Partial Biliary Diversion May Promote Long-Term Relief of Pruritus and Native Liver Survival in Children with Cholestatic Liver Diseases

Introduction Rare cholestatic liver diseases may cause debilitating pruritus in children. Partial biliary diversion (PBD) may relieve pruritus and postpone liver transplantation which is the only other alternative when conservative treatment fails. The aim was to report long-term outcome after PBD in a population of 26 million people during a 25-year period. Materials and Methods This is an international, multicenter retrospective study reviewing medical journals. Complications were graded according to the Clavien-Dindo classification system. Results Thirty-three patients, 14 males, underwent PBD at a median of 1.5 (0.3-13) years at four Nordic pediatric surgical centers. Progressive familial intrahepatic cholestasis was the most common underlying condition. Initially, all patients got external diversion, either cholecystojejunostomy (25 patients) or button placed in the gallbladder or a jejunal conduit. Early complications occurred in 14 (42%) patients, of which 3 were Clavien-Dindo grade 3. Long-term stoma-related complications were common (55%). Twenty secondary surgeries were performed due to stoma problems such as prolapse, stricture, and bleeding, or conversion to another form of PBD. Thirteen children have undergone liver transplantation, and two are listed for transplantation due to inefficient effect of PBD on pruritus. Serum levels of bile acids in the first week after PBD construction were significantly lower in patients with good relief of pruritus than in those with poor effect (13 [2-192] vs. 148 [5-383] mu mol/L; p =0.02). Conclusion PBD may ensure long-term satisfactory effect on intolerable pruritus and native liver survival in children with cholestatic liver disease. However, stoma-related problems and reoperations are common.Peer reviewe

Distinct Cholesterol Localization in Glioblastoma Multiforme Revealed by Mass Spectrometry Imaging

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults and is highly resistant to chemo- and radiotherapies. GBM has been associated with alterations in lipid contents, but lipid metabolism reprogramming in tumor cells is not fully elucidated. One of the key hurdles is to localize the lipid species that are correlated with tumor growth and invasion. A better understanding of the localization of abnormal lipid metabolism and its vulnerabilities may open up to novel therapeutic approaches. Here, we use time-of-flight secondary ion mass spectrometry (ToF-SIMS) to spatially probe the lipid composition in a GBM biopsy from two regions with different histopathologies: one region with most cells of uniform size and shape, the homogeneous part, and the other with cells showing a great variation in size and shape, the heterogeneous part. Our results reveal elevated levels of cholesterol, diacylglycerols, and some phosphatidylethanolamine in the homogeneous part, while the heterogeneous part was dominated by a variety of fatty acids, phosphatidylcholine, and phosphatidylinositol species. We also observed a high expression of cholesterol in the homogeneous tumor region to be associated with large cells but not with macrophages. Our findings suggest that ToF-SIMS can distinguish in lipid distribution between parts within a human GBM tumor, which can be linked to different molecular mechanisms

Longitudinal Follow-up of Chronic Pulmonary Manifestations in Esophageal Atresia: A Clinical Algorithm and Review of the Literature

In the past decades improved surgical techniques and better neonatal supportive care have resulted in reduced mortality of patients with esophageal atresia (EA), with or without tracheoesophageal fistula, and in increased prevalence of long-term complications, especially respiratory manifestations. This integrative review describes the techniques currently used in the pediatric clinical practice for assessing EA-related respiratory disease. We also present a novel algorithm for the evaluation and surveillance of lung disease in EA. A total of 2813 articles were identified, of which 1451 duplicates were removed, and 1330 were excluded based on review of titles and abstracts. A total of 32 articles were assessed for eligibility. Six reviews were excluded, and 26 original studies were assessed. Lower respiratory tract infection seems frequent, especially in the first years of life. Chronic asthma, productive cough, and recurrent bronchitis are the most common respiratory complaints. Restrictive lung disease is generally reported to prevail over the obstructive or mixed patterns, and, overall, bronchial hyperresponsiveness can affect up to 78% of patients. At lung imaging, few studies detected bronchiectasis and irregular cross-sectional shape of the trachea, whereas diffuse bronchial thickening, consolidations, and pleural abnormalities were the main chest X-ray findings. Airway endoscopy is seldom included in the available studies, with tracheomalacia and tracheobronchial inflammation being described in a variable proportion of cases. A complete diagnostic approach to long-term respiratory complications after EA is mandatory. In the presence of moderate-to-severe airway disease, patients should undergo regular tertiary care follow-up with functional assessment and advanced chest imaging

Axon Myelin Transfer of a Non-Enveloped Virus

We showed previously that Theiler's virus, a neurotropic non-enveloped picornavirus of mouse, traffics from the axon of infected neurons into the surrounding myelin. When this traffic is interrupted, as in the shiverer mouse which bears a mutation in the myelin basic protein gene, the virus is unable to persist in the central nervous system. In the present work, we used the Wlds mutant mouse, a strain in which axonal degeneration is considerably slowed down, to show that axon to myelin traffic takes place in the absence of axon degeneration. Our results suggest the existence of a mechanism of transfer of axonal cytoplasm into the myelin which Theiler's virus might exploit to ensure its persistence

Examining the Duration of Carryover Effect in Patients With Chronic Pain Treated With Spinal Cord Stimulation (EChO Study):An Open, Interventional, Investigator-Initiated, International Multicenter Study

Objectives: Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS. Materials and Methods: Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data. Results: In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time. Conclusions: This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms. Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03386058.</p

Appropriate referral and selection of patients with chronic pain for spinal cord stimulation: European consensus recommendations and e-health tool

Background: Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic, neuropathic-like and ischaemic pain. However, the heterogeneity of patients in daily clinical practice makes it often challenging to determine which patients are eligible for this treatment, resulting in undesirable practice variations. This study aimed to establish patient-specific recommendations for referral and selection of SCS in chronic pain. Methods: A multidisciplinary European panel used the RAND/UCLA Appropriateness Method (RUAM) to assess the appropriateness of (referral for) SCS for 386 clinical scenarios in four pain areas: chronic low back pain and/or leg pain, complex regional pain syndrome, neuropathic pain syndromes and ischaemic pain syndromes. In addition, the panel identified a set of psychosocial factors that are relevant to the decision for SCS treatment. Results: Appropriateness of SCS was strongly determined by the neuropathic or neuropathic-like pain component, location and spread of pain, anatomic abnormalities and previous response to therapies targeting pain processing (e.g. nerve block). Psychosocial factors considered relevant for SCS selection were as follows: lack of engagement, dysfunctional coping, unrealistic expectations, inadequate daily activity level, problematic social support, secondary gain, psychological distress and unwillingness to reduce high-dose opioids. An educational e-health tool was developed that combines clinical and psychosocial factors into an advice on referral/selection for SCS. Conclusions: The RUAM was useful to establish a consensus on patient-specific criteria for referral/selection for SCS in chronic pain. The e-health tool may help physicians learn to apply an integrated approach of clinical and psychosocial factors. Significance: Determining the eligibility of SCS in patients with chronic pain requires careful consideration of a variety of clinical and psychosocial factors. Using a systematic approach to combine evidence from clinical studies and expert opinion, a multidisciplinary European expert panel developed detailed recommendations to support appropriate referral and selection for SCS in chronic pain. These recommendations are available as an educational e-health tool (https://www.scstool.org/)

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030