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Background: The decision to initiate pediatric mechanical ventilation via tracheostomy ("home ventilation") is complex and parents often desire information from other parents who have faced this decision. However, parent-to-parent communication is challenging as it is difficult to connect new families to experienced families in ways that optimize informed, balanced decision-making., Objective: Create a parent-to-parent web-based tool to support decision-making about pediatric home ventilation., Patient Involvement: The tool was created based on interviews and feedback from parents., Methods: We interviewed parents who previously chose for, or against, home ventilation for their child. Interview themes and family comments guided website development. Viewer feedback was solicited via an embedded survey in the tool., Results: We created 6 composite character families to communicate 6 themes about home ventilation: 1) Considering treatment options, 2) Talking with medical team, 3) Impact on life at home, 4) Impact on relationships, 5) Experience for the child, and 6) If the child's life is short. Nine families who reviewed the draft tool felt it would have helped with their decision about home ventilation. Specifically, it supported families in thinking through what was "most important about their child's breathing problems" (7 of 9 parents) and feeling "more at peace with the decision" (8 of 9 parents). Between 6/1/20-12/31/22, nearly 5500 viewers have accessed the tool and 56 viewers completed the survey (including 13 families and 39 clinicians). Feedback from experienced families and clinicians reported the tool taught them something new., Discussion: This novel parent-to-parent tool shows promise for expanding access to balanced, family-centered information about pediatric home ventilation., Practical Value: The diverse stories and decisions let parents access multiple family perspectives. The tool's focus is on family-centric information that parents reported was usually missing from clinician counseling., Funding: This work was supported by the National Palliative Care Research Center., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

FraR, a transcriptional repressor, was postulated to regulate the metabolism of the Amadori compound fructose-asparagine (F-Asn) in the foodborne pathogen Salmonella enterica. Here, the DNA- and inducer-binding affinities and stoichiometries of FraR were determined and cross-validated by electrophoretic mobility-shift assays (EMSAs) and online buffer exchange coupled to native mass spectrometry (OBE-nMS). We demonstrate the utility of OBE-nMS to characterize protein and protein-DNA complexes that are not amenable to offline exchange into volatile buffers. OBE-nMS complemented EMSAs by revealing that FraR binds to the operator DNA as a dimer and by establishing 6-phosphofructose-aspartate as the inducer that weakens DNA binding by FraR. These results provide insights into how FraR regulates the expression of F-Asn-catabolizing enzymes and add to our understanding of the intricate bacterial circuitry that dictates utilization of diverse nutrients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Few studies have examined factors associated with health-related quality of life (HRQoL) in youth with psychogenic non-epileptic seizures (PNES). In adults, internalizing symptoms such as depression have been shown to be more closely associated with HRQoL than seizure frequency, however, this has not been studied in samples of youth. Investigations into these areas are needed in order to enhance our understanding of the impact of this condition on children and adolescents and inform future clinical intervention., Methods: The current study includes 37 youth and one of their parents who attended a clinic visit for treatment of PNES. Children and parents completed measures of psychological functioning, and medical data were extracted from patient charts., Results: Parent-reported anxiety (B=-0.45, p = 0.05) and depression (B=-0.60, p = 0.01) were related to parent-report of HRQoL; self-report of depression was related to self-reported HRQoL (B=-0.90, p < 0.001). Seizure frequency, somatic complaints, and social problems were not related to HRQoL in this sample., Conclusions: Internalizing symptoms, not seizure frequency, are associated with poorer overall functioning in youth with PNES. Interventions focused on improving anxiety and depression in addition to seizure cessation may contribute to improved HRQoL in youth with PNES more so than those focused on seizure cessation alone., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Intestinal failure (IF) is defined from a requirement or intravenous supplementation due to failing capacity to absorb nutrients and fluids. Acute IF is an acute, potentially reversible form of IF. We aimed to identify the prevalence, underlying causes and outcomes of acute IF., Methods: This point-of-prevalence study included all adult patients hospitalized in acute care hospitals and receiving parenteral nutrition (PN) on a study day. The reason for PN and the mechanism of IF (if present) were documented by local investigators and reviewed by an expert panel., Results: Twenty-three hospitals (19 university, 4 regional) with a total capacity of 16,356 acute care beds and 1237 intensive care unit (ICU) beds participated in this study. On the study day, 338 patients received PN (21 patients/1000 acute care beds) and 206 (13/1000) were categorized as acute IF. The categorization of reason for PN was revised in 64 cases (18.9% of total) in consensus between the expert panel and investigators. Hospital mortality of all study patients was 21.5%; the median hospital stay was 36 days. Patients with acute IF had a hospital mortality of 20.5% and median hospital stay of 38 days (P > 0.05 for both outcomes). Disordered gut motility (e.g. ileus) was the most common mechanism of acute IF, and 71.5% of patients with acute IF had undergone abdominal surgery. Duration of PN of ≥42 days was identified as being the best cut-off predicting hospital mortality within 90 days. PN ≥ 42 days, age, sepsis and ICU admission were independently associated with 90-day hospital mortality., Conclusions: Around 2% of adult patients in acute care hospitals received PN, 60% of them due to acute IF. High 90-day hospital mortality and long hospital stay were observed in patients receiving PN, whereas presence of acute IF did not additionally influence these outcomes. Duration of PN was associated with increased 90-day hospital mortality., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Micronized copper azole (MCA) is a lumber treatment improve longevity. In this study, the in vivo response to PM 2.5 sanding dust generated from MCA-treated lumber was compared to that of untreated yellow pine (UYP) or soluble copper azole-treated (CA-C) lumber to determine if the MCA was more bioactive than CA-C. Mice were exposed to doses (28, 140, or 280 μg/mouse) of UYP, MCA, or CA-C sanding dust using oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) lactate dehydrogenase activity was increased at 1 day post-exposure to 280 μg/mouse of MCA and CA-C compared to UYP. BALF polymorphonuclear cells were increased by MCA and CA-C. There were increases in BALF cytokines in MCA and CA-C-exposed groups at 1 day post-exposure. Lung histopathology indicated inflammation with infiltration of neutrophils and macrophages. Pulmonary responses were more severe in MCA and CA-C-exposed groups at 1 day post-exposure. MCA caused more severe inflammatory responses than CA-C at 1 day post-exposure. These findings suggest that the MCA and CA-C sanding dusts are more bioactive than the UYP sanding dust, and, moreover, the MCA sanding dust is more bioactive in comparison to the CA-C sanding dust. No chronic toxic effects were observed among all observed sanding dusts., (Published by Elsevier B.V.)

Purpose: Children with sickle cell hemoglobinopathy (SCH) can demonstrate proliferative retinopathy with vision loss, but lack of consensus exists regarding screening regimens. We sought to determine the prevalence, age at onset, and risk factors associated with sickle cell retinopathy (SCR) to inform development of screening guidelines for asymptomatic children., Design: Retrospective cohort study., Participants: Children with SCH over a 4-year period., Methods: Prevalences of any retinopathy, nonproliferative retinopathy (NPR), and proliferative retinopathy (PR), determined as proportions of all children examined, were calculated. Subgroup analyses were completed by SCH genotype. Ages at first diagnosis were reported using standard descriptive statistics. The association of potential risk factors with retinopathy were assessed using univariate and multivariate linear and logistic regression., Main Outcome Measures: Outcomes were prevalence, age at onset, and type of SCR, based on examination by an ophthalmologist. Markers of SCH severity (number of emergency room or hospital admissions for crises, number of blood transfusions, hydroxyurea therapy, transcranial Doppler-confirmed cerebral vasculopathy), genotype, gender, and race were evaluated as SCR risk factors., Results: Of 398 children (mean age, 9.6±4.6 years; range 0-18 years), 208 (52%) showed sickle cell homozygote (SS) genotype, 113 (28%) showed sickle cell hemoglobin C (SC) genotype, and 77 (19%) showed trait genotype. Forty-eight children (12.1%) demonstrated SCR, 44 of 398 children (11.1%; 95% confidence interval, 8.3%-14.5%) demonstrated NPR, and 9 of 398 children (2.3%; 95% confidence interval, 1.2%-4.2%) demonstrated PR. Prevalence was higher for SC than SS genotype for NPR (21% vs. 9%) and PR (5% vs. 1%); onset for SC genotype was earlier than that for SS genotype for NPR (youngest diagnosis 4.8 vs. 6.1 years) and PR (12.2 vs. 15.4 years). No other risk factors were associated significantly with SCR., Conclusions: Clinical markers of SCH severity assessed were not associated with SCR and are not necessary for screening guidelines. Based on our study and literature review, although screening could begin at age 5 years for NPR, screening of children without ophthalmologic symptoms to identify treatment-requiring PR could begin later, at 9 years of age for SC and 13 years of age for SS., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Pediatric patients undergoing cardiac surgeries are at an increased surgical site infection (SSI) risk, given prolonged cardiopulmonary bypasses and delayed sternal closures. At one institution, the majority of cardiac patients developed SSIs during prolonged recoveries in the cardiovascular intensive care unit (CVICU). Although guidelines have been published to reduce SSIs in the perioperative period, there have been few guidelines to reduce the risk during prolonged hospital recoveries. The aim of this project was to study a postoperative SSI reduction care bundle, with a goal of reducing cardiac SSIs by 50%, from 3.4 to 1.7 per 100 procedures., Methods: This project was conducted at a quaternary, pediatric academic center with a 20-bed CVICU. Historical control data were recorded from January 2013 through May 2015 and intervention/sustainment data from June 2015 through March 2017. A multidisciplinary SSI reduction team developed five key drivers that led to implementation of 11 postoperative SSI reduction care elements. Statistical process control charts were used to measure process compliance, and Pearson's chi-square test was used to determine differences in SSI rates., Results: Prior to implementation, there were 27 SSIs in 799 pediatric cardiac surgeries (3.4 SSIs per 100 surgeries). After the intervention, SSIs significantly decreased to 5 in 570 procedures (0.9 SSIs per 100 surgeries; p = 0.0045)., Conclusion: This project describes five key drivers and 11 elements that were dedicated to reducing the risk of SSI during prolonged CVICU recoveries from pediatric cardiac surgery, with demonstrated sustainability., (Copyright © 2018 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Intestinal failure (IF) is defined as "the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth". Functionally, it may be classified as type I acute intestinal failure (AIF), type II prolonged AIF and type III chronic intestinal failure (CIF) The ESPEN Workshop on IF was held in Bologna, Italy, on 15-16 October 2017 and the aims of this document were to highlight the current state of the art and future directions for research in IF., Methods: This paper represents the opinion of experts in the field, based on current evidence. It is not a formal review, but encompasses the current evidence, with emphasis on epidemiology, classification, diagnosis and management., Results: IF is the rarest form of organ failure and can result from a variety of conditions that affect gastrointestinal anatomy and function adversely. Assessment, diagnosis, and short and long-term management involves a multidisciplinary team with diverse expertise in the field that aims to reduce complications, increase life expectancy and improve quality of life in patients., Conclusions: Both AIF and CIF are relatively rare conditions and most of the published work presents evidence from small, single-centre studies. Much remains to be investigated to improve the diagnosis and management of IF and future studies should rely on multidisciplinary, multicentre and multinational collaborations that gather data from large cohorts of patients. Emphasis should also be placed on partnership with patients, carers and government agencies in order to improve the quality of research that focuses on patient-centred outcomes that will help to improve both outcomes and quality of life in patients with this devastating condition., (Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: The aim of the study was to evaluate the applicability of the ESPEN 16-category clinical classification of chronic intestinal failure, based on patients' intravenous supplementation (IVS) requirements for energy and fluids, and to evaluate factors associated with those requirements., Methods: ESPEN members were invited to participate through ESPEN Council representatives. Participating centers enrolled adult patients requiring home parenteral nutrition for chronic intestinal failure on March 1st 2015. The following patient data were recorded though a structured database: sex, age, body weight and height, intestinal failure mechanism, underlying disease, IVS volume and energy need., Results: Sixty-five centers from 22 countries enrolled 2919 patients with benign disease. One half of the patients were distributed in 3 categories of the ESPEN clinical classification. 9% of patients required only fluid and electrolyte supplementation. IVS requirement varied considerably according to the pathophysiological mechanism of intestinal failure. Notably, IVS volume requirement represented loss of intestinal function better than IVS energy requirement. A simplified 8 category classification of chronic intestinal failure was devised, based on two types of IVS (either fluid and electrolyte alone or parenteral nutrition admixture containing energy) and four categories of volume., Conclusions: Patients' IVS requirements varied widely, supporting the need for a tool to homogenize patient categorization. This study has devised a novel, simplified eight category IVS classification for chronic intestinal failure that will prove useful in both the clinical and research setting when applied together with the underlying pathophysiological mechanism of the patient's intestinal failure., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Electronic cigarettes (e-cigs) have fast increased in popularity but the physico-chemical properties and toxicity of the generated emission remain unclear. Reactive oxygen species (ROS) are likely present in e-cig emission and can play an important role in e-cig toxicity. However, e-cig ROS generation is poorly documented. Here, we generated e-cig exposures using a recently developed versatile exposure platform and performed systematic ROS characterization on e-cig emissions using complementary acellular and cellular techniques: 1) a novel acellular Trolox-based mass spectrometry method for total ROS and hydrogen peroxide (H 2 O 2 ) detection, 2) electron spin resonance (ESR) for hydroxyl radical detection in an acellular and cellular systems and 3) in vitro ROS detection in small airway epithelial cells (SAEC) using the dihydroethidium (DHE) assay. Findings confirm ROS generation in cellular and acellular systems and is highly dependent on the e-cig brand, flavor, puffing pattern and voltage. Trolox method detected a total of 1.2-8.9nmol H 2 O 2eq. /puff; H 2 O 2 accounted for 12-68% of total ROS. SAEC cells exposed to e-cig emissions generated up to eight times more ROS compared to control. The dependency of e-cig emission profile on e-cig features and operational parameters should be taken into consideration in toxicological studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Home parenteral nutrition (HPN) is the mainstay of treatment for patients with Type 3 intestinal failure (IF), however long term data on mortality and nutritional outcomes are limited., Objectives: To assess the long-term survival and requirements for ongoing HPN in patients receiving treatment at a UK national referral centre for intestinal failure., Methods: Patients with IF who received HPN for more than 3 months at this Intestinal Failure Unit between 1978 and 2011 had their clinical records reviewed. SPSS 20 was utilised to perform Cox regression analysis and generate Kaplan Meier curves, with the aim of identifying factors associated with death and the continued need for HPN., Results: Case notes from 545 patients were reviewed. Overall survival (OS) in patients without malignancy at commencement of IF was 93%, 71%, 59% and 28% at 1, 5, 10 and 20 years after starting treatment. Crohn's disease, mesenteric ischaemia and chronic intestinal pseudo-obstruction were associated with a better OS than scleroderma and radiation enteritis on multivariate analysis. Older age at onset of IF was associated with poor OS, while shorter small bowel length or central line sepsis was not. 15% (25/170) of deaths were due to complications of HPN (central line sepsis = 10, IF-associated liver disease = 15). Continued HPN dependence in survivors was 83%, 63%, 59% and 53% at 1, 5, 10 and 15 years, respectively. Among the 153 patients without malignancy who achieved nutritional independence from HPN, 77 (50.3%) did so after surgical reconstruction of the alimentary tract (HPN duration mean 19 months, range 3-126 months). 76 patients (49.7%) weaned from HPN without undergoing surgical reconstruction., Conclusion: This is the largest reported data set on long-term survival and dependence on HPN and will inform the indications, benefits and risks of treatment in disease specific groups. A significant proportion of patients achieved nutritional autonomy without surgical intervention., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Intestinal failure (IF) is the consequence of a reduction of gut function below the minimum necessary for the absorption of nutrients from the gastrointestinal tract. Types I and II comprise acute intestinal failure (AIF). Although its prevalence is relatively low, type II AIF is serious and requires specialist multidisciplinary care, often for prolonged periods before its resolution. The key aspects are: sepsis control, fluid and electrolyte resuscitation, optimization of nutritional status, wound care, appropriate surgery and active rehabilitation. The ESPEN Acute Intestinal Failure Special Interest Group (AIF SIG) has devised this position paper to provide a state-of-the-art overview of the management of type II AIF and to point out areas for future research., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: To describe morphologic and visual outcomes in eyes with angiographic cystoid macular edema (CME) treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (nAMD)., Design: Prospective cohort study within a randomized clinical trial., Participants: A total of 1185 CATT study subjects., Methods: Baseline fluorescein angiography (FA) images of all CATT study eyes were evaluated for CME. Grading of other characteristics on optical coherence tomography (OCT) and photographic images at baseline and during 2-year follow-up was completed by readers at the CATT Reading Centers. Three groups were created on the basis of baseline CME and intraretinal fluid (IRF) status: (1) CME, (2) IRF without CME, (3) neither CME nor IRF., Main Outcome Measures: Visual acuity (VA) and total central retinal thickness (CRT) on OCT at baseline, year 1, and year 2., Results: Among 1131 participants with images of sufficient quality for determining CME and IRF at baseline, 92 (8.1%) had CME, 766 (67.7%) had IRF without CME, and 273 (24.1%) had neither. At baseline, eyes with CME had worse mean VA (letters) than eyes with IRF without CME and eyes with neither CME nor IRF (52 vs. 60 vs. 66 letters, P < 0.001); higher mean total CRT (μm) on OCT (514 vs. 472 vs. 404, P < 0.001); and greater hemorrhage, retinal angiomatous proliferation (RAP) lesions, and classic choroidal neovascularization (CNV). All groups showed improvement in VA at follow-up; however, the CME group started and ended with the worst VA among the 3 groups. Central retinal thickness, although higher at baseline for the CME group, was similar at 1 and 2 years follow-up for all groups. More eyes with CME (65.3%) developed scarring during 2 years of follow-up compared with eyes with IRF without CME (43.8%) and eyes with neither CME nor IRF (32.5%; P < 0.001)., Conclusions: In CATT, eyes with CME had worse baseline and follow-up VA, although all groups showed similar rates of improvement in VA during 2 years of follow-up. Cystoid macular edema seems to be a marker for poorer visual outcomes in nAMD because of underlying baseline retinal dysfunction and subsequent scarring., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare baseline characteristics, visual acuity (VA), and morphologic outcomes between eyes with retinal angiomatous proliferation (RAP) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs., Design: Prospective cohort study within the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Participants: Patients with NVAMD., Methods: Reading center staff evaluated digital color fundus photographs, fluorescein angiography (FA) images, and optical coherence tomography (OCT) scans of eyes with NVAMD treated with either ranibizumab or bevacizumab over a 2-year period. Retinal angiomatous proliferation was identified by the intense intra-retinal leakage of fluorescein in combination with other associated features., Main Outcome Measures: Visual acuity; fluorescein leakage; scar; geographic atrophy (GA) on FA; retinal thickness, fluid, and subretinal hyperreflective material (SHRM) on OCT; and the number of intravitreal anti-VEGF injections at 1 and 2 years., Results: Retinal angiomatous proliferation was present in 126 of 1183 (10.7%) study eyes at baseline. Mean VA improvement from baseline was greater (10.6 vs. 6.9 letters; P = 0.01) at 1 year, but similar at 2 years (7.8 vs. 6.2 letters; P = 0.34). At 1 year, eyes with RAP were more likely to have no fluid (46% vs. 26%; P < 0.001) on OCT, no leakage on FA (61% vs. 50%; P = 0.03), and greater reduction in foveal thickness (-240 μm vs. -161 μm; P < 0.001). They were more likely to demonstrate GA (24% vs. 15%; P = 0.01) and less likely to have scarring (17% vs. 36%; P < 0.001) or SHRM (36% vs. 48%; P = 0.01). These results were similar at 2 years. The mean change in lesion size at 1 year differed (-0.27 DA vs. 0.27 DA; P = 0.02), but was similar at 2 years (0.49 DA vs. 0.79 DA; P = 0.26). Among eyes treated PRN, eyes with RAP received a lower mean number of injections in year 1 (6.1 vs. 7.4; P = 0.003) and year 2 (5.4 vs. 6.6; P = 0.025)., Conclusions: At both 1 and 2 years after initiation of anti-VEGF treatment in CATT, eyes with RAP were less likely to have fluid, FA leakage, scar, and SHRM and more likely to have GA than eyes without RAP. Mean improvement in VA was similar at 2 years., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Sample preparation for atom probe tomography of 3D semiconductor devices has proven to significantly affect field evaporation and the reliability of reconstructed data. A cross-sectional preparation method is applied to state-of-the-art Si finFET technology on SOI. This preparation approach advantageously provides a conductive path for voltage and heat, offers analysis of many fins within a single tip, and improves resolution across interfaces of particular interest. Measured B and Ge profiles exhibit good correlation with SIMS and EDX and show no signs of B clustering or pile-up near the Si/SiGe interface of the fin., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: The effectiveness of annual eye examinations in diabetic children is unclear. We sought to determine the prevalence and onset of ocular pathology in children with diabetes mellitus (DM), identify risk factors for ocular disease, and recommend a screening regimen for asymptomatic children., Design: Retrospective, consecutive cohort study., Participants: Children aged less than 18 years with type 1 or 2 DM examined over a 4-year period., Methods: All children underwent a complete eye examination, including dilated fundoscopy and cycloplegic refraction. A literature review was performed, identifying the youngest reported age and shortest reported duration of DM before the diagnosis of diabetic retinopathy (DR)., Main Outcome Measures: Prevalence of DR, cataract, high refractive error, and strabismus., Results: A total of 370 children (mean age, 11.2 years; range, 1-17.5 years) had 693 examinations, with a mean DM duration of 5.2 years (range, 0.1-16.2 years) and a mean hemoglobin A1c (HbA1c) of 8.6 (range, 5-≥14). No children had DR. A total of 12 children had cataract; 5 required extraction but were identified by decreased vision, not diabetic screening. A total of 19 children had strabismus; only 1 was microvascular paralytic strabismus. A total of 41 children had high refractive error. There were no associations between these conditions and duration or control of DM. In the literature, the youngest age at diagnosis of severe DR was 15 years, and the shortest duration of disease was 5 years., Conclusions: Diabetic retinopathy is rare in children regardless of duration and control of DM. On the basis of our study and literature review, screening examinations for type 1 diabetes could begin at age 15 years or at 5 years after the diagnosis of DM, whichever occurs later, unless the child is judged by the endocrinologist as being at unusually high risk. Other ocular complications are identifiable through existing amblyopia screening methods., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Intestinal failure (IF) is not included in the list of PubMed Mesh terms, as failure is the term describing a state of non functioning of other organs, and as such is not well recognized. No scientific society has yet devised a formal definition and classification of IF. The European Society for Clinical Nutrition and Metabolism guideline committee endorsed its "home artificial nutrition and chronic IF" and "acute IF" special interest groups to write recommendations on these issues., Methods: After a Medline Search, in December 2013, for "intestinal failure" and "review"[Publication Type], the project was developed using the Delphi round methodology. The final consensus was reached on March 2014, after 5 Delphi rounds and two live meetings., Results: The recommendations comprise the definition of IF, a functional and a pathophysiological classification for both acute and chronic IF and a clinical classification of chronic IF. IF was defined as "the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth"., Conclusions: This formal definition and classification of IF, will facilitate communication and cooperation among professionals in clinical practice, organization and management, and research., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Patients with Intestinal failure (IF) on long-term nutritional support (IF Type 3) through parenteral nutrition (PN) require invasive venous access to provide nutritional compounds. Central venous catheters (CVC) are at risk of complications including microbial infections and occlusion. Occlusions can be resolved by administering parenteral solutions to achieve patency. However, we report an alternative methodology for salvaging occluded CVCs and achieving patency using endoluminal brushing., Methods: Patients admitted with a CVC occlusion to one of the two national IF centres in the UK, were entered into a prospectively managed database and the data were then analysed retrospectively. The study used data from patients who had CVC occlusions from December 2003 to March 2006 (Cohort 1) and from April 2006 to September 2010 (Cohort 2). Cohort 1 included occluded CVCs managed using endoluminal brushing and the split of cohorts was determined by the availability of endoluminal brushes. Cohort 2 included occluded CVCs managed using a 'standard' technique of urokinase with or without adjuncts such as Ethanol, Hydrochloric acid or Sodium hydroxide. If therapy failed, the CVC was removed. Data were recorded on success of achieving patency and occurrence of re-occlusion., Results: 66 episodes of CVC occlusion from 44 patients occurred in Cohort 1, compared to 68 episodes in 45 patients in Cohort 2. There was no difference in gender, age, median time on TPN prior to occlusive episode or disease aetiology. The number of CVCs where patency was achieved was 57 (86%) in Cohort 1 compared to 34 (50%) in Cohort 2 (p < 0.0001). Consequently, the number of CVCs replaced were 9 (14%) in Cohort 1 compared to 34 (50%) in Cohort 2 (p < 0.0001). There were no complications associated with endoluminal brushing or 'standard' therapy., Conclusion: This is the first report of the safe and effective use of endoluminal brushing to manage occluded CVCs in patients requiring long-term parenteral nutrition., (Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Precis: The aim of this study was to evaluate the safety and tolerance of a soybean/MCT/olive/fish oil emulsion in intestinal failure patients on long-term parenteral nutrition. 73 patients took part in a randomized, double-blind, multi-centre study. The study demonstrates that the lipid emulsion containing four different types of oils is safe and well tolerated in long-term PN., Background & Aim: Long-term safety and efficacy of a lipid emulsion containing soybean oil, medium-chain triglycerides (MCT), olive oil and fish oil and enriched in vitamin E have not yet been evaluated in adult patients requiring long-term parenteral nutrition (PN)., Methods: Randomised, controlled, double-blind, multicentre study in 73 patients with stable intestinal failure, requiring PN with either soybean/MCT/olive/fish emulsion (SMOFlipid, n = 34) or soybean emulsion (Intralipid, control n = 39) for 4 weeks. Safety and tolerance were monitored with standard clinical laboratory parameters, adverse events (AEs, according to the Common Terminology Criteria for Adverse Events (CTCAE) classification v 3.0) and vital signs. Fatty acid pattern in red blood cell phospholipids and plasma lipoproteins, serum Vitamin E, Interleukin (IL)-6, and soluble tumour necrosis (s-TNF)-receptor(R)II were also evaluated., Results: Mean concentrations of alanine transaminase (ALT), aspartate transaminase (AST) and total bilirubin, whilst remaining within the reference range, were significantly lower with soybean/MCT/olive/fish (SMOF) oil emulsion after the treatment period compared to control. Eicosapentaenoic acid, docosahexaenoic acid and n-3/n-6 fatty acid ratio increased in the SMOF group, while they remained unchanged in the control in plasma and RBC. Serum α-tocopherol concentrations significantly increased in the study group compared to control (p = 0.0004). IL-6 and sTNF-RII levels did not change during the study period. Grade 4 (serious) adverse events occurred in 2 SMOF patients and in 8 control patients (p = 0.03)., Conclusions: Soybean/MCT/olive/fish emulsion was safe and well tolerated over 4 weeks and leads to positive change in fatty acids profile., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background and Aims: Glycoprotein 6 (GP6) is a platelet-specific collagen receptor implicated in the thrombotic pathway to acute myocardial infarction (AMI), but a possible genetic relationship between GP6 and AMI is poorly understood. We tested for the genetic association between AMI and single nucleotide polymorphisms (SNPs) in 24 loci, including GP6., Methods and Results: We conducted a case-control study of AMI and GP6 in a community-based population (n = 652 cases, 625 controls). We also examined men and women separately and stratified the latter by use of hormone replacement therapy (HRT). Among both sexes, the strongest association was for a protective missense polymorphism (rs1163662) in the GP6 gene (OR = 0.70; Bonferroni-adjusted p < 0.05). SNPs in GP6 were also strongly associated with AMI among women who reported ever taking HRT, but not among women who never took HRT. Haplotype analyses were consistent with the single-SNP findings., Conclusions: In this sample of white non-Hispanic men and women, several SNPs in GP6 were significantly related to risk of AMI. Development of pharmacologic therapy directed towards platelet activity and thrombosis may reduce the incidence of AMI among at-risk groups., (Copyright © 2009 Elsevier B.V. All rights reserved.)

We recently reported long-term organ allograft survival without ongoing immunosuppression in four of five patients receiving combined kidney and bone marrow transplantation from haploidentical donors following nonmyeloablative conditioning. In vitro assays up to 18 months revealed donor-specific unresponsiveness. We now demonstrate that T cell recovery is gradual and is characterized by memory-type cell predominance and an increased proportion of CD4⁺ CD25⁺ CD127⁻ FOXP3⁺ Treg during the lymphopenic period. Complete donor-specific unresponsiveness in proliferative and cytotoxic assays, and in limiting dilution analyses of IL-2-producing and cytotoxic cells, developed and persisted for the 3-year follow-up in all patients, and extended to donor renal tubular epithelial cells. Assays in two of four patients were consistent with a role for a suppressive tolerance mechanism at 6 months to 1 year, but later (≥ 18 months) studies on all four patients provided no evidence for a suppressive mechanism. Our studies demonstrate, for the first time, long-term, systemic donor-specific unresponsiveness in patients with HLA-mismatched allograft tolerance. While regulatory cells may play an early role, long-term tolerance appears to be maintained by a deletion or anergy mechanism., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Five patients with end-stage kidney disease received combined kidney and bone marrow transplants from HLA haploidentical donors following nonmyeloablative conditioning to induce renal allograft tolerance. Immunosuppressive therapy was successfully discontinued in four patients with subsequent follow-up of 3 to more than 6 years. This allograft acceptance was accompanied by specific T-cell unresponsiveness to donor antigens. However, two of these four patients showed evidence of de novo antibodies reactive to donor antigens between 1 and 2 years posttransplant. These humoral responses were characterized by the presence of donor HLA-specific antibodies in the serum with or without the deposition of the complement molecule C4d in the graft. Immunofluorescence staining, ELISA assays and antibody profiling using protein microarrays demonstrated the co-development of auto- and alloantibodies in these two patients. These responses were preceded by elevated serum BAFF levels and coincided with B-cell reconstitution as revealed by a high frequency of transitional B cells in the periphery. To date, these B cell responses have not been associated with evidence of humoral rejection and their clinical significance is still unclear. Overall, our findings showed the development of B-cell allo- and autoimmunity in patients with T-cell tolerance to the donor graft.

The SH2 domain of the C-terminal Src kinase [Csk] contains a unique disulfide bond that is not present in other known SH2 domains. To investigate whether this unusual disulfide bond serves a novel function, the effects of disulfide bond formation on catalytic activity of the full-length protein and on the structure of the SH2 domain were investigated. The kinase activity of full-length Csk decreases by an order of magnitude upon formation of the disulfide bond in the distal SH2 domain. NMR spectra of the fully oxidized and fully reduced SH2 domains exhibit similar chemical shift patterns and are indicative of similar, well-defined tertiary structures. The solvent-accessible disulfide bond in the isolated SH2 domain is highly stable and far from the small lobe of the kinase domain. However, reduction of this bond results in chemical shift changes of resonances that map to a cluster of residues that extend from the disulfide bond across the molecule to a surface that is in direct contact with the small lobe of the kinase domain in the intact molecule. Normal mode analyses and molecular dynamics calculations suggest that disulfide bond formation has large effects on residues within the kinase domain, most notably within the active-site cleft. Overall, the data indicate that reversible cross-linking of two cysteine residues in the SH2 domain greatly impacts catalytic function and interdomain communication in Csk.

Six patients with renal failure due to multiple myeloma (MM) received simultaneous kidney and bone marrow transplantation (BMT) from HLA-identical sibling donors following nonmyeloablative conditioning, including cyclophosphamide (CP), peritransplant antithymocyte globulin and thymic irradiation. Cyclosporine (CyA) was given for approximately 2 months posttransplant, followed by donor leukocyte infusions. All six patients accepted their kidney grafts long-term. Three patients lost detectable chimerism but accepted their kidney grafts off immunosuppression for 1.3 to >7 years. One such patient had strong antidonor cytotoxic T lymphocyte (CTL) responses in association with marrow rejection. Two patients achieved full donor chimerism, but resumed immunosuppression to treat graft-versus-host disease. Only one patient experienced rejection following CyA withdrawal. He responded to immunosuppression, which was later successfully withdrawn. The rejection episode was associated with antidonor Th reactivity. Patients showed CTL unresponsiveness to cultured donor renal tubular epithelial cells. Initially recovering T cells were memory cells and were enriched for CD4+CD25+ cells. Three patients are in sustained complete remissions of MM, despite loss of chimerism in two. Combined kidney/BMT with nonmyeloablative conditioning can achieve renal allograft tolerance and excellent myeloma responses, even in the presence of donor marrow rejection and antidonor alloresponses in vitro.

The SH2 domain is required for high catalytic activity in the COOH-terminal Src kinase (Csk). Previous solution studies suggest that a short peptide sequence, the SH2-kinase linker, provides a functional connection between the active site and the distal SH2 domain that could underlie this catalytic phenomenon. Substitutions in Phe183 (tyrosine, alanine, and glycine), a critical hydrophobic residue in the linker, result in large decreases in substrate turnover and large increases in the K(m) for ATP. Indeed, F183G possesses kinetic parameters that are similar to that for a truncated form of Csk lacking the SH2 domain, suggesting that a single mutation disrupts communication between this domain and the active site. Based on equilibrium and stopped-flow fluorescence experiments, the elevated K(m) values for the mutants are due to changes in the rates of phosphoryl transfer and not to reduced ATP-binding affinities. Based on hydrogen-deuterium exchange experiments, glycine substitution reduces flexibility in several polypeptide regions in Csk, tyrosine substitution increases flexibility, and alanine substitution leads to mixed effects compared to wild-type. Normal mode analysis indicates that Phe183 and its environment are under strain, a theoretical finding that supports the results of mutations. Overall, the data indicate that domain-domain interactions, controlled through the SH2-kinase linker, provide a dynamic balance within the Csk framework that is ideal for efficient phosphoryl transfer in the active site.

Anti-CD154 (CD40L) monoclonal antibody (mAb) plus bone marrow transplantation (BMT) in mice receiving CD8 cell-depleting mAb leads to long-term mixed hematopoietic chimerism and systemic donor-specific tolerance through peripheral and central deletional mechanisms. However, CD4(+) T-cell tolerance is demonstrable in vitro and in vivo rapidly following BMT, before deletion of donor-reactive CD4 cells is complete, suggesting the involvement of other mechanisms. We examined these mechanisms in more detail. Spot enzyme-linked immunosorbent (ELISPOT) analysis revealed specific tolerization (within 4 to 15 days) of both T helper 1 (Th1) and Th2 cytokine responses to the donor, with no evidence for cytokine deviation. Tolerant lymphocytes did not significantly down-regulate rejection by naive donor-reactive T cells in adoptive transfer experiments. No evidence for linked suppression was obtained when skin expressing donor alloantigens in association with third-party alloantigens was grafted. T-cell receptor (TCR) transgenic mixing studies revealed that specific peripheral deletion of alloreactive CD4 T cells occurs over the first 4 weeks following BMT with anti-CD154. In contrast to models involving anti-CD154 without BMT, BMT with anti-CD154 leads to the rapid induction of anergy, followed by deletion of pre-existing donor-reactive peripheral CD4(+) T cells; the rapid deletion of these cells obviates the need for a regulatory cell population to suppress CD4 cell-mediated alloreactivity.

Long-term multilineage chimerism is achieved in CD45 congenic mice receiving high bone marrow doses with or without mediastinal irradiation (MI). Increased donor chimerism results in MI-treated compared with nonirradiated animals, suggesting that MI makes "space" for engraftment of donor pluripotent hematopoietic stem cells (PHSCs). We have now examined whether space is systemic or whether increased engraftment of donor marrow in locally irradiated mice is confined to the irradiated bones. While increased donor chimerism was observed in irradiated bones compared with nonirradiated bones of MI-treated animals 4 weeks following bone marrow transplantation (BMT), these differences were minimal by 40 weeks. MI-treated chimeras contained more adoptively transferable donor PHSCs in the marrow of both irradiated and distant bones compared with non-MI-treated chimeras. Similar proportions of donor PHSCs were present in irradiated and nonirradiated bones of locally irradiated mice at both 4 and 40 weeks. Irradiated bones contained more donor short-term repopulating cells than distant bones at 4 weeks, but not 40 weeks, after BMT. Our study suggests that local proliferation of donor PHSCs in mice receiving local irradiation rapidly leads to a systemic increase in donor PHSC engraftment.

We used the Tc1/mariner family transposable element Sleeping Beauty (SB) for transgenesis and long-term expression studies in the zebrafish (Danio rerio), a popular organism for clinical disease, vertebrate patterning, and cell biology applications. SB transposase enhanced the transgenesis and expression rate sixfold (from 5 to 31%) and more than doubled the total number of tagged chromosomes over standard, plasmid injection-based transgenesis methods. Molecular analysis of these loci demonstrated a precise integration of these elements into recipient chromosomes with genetic footprints diagnostic of transposition. GFP expression from transposase-mediated integrants was Mendelian through the eighth generation. A blue-shifted GFP variant (BFP) and a red fluorescent protein (DsRed) were also useful transgenesis markers, indicating that multiple reporters are practical for use with SB in zebrafish. We showed that SB is suitable for tissue-specific transgene applications using an abbreviated gamma-crystallin GFP cassette. Finally, we describe a general utility transposon vector for chromosomal engineering and molecular genetics experiments in zebrafish. Together, these data indicate that SB is an efficient tool for transgenesis and expression in zebrafish, and that the transposon will be useful for gene expression in cell biology applications as well as an insertional mutagen for gene discovery during development.

Anti-CD40L mAb plus bone marrow transplantation (BMT) and recipient CD8 T-cell depletion permits long-term mixed hematopoietic chimerism and systemic donor-specific tolerance to be achieved across full MHC barriers. Initial tolerance is characterized by peripheral deletion of donor-reactive CD4 cells. In regimens using costimulatory blockade without BMT to achieve allograft survival, cyclosporine inhibited graft survival, suggesting that the combination may not be clinically applicable. We assessed the role of cyclosporine-sensitive mechanisms and the mechanisms of T-cell apoptosis involved in the induction of early peripheral CD4+ T-cell tolerance by BMT with anti-CD40L. Neither a short course of cyclosporine (14 days) nor the absence of FAS-mediated activation-induced cell death (AICD) blocked the induction or maintenance of donor-specific tolerance. IL-2 production was not associated with tolerance induction, consistent with the lack of a role for Fas-mediated AICD. Mice in which passive T-cell death was impaired because of constitutive expression of a Bcl-xL transgene did not develop tolerance with this protocol. These data confirm that deletion of donor-reactive T cells is critical for the induction of mixed chimerism and tolerance. However, the mechanisms involved may differ from those involved in costimulatory blockade regimens that do not include BMT.

Aims: This study was undertaken to report indications and practice of home enteral nutrition (HEN) in Europe., Methods: A questionnaire on HEN practice was sent to 23 centres from Belgium (B), Denmark (D), France (F), Germany (G), Italy (I), Poland (P), Spain (S) and the United Kingdom (UK). This involved adult patients newly registered in HEN programme from 1 January 1998 to 31 December 1998., Results: A total of 1397 patients (532 women, 865 men) were registered. The median incidence of HEN was 163 patients/million inhabitants/year (range: 62-457). Age distribution was 7.5%, 16-40 years; 37.1%, 41-65 years; 34.5%, 66-80 years and 20.9% >80 years. The chief underlying diseases were a neurological disorder (49.1%), or head and neck cancer (26.5%); the main reason for HEN was dysphagia (84.6%). A percutaneous endoscopic gastrostomy (58.2%) or a naso-gastric tube (29.3%) were used to infuse commercial standard or high energy diets (65.3%), or fibre diets (24.5%); infusion was cyclical (61.5%) or bolus (34.1%). Indications and feeds were quite similar throughout the different centres but some differences exist concerning the underlying disease. There was greater variation in the choice of tubes and mode of infusion. In F, G, I, S, and UK, costs of HEN are fully funded. In B, D, and P patients have to pay part or all of the charges., Conclusions: In Europe, HEN was utilised mainly in dysphagic patients with neurological disorders or cancer, using a standard feed via a PEG. However, there were important differences among the countries in the underlying diseases treated, the routes used, the mode of administration and the funding.

Previous kinetic studies demonstrated that nucleotide-derived conformational changes regulate function in the COOH-terminal Src kinase. We have employed enhanced methods of hydrogen-deuterium exchange-mass spectrometry (DXMS) to probe conformational changes on CSK in the absence and presence of nucleotides and thereby provide a structural framework for understanding phosphorylation-driven conformational changes. High quality peptic fragments covering approximately 63% of the entire CSK polypeptide were isolated using DXMS. Time-dependent deuterium incorporation into these probes was monitored to identify short peptide segments that exchange differentially with solvent. Regions expected to lie in loops exchange rapidly, whereas other regions expected to lie in stable secondary structure exchange slowly with solvent implying that CSK adopts a modular structure. The ATP analog, AMPPNP, protects probes in the active site and distal regions in the large and small lobes of the kinase domain, the SH2 domain, and the linker connecting the SH2 and kinase domains. The product ADP protects similar regions of the protein but the extent of protection varies markedly in several crucial areas. These areas correspond to the activation loop and helix G in the kinase domain and several inter-domain regions. These results imply that delivery of the gamma phosphate group of ATP induces unique local and long-range conformational changes in CSK that may influence regulatory motions in the catalytic pathway.

Introduction: The prevalence of deranged liver function tests (LFT) in patients on long-term home parenteral nutrition (HPN) is poorly documented. The aim of our study was to document the prevalence of this complication and possible associated factors., Method: Retrospective analysis of case notes of 107 patients on HPN was performed. Deranged LFT was defined as any biochemical parameter of LFT that is 1.5 times above the reference range., Results: There were 39 males and the median age was 51 (range 20-73) years old. Median duration of HPN was 40 (range 6-252) months. Underlying diagnoses were Crohn's disease (40%), ischaemic bowel disease in 28.1% (arterial or venous), post-surgical intestinal adhesion and fistula (16.9%) and others (21.7%). The mean energy intake from HPN was 1003+/-544(SD) kcal/day with 845+/-474 kcal/day from glucose, 157+/-127 kcal/day from fat and mean nitrogen intake was 6.2+/-3.6 g/day. Raised alkaline phosphatase (mean 197+/-143(SD)U/L) was the most common abnormality (40 patients). Two patients had hyperbilirubinaemia; one patient had hereditary spherocytosis and in the other patient, the cause could be attributed to HPN with bilirubin of 54 micromol/l. Fifty-one patients (47.7%) had deranged LFT as judged from raised parameters on LFT. Abnormality in LFT was transient in nine patients. For the other 42 patients (39%), abnormalities in LFT remained stable for median duration of follow-up of 18.5 (range 3-180) months. No patients developed decompensated liver disease. On univariate analysis, length of small bowel of less than 100 cm, a higher total caloric intake from HPN (mean 1117+/-486 kcal against 907+/-576 kcal, P<0.05), and higher daily caloric intake from HPN in relation to calculated daily energy requirement (70+/-32% against 57+/-36%) were noted to be significantly associated with deranged LFT. However, on multivariate analysis, length of small bowel of less than 100 cm was the only significant variable for deranged LFT., Conclusion: Our finding showed the prevalence of deranged LFT to be 39% and raised alkaline phosphatase was the most common abnormality. Length of small bowel of less than 100 cm was found to be a significant independent variable for deranged LFT and the reason for this observation could be due to higher parenteral caloric intake. In our experience, LFT abnormalities are associated with a good prognosis as none of the patients developed decompensated liver disease.

We have previously shown that high levels of multiline-age mixed hematopoietic chimerism and systemic T-cell tolerance can be achieved in mice without myeloablation through the use of anti-CD40L and costimulatory blockade alone (plus CTLA4Ig) or with recipient CD8 depletion and allogeneic bone marrow transplantation. Chimeric mice permanently accept donor skin grafts (> 100 days), and rapidly reject third-party grafts. The mechanisms by which costimulatory blockade facilitates the engraftment of allogeneic hematopoietic cells have not been defined. To further understand the in vivo mechanisms by which the administration of anti-CD40L mAb facilitates the engraftment of donor bone marrow and rapidly tolerizes CD4+ T cells, we analyzed the establishment of chimerism and tolerance in CD40L -/- mice. We demonstrate here that anti-CD40L mAb treatment is required only to prevent CD40L/CD40 interactions, and that no signal to the T cell through CD40L is necessary for the induction of CD4+ tolerance. Peripheral deletion of donor-reactive CD4+ T cells occurs rapidly in CD40L -/- mice receiving bone marrow transplantation (BMT), indicating that this deletion in the presence of anti-CD40L is not due to targeting of activated CD4+ cells by the antibody. Complete CD4+ cell tolerance is observed by both skin graft acceptance and in vitro assays before deletion is complete, indicating that additional mechanisms play a role in inducing CD4+ T-cell tolerance as the result of BMT in the presence of CD40/CD40L blockade.

Background: Home parenteral nutrition (HPN) is a lifesaving treatment in patients with intestinal failure. Dependency of nutritional support becomes permanent for the majority of patients who had received HPN for at least 2 years. The alternative to long term HPN in selected patients is intestinal transplantation., Aims: To study some of the clinical, social and rehabilitation aspects of long-term HPN treatment., Methods: A survey was performed in nine European HPN centres. The questionnaire covered epidemiologic data, underlying diseases, intestinal anatomy, nutritional support and status, marital status, rehospitalization rate, HPN complications, rehabilitation score, drugs use, coexistent diseases and interest in intestinal transplantation. For some items, data were collected within 12 months prior to the evaluation., Results: This survey included 228 patients with a median age of 49 years. The median duration of HPN was 7 years (range 2--24 years). Short bowel length less than 100 cm was reported in 65% of patients with a predominance of end-jejunostomy or jejuno-colonic anastomosis. Global subjective nutritional status was normal in 79% of the patients, who were supplied with a mean number of 5.6 bags of parenteral nutrition weekly. Rehospitalizations within the 12 months prior to evaluation accounted for a mean period of 23 days and were due to HPN complications in half of the cases. Catheter-related sepsis was the most frequent HPN-complication. Bone metabolism disorders, which seemed to be more common than liver diseases, were directly related to HPN duration. One-third of the HPN patients was regularly consuming analgesics or opiates. HPN impair complete rehabilitation status but may improve the status of patients who had a very low rehabilitation score before starting HPN. An interest of intestinal transplantation was noted in only 10% of medical teams and in 8% of HPN patients., Conclusions: This study is the largest European survey on long-term HPN patients with long standing or permanent intestinal failure. Data enlighten clinical, social and rehabilitation aspects of patients who could face the option of intestinal transplantation in the future., (Copyright 2001 Harcourt Publishers Ltd.)

Rationale: Home Artificial Nutrition (HAN) has been an expanding area over the last 30 years. HAN programs have been often developed prior to the regulation by the National Health Systems (NHS) leading to different policies within European countries. The aim of this study was to compare legislation regarding HAN in Europe., Method: The Group elaborated two structured questionnaires (one for Home Enteral Nutrition--HEN--and one for Home Parenteral Nutrition--HPN) which were presented to all the members of the HAN-Working group and to the 21 ESPEN Council members., Results: Twelve questionnaires were returned, covering for more than 375 million inhabitants. HEN: regulated in seven countries, Italy and France being the first to implement reimbursement policy in 1988. Except in France, Croatia and the Czech Rep almost any physician can prescribe HEN. NHS totally or partially fund HEN, although in Austria and Israel expenses are paid for the patients. Provision of enteral diets and equipment varies widely within countries. As in HPN, most of the countries have written guidelines for health care workers and for patients. HPN: legislated in six countries, Denmark being the first in 1975. HPN programs are restricted to a few hospitals and patients are followed by Nutrition Support Teams (NST). The budget for HPN is 100% supported by NHS. Hospital pharmacy, private pharmacists and Home Care companies are involved in a different degree in providing and distributing solutions and disposables., Conclusions: HPN regulation preceded HEN regulation by 10-20 years. Due to this longer experience and high level of care, HPN patients are usually followed by NST. Despite different policies, funding is relatively uniform, NHS supporting most of the expenses for HAN. ESPEN could play a key role developing common standards for HAN all over Europe., (Copyright 2001 Harcourt Publishers Ltd.)

Background and Aims: In the UK, cerebrovascular accident (CVA) is the third commonest cause of death and the commonest diagnosis in patients receiving home enteral feeding (HETF). This study aimed to use data from the British Artificial Nutrition Survey (BANS) collected between 1996 and 1999 to assess the outcome of patients on HETF, including mortality, return to oral feeding, level of physical activity, and level of dependency, which has resource implications., Results: it is estimated that about 1.7% of all patients suffering a CVA in the UK between 1996 and 1999 received HETF. At one year, 29.6% died while receiving HETF and another 13% returned to oral feeding. Mortality increased with age and was twice as high in those managed in nursing homes compared to those in their own homes. The patients receiving tube feeding spent only 0.6% of their time in hospital. A total of 43.9% of patients were bed-bound at home (1.9% unconscious) and an additional 30.3% were house-bound. Only 21.2% were independent, and the majority were totally dependent on their carers. In CVA patients on HETF the level of dependency was greater than for those with all types of diagnoses (n=12,997)., Conclusion: This study has described the outcome of a large number of patients receiving HETF in the UK. Since patients spent less than 1% of their time in hospital, HETF relieves pressure on the expensive hospital environment, but places more demands on the carers, who have to deal with severely disabled patients. Recovery of swallowing function should be assessed intermittently to prevent unnecessary HETF., (Copyright 2001 Harcourt Publishers Ltd.)

A cell-based, lawn format assay utilizing an in situ photocleavage method has been developed that allows the rapid examination of large bead-based compound libraries as discrete molecules. The format uses frog melanophore cells in a contiguous, adherent, confluent layer in small petri dishes covered with a 0.5-1-mm layer of agarose containing 130 micron diameter TentaGel beads at a density of 2-20 beads/mm2. Employing this technique a 9-mer, 442,368-member peptide library (designed around the 13 amino acid alpha-MSH peptide sequence) made up of 12 separate pools of 36,864 peptides/pool was assayed. Initially, a fraction (approximately 10%) of each pool was scanned (approximately 3700 beads from each pool) in 60-mm petri dishes to identify the most active pools. Upon direct photocleavage of the beads with UV light (365 nm), each petri dish was photographed over a 60-min period with a CCD camera to record changes in light intensity as an index of melanosome dispersion. Active beads were those that were surrounded by a localized decrease in light transmittance indicating melanosome dispersed cells. Upon examination with a dissecting microscope, single beads centrally located to a circular array of dispersed cells were identified and removed from the agarose and sequenced by Edman degradation to determine the peptide sequence. Re-synthesized peptides were re-examined against alpha-MSH receptor to confirm and quantify the activity. Several 9-mer peptides were identified with potencies similar to the natural 13-mer peptide. This method allows for the rapid screening of large bead-based photo-cleavable peptide libraries with the advantage that each compound is screened as a discrete molecule in a well-less format.

A retrospective survey on home parenteral nutrition (HPN) in Europe was performed from January to December 1997. Data were compared to a similar study performed in 1993. A questionnaire of HPN practice was designed by the members of the ESPEN-HAN group. This involved adult patients (older than 16 years) newly registered in an HPN program between 1 January and 31 December 1997 and included: number of patients, underlying diseases and a 6-12 month outcome. Incidence and prevalence (at 1.1.1998) of adult HPN were calculated according to the estimated total population in 1997 for the countries in which more than 80% of HPN patients were reported.A total of 494 patients were registered in 73 centres from nine countries (Belgium (B), Denmark (D), France (F), Poland (P), Spain (S), Sweden (Sw), United Kingdom (UK), The Netherlands (N) and Germany (G). The underlying diseases for HPN in 494 patients were cancer (39%), Crohn's (19%), vascular diseases (15%), radiation enteritis (7%), AIDS (2%), other diseases with intestinal failure (18%). Incidence (patients/million inhabitants/year) were in N (3), F. (2.9), D. (2.8), B. (2.6), UK (1. 2), S (0.7) and P (0.36), respectively. Prevalence were in D. (12.7). U.K. (3.7), N. (3.7), F (3.6), B (3.0), P (1.1), S (0.65). After this 6-12 months follow-up (n=284), the mortality was respectively 4% in Crohn's disease, 13% in vascular diseases, 16% in others, 21% in radiaton enteritis, 34% in AIDS, 74% in cancer. Incidences and prevalences modestly increased in these seven European countries in 1997 in comparison to 1993. The percentages of underlying diseases in these countries remained similar except for AIDS that significantly decreased (from 7% to 2%). Outcomes did not significantly differ in the 4-year period except for AIDS (34% instead of 88% mortality) and could have been related to newer, more efficacious therapy., (Copyright 1999 Harcourt Publishers Ltd.)

The purpose of this work was (1) to determine if useful in vivo pharmacokinetic data could be obtained after simultaneous administration of 5-22 compounds of a chemically congeneric series to dogs and (2) to determine if structure-pharmacokinetic relationships could be derived from such studies. Mixtures of structurally related alpha-1 antagonist compounds (5-22) were administered intravenously to conscious dogs. Blood samples were taken over the next 24 h and analyzed by LC/MS to determine plasma levels and pharmacokinetics of each compound. The pharmacokinetics of 17 of these compounds were also determined after individual administration. Results obtained in the N-in-One format for 17 compounds correlated well with results obtained when these same compounds were administered individually. The N-in-One method is a useful method for obtaining pharmacokinetic data on 5-20 molecules in a single animal at one time. The increased throughput in obtaining important pharmacokinetic information should enhance the drug discovery process. In addition, it was possible to determine the extent to which various chemical substitutions did or did not affect pharmacokinetic parameters.

Objective: To determine the clinical utility of placing airway stents to facilitate weaning in ventilator-dependent patients with large airway obstruction., Methods: A chart review of mechanically ventilated patients who received expandable metal airway stents to attempt a facilitation of weaning., Results: Eight patients, 3 women and 5 men, ranging in age from 37 to 82 years, had respiratory failure associated with large airway obstruction and underwent flexible bronchofluoroscopic placement of 12 expandable metal stents (7 Wallstents [Schneider; Minneapolis, MN], 2 Palmaz [Johnson & Johnson; Warren, NJ], and 3 Ultraflex [Microinvasive; Natick, MA]). Six had respiratory failure that was secondary to malignant airway disease, and two had benign airway disease. Seven patients with tracheal or mainstem bronchial obstruction were weaned from the ventilator within 0 to 11 days of stent placement after having previously required mechanical ventilation from 2 to 52 days. There were no associated complications. Following prolonged attempts at weaning, one patient with lobar bronchus obstruction died after mechanical ventilation was withdrawn., Conclusions: Expandable metal airway stents may be safely deployed in mechanically ventilated patients and can facilitate weaning from the mechanical ventilator. Mechanically ventilated patients with tracheal and mainstem bronchus obstruction are the best candidates for deployment of expandable airway stents to facilitate weaning.

Glycated haemoglobin (Hb A1c) was used as a marker of long-term hyperglycaemia in patients receiving high glucose loads for home parenteral nutrition (HPN). Thirty-six patients received a median weekly glucose delivery of 2000 g (800-4200) at a median infusion rate of 11.8 mg/kg/min (5.0-19.2). There was no correlation between Hb A1c (median- 3.1%, range 2.0-6.3%) and glucose infusion rate or weekly glucose load. It is concluded that significant prolonged hyperglycaemia does not appear to be a problem in patients on HPN managed by this unit.

A retrospective survey was performed in 1994, involving 496 adult home parenteral nutrition (HPN) cases, newly enrolled in the year 1993 from 13 European countries from 75 centres. From the 8 countries having registered more than 80% of cases (423 patients), incidence and prevalence ranged from 0.2 to 4.6 and 0.3 to 12.2 patients/10(6) population/year. In the patients studied, the diagnosis was cancer (42%), Crohn's disease (15%), vascular diseases (13%), radiation enteritis (8%), AIDS (4%) and other nonmalignant non-AIDS diseases (18%). Short bowel syndrome and intestinal obstruction were the two major indications for HPN in 31% and 22%, respectively. Seventy-three percent of the centres had a nutrition team. HPN was administered through a tunnelled venous central catheter in 73%, cyclical nocturnal infusions were used in 90% of patients, and intravenous feeding was the sole source of nutrition in 33%. Only 44% undertook HPN unaided. The present report indicates that cancer has now become the main indication for HPN in Europe; there was, however, a heterogeneous distribution of diseases amongst the reporting countries. The observed 9 (6-12)-month probability of survival was poor in AIDS (n = 8; 12%) and cancer patients (n = 78; 29%) but better for the other HPN indications (n = 115; 92%).

A multicenter clinical trial conducted by the authors compared the desensitizing efficacy of a new 5 percent potassium nitrate: 0.243 percent sodium fluoride dentifrice along with two clinically proven, commercially available desensitizing dentifrices to a placebo dentifrice. Sensitivity to cold air and tactile stimulation, along with patients' subjective assessments, were evaluated to assess the dentinal desensitizing efficacy of the test dentifrices. Results demonstrated that after four weeks, participants who used the new dentifrice formulation experienced significant decreases in dentinal sensitivity compared to the placebo group for all measured indexes.

Quality of life was assessed in 37 patients receiving home parenteral nutrition (HPN) for intestinal failure. A questionnaire was developed specifically for this purpose and the results were compared with those obtained by subjective assessment using a simple linear scale. The majority of patients (n = 26, 70.3%) had a good objective quality of life and most (n = 16, 53.3%) of those eligible (n = 30, 81.1%) did not express an interest in intestinal transplantation. Despite the apparent good quality of life enjoyed by patients receiving HPN, there were numerous areas in which patients with intestinal failure felt that their quality of life left much to be desired: many patients reported significant psychological symptoms (n = 15, 40.5%) sexual (n = 10, 27.0%) and social dysfunction (n = 19, 51.3%) and most patients with intestinal failure were unable to return to work (n = 24, 88.9%). Detailed quality of life assessment reveals that there is much still to be done to ensure that provision of care for patients with intestinal failure involves not only prolongation of life but also an improvement in quality of life.

One hundred normal upper extremities in 50 adults were sequentially studied in a Bledsoe brace, which limited elbow motion. The amount of flexion and extension of the elbow was serially limited by 15 degree increments. At each setting, the subjects were asked to perform 12 activities of daily living. The percentage of subjects who completed each task with the specified range of motion was determined. Overall, 49 of the subjects performed all of the tasks with extension limited at 75 degrees and flexion limited at 120 degrees. By isolating the allowable range of motion of the elbow and allowing for compensatory motions and strategies of the normal adjacent joints, the functional elbow range of motion is established as 75 degrees-120 degrees flexion. Thus, the functional status of a patient with a specific elbow range of motion can be predicted more accurately.