Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations.

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.

A scoping review of the role of primary care providers and primary care-based interventions in the treatment of pediatric eating disorders.

Youth with eating disorders are often cared for by specialized interdisciplinary teams in pediatric tertiary care centers. Enhanced involvement of primary care providers may provide added benefits to patients because it offers improved access, better continuity of care, and possibly less financial burden. This paper aims to synthesize and assess the literature on the role of the primary care provider in treating pediatric eating disorders in order to identify an optimal model of shared care. Sources were identified by entering search terms in 10 databases. Eligible sources were English publications focusing on primary care-based interventions for eating disorders in youth (=<24 years). The search yielded 5,516 unique citations. Of these, 61 were ultimately included. Sources fell into two categories: (1) primary research (n = 3) and (2) reviews with recommendations for primary care providers (n = 58). The primary studies considered the primary care provider conducting behavioral therapy and guided self-help. Review articles suggested providing education, assessing for hospitalization, aiding in weight restoration, managing complications, referring, and coordinating care. Limited evidence exists that can guide effective primary care-based interventions for the treatment of pediatric eating disorders. Further research is needed to develop and evaluate interventions for the treatment of pediatric eating disorders in primary care settings so that best practices can be identified.

Long-term Use of Proton Pump Inhibitors Is Associated With Increased Microbial Product Translocation, Innate Immune Activation, and Reduced Immunologic Recovery in Patients With Chronic Human Immunodeficiency Virus-1 Infection.

BACKGROUND: Translocation of microbial products from the damaged gut causes increased immune activation in human immunodeficiency virus (HIV). Proton pump inhibitors (PPIs) predispose to bacterial overgrowth in the gut. We hypothesized that long-term use of PPIs is associated with greater microbial translocation and immune activation in HIV. METHODS: HIV-infected persons on suppressive antiretroviral therapy (ART), including those receiving long-term PPIs (PPI+ group) or not (PPI- group), were enrolled. We determined CD38+HLA-DR+CD8+ (activated) T-cell frequency, and plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and intestinal fatty acid binding protein (I-FABP). RESULTS: We recruited 77 HIV-infected participants (37 PPI+ and 40 PPI-) and 20 HIV-uninfected volunteers. PPI+ subjects were older and more likely to have hypertension and receive statins than PPI-. Nadir and enrollment CD4 counts, activated T-cells, and time on ART were similar in both groups. PPI+ group had higher sCD14 (2.15 vs. 1.50 mcg/mL, P < .01), and LBP (21.78 vs. 18.28 mcg/mL, P = .02) but lower I-FABP levels (608.5 vs. 2281.7 pg/mL, P = .05) than PPI-. In multivariate analysis, sCD14 levels remained associated with PPIs. In the year prior to enrollment, PPI+ group lost more CD4 cells than PPI- (-18 vs. 54 cells/mm3, P = .03). HIV-infected subjects had higher immune activation and microbial translocation biomarkers than uninfected volunteers. CONCLUSION: In HIV, long-term use of PPIs was associated with increased microbial translocation, innate immune activation, and reduced immune reconstitution. Further studies are needed to evaluate the clinical implications of our findings. In the meantime, cautious use of PPIs is advised.

Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.

Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study).

BACKGROUND: In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse. METHODS: In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enrolled in the prospective European INES trials. RESULTS: Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) (P<0.0001). Progression-free survival was poorer in patients whose tumours harboured SCA, in the whole population and in trials INES99.1 and INES99.2, in the absence of clinical symptoms (log-rank test, P=0.0001, P=0.04 and P=0.0003, respectively). In multivariate analysis, a SCA genomic profile was the strongest predictor of poorer progression-free survival. CONCLUSION: In infants with stage 4s MYCN-non-amplified NB, a SCA genomic profile identifies patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas in infants with localised unresectable NB, a genomic profile characterised by the absence of SCA identifies patients in whom treatment reduction might be possible. These findings will be implemented in a future international trial.

Prevention of the ß-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures.

BACKGROUND: Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by ß-amyloid (Aß) peptides, the nuclear factor-kappa B (NF-κB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-κB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Aß42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia. METHODS: Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Aß neurotoxicity (72 h), co-cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1ß, and IL-6 were assessed by ELISA. Levels of PT451-PKR and activation of IκB, NF-κB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of PT451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test RESULTS: In these co-cultures, PKR inhibition prevented Aß42-induced activation of IκB and NF-κB, strongly decreased production and release of tumor necrosis factor (TNFα) and interleukin (IL)-1ß, and limited apoptosis. CONCLUSION: In spite of the complexity of the innate immune response, PKR inhibition could be an interesting anti-inflammatory strategy in AD.

Assessing HER2 gene amplification as a potential target for therapy in invasive urothelial bladder cancer with a standardized methodology: results in 1005 patients.

BACKGROUND: This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression and its relationship with gene amplification in invasive bladder carcinoma, using the same criteria than for breast cancer. PATIENTS AND METHODS: In 1005 patients, paraffin-embedded tissues of transurethral resection or cystectomy were evaluated by immunohistochemistry (IHC), using antibodies against HER2. All samples with a 2+ or 3+ HER2 overexpression were evaluated by FISH. RESULTS: HER2 overexpression was observed in 93 (9.2%) tumors (2+: 42 tumors and 3+: 51 tumors). Using FISH, all HER2 3+ tumors had a gene amplification, whereas no amplification was found in 2+ tumors. Intratumoral heterogeneity was observed in 35% of cases. These tumors showed the same heterogeneous pattern, with adjacent 3+ positive and negative areas by both IHC and FISH. CONCLUSIONS: This study showed that 5.1% of invasive bladder carcinomas had a HER2 gene amplification. These findings may have clinical implications for the management of patients with HER2-positive locally advanced or metastatic bladder cancer, as they could be potential candidates for targeted therapy.

Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network.

BACKGROUND: Xp11 translocation renal cell carcinoma (RCC) is an RCC subtype affecting 15% of RCC patients <45 years. We analyzed the benefit of targeted therapy [vascular endothelial growth factor receptor (VEGFR)-targeted agents and/or mammalian target of rapamycin (mTOR) inhibitors] in these patients. PATIENTS AND METHODS: Patients with Xp11 translocation/TFE3 fusion gene metastatic RCC who had received targeted therapy were identified. Nuclear TFE3 positivity was confirmed by reviewing pathology slides. Responses according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Overall, 53 patients were identified; 23 had metastatic disease, and of these 21 had received targeted therapy (median age 34 years). Seven patients achieved an objective response. In first line, median PFS was 8.2 months [95% confidence interval (CI) 2.6-14.7 months] for sunitinib (n = 11) versus 2 months (95% CI 0.8-3.3 months) for cytokines (n = 9) (log-rank P = 0.003). Results for further treatment (second, third, or fourth line) were as follows: all three patients receiving sunitinib had a partial response (median PFS 11 months). Seven of eight patients receiving sorafenib had stable disease (median PFS 6 months). One patient receiving mTOR inhibitors had a partial response and six patients had stable disease. Median OS was 27 months with a 19 months median follow-up. CONCLUSION: In Xp11 translocation RCC, targeted therapy achieved objective responses and prolonged PFS similar to those reported for clear-cell RCC.

Necrotizing cerebellitis and cerebellar atrophy caused by Neospora caninum infection: magnetic resonance imaging and clinicopathologic findings in seven dogs.

BACKGROUND: Adult dogs with neosporosis can develop a variety of neurologic signs. No area of predilection within the nervous system so far has been identified in adult dogs. OBJECTIVES: To document neosporosis as a cause of progressive cerebellar ataxia and cerebellar atrophy in dogs. ANIMALS: Seven client-owned dogs. METHODS: Retrospective, descriptive study. RESULTS: Age at diagnosis ranged from 1 year 6 months to 9 years 11 months. Neuroanatomic localization indicated cerebellar and brainstem disease in 6 dogs and a central vestibular lesion in 1 dog. In all 7 dogs, there was moderate to marked bilaterally symmetrical cerebellar atrophy, with the atrophied cerebellum being surrounded by a region of T2-weighted hyperintense and T1-weighted hypointense signal. Cerebrospinal fluid (CSF) analysis in all but 1 dog showed mononuclear pleocytosis and high protein concentration. Polymerase chain reaction testing for Neospora caninum performed on the CSF was positive in 4/5 dogs tested and there was a high titer of serum antibodies to N. caninum (> or = 1 : 800) in all 6 dogs tested. Postmortem examination in 1 dog confirmed cerebellar atrophy and multifocal nonsuppurative encephalitis with areas of malacia and leptomeningitis. All of the remaining 6 dogs were treated with some combination of clindamycin, trimethoprim, sulfadiazine, and pyrimethamine. Two dogs were euthanized because of deterioration or relapse of neurologic signs, but treatment of the remaining 4 dogs resulted in improvement (3 dogs) or resolution (1 dog) of neurologic signs. CONCLUSIONS AND CLINICAL IMPORTANCE: Neosporosis is an important cause of progressive cerebellar ataxia and cerebellar atrophy in adult dogs.

Asymptomatic carriage of extensively drug-resistant bacteria (eXDR), a simple way to assess spontaneous clearance.

The duration of eXDR carriage depends on several factors that might be difficult to recover. We aim to assess the duration of eXDR carriage by using a simple to recover parameter: the number of consecutive negative screening. 131 eXDR carriers (51 VRE and 80 CPE) were included. The number of consecutive negative screenings was strongly associated with eXDR clearance. All patients displaying at least three negative screenings over a seven-month period were never screened positive thereafter. Taking into account the number of negative screenings as a part of a case-by-case risk assessment would be helpful for the decision to maintain or lift eXDR-focused precautions.

[Encopresis revealing myotonic dystrophy in 2 children]. / Encoprésie révélatrice d'une dystrophie myotonique de Steinert : à propos de 2 observations.

Gastrointestinal symptoms are very frequent in myotonic dystrophy but largely unrecognized. They can be the revealing factors of the disease. We report 2 cases of 10 and 17-year-old children with persistent encopresis starting at the age of 3 and 5 years in spite of laxative treatment. Neurological examination and anorectal manometry provided the diagnosis of myotonic dystrophy. Procainamide treatment was introduced and the digestive symptoms improved. Any child with encopresis should have complete evaluation to rule out the diagnosis of myotonic dystrophy and physicians should look for upper and/or lower gastrointestinal symptoms in every patient with myotonic dystrophy.

Toxigenic Clostridium difficile carriage in general practice: results of a laboratory-based cohort study.

OBJECTIVES: Reported rates of community-acquired Clostridium difficile infections (CDIs) have been increasing. However, the true burden of the disease in general practice is unknown in France. Our objective was to determine the incidence of toxigenic C. difficile carriage and the percentage of stool samples prescribed by general practitioners (GPs) which contained free C. difficile toxins. METHODS: During an 11-month period, all stool samples submitted for any enteric pathogen detection to 15 different private laboratories in Paris and the surrounding areas were tested for C. difficile, irrespective of the GPs' request. A clinical questionnaire was completed for each patient. Stool samples were screened using a rapid simultaneous glutamate dehydrogenase and toxins A/B detection test: any positive result (glutamate dehydrogenase or toxin) was further confirmed by the stool cytotoxicity assay (CTA) on MRC-5 cells and by toxigenic culture (TC) at a central laboratory. The C. difficile isolates were characterized by PCR ribotyping. RESULTS: A total of 2541 patients (1295 female, 1246 male) were included. The incidences of patients with a positive toxigenic culture and a positive CTA were 3.27% (95% CI 2.61%-4.03%) and 1.81% (95% CI 1.33%-2.41%), respectively. GPs requested C. difficile testing in only 12.93% of the stool samples, detecting 52.30% of all TC-positive patients. The 83 toxigenic C. difficile strains belonged to 36 different PCR ribotypes. CONCLUSIONS: Toxigenic C. difficile carriage is frequent in general practice but remains under-recognized. It may affect young patients without previous antimicrobial therapy or hospitalization.

Chiari-like malformation and syringomyelia in normal cavalier King Charles spaniels: a multiple diagnostic imaging approach.

OBJECTIVES: The objectives of the study were (1) to report the incidence of Chiari-like malformation and syringomyelia in a normal French cavalier King Charles spaniel breeding population; (2) to precise the standard computed tomography dimensions of the caudal fossa and (3) to investigate the use of ultrasonography in diagnosis of this syndrome. METHODS: Clinically normal adult cavalier King Charles spaniel underwent ultrasonographic examination of the spinal cord and caudal fossa. Computed tomography was used to measure the caudal fossa and magnetic resonance imaging allowed syringomyelia and cerebellar herniation identification. RESULTS: Of the 16 dogs in the study, seven had syringomyelia (43.7 per cent). All dogs had cerebellar herniation, suggesting Chiari-like malformation and also a tendency to occipital dysplasia. Computed tomography measurements of the caudal fossa are reported. In one dog, a syrinx was identified by ultrasonography. The only difference between dogs with or without syringomyelia was that dogs with Chiari-like malformation/syringomyelia were statistically older. CLINICAL SIGNIFICANCE: The incidence of Chiari-like malformation and syringomyelia may be high in an asymptomatic population of cavalier King Charles spaniel . Computed tomography measurements reported in this study should now be compared with those of a symptomatic population to evaluate the hypothesis that dogs with Chiari-like malformation/syringomyelia syndrome have a smaller caudal fossa. This study did not identify a smaller caudal fossa in an asymptomatic cavalier King Charles spaniel population with syringomyelia. Ultrasonography probably has a low sensitivity for diagnosis of Chiari-like malformation/syringomyelia.

How to: diagnose infection caused by Clostridium difficile.

BACKGROUND: Clostridium difficile is recognized as the major agent responsible for nosocomial diarrhoea. In the context of recent increase in the incidence and severity of C. difficile infections (CDI), an accurate diagnosis is essential for optimal treatment and prevention, but continues to be challenging. AIMS: The present article reviews each key step of CDI diagnosis including stool selection, methods and strategies used, and interpretation of the results. SOURCES: The most recent guidelines for CDI diagnosis published by scientific societies were reviewed. CONTENT: CDI diagnosis is based on clinical presentation and laboratory tests confirming the presence of toxigenic strain or toxins in stools. Stool selection is crucial and can be improved by implementing rejection criteria and a strict policy for appropriate testing. Multiple laboratory tests detecting different targets (free toxin or presence of a potentially toxigenic strain) are commercially available. However, none of these tests combine high sensitivity and specificity to diagnose CDI, low hands-on time and low cost. An optimized diagnosis can be achieved by implementing a two- or three-step algorithm. Algorithms currently recommended by the ESCMID comprise a screening test with high sensitivity followed by a more specific test to detect free toxins. Presence of free toxins in stools has been shown to better correlate with severe outcome whereas nucleic acid amplification tests may lead to an over-diagnosis by detecting asymptomatic carriers of a toxigenic strain. IMPLICATION: To date, no single test can accurately diagnose CDI. Guidelines from the ESCMID recommend a two- or three-step algorithm for optimal CDI detection.

[Pain in children with neurological impairment: A review from the French Pediatric Neurology Society]. / La douleur chez l'enfant en situation de handicap neurologique : mise au point de la Commission « déficience intellectuelle et handicap ¼ de la Société française de neurologie pédiatrique.

Management of pain is one of the major expectations of children with neurological impairment and their families. The medical literature is poor on this topic accounting for approximately 0.15 % of the publications on pain in general. The objective of the French Pediatric Neurology Society was to review the current knowledge on this topic. Bibliographic research was conducted with PubMed and RefDoc for publications between 1994 and 2014 in French or English. A total of 925 articles were retrieved and 92 were selected for review. Pain is common in this population: a 2-week survey indicated that pain occurs in 50-75 % of children. Pain negatively impacts the quality of life of children and their parents. Children with neurological impairment express their pain with pain expression patterns and specific patterns common to children (change of tone, abnormal movements, spasticity, paradoxical reactions, such as laughter, self-injury or vasomotor dysfunction). Some children with neurological impairment are able to use self-report pain scales. If not, observational measures should be used. Behavioral rating scales specifically designed for this population are more sensitive than others. Scales must be selected according to children's communication skills, type of pain, and the context. Sometimes behavioral changes are the only expression of pain: any change in sleep, tone, feeding, or mood must suggest pain in this population. Management of pain remains difficult. There are no specific guidelines. Procedural pain management guidelines and the usual analgesic drugs can be used in children with neurological impairment with specific concerns regarding tolerance and side effects. These children are particularly at risk for neuropathic pain. A multidisciplinary approach is helpful, involving physicians, nurses, physiotherapists, psychologists and parents.

Environmental contamination by bacteria in hospital washrooms according to hand-drying method: a multi-centre study.

BACKGROUND: Hand hygiene is a fundamental component of infection prevention, but few studies have examined whether hand-drying method affects the risk of dissemination of potential pathogens. AIM: To perform a multi-centre, internal-crossover study comparing bacterial contamination levels in washrooms with hand-drying by either paper towels (PT) or jet air dryer (JAD; Dyson). METHODS: A total of 120 sampling sessions occurred over 12 weeks in each of three hospitals (UK, France, Italy). Bacteria were cultured from air, multiple surfaces, and dust. Washroom footfall (patients/visitors/staff) was monitored externally. FINDINGS: Footfall was nine times higher in UK washrooms. Bacterial contamination was lower in PT versus JAD washrooms; contamination was similar in France and the UK, but markedly lower in Italian washrooms. Total bacterial recovery was significantly greater from JAD versus PT dispenser surfaces at all sites (median: 100-300 vs 0-10 cfu; all P < 0.0001). In the UK and France, significantly more bacteria were recovered from JAD washroom floors (median: 24 vs 191 cfu, P < 0.00001). UK meticillin-susceptible Staphylococcus aureus recovery was three times more frequent and six-fold higher for JAD vs PT surfaces (both P < 0.0001). UK meticillin-resistant S. aureus recovery was three times more frequent (21 vs 7 cfu) from JAD versus PT surfaces or floors. Significantly more enterococci and extended-spectrum ß-lactamase (ESBL)-producing bacteria were recovered from UK JAD versus PT washroom floors (P < 0.0001). In France, ESBL-producing bacteria were recovered from dust twice as often during JAD versus PT use. CONCLUSION: Multiple examples of significant differences in surface bacterial contamination, including by faecal and antibiotic-resistant bacteria, were observed, with higher levels in JAD versus PT washrooms. Hand-drying method affects the risk of (airborne) dissemination of bacteria in real-world settings.

The research gap in chronic paediatric pain: A systematic review of randomised controlled trials.

BACKGROUND AND OBJECTIVE: Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain. METHODS: We performed a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. We included RCTs that involved children and adolescents (3 months-18 years) and evaluated the use of pharmacological or non-pharmacological intervention(s) in the context of pain persisting or re-occurring for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias (ROB) Tool. RESULTS: A total of 58 RCTs were identified and numbers steadily increased over time. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 47.5 participants (Q1,Q3: 32, 70). Forty-five percent of RCTs included both adults and children and the median of the mean ages at inclusion was 12.9 years (Q1,Q3: 11, 15). Testing of non-pharmacological interventions was predominant and only 5 RCTs evaluated analgesics or co-analgesics. Abdominal pain, headache/migraine and musculoskeletal pain were the most common types of chronic pain among participants. Methodological quality was poor with 90% of RCTs presenting a high or unclear ROB. CONCLUSIONS: Evaluation of analgesics targeting chronic pain relief in children and adolescents through RCTs is marginal. Infants and children with long-lasting painful conditions are insufficiently represented in RCTs. We discuss possible research constraints and challenges as well as methodologies to circumvent them. SIGNIFICANCE: There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non-pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long-lasting diseases.

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors.

To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were co-amplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

Themes arising in clinical consultation for therapists implementing family-based treatment for adolescents with anorexia nervosa: a qualitative study.

BACKGROUND: Our study aims to explore and describe themes arising in sessions of clinical consultation with therapists implementing Family-Based Treatment (FBT) for adolescents with Anorexia Nervosa (AN). There is currently no literature describing the content of clinical consultation for FBT. Thus, this knowledge will add to the evidence-base on what therapists need from consultants in ongoing clinical consultation. METHODS: Eight therapists at four sites participated in this study, which spanned a two-year period. Following a two-day training workshop, each therapist treated at least one adolescent patient presenting with a restrictive eating disorder with FBT, focusing on adherence to the treatment manual. Clinical consultation sessions occurred monthly and were led by an external FBT expert. Thirty-five (average per site = 9) audio recorded group clinical consultation sessions were transcribed verbatim and coded for themes. Twenty percent of the transcripts were double-coded to ensure consistency. Fundamental qualitative description guided the sampling and data collection. RESULTS: Thematic content analysis revealed ten common themes relating to the provision of clinical consultation to therapists implementing FBT in clinical practice: encouraging parental meal time supervision,discussing the role of mothers, how to align parents, ensuring parental buy-in, when to transition to Phase 2, weighing the patient and the patients' knowledge of their weight, the role of siblings in FBT sessions, how best to manage patient co-morbidities, the role of the father in FBT and how best to manage the family meal. CONCLUSIONS: In conclusion, clinical consultation themes aligned with many of the central tenets of FBT, including how to help parents align their supportive approach during the refeeding process, and how to help parents assume control of eating disordered behaviours. This knowledge helps to guide consultants to anticipate common issues brought forward by therapists attempting to implement FBT.