Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency

Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe-4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis

META Score: An International Consensus Scoring System on Mesh-Tissue Adhesions

Background: Currently, the lack of consensus on postoperative mesh-tissue adhesion scoring leads to incomparable scientific results. The aim of this study was to develop an adhesion score recognized by experts in the field of hernia surgery. Methods: Authors of three or more previously published articles on both mesh-tissue adhesion scores and postoperative adhesions were marked as experts. They were queried on seven items using a modified Delphi method. The items concerned the utility of adhesion scoring models, the appropriateness of macroscopic and microscopic variables, the range and use of composite scores or subscores, adhesion-related complications and follow-up length. This study comprised two questionnaire-based rounds and one consensus meeting. Results: The first round was completed by 23 experts (82%), the second round by 18 experts (64%). Of those 18 experts, ten were able to participate in the final consensus meeting and all approved the final proposal. From a total of 158 items, consensus was reached on 90 items. The amount of mesh surface covered with adhesions, tenacity and thickness of adhesions and organ involvement was concluded to be a minimal set of variables to be communicated separately in each future study on mesh adhesions. Conclusion: The MEsh Tissue Adhesion scoring system is the first consensus-based scoring system with a wide backing of renowned experts and can be used to assess mesh-related adhesions. By including this minimal set of variables in future research interstudy comparability and objectivity can be increased and eventually linked to clinically relevant outcomes

Long-term outcome of liver transplantation for unresectable liver metastases from neuroendocrine neoplasms: a Belgian retrospective multi-centre study

peer reviewedBackground: Liver transplantation (LT) is the only curative treatment for unresectable liver metastases from neuroendocrine neoplasms (NEN-Liver-Mets). While recurrence is frequent after LT, there is limited data available in the literature on the outcome of recurrent patients. Methods: We retrospectively reviewed the medical records of all patients who underwent LT by NEN-Mets at the six LT centres in Belgium from 1986 to 2020. Patient and tumour characteristics, indication for transplantation, overall survival (OS), disease-free survival (DFS), and tumour recurrence and outcomes were analysed. Results: Forty patients underwent a LT for NEN-Liver-Mets in Belgium. Twenty-nine patients were male (74.2%) with a mean age of 41.9 and 47.1 years at the time of NEN diagnosis and LT, respectively. WHO classification was available for 32 patients and changed over time (see table below). OS post-LT at 1-, 5-, and 10-years are: 84,3%, 65,0% and 54,6% respectively, while the overall DFS are: 76.3%, 44.5% and 38.2% in the same intervals. Patients transplanted after 2010 showed better OS at 5-and 10-years (74.8% and 74.8%) when compared with patients transplanted before (60,0% and 49.5%). Twenty patients (50%) presented a NEN recurrence, of this, 14 (70%) were transplanted before 2010 and only 6 (30%) were transplanted afterwards (p=0.03). The median time for recurrence diagnosis was 12.3 months (range: 5.1 to 69.2). The most frequent recurrence treatments were surgical resection, somatostatin analogs, chemotherapy, and sunitinib therapy (8, 6, 6, and 4 patients, respectively). Survival rates were 89.5% and 56.1% at 1- and 5-years after recurrence diagnosis.Conclusions: Patients transplanted for unresectable NEN-Liver metastases had good long-term survival. Although the total recurrence rate is high, it decreased dramatically after 2010, probably due to better patient selection. Furthermore, recurrence treatment should be recommended as it may prolong patient survival

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Laparoscopic Liver Surgery Training Course on Thiel-Embalmed Human Cadavers: Program Evaluation, Trainer’s Long-Term Feedback and Steps Forward

Objectives: The purpose of this study was to evaluate the feedback of participants upon laparoscopic liver surgery (LLS) course on Thiel-embalmed human bodies. Methods: From 2010 to 2017, ten LLS masterclasses have been organized by the Department of Hepatobiliary Surgery at Ghent University Hospital. A 23-question anonymous survey was electronically sent to 119 participants between November 2017 and January 2018, exploring their characteristics and asking for evaluation of the course. The obstacles for implementing LLS in their centers have been assessed. Results: Sixty-four surgeons (53.8%) responded to the survey; 42 (65.6%) were employed at a university hospital; and 39 (60.9%) were in the first decade of their practice as a consultant surgeon. Forty-three (67.2%) surgeons reported an increased percentage of LLS cases afterward. Training on Thiel cadavers was considered superior (49.2%) to other training options including proctoring in the operating room (34.9%), virtual reality (6.3%), video training (4.8%) and practicing on pigs (4.8%). Obstacles identified contained inadequate training, patient’s referral pattern, financial issues, lack of dedicated surgical team and time constrains. Conclusions: This survey revealed that a structured short-time program incorporating interactive discussion, live operations and hands-on training on human bodies under proctorship may enhance efficient training in laparoscopic liver surgery. In a step forward for upcoming courses, the importance of team building has to be addressed

Belgian prospective registry on laparoscopic liver surgery compared to open procedures: 3-year snapshot of multi centric activity

The Belgian Registry on Laparoscopic Liver Surgery is a prospective, non-compulsory, online registry of laparoscopic (LLS) and open (OLS) liver procedures, endorsed in 2016 by the Belgian Section of Hepato-Biliary and Pancreatic Surgery. The primary aim is to assess the evolution of laparoscopic liver surgery compared to the standard open approach in Belgium. Methods: Participating centers included, through a secured SSL server (www.brells.org), all consecutive liver surgeries from 2017 to 2019. Demographic, pre- intra- and postoperative data of all consecutive LLS and OLS were recorded. Results: In total 13 centers participated to the study. 1531 procedures were recorded (841 LLS and 690 OLS) in 1408 patients. Demographics of patients were similar between LLS and OLS. Indication for surgery were 57% liver metastases (49% LLS, 51% OLS), 29% primary liver tumors (57% LLS, 43% OLS) and 16% benign diseases (73%LLS, 27% OLS). Exclusive local thermal ablation (LA) accounted for 118 procedures. Excluding LA from analysis, rate of major hepatectomies was 18,2% (n=258) and median Ghent difficulty score was 5,6 (4,8 LLS vs 6,5 OLS). LLS were converted to OLS in 3,3% of cases. Overall morbidity and mortality were significantly lower in LLS compared to OLS respectively 27% vs 53% and 0,6% vs 2,9%. Length of hospital stay was significantly shorter in LLS (Median 4 vs 7 days). Conclusions: LLS are wide spreading in Belgium accounting globally to 55% of all liver surgeries. In selected patients, LLS are safe, advantageous and reproducible in major HPB centers. A low morbidity has been prospectively confirmed

BReLLS, Belgian Prospective Registry on consecutive laparoscopic and open liver surgery: Results of the first 18 months enrollment

Objectives. The BReLLS (Belgian Registry on Laparoscopic Liver Surgery) project is a prospective, non-compulsory, online registry of laparoscopic (LLS) and open (OLS) liver procedures, endorsed by the Belgian Section of Hepato-Biliary and Pancreatic Surgery in 2016. The primary aim is to monitor the evolution and spreading of LLS in Belgium. The secondary aim is to evaluate the cost/benefit ratio of LLS in order to allow appropriate reimbursement. Methods. The BReLLS is accessible through a secured SSL server (www.brells.org). Participating centers prospectively record pre-operative, intra-operative and postoperative (90-day morbidity and follow-up) data of all consecutive LLS and OLS. Statistics are generated real-time and are available to each participating center. An audit is planned after the first 2-years of patients enrollment with early oncological follow-up. Results. From February 2017 to October 2018, 12 centers have joint the BReLLS reporting data of 630 procedures (390 LLS and 240 OLS). Indication for LLS were colorectal metastases (46.4%), hepatocellular-carcinoma (17.2%), benign diseases (17%), other metastases (14.1%) and mixed various pathologies (5.3%). LLS encompassed major hepatectomies (16.5%), sectionectomies (14.1%), mono or bi-segmentectomies (20.3%) and sub-segmentectomies (49.1%). LLS were converted to OLS in 4.1% of cases. Overall morbidity was 9.7% for LLS and 29.7% for OLS (p=.0001). Major morbidity (Clavien-Dindo ≥ IIIb) occurred in 1.5% and 5.8% of LLS and OLS (p=.004). 90-days mortality following LLS was nihil vs 1.6% (n=4) for OLS (p=.027). Conclusions. LLS are wide spreading in Belgium. In selected patients, LLS are safe, advantageous and reproducible in major HPB centers. A low morbidity has been prospectively confirmed. Further (ongoing) evaluation will focus on the selection criteria for patients undergoing LLS eventually defining the limits of the minimally invasive approach for malignant diseases