Multicenter Network Research Articles

Facilitating Emergency Care Research Networks: Integration into the Clinical Translational and Science Award (CTSA) Infrastructure

Emergency care research (ECR) does not fit neatly into the traditional National Institutes of Health (NIH) funding model, because emergency research involves undifferentiated disease presentations involving multiple disciplines and time-sensitive interventions. A task force of emergency care researchers and other stakeholders was convened to discuss the present and future state of clinical research networks. Integration of ECR with the Clinical Translational and Science Award (CTSA) program through a multidisciplinary emergency care research network (ECRN) would obviate the duplication of research efforts by disease-specific or institute-specific multicenter networks and reduce startup and maintenance costs. Strategies to enhance integration must include the training of emergency physician investigators in biostatistical and epidemiologic methods, as well as educating collaborative investigators in emergency care-related methodologies. Thus, an ECRN would be of great benefit to CTSA awardees and applicants and should be considered a priority.

Surveillance programs for detection and characterization of emergent pathogens and antimicrobial resistance: results from the Division of Infectious Diseases, UNIFESP

Several epidemiological changes have occurred in the pattern of nosocomial and community acquired infectious diseases during the past 25 years. Social and demographic changes possibly related to this phenomenon include a rapid population growth, the increase in urban migration and movement across international borders by tourists and immigrants, alterations in the habitats of animals and arthropods that transmit disease, as well as the raise of patients with impaired host defense abilities. Continuous surveillance programs of emergent pathogens and antimicrobial resistance are warranted for detecting in real time new pathogens, as well as to characterize molecular mechanisms of resistance. In order to become more effective, surveillance programs of emergent pathogens should be organized as a multicenter laboratory network connected to the main public and private infection control centers. Microbiological data should be integrated to guide therapy, adapting therapy to local ecology and resistance patterns. This paper presents an overview of data generated by the Division of Infectious Diseases, Federal University of São Paulo, along with its participation in different surveillance programs of nosocomial and community acquired infectious diseases.

Skin sensitizing properties of the ethanolamines mono‐, di‐, and triethanolamine. Data analysis of a multicentre surveillance network (IVDK*) and review of the literature

Numerous publications address the skin sensitizing potential of the short chain alkanolamines triethanolamine (TEA), diethanolamine (DEA), monoethanolamine (MEA), which are not skin sensitizing according to animal studies. Regarding TEA, we analysed patch test data of 85,098 patients who had been tested with TEA 2.5% petrolatum by Information Network of Departments of Dermatology (IVDK) to identify particular exposures possibly associated with an elevated risk of sensitization. Altogether, 323 patients (0.4%) tested positive. The profile of patch test reactions indicates a slightly irritant potential rather than a true allergic response in many cases. Although used widely, no exposure associated with an increased risk of TEA sensitization was identified. Therefore, the risk of sensitization to TEA seems to be very low. MEA and DEA were patch tested in a much more aimed fashion in 9602 and 8791 patients, respectively when prevalence of contact allergy was 3.8% and 1.8%. MEA is the prominent allergen in metalworkers with exposure to water-based metalworking fluids (wbMWFs); DEA is probably used in cutting fluids less frequently nowadays. Chronic damage to the skin barrier resulting from wbMWF, the alkalinity of ethanolamines (increasing from TEA to MEA), and other cofactors may contribute to a notable sensitization risk.

Wirksamkeit und Wirkmechanismen von Psychotherapie bei der Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) bei Kindern und Erwachsenen

The multicentre network being funded in the context of the program of the German Federal Ministry of Education and Research (BMBF) on psychotherapy research is investigating effects and mechanisms of psychotherapy in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. Single projects are focussing (1) on the investigation of the efficacy of psychotherapy, stimulant medication, a combination of both and a control condition for the treatment of ADHD in adults, (2) on the investigation of the enhancement of the efficacy of parent training for children's ADHD by a precedent treatment of ADHD in affected mothers and (3) on the study of associations between neurobiological markers (neuroimaging, genetic variations) and treatment outcome. In the clinical trials modern standards of psychotherapy research are taken into account (e.g. sample size based on power calculation, randomized controlled trial, use of treatment manuals, measures to ensure treatment fidelity, blind observer rating of outcome, intention to treat analysis). Results are supposed to strengthen the evidence base of the treatment of ADHD and to contribute to a better understanding of the mechanisms of therapeutic change. On the one hand our network reinforces the co-operation of general psychiatry and child and adolescent psychiatry in diagnosis and treatment of ADHD over the lifespan, on the other hand the association between clinical and fundamental research is strengthened.

Treatment and Outcomes of Pelvic Malunions and Nonunions: A Systematic Review

Although acute management of pelvic fractures and their long-term functional outcome have been widely documented, important information regarding malunion and nonunion of these fractures is sparse. Despite their relative rarity, malunions and nonunions cause disabling symptoms and have major socioeconomic implications. We analyzed the factors predisposing a pelvic injury to develop malunion/nonunion, the clinical presentation of these complications, and the efficacy of the reported operative protocols in 437 malunions/nonunions of 25 clinical studies. Treatment of these demanding complications appeared effective in the majority of the cases: overall union rates averaged 86.1%, pain relief as much as 93%, patient satisfaction 79%, and return to a preinjury level of activities 50%. Nevertheless, the patient should be informed about the incidence of perioperative complications, including neurologic injury (5.3%), symptomatic vein thrombosis (5.0%), pulmonary embolism (1.9%), and deep wound infection (1.6%). For a successful outcome, a thorough preoperative plan and methodical operative intervention are essential. In establishing effective evidence-based future clinical practice, the introduction of multicenter networks of pelvic trauma management appears a necessity. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Übertragbarkeit von Studienergebnissen in die Versorgung aus Sicht des klinischen Alltags: Nicht-pharmakologische Interventionen (Chirurgie)

In surgery, too, randomized clinical trials (RCTs) are the scientific method of choice for proving the effectiveness of a new intervention or the superiority of an innovative technique over an established one. However, there are particular challenges in surgical studies regarding the equality of structure, of treatments and observation in the study groups. The design of valid study protocols in surgery is very complex, which is the reason for the relatively small number of high-quality RCTs in surgical literature. Pragmatic studies offer a promising approach to the implementation of surgical innovations in health care. The German Society of Surgeons supports the conduct of multicentre clinical studies by providing the relevant structures (study centre, multicentre network CHIR-Net). Good clinical and comparative health care effectiveness research in surgery also needs stronger academic appreciation as a career incentive for young academic surgeons.

Líneas estratégicas de orientación de los servicios de salud con una perspectiva de futuro

The Health Map of Catalonia includes a set of strategic lines which constitute a framework for the alignment of objectives in the public healthcare system and which are elements of guidance in the evolution of the healthcare model with regard to the future. The strategic lines are grouped into 10 major themes which deal with the health policy and service policy (priorities and objectives of the system); the role of the citizens as protagonists; interaction between professionals and patients; comprehensive care and continuity in healthcare; collaboration between teams of professionals in multi-centre networks; professional development; information and communication technologies aiding in clinical decisions and relationships between professionals; the triumvirate of accessibility, quality and efficiency; the participation of citizens, institutions, professionals and organisations in the operation of services; and, finally, the assessment, to give an account of the above and take action.

Stérilisations retardées du liquide céphalorachidien au cours des méningites à pneumocoque de l'enfant

Delayed cerebrospinal fluid sterilization is defined by a positive second lumbar puncture, recommanded according to the guidelines from the French Consensus Conference of 1996 between the 36th and 48th hours after the beginning of antibiotics prescribed for pneumococcal meningitis. The aim of this study was to analyze specifically delayed cerebrospinal fluid sterilization, identified during the first 5 years of the French observatory of children bacterial meningitis. The Groupe de Pathologie Infectieuse Pédiatrique (GPIP) and Association Clinique et Thérapeutique Infantile du Val de Marne (ACTIV) has set up since the first of January 2001 a descriptive national multicenter network, to determine incidence, main characteristics, and prognosis of bacterial meningitis in children. A questionnaire, available in all paediatric unit taking care of bacterial meningitis, was completed by a referral doctor. It contained reasons for inclusion in the study, anamnesis, clinical examination, treatment, pneumococcal characteristics, and short term prognosis. Delayed cerebrospinal fluid sterilization were identified, and the analysis of their medical records completed the questionnaire. From 1st January 2001 to 31 December 2005, 616 pneumococcal meningitis were identified. Among them, 442 had a second lumbar puncture, and 8 had delayed cerebrospinal fluid sterilization. The analyis of their medical records were reviewed to describe their characteristics. Two had an osteomeningeal breach, one a ventriculoperitoneal valve. All received previously an antibiotic, and were treated with a curative antibiotic by cephalosporins. Vancomycin was given in 6 cases. The antibiotic was inadapted to the French guidelines for 1 patient. There are 4 vaccine type pneumococci and only 1 strain was resistant to penicillin, and intermediate to cephalosporins. The controlled lumbar puncture was made between 36.5 and 179.4hours after beginning antibiotics. One patient has received a double dose of steroids. Three were in a coma, had convulsions, and were ventilated, none died. One patient has a sequellar paired deafness, two a severe disability, four a normal psychomotor development. The delay of sterilization is a rare situation and represented only 1.8 % of pneumococcal meningitis during the first five years of the observatory. These results suggest that a second lumbar puncture to assess sterilization could be proposed only in cases of unfavourable clinical course, MIC greater than or equal 0.5mg/l to 3GC, risk factors for delayed cerebrospinal fluid sterilization and high bacterial inoculum.

Acetaminophen‐related acute liver failure in the United States

Acetaminophen overdoses are the number one cause of acute liver failure (ALF) in the United States; they account for 50% of all cases of ALF and carry a 30% mortality. Nevertheless, acetaminophen is a highly successful product with sales easily exceeding a billion dollars annually. A narcotic-containing acetaminophen preparation is the number one generic drug sold in the United States. Historically, a strong association was claimed with alcohol as a co-factor and the accidental nature of ingestions was emphasized but the association with alcohol remains a matter of debate. Recently, a very reliable assay has been developed which detects a byproduct of the toxic reaction, acetaminophen-CYS adducts, protein-acetaminophen compounds that are released from damaged hepatocytes in similar fashion to aminotransferases. The US Acute Liver Failure Study Group is a multi-center network established to gather data prospectively on all forms of acute liver failure, a rare but often fatal condition. The group has data on more than 500 acetaminophen cases and described 275 of them in detail in a recent paper. The clinical pattern of presentation is somewhat different in the US compared with the UK, since nearly half are considered to be unintentional, the result of overuse of acetaminophen-containing compounds for pain relief, without suicidal intent. Despite the relatively good prognosis for acetaminophen overdoses, 30% die once acute liver failure occurs and this is the largest cause of death in the entire ALF registry.

Application of BMP-7 to tibial non-unions: A 3-year multicenter experience

The effective treatment of the often debilitating, longlasting and large-asset-consuming complication of fracture non-unions has been in the centre of scientific interest the last decades. The use of alternative bone substitutes to the gold standard of autologous graft includes the osteoinductive molecules named bone morphogenetic proteins (BMPs). A multicenter registry and database (bmpusergroup.co.uk) focused on the application of BMP-7/OP-1 was created in December 2005. We present the preliminary results, using the prospective case-series of aseptic tibial non-unions as an example. Sixty-eight patients fulfilled the inclusion criteria for this observational study, with a minimum follow-up of 12 months. The median duration of tibial non-union prior to BMP-7 application was 23 months (range 9-317 mo). Patients had undergone a median of 2 (range 0-11) revision procedures prior to the administration of BMP-7. In 41% the application of BMP-7 was combined with revision of the fixation at the non-union site. Non-union healing was verified in 61 (89.7%) in a median period of 6.5 months (range 3-15 mo). No adverse events or complications were associated with BMP-7 application. The safety and efficacy of BMP-7 was verified in our case series, and was comparable to the existing evidence. The establishment of multicenter networks and the systematic and long-term follow- up of these patients are expected to provide further information and significantly improve our understanding of this promising osteoinductive bone substitute.

The Fellows’ Pelvic Research Network (FPRN)

Clinical trials are crucial to the practice and advancement of medicine. Research studies are designed to answer specific questions about new drugs, devices, and therapies and to identify new ways of using known treatments. During the last decade, multicenter studies have become more common. Networks have been established in various fields to facilitate collaborative efforts to develop and perform clinical trials related to specific disorders, allowing more timely recruitment and completion of studies as well as increasing the generalizability of the results. In urogynecology, the National Institutes of Health has dedicated funds to two active multicenter clinical trial networks: (1) the Urinary Incontinence Treatment Network includes urologists and urogynecologistsfrom ninecentersacrosstheUSA; and(2)thePelvic Floor Disorders Network, which includes seven US centers. Participating sites were competitively selected, and both networks are in the second 5-year cycle. Through highquality research trials, both networks have successfully

Ethical and logistical considerations of multicenter parental bereavement research.

Multicenter research has the potential to recruit participants with diverse racial, ethnic, and geographic backgrounds and is essential for understanding heterogeneity in bereavement. The National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) is a multicenter network charged with conducting research on the pathophysiology and management of critical illness in childhood. Among its research activities, the CPCCRN has undertaken research in parental bereavement because most childhood deaths in the United States occur in hospitals, primarily in critical care units. The purpose of this paper is to discuss ethical and logistical issues found by the CPCCRN to be problematic to multicenter research with bereaved parents and to explore research strategies that may be practicably implemented. Ethical and logistical challenges encountered by the CPCCRN included issues of privacy; confidentiality; voluntariness; minimizing risks; working with multiple institutional review boards; researcher qualifications, training and support; and methods of data collection. Strategies to address these challenges included local recruitment of participants; flexibility in consent methods across sites; participant options for methods of data collection; involvement of local bereavement support services; central training of researchers with systematic monitoring and opportunities for support; and use of a secure Web-based collaborative workspace. Multicenter parental bereavement research has distinct ethical issues that must be addressed by the logistics of the research plan. Greater attention to the issues identified may facilitate research to reduce adverse mental and physical health outcomes in a diverse population of bereaved individuals.

Extremely low birthweight infants – the interplay between outcomes and ethics

Extremely low birthweight infants – the interplay between outcomes and ethics

The validity of rating patch test reactions based on digital images

The proper reading of patch test (PT) reactions, based on morphological criteria, is of utmost importance. Digital images are increasingly used for medical training. To assess the diagnostic validity of readings of 20 digital images of various PT reaction grades by congress attendants. 122 volunteers took a PT quiz offered during the 8th ESCD meeting, September 2006, Berlin. No information on the respective allergen was given, nor the gold standard grading determined by an European Environmental and Contact Dermatitis Research Group (EECDRG) expert panel was disclosed while the quiz was open. Overall, 63.5% of all ratings agreed 'exactly' with the gold standard, and 87.8% 'grossly', that is, with regard to the distinction between non-positive [doubtful or irritant (IR)] and positive (+, ++, and +++) reactions. Most images prompted a fair proportion of correct classifications. The distinction between doubtful and + and between +++, and strong bullous IR reactions proved partly difficult, probably because of blinding of the test substance. The least experienced in particular tended to misclassify IR reactions. The rating of digital images of PT reactions represents just 1 particular, isolated aspect of PT evaluation. Results were largely valid. Thus, the method could be used for continuing medical education, and for standardization in multicentre networks.

Expectations and Strategies Regarding Islet Transplantation: Metabolic Data From the GRAGIL 2 Trial

Whether islet transplantation should be aimed at restoring insulin independence or providing adequate metabolic control is still debated. The GRAGIL2 trial was designed as a phase 1-2 study where primary outcome was the rate of insulin independence, and secondary outcome was the success rate defined by a composite score based upon basal C-peptide, HbA1c, hypoglycemic events, and exogenous insulin needs. C-peptide negative type 1 brittle diabetic patients experiencing severe hypoglycemia were eligible to receive a maximum of two islet preparations totalizing 10,000 IE/kg or more, with a threshold of 5,000 IE/kg for the first infusion, according to the Edmonton protocol, within the Swiss-French GRAGIL multicentric network. A sequential analysis with a triangular test was performed in every five patients after 6- and 12-month follow-up. Maximal inefficiency was set at 40% and minimal efficiency at 66%. From September 2003 to October 2005, 10 patients were included. Median waiting time was 6.7 months (first injection) and 9 weeks (second injection). All but one patient received 11,089+/-505 IE/kg: one received a single graft of 5398 IE/kg. At 6 months, insulin independence and composite success rates were 6 of 10 and 6 of 10, respectively. At 12 months, insulin independence was observed in 3 of 10 patients and success in 5 of 10 patients. Based upon our sequential analysis settings, islet transplantation failed to achieve the primary goal, insulin independence, but tended to succeed in reaching the secondary goal, successful metabolic control. Currently it appears to be a successful biological closed-loop glucose control method for brittle diabetes.

MULTICENTER NETWORK AND SYNCHRONIZATION

This paper proposes a new complex network: multicenter network. Coupled maps on two different types of network, coupled map lattices with nearest neighbors and multicenter network, are investigated. Both theoretical analysis and numerical simulation show that the synchronization of coupled map is much easier than that on the regular network.

Genetic and Molecular Factors in Drug-Induced Liver Injury: A Review

The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic "dose-dependent" Type A reactions ii) "idiosyncratic" or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.

GH deficiency with central precocious puberty: a new rare disorder associated with a developmental defect of the hypothalamic–pituitary area

GH deficiency (GHD) associated with central precocious puberty (CPP) has been widely reported in cases of arachnoid cyst, septo-optic dysplasia, brain tumors, or after cerebral radiation therapy. However, idiopathic GHD associated with CPP has been reported in only one isolated case. To evaluate the occurrence and clinical features of the association of nonacquired GHD and CPP. This was a retrospective multicenter study. The study population was identified through a French nationwide multicenter network (about 3000 patients). We reviewed the medical records of all subjects diagnosed with nonacquired GHD and CPP, with or without developmental abnormalities of the hypothalamic-pituitary axis on cerebral magnetic resonance imaging (MRI), and without any known associated anomaly. We identified four patients with either isolated GHD (n=1) or multiple anterior pituitary hormone deficiencies (n=3). Clinical signs of CPP occurred at 6.4 +/- 2.3 years in boys and 7.5 +/- 0.5 years in girls, and GnRH analog therapy was started at 4.2 +/- 1.6 years after the initiation of recombinant human GH treatment. Cerebral MRI demonstrated ectopic neurohypophysis associated with anterior pituitary hypoplasia in three out of the four patients. The morphology and position of the anterior pituitary and neurohypophysis were normal in one patient who displayed a persistence of the craniopharyngeal canal. CPP is very rare in patients with nonacquired GHD and is mostly associated with developmental defects in the hypothalamic-pituitary area. Whether molecular mechanisms governing development and activation of the hypothalamic-pituitary axis share dependent factors remains to be explored.

An Ideal Assortative Network and Synchronization

This paper proposes a novel complex network withassortative property based on multi-center networks. The average path lengthand clustering coefficient of the network are calculated, and the impact onthe network topology is investigated. A simple dynamic system established onthe proposed network is used to analyze how the assortative property of thenetwork affects synchronization.

The MFMU cesarean registry: Risk factors for neonatal sepsis among women with chorioamnionitis

Risk factors for neonatal sepsis include chorioamnionitis and cesarean delivery after labor. Delivery after chorioamnionitis typically results in a sepsis evaluation (blood work, spinal tap) for the infant, although at term the yield is low. The objective of this study was to identify predictors of neonatal sepsis in women at term who delivered by cesarean with chorioamnionitis during labor. Using a multicenter network of 19 sites, women with a singleton term gestation (≥37wk) with information on chorioamnionitis and neonatal sepsis who delivered by cesarean were studied from 1999-2002. Chorioamnionitis was diagnosed clinically, neonatal sepsis was proven by blood culture. 2,749 women had chorioamnionitis and of these, 38 (1.4%) had proven neonatal sepsis. Maternal demographics (age, nulliparity, GA delivery) were not related to the risk of neonatal sepsis. Intrapartum factors are in Table. At term, infants born by cesarean with chorioamnionitis do not have identifiable risk factors for neonatal sepsis that would refine which infants should undergo a sepsis evaluation.Tabled 1SepsisNo SepsisPGBS positive2 (5%)227 (8%)0.8Labor or induction38 (100%)2675 (99%)1.0Labor length (h)21.6±8.921.3±11.20.3Duration ROM (h)14.0±6.615.4±14.11.0IUPC33 (87%)2216 (82%)0.4Persistent fetal tachycardia27 (71%)1470 (55%)0.04Persistent mat tachycardia22 (58%)1152 (43%)0.06Max maternal temp101.2±1.1100.9±0.80.2Maternal leukocytosis3 (9%)173 (7%)0.7Malodorous discharge3 (8%)124 (5%)0.4Uterine tenderness6 (18%)207 (8%)0.055 min Apgar <32 (5%)9 (0.3%)<.001 Open table in a new tab