.7%, 21-30 cases in 22.2%, and > 30 cases in 22.2%. The registry was felt to be extremely important for both safety improvement and educational purposes by 94.5% of the centers.