Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation

Constitutive NF-κB activation in IECs induces inflammatory cytokines and chemokines in the lamina propria, but does not result in overt tissue damage unless acute inflammatory insults are present, causing TNF-dependent destruction and barrier disruption

Central coordination as an alternative for local coordination in a multicenter randomized controlled trial: the FAITH trial experience

Contains fulltext : 110505.pdf (publisher's version ) (Open Access)BACKGROUND: Surgeons in the Netherlands, Canada and the US participate in the FAITH trial (Fixation using Alternative Implants for the Treatment of Hip fractures). Dutch sites are managed and visited by a financed central trial coordinator, whereas most Canadian and US sites have local study coordinators and receive per patient payment. This study was aimed to assess how these different trial management strategies affected trial performance. METHODS: Details related to obtaining ethics approval, time to trial start-up, inclusion, and percentage completed follow-ups were collected for each trial site and compared. Pre-trial screening data were compared with actual inclusion rates. RESULTS: Median trial start-up ranged from 41 days (P25-P75 10-139) in the Netherlands to 232 days (P25-P75 98-423) in Canada (p = 0.027). The inclusion rate was highest in the Netherlands; median 1.03 patients (P25-P75 0.43-2.21) per site per month, representing 34.4% of the total eligible population. It was lowest in Canada; 0.14 inclusions (P25-P75 0.00-0.28), representing 3.9% of eligible patients (p < 0.001). The percentage completed follow-ups was 83% for Canadian and Dutch sites and 70% for US sites (p = 0.217). CONCLUSIONS: In this trial, a central financed trial coordinator to manage all trial related tasks in participating sites resulted in better trial progression and a similar follow-up. It is therefore a suitable alternative for appointing these tasks to local research assistants. The central coordinator approach can enable smaller regional hospitals to participate in multicenter randomized controlled trials. Circumstances such as available budget, sample size, and geographical area should however be taken into account when choosing a management strategy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00761813

A multicenter randomized controlled trial evaluating the effect of small stitches on the incidence of incisional hernia in midline incisions

Contains fulltext : 95575.pdf (publisher's version ) (Open Access)BACKGROUND: The median laparotomy is frequently used by abdominal surgeons to gain rapid and wide access to the abdominal cavity with minimal damage to nerves, vascular structures and muscles of the abdominal wall. However, incisional hernia remains the most common complication after median laparotomy, with reported incidences varying between 2-20%. Recent clinical and experimental data showed a continuous suture technique with many small tissue bites in the aponeurosis only, is possibly more effective in the prevention of incisional hernia when compared to the common used large bite technique or mass closure. METHODS/DESIGN: The STITCH trial is a double-blinded multicenter randomized controlled trial designed to compare a standardized large bite technique with a standardized small bites technique. The main objective is to compare both suture techniques for incidence of incisional hernia after one year. Secondary outcomes will include postoperative complications, direct costs, indirect costs and quality of life. A total of 576 patients will be randomized between a standardized small bites or large bites technique. At least 10 departments of general surgery and two departments of oncological gynaecology will participate in this trial. Both techniques have a standardized amount of stitches per cm wound length and suture length wound length ratio's are calculated in each patient. Follow up will be at 1 month for wound infection and 1 year for incisional hernia. Ultrasound examinations will be performed at both time points to measure the distance between the rectus muscles (at 3 points) and to objectify presence or absence of incisional hernia. Patients, investigators and radiologists will be blinded during follow up, although the surgeon can not be blinded during the surgical procedure. CONCLUSION: The STITCH trial will provide level 1b evidence to support the preference for either a continuous suture technique with many small tissue bites in the aponeurosis only or for the commonly used large bites technique

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

The Prospective Dutch Colorectal Cancer (PLCRC) cohort: real-world data facilitating research and clinical care

Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the “real-world”. Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013–2016 and 2017–Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017–Aug’19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC’s representativeness and its contribution to a learning healthcare system

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Systematic review and meta-analysis concerning therapeutic temperature management after cardiac arrest and the risk of bleeding

Einleitung Die Prognose nach Herzkreislaufstillstand ist trotz moderner Intensivmedizin weiterhin schlecht, die Mortalität liegt nach wie vor bei etwa 90%. Von den überlebenden Patienten hat ca. ein Drittel schwere neurologische Folgeschäden. Therapeutisches Temperatur Management (TTM) stellt die bisher einzige Therapie dar, bei der ein signifikanter Einfluss auf Überleben und neurologisches Outcome nachgewiesen werden konnte. Ein mögliches Blutungsrisiko unter TTM wurde bisher nur in kleineren Studien oder Fallserien untersucht, in denen keine abschließende Aussage bezüglich einer klinisch relevanten Blutungsneigung gemacht werden konnte. Methodik Im September 2013 wurde eine systematische Literaturrecherche in den medizinischen Datenbanken MEDLINE, EMBASE sowie CENTRAL durchgeführt. Die relevanten Studien wurden anhand der ILCOR Guidelines in Bezug auf Evidenzgrad sowie Qualität hin beurteilt. Die unter TTM aufgetretenen Blutungen wurden entsprechend der BARC Kriterien bezüglich ihrer Schwere eingeteilt. Hierfür wurden, z.T. in ausführlicher Rücksprache mit den jeweiligen Autoren, weitere, bisher unveröffentlichte Daten erhoben. Im Anschluss wurde eine Metaanalyse zur Blutungsneigung unter TTM, differenziert für Blutungen jeder Schwere sowie transfusionsbedürftige Blutungen, durchgeführt. Ergebnisse Von initial 941 Studien wurden 34 in die Literaturübersicht eingeschlossen. Davon wurden fünf Studien mit insgesamt 599 Patienten in die Metaanalyse zu Blutungen jeder Schwere eingeschlossen. Hier zeigte sich ein Trend hin zu einer gesteigerten Blutungsneigung unter TTM (RR: 1,30, 95% Cl: 0,97-1,74), welcher jedoch nicht das Signifikanzniveau erreichte (p = 0,085). 7 Studien mit insgesamt 599 Patienten wurden in die Metaanalyse zu transfusionsbedürftigen Blutungen eingeschlossen. Es zeigte sich kein signifikanter Unterschied bezüglich der Inzidenz an schweren Blutungen mit einer Risk Ratio von 0,97 (95% Cl: 0,61-1,56, p = 0,909). Schlussfolgerungen Die durchgeführte Metaanalyse konnte kein signifikant erhöhtes Risiko für Blutungen oder eine erhöhte Transfusionspflichtigkeit unter TTM nach Reanimation zeigen. Eine Ablehnung eines TTM nach erfolgreicher Reanimation aufgrund einer möglichen Blutungsgefahr ist daher nicht gerechtfertigt. Der Einsatz bei bereits vorliegender Blutung bleibt eine individuelle Entscheidung.Objective Despite all developments in modern intensive care cardiac arrest is still associated with a poor prognosis. Mortality is high and within the survivors about 30 % have neurological impairment. Until now Therapeutic Temperature Management (TTM) is the only therapy with proven significant impact on mortality and neurological outcome. However, TTM might be associated with an increased risk of bleeding. There are only small studies and case series investigating this possible side effect which were not able to give distinct evidence. Methods A systematic search of the literature was conducted in September 2013 using the databases MEDLINE, EMBASE and CENTRAL. Relevant studies where assessed concerning their level of evidence as well as their quality in respect to the ILCOR Guidelines. Bleeding complications where allocated concerning their severity using the BARC criteria. For this purpose new unpublished data was imposed in detailed correspondence with the authors. A meta-analysis concerning bleeding complications under TTM differentiated into bleeding of all severity and bleeding requiring transfusion was performed. Results Out of 941 studies identified by the initial literature search 34 matched our predefined criteria and were thus included in the literature review. Out of those five studies including 599 patients where summarized in the meta-analysis concerning bleeding of all severity. A trend was shown towards a higher risk of bleeding under TTM treatment (RR: 1.30, 95% CI: 0.97-1.74%) which did not reach significance (p=0.085). Seven studies including 599 patients were included in the meta-analysis concerning bleeding requiring transfusion. No significant difference between severe bleedings could be found (RR: 0.97, 95% CI: 0.61-1.56, p=0.909). Conclusions The meta- analysis did nether show a significantly increased risk of bleeding nor an increased need for blood transfusions under TTM. To refuse temperature management after cardiac arrest because of possible bleeding complications cannot be justified. Use of TTM in cases with pre-existing acute bleeding needs still an individual decision

Interactive exploration of adverse events and multimorbidity in CKD

Abstract Background and hypothesis Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. Methods The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30–60 or &gt;60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. Results Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. Conclusion This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning