Methodological considerations in injury burden of disease studies across Europe: a systematic literature review.

BACKGROUND: Calculating the disease burden due to injury is complex, as it requires many methodological choices. Until now, an overview of the methodological design choices that have been made in burden of disease (BoD) studies in injury populations is not available. The aim of this systematic literature review was to identify existing injury BoD studies undertaken across Europe and to comprehensively review the methodological design choices and assumption parameters that have been made to calculate years of life lost (YLL) and years lived with disability (YLD) in these studies. METHODS: We searched EMBASE, MEDLINE, Cochrane Central, Google Scholar, and Web of Science, and the grey literature supplemented by handsearching, for BoD studies. We included injury BoD studies that quantified the BoD expressed in YLL, YLD, and disability-adjusted life years (DALY) in countries within the European Region between early-1990 and mid-2021. RESULTS: We retrieved 2,914 results of which 48 performed an injury-specific BoD assessment. Single-country independent and Global Burden of Disease (GBD)-linked injury BoD studies were performed in 11 European countries. Approximately 79% of injury BoD studies reported the BoD by external cause-of-injury. Most independent studies used the incidence-based approach to calculate YLDs. About half of the injury disease burden studies applied disability weights (DWs) developed by the GBD study. Almost all independent injury studies have determined YLL using national life tables. CONCLUSIONS: Considerable methodological variation across independent injury BoD assessments was observed; differences were mainly apparent in the design choices and assumption parameters towards injury YLD calculations, implementation of DWs, and the choice of life table for YLL calculations. Development and use of guidelines for performing and reporting of injury BoD studies is crucial to enhance transparency and comparability of injury BoD estimates across Europe and beyond.

Risk factors and their contribution to population health in the European Union (EU-28) countries in 2007 and 2017.

BACKGROUND: The Global Burden of Disease (GBD) study has generated a wealth of data on death and disability outcomes in Europe. It is important to identify the disease burden that is attributable to risk factors and, therefore, amenable to interventions. This paper reports the burden attributable to risk factors, in deaths and disability-adjusted life years (DALYs), in the 28 European Union (EU) countries, comparing exposure to risks between them, from 2007 to 2017. METHODS: Retrospective descriptive study, using secondary data from the GBD 2017 Results Tool. For the EU-28 and each country, attributable (all-cause) age-standardized death and DALY rates, and summary exposure values are reported. RESULTS: In 2017, behavioural and metabolic risk factors showed a higher attributable burden compared with environmental risks, with tobacco, dietary risks and high systolic blood pressure standing out. While tobacco and air quality improved significantly between 2007 and 2017 in both exposure and attributable burden, others such as childhood maltreatment, drug use or alcohol use did not. Despite significant heterogeneity between EU countries, the EU-28 burden attributable to risk factors decreased in this period. CONCLUSION: Accompanying the improvement of population health in the EU-28, a comparable trend is visible for attributable burden due to risk factors. Besides opportunities for mutual learning across countries with different disease/risk factors patterns, good practices (i.e. tobacco control in Sweden, air pollution mitigation in Finland) might be followed. On the opposite side, some concerning cases must be highlighted (i.e. tobacco in Bulgaria, Latvia and Estonia or drug use in Czech Republic).

Activity-Dependent Neuroplasticity Induced by an Enriched Environment Reverses Cognitive Deficits in Scribble Deficient Mouse.

Planar cell polarity (PCP) signaling is well known to play a critical role during prenatal brain development; whether it plays specific roles at postnatal stages remains rather unknown. Here, we investigated the role of a key PCP-associated gene scrib in CA1 hippocampal structure and function at postnatal stages. We found that Scrib is required for learning and memory consolidation in the Morris water maze as well as synaptic maturation and NMDAR-dependent bidirectional plasticity. Furthermore, we unveiled a direct molecular interaction between Scrib and PP1/PP2A phosphatases whose levels were decreased in postsynaptic density of conditional knock-out mice. Remarkably, exposure to enriched environment (EE) preserved memory formation in CaMK-Scrib-/- mice by recovering synaptic plasticity and maturation. Thus, Scrib is required for synaptic function involved in memory formation and EE has beneficiary therapeutic effects. Our results demonstrate a distinct new role for a PCP-associated protein, beyond embryonic development, in cognitive functions during adulthood.

Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a "quantitative code".

The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests.

Validation Rules as a First Step for Data Quality: Pharmacovigilance Application in Portugal.

Tracking and reporting Adverse Drug Reactions (ADRs) is crucial for patient safety. This work aims to improve the data quality of the SIRAI application in Portugal by developing data validation rules and a scoring system for each record and the overall dataset. The goal is to enhance the effectiveness of the SIRAI application in monitoring adverse drug reactions.

Burden of disease attributable to risk factors in European countries: a scoping literature review.

OBJECTIVES: Within the framework of the burden of disease (BoD) approach, disease and injury burden estimates attributable to risk factors are a useful guide for policy formulation and priority setting in disease prevention. Considering the important differences in methods, and their impact on burden estimates, we conducted a scoping literature review to: (1) map the BoD assessments including risk factors performed across Europe; and (2) identify the methodological choices in comparative risk assessment (CRA) and risk assessment methods. METHODS: We searched multiple literature databases, including grey literature websites and targeted public health agencies websites. RESULTS: A total of 113 studies were included in the synthesis and further divided into independent BoD assessments (54 studies) and studies linked to the Global Burden of Disease (59 papers). Our results showed that the methods used to perform CRA varied substantially across independent European BoD studies. While there were some methodological choices that were more common than others, we did not observe patterns in terms of country, year or risk factor. Each methodological choice can affect the comparability of estimates between and within countries and/or risk factors, since they might significantly influence the quantification of the attributable burden. From our analysis we observed that the use of CRA was less common for some types of risk factors and outcomes. These included environmental and occupational risk factors, which are more likely to use bottom-up approaches for health outcomes where disease envelopes may not be available. CONCLUSIONS: Our review also highlighted misreporting, the lack of uncertainty analysis and the under-investigation of causal relationships in BoD studies. Development and use of guidelines for performing and reporting BoD studies will help understand differences, avoid misinterpretations thus improving comparability among estimates. REGISTRATION: The study protocol has been registered on PROSPERO, CRD42020177477 (available at: https://www.crd.york.ac.uk/PROSPERO/ ).

Clotting, immune system, and venous thrombosis in lung adenocarcinoma patients: a prospective study.

Thrombosis is highly prevalent in cancer patients, being accepted as a bad prognosis marker. The importance of various mechanisms involved in the thrombophilic state of lung cancer patients is not well understood. In this prospective study, involving 109 unselected patients with lung adenocarcinoma, thrombosis was present in 24% of patients and affected survival in a bivariable model. However, in a multivariable evaluation, considering all the factors under study, only LAC and IgM anti-beta(2) GP I modified thrombosis risk, whereas in a Kaplan-Meyer regression model, thrombosis, IL-6, LAC, factor VIII, and IgM anti-beta(2) GP I interfered with patient's survival.

Lupus anticoagulant activity as a thrombosis risk factor in lung adenocarcinoma patients.

There is a high incidence of thrombosis in cancer patients. Retrospective studies indicate that lupus anticoagulant (LA) antibodies can be a thrombosis risk factor in cancer. In 77 patients with different forms of cancer LA and thrombosis incidence were retrospectively evaluated. In a prospective study, with 42 lung adenocarcinoma patients, we measured plasma LA, fibrinogen, factor VIII (FVIII), and thrombosis incidence. A high frequency of LA and thrombosis were observed in both studies. In isolation LA, increased levels of FVIII and fibrinogen could not be considered good markers for the development of thrombosis.

Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.

The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.