c4c: Paediatric pharmacovigilance: Methodological considerations in research and development of medicines for children - A c4c expert group white paper

Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population-specific factors (e.g., more frequent use of off-label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life-cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post-marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record-linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit–risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life-cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs

Antenatal and perinatal factors influencing neonatal blood pressure: a systematic review

Objective A comprehensive understanding of the factors contributing to perinatal blood pressure is vital to ensure optimal postnatal hemodynamic support. The objective of this study was to review existing literature on maternal and perinatal factors influencing blood pressure in neonates up to 3 months corrected age. Methods A systematic search of published literature in OVID Medline, OVID Embase and the COCHRANE library identified publications relating to maternal factors affecting blood pressure of neonates up to corrected age of 3 months. Summary data were extracted and compared (PROSPERO CRD42018092886). Results Of the 3683 non-duplicate publications identified, 44 were eligible for inclusion in this review. Topics elicited were sociodemographic factors, maternal health status, medications, smoking during pregnancy, and cord management at birth. Limited data were available for each factor. Results regarding the impact of these factors on neonatal blood pressure were inconsistent across studies. Conclusions There is insufficient evidence to draw definitive conclusions regarding the impact of various maternal and perinatal factors on neonatal blood pressure. Future investigations of neonatal cardiovascular therapies should account for these factors in their study design. Similarly, studies on maternal diseases and perinatal interventions should include neonatal blood pressure as part of their primary or secondary analyses

Assessment of sanitary conditions in stands of Norway spruce (Picea abies Karst.) damaged by spruce bud scale (Physokermes piceae Schrnk.)

Spruce bud scale (Physokermes piceae Schrnk.) affects tree growth directly and indirectly. Direct injury appears in the form of tissue damage, as insects suck sap from tree phloem. Indirect injury appears as “honeydew”, which results in negative effects on tree growth. Plant sap is saturated with various carbohydrates called photosynthates that are difficult for scaly insects to digest. Therefore it is secreted in excrements, which are subsequently a food source for the black sooty mold (Apiosporium pinophilum Fuckel). The fungus covers needles blocking stomata, causing decreased transpiration and photosynthesis. An inexplicable wither of Norway spruce was reported in Latvia during 2010 due to black sooty mold. However, spruce bud scale was not evident. In 2011, mass propagation of spruce bud scale was observed following the 2010 Norway spruce loss. One objective of this research was to determine if Kraft tree growth classes could be applied to establish the factors responsible for tree foliage damage. Six 21 - 40 year old (second age class) Norway spruce stands were evaluated. Two circular sample plots with a 7.98 m radius, and a 200-m2 area were randomly established per each forest stand hectare. Diameter at breast height (dbh, 1.3 m), and height of approximately 30 trees was measured to model a trend. For all trees, Kraft class, and foliage damage level caused by spruce bud scale and black sooty mold were determined. Significant differences were not observed in tree damage levels among stands, however significant differences among damage levels in different Kraft classes were detected (F = 3.45 > Fcrit. = 2.80, α = 0.05 > P = 0.02) found. Overall damage intensity was 29.3 %. Total forestry loss was 1153 LVL (1640 EUR) for all surveyed stands (10 ha), and 115 LVL (164 EUR) per hectare

Method of blood pressure measurement in neonates and infants: a systematic review and analysis

Objectives: To determine the recommended blood pressure (BP) measurement methods in neonates after systematically analyzing the international literature regarding proper BP cuff size and measurement location and method. Study Design: A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library and CINAHL from 1946 to 2017 on BP in neonates < 3 months of age (PROSPERO ID CRD42018092886). Study data was extracted and analyzed with separate analysis of Bland-Altman studies comparing measurement methods. Results: Of 3587 non-duplicate publications identified, 34 were appropriate for inclusion in the analysis. Four studies evaluating BP cuff size support a recommendation for a cuff width to arm circumference ratio of ~0.5. Studies investigating measurement location identified the upper arm as the most accurate and least variable location for oscillometric BP measurement. Analysis of studies using Bland-Altman methods for comparison of intra-arterial to oscillometric BP measurement show that the two methods correlate best for mean arterial pressure (MAP) whereas systolic BP (SBP) by the oscillometric method tends to over-estimate intra-arterial SBP. Compared to intra-arterial methods, SBP, diastolic BP, and MAP by oscillometric methods are less accurate and precise, especially in neonates with a MAP <30mmHg. Conclusions: Proper BP measurement is critical in neonates with naturally lower BP and attention to BP cuff size, location, and method of measurement are essential. With decreasing use of intra-arterial catheters for long term BP monitoring in neonates, further studies are urgently needed to validate and develop oscillometric methodology with enhanced accuracy

Development of a neonatal adverse event severity scale through a Delphi consensus approach

Background: Assessment of the seriousness, expectedness and causality are necessary for any adverse event (AE) in a clinical trial. In addition, assessing AE severity helps determine the importance of the AE in the clinical setting. Standardisation of AE severity criteria could make safety information more reliable and comparable across trials. Although standardised AE severity scales have been developed in other research fields, they are not suitable for use in neonates. The development of an AE severity scale to facilitate the conduct and interpretation of neonatal clinical trials is therefore urgently needed. / Methods: A stepwise consensus process was undertaken within the International Neonatal Consortium (INC) with input from all relevant stakeholders. The consensus process included several rounds of surveys (based on a Delphi approach), face-to-face meetings and a pilot validation. / Results: Neonatal AE severity was classified by five grades (mild, moderate, severe, life threatening or death). AE severity in neonates was defined by the effect of the AE on age appropriate behaviour, basal physiological functions and care changes in response to the AE. Pilot validation of the generic criteria revealed κ=0.23 and guided further refinement. This generic scale was applied to 35 typical and common neonatal AEs resulting in the INC neonatal AE severity scale (NAESS) V.1.0, which is now publicly available. / Discussion: The INC NAESS is an ongoing effort that will be continuously updated. Future perspectives include further validation and the development of a training module for users

Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine & Headache Alliance

Background: New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. Methods: We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. Results: There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. Conclusions: This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities

Language politics and practices in the Baltic states

This monograph provides an overview of the language situation in the three Baltic countries: Estonia, Latvia and Lithuania. It examines the recent change in language regimes that the Baltic States have deliberately brought about since the restitution of their independence, the nature of these changes, the opposition they have engendered and the linguistic, political and social consequences of these policies, both locally and internationally. First, an overview is provided on the historical background to contextualise and present language policy issues in the Baltic. Then attempts to overturn major aspects of Soviet language policy and to re-institute the national language are highlighted. Aspects of the current language situation covered include a special focus on bilingual and multilingual language use in the Baltic multiethnic settings. Detailed attention is also paid to language provision in the diverging educational settings, as well as to methods of assessment. This is followed by a discussion of attitudes to language use, standardisation, testing, languages and language variants. In conclusion the scholarly treatment of Baltic language policy issues is examined, concluding with an evaluation of the contribution of the Baltic States to our overall understandings of language policy and its complexities