National Institute of Health Dr. Ricardo Jorge
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Familial hypercholesterolemia variant classification by the Clinical Genome Resource expert panel
Get PDFhipercolesterolemia familiar (FH) é a patologia monogénica mais comum
e caracteriza-se por valores muito elevados de colesterol em circulação,
levando à sua deposição nas artérias e causando aterosclerose prematura.
Indivíduos com FH têm variantes patogénicas, principalmente no gene
LDLR (>90%), mas também nos genes APOB e PCSK9, genes estes muito
importantes no metabolismo lipídico. O diagnóstico genético é o diagnóstico
definitivo, mas existem atualmente mais de 3500 variantes diferentes no
LDLR listadas na ClinVar, e no início deste trabalho, 565 apresentavam
classificações conflituosas de patogenicidade, não permitindo assim
confirmar o diagnóstico clínico nos indivíduos portadores destas variantes.
Neste trabalho apresentamos o progresso da classificação de variantes no
LDLR pelo FH Variant Curation Expert Panel (VCEP) do Clinical Genome
Resource (ClinGen), segundo a recomendação publicada pelo mesmo grupo
para classificação de variantes no gene LDLR.
No processo de classificação das variantes no gene LDLR, laboratórios
associados enviam dados internos de casos índex com a variante em
estudo, que são colocados no Variant Curation Interface e complementados
com evidências publicadas em artigos científicos e outros dados obtidos
de outras bases de dados como descrito na recomendação. Cada variante
é avaliada por um biocurador sénior ou dois juniores e aprovada por três
revisores antes de ser publicada oficialmente na ClinVar.
Atualmente avaliámos 531 variantes no gene LDLR. O FH VCEP classificou
5% destas variantes como benignas/provavelmente benignas, 39% como
patogénicas/provavelmente patogénicas, 48% como variantes de significado
incerto, 1% como conflituosas e 7% estão ainda em avaliação. As
classificações definitivas aumentaram de 34% para 44%, e as classificações
conflituosas diminuíram de 56% para 1%.
O trabalho do FH VCEP visa melhorar o diagnóstico genético da FH, para o
qual a classificação correta das variantes no LDLR é de extrema importância.
As recomendações do FH VCEP diminuem significativamente as classificações
conflituosas, melhorando o diagnóstico da FH no mundo inteiro.Familial hypercholesterolemia (FH) is the most common monogenic
disorder and is characterized by very high levels of circulating cholesterol,
leading to its deposition in ar teries and causing premature atherosclerosis.
Individuals with FH have pathogenic variants, mainly in LDLR gene (>90%),
but also in APOB and PCSK9 genes, which are highly impor tant genes in
lipid metabolism. Genetic diagnosis is the definite diagnosis, but there are currently over 3500 different variants in LDLR listed in ClinVar and, at the
beginning of this work, 565 had conflicting classifications of pathogenicity,
thus not confirming the clinical diagnosis in individuals carrying these
variants. In this work, we present the progress of LDLR variant classification
by the Clinical Genome Resource’s (ClinGen) FH Variant Curation Expert
Panel (VCEP), according to the LDLR consensus variant classification
recommendations published by said group.
In the process of classifying LDLR variants, associated labs send internal
data on index cases with the variants under study, which is uploaded into
the Variant Curation Interface (VCI) and supplemented by evidence published
in literature and data obtained from other databases, as described in the
recommendations. Each variant is assessed by one senior or two junior
biocurators and approved by three reviewers before being officially published
to ClinVar.
We have currently evaluated 531 LDLR variants. FH VCEP classified 5% of
the variants as benign/likely benign, 39% as pathogenic/likely pathogenic,
48% as variants of uncertain significance, 1% as conflicting and 7% are still
under evaluation. Definite classifications increased from 34% to 44%, and
conflicting classifications decreased from 56% to 1%.
Efforts of the FH VCEP aim to improve FH genetic diagnosis, for which the
correct LDLR variant classification is of utmost importance. FH VCEP’s
recommendations significantly decrease conflicting classifications, improving
the diagnosis of FH worldwide.info:eu-repo/semantics/publishedVersio
Vector Surveillance Network - sandflies: the importance of the surveillance of a lesser-known vector
Get PDFO programa REVIVE (Rede de Vigilância de Vetores) resulta de colaboração
entre a Direção-Geral da Saúde, as Administrações Regionais de Saúde do Algarve,
Alentejo, Centro, Lisboa e Vale do Tejo e Norte, a Direção Regional da
Saúde da Madeira, a Direção Regional da Saúde dos Açores e o Instituto Nacional
de Saúde Doutor Ricardo Jorge. No âmbito do REVIVE é realizada a vigilância
entomológica, a nível nacional, de mosquitos (Culicidae) desde 2008,
carraças (Ixodidae) desde 2011 e flebótomos (Psychodidae) desde 2016.
Para se determinar o risco de emergência de doenças transmitidas por flebótomos
é indispensável desenvolver procedimentos para uma vigilância
entomológica sistematizada. Desta forma, anualmente, de maio a outubro,
técnicos colhem, com armadilhas luminosas CDC, flebótomos em todo o
território de Portugal continental. Os insetos provenientes das colheitas
são enviados para o Centro de Estudos de Vetores e Doenças Infeciosas
do Instituto Nacional de Saúde Doutor Ricardo Jorge, para identificação
de espécies e deteção de agentes patogénicos, nomeadamente flebovírus
e Leishmania spp. Contrariamente ao que aconteceu com os culicídeos a
partir de 2008 ou com os ixodídeos, a partir de 2011, a vigilância dos flebótomos
tem vindo a ser implementada de uma forma gradual desde 2016.
Verifica-se que a monitorização destes vetores, apesar de ter sofrido constrangimentos
devido à pandemia, tem vindo a aumentar substancialmente
nos últimos anos.
O objetivo deste trabalho é apresentar, de uma forma sucinta, os resultados
obtidos na vigilância de flebótomos em 2023, e no período que decorreu 2016
a 2022, em Portugal continental, realçando os principais riscos em saúde pública
relacionados com este vector em Portugal.The REVIVE programme (Vector Surveillance Network) is the result of a
collaboration between the General Directorate of Health, the Regional
Health Administrations of the Algarve, Alentejo, Centro, Lisbon and Tagus
Valley and Nor th, the Regional Health Directorate of Madeira, the Regional
Health Directorate of the Azores and the National Institute of Health Dr
Ricardo Jorge. Within the scope of REVIVE, entomological surveillance is
carried out at national level for mosquitoes (Culicidae) since 2008, ticks
(Ixodidae) since 2011 and sandflies (Psychodidae) since 2016. To determine the risk of emergence of diseases transmit ted by sandflies,
it is essential to develop procedures for systematized entomological
sur veillance. Therefore, ever y year, from May to October, technicians
collect sandflies throughout mainland Por tugal using CDC light traps.
The collected insects are sent to the Centre for Vectors and Infectious
Diseases Research, National Institute of Health Dr Ricardo Jorge, for
species identification and detection of pathogens, namely phleboviruses
and Leishmania spp. Contrar y to what happened with culicids or with
ixodids, the sur veillance of sandflies has been implemented gradually,
since 2016. It appears that the monitoring of these vectors, despite
having suf fered constraints due to the pandemic, has been increasing
substantially in recent years.
The objective of this work is to succinctly present the results obtained in
the sur veillance of sandflies in 2023, and in the period from 2016 to 2022,
in mainland Por tugal, highlighting the main public health risks related to
this vector in Portugal.info:eu-repo/semantics/publishedVersio
Global, regional, and national burden of heatwave-related mortality from 1990 to 2019: A three-stage modelling study
No full textMCC Collaborative Research Network: Portugal - Instituto Nacional de Saúde Dr. Ricardo Jorge (Susana das Neves Pereira da Silva, Department of Epidemiology; Joana Madureira, Department of Environmental Health).Background: The regional disparity of heatwave-related mortality over a long period has not been sufficiently assessed across the globe, impeding the localisation of adaptation planning and risk management towards climate change. We quantified the global mortality burden associated with heatwaves at a spatial resolution of 0.5°×0.5° and the temporal change from 1990 to 2019.
Methods and findings: We collected data on daily deaths and temperature from 750 locations of 43 countries or regions, and 5 meta-predictors in 0.5°×0.5° resolution across the world. Heatwaves were defined as location-specific daily mean temperature ≥95th percentiles of year-round temperature range with duration ≥2 days. We first estimated the location-specific heatwave-mortality association. Secondly, a multivariate meta-regression was fitted between location-specific associations and 5 meta-predictors, which was in the third stage used with grid cell-specific meta-predictors to predict grid cell-specific association. Heatwave-related excess deaths were calculated for each grid and aggregated. During 1990 to 2019, 0.94% (95% CI: 0.68-1.19) of deaths [i.e., 153,078 cases (95% eCI: 109,950-194,227)] per warm season were estimated to be from heatwaves, accounting for 236 (95% eCI: 170-300) deaths per 10 million residents. The ratio between heatwave-related excess deaths and all premature deaths per warm season remained relatively unchanged over the 30 years, while the number of heatwave-related excess deaths per 10 million residents per warm season declined by 7.2% per decade in comparison to the 30-year average. Locations with the highest heatwave-related death ratio and rate were in Southern and Eastern Europe or areas had polar and alpine climates, and/or their residents had high incomes. The temporal change of heatwave-related mortality burden showed geographic disparities, such that locations with tropical climate or low incomes were observed with the greatest decline. The main limitation of this study was the lack of data from certain regions, e.g., Arabian Peninsula and South Asia.
Conclusions: Heatwaves were associated with substantial mortality burden that varied spatiotemporally over the globe in the past 30 years. The findings indicate the potential benefit of governmental actions to enhance health sector adaptation and resilience, accounting for inequalities across communities.Author summary: 1. Why was this study done?- Although exposure to heatwave has been associated with increased risk of excess deaths and certain temporal attenuation observed, the evidence mainly comes from limited locations; -The regional disparity in heatwave-related mortality burden over a long period has not been adequately quantified across the globe.
2. What did the researchers do and find?: - Heatwave-related excess deaths were predicted to each grid cell (0.5°×0.5°) across the globe between 1990 and 2019 using a three-stage modelling framework; - During 1990 to 2019 warm seasons, 153,078 deaths were associated with heatwaves (nearly half in Asia), which accounted for 0.94% of all deaths and equated 236 deaths per 10 million residents. The global heatwave-related excess death rate declined by 7.2% per decade in comparison to the 30-year average; - Heatwave-related mortality showed complex regional disparities, such that Southern and Eastern Europe or areas had polar and alpine climates, and/or their residents had high incomes had the greatest cumulative burden while certain locations in Oceania or those with tropical climate or low incomes were observed with the greatest decline over decades.
3. What do these findings mean?: - These regional disparities suggest the necessity of considering the cumulation and temporal change of mortality burden for evaluating the historical health impact of climate change and developing time-efficient adaptation strategies for a certain área; - Localised adaptation planning and risk management should be encouraged across all levels of government, with considering subnational capacities and inequalities; - Lack of time-series death data from certain regions, e.g., Arabian Peninsula and South Asia, may reduce the prediction accuracy in those regions
Comparison of series and parallel reactance to identify changes in intracellular water in response to physical training in athletes during a sports season
No full textObjective: Cross-sectional evidence has demonstrated that parallel reactance obtained by bioelectrical impedance analysis (BIA) may be an alternative to the regularly used series of measurements to predict intracellular water (ICW) in athletes. However, we are not aware of any studies that have determined the predictive role or compared the effectiveness of both series and parallel reactance for tracking ICW changes during an athletic season. The main aim of this study was to determine the predictive role and compare both series and parallel reactance (Xc) in tracking ICW during an athletic season.
Research methods and procedures: This longitudinal study analyzed 108 athletes in the preparatory and competitive periods. Using dilution techniques, total body water (TBW) and extracellular water (ECW) were determined and ICW was calculated. Resistance (R), Xc, and impedance (Z) standardized for height were obtained through BIA spectroscopy using a frequency of 50kHz in a series array and then mathematically transformed in a parallel array.
Results: Multiple regression analyses showed that only changes in parallel Xc and capacitance (CAP) (P < 0.05) were predictors of delta ICW during the sports season. In contracts, this was not the case for Xcs. Both changes in R and Z, series and parallel, predicted similarly the changes in ECW and TBW (P < 0.05) in athletes.
Conclusion: Our findings highlight the potential of parallel BIA values to detect changes in body water compartments over a competitive season. These data provide preliminary evidence that changes in parallel Xc/H, and ultimately CAP, represent valid markers of alterations in cell volume during a sports season.Highlights: - This study highlights the potential of parallel bioelectrical impedance analysis values to detect changes in body water compartments over a competitive season; - Alterations in Xc in parallel and capacitance are the best predictors of changes in intracellular water over a sports season in athletes; - Resistance and impedance indirectly predict changes in extracellular water and total body water in athletes using series or parallel arrays.R.F., F.J., and C.L.N. were each supported with a Ph.D. scholarship from the Portuguese Foundation for Science and Technology. Portuguese Foundation for Science and Technology (2020.05397.BD; 2021.07122.BD)info:eu-repo/semantics/publishedVersio
HBM4EU E-waste study: Assessing persistent organic pollutants in blood, silicone wristbands, and settled dust among E-waste recycling workers in Europe
No full textE-waste recycling is an increasingly important activity that contributes to reducing the burden of end-of-life electronic and electrical apparatus and allows for the EU's transition to a circular economy. This study investigated the exposure levels of selected persistent organic pollutants (POPs) in workers from e-waste recycling facilities across Europe. The concentrations of seven polychlorinated biphenyls (PCBs) and eight polybrominated diphenyl ethers (PBDEs) congeners were measured by GC-MS. Workers were categorized into five groups based on the type of e-waste handled and two control groups. Generalized linear models were used to assess the determinants of exposure levels among workers. POPs levels were also assessed in dust and silicone wristbands (SWB) and compared with serum. Four PCB congeners (CB 118, 138, 153, and 180) were frequently detected in serum regardless of worker's category. With the exception of CB 118, all tested PCBs were significantly higher in workers compared to the control group. Controls working in the same company as occupationally exposed (Within control group), also displayed higher levels of serum CB 180 than non-industrial controls with no known exposures to these chemicals (Outwith controls) (p < 0.05). BDE 209 was the most prevalent POP in settled dust (16 μg/g) and SWB (220 ng/WB). Spearman correlation revealed moderate to strong positive correlations between SWB and dust. Increased age and the number of years smoked cigarettes were key determinants for workers exposure. Estimated daily intake through dust ingestion revealed that ΣPCB was higher for both the 50th (0.03 ng/kg bw/day) and 95th (0.09 ng/kg bw/day) percentile exposure scenarios compared to values reported for the general population. This study is one of the first to address the occupational exposure to PCBs and PBDEs in Europe among e-waste workers through biomonitoring combined with analysis of settled dust and SWB. Our findings suggest that e-waste workers may face elevated PCB exposure and that appropriate exposure assessments are needed to establish effective mitigation strategies.Highlights: - E-waste workers showed higher PCB exposure than the control group; - GLM indicated age, type of processed e-waste and smoking as key determinants; - PBDEs and PCBs showed moderate to strong positive correlations between SWB and dust; - ΣPCB EDI in workers was higher than in general population, but below RfD.Adam Cseresznye acknowledges the Flemish Exposome Project (Flexigut - FFB200392) for his PhD fellowship. Paulien Cleys was supported by the Research Foundation – Flanders-Belgium (FWO) under Grant number 1S70820N, which provided her a PhD fellowship at the University of Antwerp. Yu Ait Bamai acknowledges a fellowship from the Japan Society for the Promotion of Science (JSPS) through the Fund for the Promotion of Joint International Research (Fostering Joint International Research (A), grant number 19KK0288). Giulia Poma was supported by the Exposome Centre of Excellence of the University of Antwerp (BOF grant, Antigoon database number 41222). This project has also received funding from the European Union’s Horizon 2020research and innovation program under grant agreement No 733032 (HBM4EU). In addition, the Finnish Work Environment fund participated in financing this work (grant number 200345).info:eu-repo/semantics/publishedVersio
Emergence of ST131 carrying carbapenemase genes, European Union/European Economic Area, August 2012 to May 2024
No full textAnalysis of 594 isolates of sequence type (ST)131 and its single locus variants carrying carbapenemase genes from 17 European Union/European Economic Area countries revealed acquisition of 18 carbapenemase variants, mainly in ST131 clades A and C. Most frequent were (n = 230) and (n = 224), detected in 14 and 12 countries, respectively. Isolates carrying have increased rapidly since 2021. The increasing detection of carbapenemase genes in the high-risk lineage ST131 is a public health concern
Genomic epidemiology of fluoroquinolone-resistant strains of Shigella sonnei and Shigella flexneri in the Iberian Peninsula from 2015 to 2022
No full textFluoroquinolone-resistance in Shigella is among the serious antimicrobial resistance (AMR) threats. We investigated the genomic epidemiology of fluoroquinolone resistant (FQR) strains of S. sonnei and S. flexneri from 2015 to 2022 in Spain and Portugal. We determined the AMR profiles of 416 isolates (S. flexneri and S. sonnei) and FQR isolates were subjected to whole-genome sequencing. The percentage of FQR isolates gradually increased to reach 38% and 80% of S. flexneri and S. sonnei isolates, respectively in 2022. S. sonnei isolates from men were significantly more likely to be FQR (RR = 4.9, 95% CI = 2.7- 9.0). Genomic analysis revealed two major genetic clusters of FQR S. sonnei from the CipR.MSM5 lineage, previously associated with extreme antimicrobial resistance and transmission in men having sex with men. This study contributes to a better understanding of FQR shigellosis transmission and highlights the added value of enhanced surveillance for these pathogens
Seasonality of mortality under climate change: a multicountry projection study
No full textBackground: Climate change can directly impact temperature-related excess deaths and might subsequently change the seasonal variation in mortality. In this study, we aimed to provide a systematic and comprehensive assessment of potential future changes in the seasonal variation, or seasonality, of mortality across different climate zones.
Methods: In this modelling study, we collected daily time series of mean temperature and mortality (all causes or non-external causes only) via the Multi-Country Multi-City Collaborative (MCC) Research Network. These data were collected during overlapping periods, spanning from Jan 1, 1969 to Dec 31, 2020. We projected daily mortality from Jan 1, 2000 to Dec 31, 2099, under four climate change scenarios corresponding to increasing emissions (Shared Socioeconomic Pathways [SSP] scenarios SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5). We compared the seasonality in projected mortality between decades by its shape, timings (the day-of-year) of minimum (trough) and maximum (peak) mortality, and sizes (peak-to-trough ratio and attributable fraction). Attributable fraction was used to measure the burden of seasonality of mortality. The results were summarised by climate zones.
Findings: The MCC dataset included 126 809 537 deaths from 707 locations within 43 countries or areas. After excluding the only two polar locations (both high-altitude locations in Peru) from climatic zone assessments, we analysed 126 766 164 deaths in 705 locations aggregated in four climate zones (tropical, arid, temperate, and continental). From the 2000s to the 2090s, our projections showed an increase in mortality during the warm seasons and a decrease in mortality during the cold seasons, albeit with mortality remaining high during the cold seasons, under all four SSP scenarios in the arid, temperate, and continental zones. The magnitude of this changing pattern was more pronounced under the high-emission scenarios (SSP3-7.0 and SSP5-8.5), substantially altering the shape of seasonality of mortality and, under the highest emission scenario (SSP5-8.5), shifting the mortality peak from cold seasons to warm seasons in arid, temperate, and continental zones, and increasing the size of seasonality in all zones except the arid zone by the end of the century. In the 2090s compared with the 2000s, the change in peak-to-trough ratio (relative scale) ranged from 0·96 to 1·11, and the change in attributable fraction ranged from 0·002% to 0·06% under the SSP5-8.5 (highest emission) scenario.
Interpretation: A warming climate can substantially change the seasonality of mortality in the future. Our projections suggest that health-care systems should consider preparing for a potentially increased demand during warm seasons and sustained high demand during cold seasons, particularly in regions characterised by arid, temperate, and continental climates.The Environment Research and Technology Development Fund of the Environmental Restoration and Conservation Agency, provided by the Ministry of the Environment of Japan
Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS
No full textThis article belongs to the Special Issue Neonatal Screening in Europe: On the Brink of a New Era.The Portuguese Neonatal Screening Program (PNSP) conducts nationwide screening for rare diseases, covering nearly 100% of neonates and screening for 28 disorders, including 24 inborn errors of metabolism (IEMs). The study's purpose is to assess the epidemiology of the screened metabolic diseases and to evaluate the impact of second-tier testing (2TT) within the PNSP. From 2004 to 2022, 1,764,830 neonates underwent screening using tandem mass spectrometry (MS/MS) to analyze amino acids and acylcarnitines in dried blood spot samples. 2TT was applied when necessary. Neonates with profiles indicating an IEM were reported to a reference treatment center, and subsequent biochemical and molecular studies were conducted for diagnostic confirmation. Among the screened neonates, 677 patients of IEM were identified, yielding an estimated birth prevalence of 1:2607 neonates. The introduction of 2TT significantly reduced false positives for various disorders, and 59 maternal cases were also detected. This study underscores the transformative role of MS/MS in neonatal screening, emphasizing the positive impact of 2TT in enhancing sensitivity, specificity, and positive predictive value. Our data highlight the efficiency and robustness of neonatal screening for IEM in Portugal, contributing to early and life-changing diagnoses
Moving towards a core measures set for patient safety in perioperative care: An e-Delphi consensus study
No full textCorrection: PLoS One. 2025 Jan 2;20(1):e0317063. doi: 10.1371/journal.pone.0317063. eCollection 2025A Core Measures Set (CMS) is an agreed standardized group of measures that should be assessed and reported in research for a specific condition or clinical area. This study undertook the development of a CMS for Patient Safety through a two-round, web-based Delphi consensus approach, in the context of the "Improving quality and patient SAFEty in surgical care through STandardisation and harmonization of perioperative care in Europe" (SAFEST) project-a collaborative, patient-centered and evidence-based European Union-funded project that aims to generate action-oriented evidence in perioperative care. We developed an Initial List of Measures via an umbrella review following the deployment of an e-Delphi method with an inclusive panel of experts to prioritize measures towards a consensualized Final List of Measures. All measures were rigorously assessed for both importance and feasibility. After the two rounds of the e-Delphi consensus method we observed 13 preoperative measures (40.6% of the initial number), 24 intraoperative measures (66.7%), 25 postoperative measures (20.3%) and 23 mixed period measures (41.1%) met consensus criteria for both importance and feasibility. Higher scores were detected in importance ratings compared to feasibility across all groups of measures. Importantly, numeric averages regarding pain-related measures differed in the assessment of patients when compared to that of Healthcare Professionals (HCPs). This work not only informs future SAFEST iterations but also sets a precedent for research into valid, patient-centered, and action-oriented perioperative safety measures.info:eu-repo/semantics/publishedVersio