A Principles Framework for Digital Provision of Medical Information for Healthcare Professionals.

European pharmaceutical companies have a legal requirement to provide non-promotional medical information (MI) services to support healthcare professionals (HCPs) using their medicinal products. While we are seeing an increased HCP preference and expectation towards digital channels, the lack of a compliance framework relating to the provision of non-promotional MI services is a key factor complicating and compromising the ability for companies to meet this need. Meanwhile, the internet is dominated by a large volume of unregulated, easy access, and potentially low-quality information from diverse sources. The Medical Information Leaders in Europe (MILE) association is therefore proposing a framework of principles to support pharmaceutical companies with the digital provision of MI services; these relate to digital access to non-promotional, medicinal product information to support clinical decision making and patient care. The three established European national MI associations have already considered the framework and expressed their endorsement. MILE continues to invite stakeholders, including pharmaceutical companies, regulators, national industry associations and healthcare professional bodies to engage and help refine and implement this framework. This publication does not constitute legal advice; decision making and accountability remains with each pharmaceutical company.

Construction and validation of a scale of sexual self-concept for the elderly Chilean population.

BACKGROUND: Sexual self-concept has a central role in the life of the elderly population. Indeed, their sexual self-concept has significant and positive relationships with their satisfaction with life, pleasure, and willingness to interact with others. However, social-cultural prejudice means that the elderly are considered asexual individuals, harming their sexual self-concept. This prejudice is prominent in Chile, where the elderly do not have access to clear information about their sexuality. However, research on the Chilean elderly population is still in its infancy and requires more attention. Hence, this research aims to construct and validate a scale of sexual self-concept for the elderly Chilean population to cover this identified gap in the literature. METHODS: Sixty items were integrated into the first version of the scale. Ten external judges were asked to assess the content validity. Twenty-eight items were maintained. Subsequently, an instrumental and cross-sectional design was implemented with a non-probabilistic sampling (N = 188). Items were refined with corrected homogeneity indices and conditional estimates of Cronbach's alpha and Omega coefficient. RESULTS: A final scale of nine items equally distributed in three dimensions was obtained: Sexual self-efficacy (ω = 0.867), Sexual assertiveness (ω = 0.764), and Sexual self-esteem (ω = 0.803). The confirmatory factor analysis reflects that the theoretical model has an adequate fit (CFI = .989; TLI = .984; RMSEA = .086). CONCLUSIONS: The data analyses confirmed that the scale has adequate psychometric properties. This scale can be used for multidimensional measurements of sexual self-concept in the elderly in Chile. Further research can confirm its psychometric properties in different settings within the Spanish language population.

The Critical Need to Build a European Governance Model for Online Access to Medical Information Services: A Position Paper.

European pharmaceutical companies have a legal requirement to provide non-promotional Medical Information (MI) services to support healthcare professionals (HCPs) who are using their medicinal products. While the industry has self-regulating bodies with established Codes of Practice, these mainly focus on promotional messaging and commercial activities. In the absence of similar frameworks for MI, such services struggle to understand how to meet HCP digital expectations, often in fear of breaching the promotional codes. This is limiting access to the wealth of non-promotional patient-focussed information held within the industry. Meanwhile, a large volume of unregulated, low-quality information can be readily found on the internet. To understand the current status, the Medical Information Leaders in Europe (MILE) industry association performed a benchmarking survey which explored the online MI service provision of 13 mid-large pharmaceutical companies across Europe. This highlighted a great diversity in approach in terms of geographical coverage and content. Visibility and access for HCPs is complex, compromising online engagement and website utilisation. This MILE position paper highlights the critical need to establish a clear governance model, which empowers pharmaceutical company MI functions to provide unbranded, non-promotional, medicinal product information sources to support HCP online information needs. It is essential to build confidence, transparency and trust by establishing a practical quality framework with principles and standards for online MI services for HCPs.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Asymptomatic progressive multifocal leukoencephalopathy: a case report and review of the literature.

BACKGROUND: We report the development of asymptomatic progressive multifocal leukoencephalopathy in a patient with multiple sclerosis on natalizumab therapy. Progressive multifocal leukoencephalopathy often presents with debilitating neurologic symptoms. Very few cases have documented a completely asymptomatic course of the disease. CASE PRESENTATION: A 26-year-old white woman with multiple sclerosis was treated with natalizumab. She was diagnosed as having progressive multifocal leukoencephalopathy based on characteristic magnetic resonance imaging lesions after 27 infusions of natalizumab. She had no neurologic deficits at the time of diagnosis and John Cunningham virus in cerebrospinal fluid was detected at 15 copies/ml. She was initially treated with mefloquine and mirtazapine and remained asymptomatic for 3 months. She later developed worsening magnetic resonance imaging lesions related to immune reconstitution inflammatory syndrome. At that time, she received intravenously administered immunoglobulin and high-dose intravenously administered methylprednisolone with radiologic improvement of the lesions. CONCLUSIONS: Our case report illustrates that early detection of asymptomatic progressive multifocal leukoencephalopathy and its subsequent treatment resulted in a benign clinical course. In consideration of the additional small number of cases of asymptomatic progressive multifocal leukoencephalopathy that have been reported, we conclude that routine magnetic resonance imaging surveillance is important for patients with multiple sclerosis who are at high risk for developing natalizumab-associated progressive multifocal leukoencephalopathy.

Autoimmune septin-5 cerebellar ataxia.

OBJECTIVE: To report a form of autoimmune cerebellar ataxia in which antibodies target septin-5, a guanosine triphosphate (GTP)-binding neural protein involved in neurotransmitter exocytosis. METHODS: Archived sera and CSF specimens with unclassified synaptic antibodies were re-evaluated by tissue-based indirect immunofluorescence assay. Autoantigens were identified by Western blot and mass spectrometry. Recombinant protein assays (Western blot, cell based, and protein screening array) confirmed antigen specificity. RESULTS: Serum and CSF from 6 patients produced identical synaptic immunoglobulin G (IgG) staining patterns of synaptic regions (neuropil) of the mouse cerebrum and cerebellum. The molecular layer of the cerebellum and the thalamus demonstrated stronger immunoreactivity than the midbrain, hippocampus, cortex, and basal ganglia. The antigen revealed by mass spectrometry analysis of immunoprecipitated cerebellar proteins and confirmed by recombinant protein assays was septin-5. All 4 patients with records available had subacute onset of cerebellar ataxia with prominent eye movement symptoms (oscillopsia or vertigo). None had cancer detected. Improvements occurred after immunotherapies (2) or spontaneously (1). One patient died. CONCLUSION: Septin-5 IgG represents a biomarker for a potentially fatal but treatable autoimmune ataxia.

Molecular assays for the diagnosis of sepsis in neonates.

BACKGROUND: Microbial cultures for diagnosis of neonatal sepsis have low sensitivity and reporting delay. Advances in molecular microbiology have fostered new molecular assays that are rapid and may improve neonatal outcomes. OBJECTIVES: To assess the diagnostic accuracy of various molecular methods for the diagnosis of culture-positive bacterial and fungal sepsis in neonates and to explore heterogeneity among studies by analyzing subgroups classified by gestational age and type of sepsis onset and compare molecular tests with one another. SEARCH METHODS: We performed the systematic review as recommended by the Cochrane Diagnostic Test Accuracy Working Group. On 19 January 2016, we searched electronic bibliographic databases (the Cochrane Library, PubMed (from 1966), Embase (from 1982), and CINAHL (from 1982)), conference proceedings of the Pediatric Academic Societies annual conference (from 1990), clinical trial registries (ClinicalTrials.gov, International Standard Randomised Controlled Trial Number (ISRCTN) registry, and World Health Organization (WHO) International Clinical Trials Platform (ICTRP) Search portal), and Science Citation Index. We contacted experts in the field for studies. SELECTION CRITERIA: We included studies that were prospective or retrospective, cohort or cross-sectional design, which evaluated molecular assays (index test) in neonates with suspected sepsis (participants) in comparison with microbial cultures (reference standard). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the methodologic quality of the studies and extracted data. We performed meta-analyses using the bivariate and hierarchical summary receiver operating characteristic (HSROC) models and entered data into Review Manager 5. MAIN RESULTS: Thirty-five studies were eligible for inclusion and the summary estimate of sensitivity was 0.90 (95% confidence interval (CI) 0.82 to 0.95) and of specificity was 0.93 (95% CI 0.89 to 0.96) (moderate quality evidence). We explored heterogeneity by subgroup analyses of type of test, gestational age, type of sepsis onset, and prevalence of sepsis and we did not find sufficient explanations for the heterogeneity (moderate to very low quality evidence). Sensitivity analyses by including studies that analyzed blood samples and by good methodology revealed similar results (moderate quality evidence). AUTHORS' CONCLUSIONS: Molecular assays have the advantage of producing rapid results and may perform well as 'add-on' tests.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

"Las Dos Cosas," or Why Mexican American Mothers Breast-Feed, But Not for Long.

OBJECTIVES: To determine why mothers in El Paso, Texas, choose to breast-feed but not exclusively and why breast-feeding duration is short. METHODS: This was a cross-sectional observational study of 300, mostly Mexican American, low-income mothers delivering at a county hospital who answered questions about breast-feeding and formula feeding, sociodemographics, and health habits. RESULTS: Most mothers (92.6%) in our study initiated breast-feeding, but only 20.3% breast-fed exclusively at the time of hospital discharge. Most mothers (73%) self-identified as Mexicans or Mexican Americans living on the border of the United States and Mexico. Mothers in our study chose to breast-feed if they decided to breast-feed during pregnancy, had breast-fed a previous child, had support from a female relative, and had attended college. Distinctively, most mothers in our study chose "las dos cosas" or to breast-feed and formula feed together early after birth. Acculturation failed to explain the breast-feeding decisions. CONCLUSIONS: Mexican American mothers who decided to breast-feed during pregnancy, breast-fed another child, attended college, and enlist a female relative's breast-feeding help were more likely to choose breast-feeding exclusively. Most Mexican American low-income mothers in our study chose "las dos cosas."

The genetic and genomic background of multiple myeloma patients achieving complete response after induction therapy with bortezomib, thalidomide and dexamethasone (VTD).

The prime focus of the current therapeutic strategy for Multiple Myeloma (MM) is to obtain an early and deep tumour burden reduction, up to the level of complete response (CR). To date, no description of the characteristics of the plasma cells (PC) prone to achieve CR has been reported. This study aimed at the molecular characterization of PC obtained at baseline from MM patients in CR after bortezomib-thalidomide-dexamethasone (VTD) first line therapy.One hundred and eighteen MM primary tumours obtained from homogeneously treated patients were profiled both for gene expression and for single nucleotide polymorphism genotype. Genomic results were used to obtain a predictor of sensitivity to VTD induction therapy, as well as to describe both the transcription and the genomic profile of PC derived from MM with subsequent optimal response to primary induction therapy.By analysing the gene profiles of CR patients, we identified a 5-gene signature predicting CR with an overall median accuracy of 75% (range: 72%-85%). In addition, we highlighted the differential expression of a series of genes, whose deregulation might explain patients' sensitivity to VTD therapy. We also showed that a small copy number loss, covering 606Kb on chromosome 1p22.1 was the most significantly associated with CR patients.

The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis.

IMPORTANCE: This study describes what is, to our knowledge, the previously unknown effect of glatiramer acetate therapy on B cells in patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To determine whether glatiramer acetate therapy normalizes dysregulated B-cell proliferation and cytokine production in patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Twenty-two patients with MS who were receiving glatiramer acetate therapy and 22 treatment-naive patients with MS were recruited at The University of Texas Southwestern Medical Center MS clinic. Cell samples from healthy donors were obtained from HemaCare (Van Nuys, California) or Carter Blood Bank (Dallas, Texas). Treatment-naive patients with MS had not received any disease-modifying therapies for at least 3 months before the study. EXPOSURES: Glatiramer acetate therapy for at least 3 months at the time of the study. MAIN OUTCOMES AND MEASURES: B-cell phenotype and proliferation and immunoglobulin and cytokine secretion. RESULTS: A restoration of interleukin 10 production by peripheral B cells was observed in patients undergoing glatiramer acetate therapy as well as a significant reduction of interleukin 6 production in a subset of patients who received therapy for less than 32 months. Furthermore, proliferation in response to high-dose CD40L was altered and immunoglobulin production was elevated in in vitro-activated B cells obtained from patients who received glatiramer acetate. CONCLUSIONS AND RELEVANCE: Glatiramer acetate therapy remodels the composition of the B-cell compartment and influences cytokine secretion and immunoglobulin production. These data suggest that glatiramer acetate therapy affects several aspects of dysregulated B-cell function in MS that may contribute to the therapeutic mechanisms of glatiramer acetate.

De novo interstitial duplication of 15q11.2-q13.1 with complex maternal uniparental trisomy for the 15q11-q13 region in a patient with Prader-Willi syndrome.

Prader-Willi syndrome is caused by the lack of paternal contribution for the imprinted 15q11-q13 region that originates through a number of mechanisms such as paternal deletion of 15q11-q13, maternal uniparental disomy, or by an imprinting defect due to epimutations in the paternal imprinting center. In the present report, we describe a female patient with complex maternal uniparental trisomy for the 15q11-q13 Prader-Willi syndrome critical region due to a de novo interstitial duplication of 15q11-q13 region that is present in one of the maternal homologs. As a result, the patient has three maternally derived copies of the Prader-Willi syndrome critical region and absence of paternal 15 contribution and thus, presents with a Prader-Willi syndrome phenotype with risk for developing additional phenotypes (e.g., autism and psychiatric phenotypes) characteristic of maternally derived duplications of this region. We suggest that this is a rather unique mechanism leading to Prader-Willi syndrome that has not been previously reported.

Current and emerging therapies in multiple sclerosis: a systematic review.

Multiple sclerosis (MS) is a potentially disabling chronic autoimmune neurological disease that mainly affects young adults. Our understanding of the pathophysiology of MS has significantly advanced in the past quarter of a century. This has led to the development of many disease-modifying therapies (DMTs) that prevent exacerbations and new lesions in patients with relapsing remitting MS (RRMS). So far there is no drug available that can completely halt the neurodegenerative changes associated with the disease. It is the purpose of this review to provide concise information regarding mechanism of action, indications, side effects and safety of Food and Drug Administration and European Medicines Agency approved agents for MS, emerging therapies, and drugs that can be considered for off-label use in MS.

Molecular assays in the diagnosis of neonatal sepsis: a systematic review and meta-analysis.

BACKGROUND: Microbial cultures for diagnosis of neonatal sepsis suffer from low sensitivity and reporting delay. Advances in molecular microbiology have fostered new molecular assays that are rapid and may improve neonatal outcomes. OBJECTIVES: We assessed whether molecular assays have sufficient sensitivity (>0.98) and specificity (>0.95) to replace microbial cultures in the diagnosis of neonatal sepsis and explored heterogeneity by use of subgroup analyses based on the type of assay, gestational age of the neonate, and type of sepsis onset. METHODS: We performed the systematic review as recommended by the Cochrane Diagnostic Test Accuracy Working Group. Electronic bibliographic databases, conference abstracts, personal files, and reference lists of identified articles were searched. We included studies of case-control or consecutive series design, which evaluated molecular assays (index test) in neonates with suspected sepsis (participants) in comparison with microbial cultures (reference standard). Two reviewers independently assessed the methodologic quality of the studies and extracted data. RESULTS: A bivariate random-effects model was used for meta-analysis of the 23 included studies, and summary estimates of sensitivity and specificity with 95% confidence intervals (CIs) were generated. Mean sensitivity and specificity were 0.90 (95% CI: 0.78-0.95) and 0.96 (95% CI: 0.94-0.97), respectively. Real-time polymerase chain reaction (PCR) and broad-range conventional PCR had higher sensitivity and specificity than other assays. Sufficient data were not available to evaluate gestational-age and sepsis-type subgroups. CONCLUSION: Molecular assays do not have sufficient sensitivity to replace microbial cultures in the diagnosis of neonatal sepsis but may perform well as "add-on" tests.

Molecular microbiological methods in the diagnosis of neonatal sepsis.

Neonatal sepsis is a major cause of neonatal mortality and morbidity. The current gold standard for diagnosis of sepsis, namely blood culture, suffers from low sensitivity and a reporting delay of approximately 48-72 h. Rapid detection of sepsis and institution of antimicrobial therapy may improve patient outcomes. Rapid and sensitive tests that can inform clinicians regarding the institution or optimization of antimicrobial therapy are urgently needed. The ideal diagnostic test should have adequate specificity and negative predictive value to reliably exclude sepsis and avoid unnecessary antibiotic therapy. We comprehensively searched for neonatal studies that evaluated molecular methods for diagnosis of sepsis. We identified 19 studies that were assessed with respect to assay methodology and diagnostic characteristics. In addition, we also reviewed newer molecular microbiological assays of relevance that have not been fully evaluated in neonates. Molecular methods offer distinct advantages over blood cultures, including increased sensitivity and rapid diagnosis. However, diagnostic accuracy and cost-effectiveness should be established before implementation in clinical practice.

Gastroenteritis: programa para la mortalidad en el medio rural

Se hace un diagnóstico de la situación de la gastroenteritis y las enfermedades diarréicas (AU) del Estado Cojedes, encontrandose que esta ocupa el 6§ lugar de la mortalidad general y el 2§ de la mortalidad infantil. Se señalan las prioridades a tener en cuenta para disminuir la morbimortalidad infantil causada por la Gastroenteritis y otras enfermedades diarréicas