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AIMS: Effective therapy to improve exercise capacity in Fontan patients is lacking. Leg-focused high-weight resistance training might augment the peripheral muscle pump and thereby improve exercise capacity. METHODS AND RESULTS: This randomized semi-cross-over controlled trial investigated the effects of a 12-week leg-focused high-weight resistance training plus high-protein diet, on (sub)maximal exercise capacity, cardiac function (assessed with cardiovascular magnetic resonance), muscle strength, and quality of life in paediatric Fontan patients. Twenty-eight paediatric Fontan patients were included, 27 patients, (median age 12.9 [10.5-15.7]), and successfully completed the programme. Peak oxygen uptake (PeakVO2) at baseline was reduced [33.3â mL/kg/min (27.1-37.4), 73% (62-79) of predicted]. After training PeakVO2/kg and Peak workload improved significantly with +6.2â mL/kg/min (95%CI: 3.4-9.0) (+18%) P < 0.001 and +22 Watts (95%CI: 12-32) (+18%) P < 0.001, respectively, compared to the control period. Indexed single ventricle stroke volume increased significantly [43â mL/beat/m2 (40-49) vs. 46 (41-53), P = 0.014], as did inferior vena cava flow [21â mL/beat/m2 (18-24) vs. 23 (20-28), P = 0.015], while superior vena cava flow remained unchanged. The strength of all measured leg-muscles increased significantly compared to the control period. Self-reported quality of life improved on the physical functioning and change in health domains of the child health questionnaire, parent-reported quality of life improved the bodily pain, general health perception, and change in health domains compared to the control period. CONCLUSION: In a relatively large group of 27 older Fontan children, 12-weeks of leg-focused high-weight resistance training improved exercise capacity, stroke volume, (sub)maximal exercise capacity, muscle strength, and domains of quality of life. REGISTRATION: International Clinical Trials: Trial NL8181.
Is leg-focused high-weight resistance training an effective therapy to improve reduced exercise capacity in patients with a Fontan circulation? Key Finding: Twelve weeks of leg-focused high-weight resistance training in children with a Fontan circulation improved exercise capacity, single ventricular stroke volume, (sub)maximal exercise capacity, muscle strength, and physical domains of quality of life. Take-home Message: Leg-focused high-weight resistance training results in improved exercise capacity, cardiac function, and quality of life patients with a Fontan circulation. Patients with a Fontan circulation should be motivated to perform lower limb strengthening exercises.
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Técnica de Fontan , Treinamento Resistido , Criança , Humanos , Teste de Esforço , Tolerância ao Exercício/fisiologia , Perna (Membro) , Qualidade de Vida , Volume Sistólico/fisiologia , Veia Cava Superior , AdolescenteRESUMO
BACKGROUND: In 2011 a 12 weeks personalized exercise training program in 23 mildly affected adult late onset Pompe patients (age 19.6-70.5 years) improved endurance, muscle strength and function. Data on long-term effects of this program or of other physical activity in Pompe disease are absent. This retrospective cohort study aimed to explore effects of long-term healthy physical activity according to the WHO norm and the former exercise training program on the disease course. RESULTS: A total of 29 adult late onset Pompe patients were included: 19 former exercise training program participants and 10 comparable control patients. Patients, who based on interviews, met the 2010 WHO healthy physical activity norm (active, n = 16) performed better on endurance (maximal cardiopulmonary exercise test), muscle strength and function compared to patients not meeting this norm (inactive, n = 13) (p < 0.05). Majority of the outcomes, including endurance and manually tested muscle strength, tended to be higher in the active patients of the 2011 training cohort who continued the program compared to active control patients (p > 0.05). CONCLUSION: In Pompe disease long-term healthy physical activity according to the 2010 WHO norm leads to physical benefits and a personalized exercise training program may have additional favorable effects and both should be recommended as standard of care.
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Terapia por Exercício , Doença de Depósito de Glicogênio Tipo II , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Exercício Físico , Seguimentos , Doença de Depósito de Glicogênio Tipo II/terapia , Força Muscular/fisiologia , Resistência Física/fisiologia , Estudos RetrospectivosRESUMO
Fontan circulation is a highly abnormal circulatory state that may affect various organ systems. The effect on body composition is an important factor to assess the condition of the patient. This systematic review assesses body composition and possibly related adverse outcomes in patients with a Fontan circulation, to provide an overview of current insights. Studies evaluating body composition by compartment (either fat mass or lean/muscle mass) in Fontan patients published up to April 2023 were included in this systematic review. Of 1392 potential studies, 18 studies met the inclusion criteria. In total, body composition measurements of 774 Fontan patients were included. Body composition was measured using dual-energy X-ray absorptiometry (DXA) (n = 12), bioelectrical impedance analysis (BIA) (n = 5), computer tomography (CT) (n = 1), or magnetic resonance imaging (MRI) (n = 1). All studies reported a normal body mass index (BMI) in Fontan patients, compared to controls. Five out of nine studies reported significantly higher body fat values, and twelve out of fifteen studies reported significantly lower muscle or lean mass values in the Fontan population compared to the healthy population. Unfavorable body composition in Fontan patients was associated with decreased exercise capacity, worse cardiac function, and adverse outcomes including hospital admissions and death. Conclusions: Despite having a normal BMI, Fontan patients have an increased fat mass and decreased muscle mass or lean mass compared to the healthy population. This unfavorable body composition was associated with various adverse outcomes, including a decreased exercise capacity and worse cardiac function. What is Known: ⢠Patients with a Fontan circulation have a decreased exercise capacity compared to healthy peers, an unfavorable body composition might be a contributor to their impaired exercise capacity. What is New: ⢠Fontan patients are predisposed to an unfavorable body composition, characterized by increased fat mass and decreased muscle mass accompanied by a normal BMI compared to the healthy population. ⢠Among others, unfavorable body composition was associated with decreased exercise capacity, cardiac function, and increased morbidity in patients with a Fontan circulation.
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Tecido Adiposo , Composição Corporal , Humanos , Composição Corporal/fisiologia , Imageamento por Ressonância Magnética , Absorciometria de Fóton , Impedância Elétrica , Índice de Massa CorporalRESUMO
INTRODUCTION: The aims of this study were to provide an overview of the cardiac stress response in Fontan patients and of the use, safety and clinical value of stress imaging in Fontan patients. METHODS: Studies evaluating cardiac function using stress imaging in Fontan patients published up until 12 December 2021 were included in this review. RESULTS: From 1603 potential studies, 32 studies met the inclusion criteria. In total, stress imaging tests of 728 Fontan patients were included. Cardiac function was most often measured using physical stress (61%), all other studies used dobutamine-induced stress. Stroke volume (SV) increased in most studies (71%), mean SV at rest ranged from 27â¯mL/m2 to 60â¯mL/m2 versus 27â¯mL/m2 to 101â¯mL/m2 during stress, and increased with an average of 4%. Ejection fraction increased in almost all studies, whereas both end-systolic volume and end-diastolic volume decreased during stress. Higher heart rates were obtained with physical stress (82-180) compared to dobutamine induced stress (73-128). Compared to controls, increases in heartrate and SV were lower and end-diastolic volume decreased abnormally in 75% of reporting studies. No major adverse events were reported. Poorer cardiac stress response was related to decreased exercise capacity and higher risk for long-term (adverse) outcomes in Fontan patients. DISCUSSION: Cardiac stress response in Fontan patients differs from healthy subjects, reflected by lower increases in heart rate, diminished preload and decreased cardiac output, especially during higher levels of exercise. Stress imaging is safe, however the added clinical value needs to be investigated in more detail.
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Técnica de Fontan , Cardiopatias Congênitas , Humanos , Técnica de Fontan/efeitos adversos , Técnica de Fontan/métodos , Dobutamina , Coração , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/cirurgia , Imagem Cinética por Ressonância MagnéticaRESUMO
The ability to feed on a sugar-containing diet depends on a gene regulatory network controlled by the intracellular sugar sensor Mondo/ChREBP-Mlx, which remains insufficiently characterized. Here, we present a genome-wide temporal clustering of sugar-responsive gene expression in Drosophila larvae. We identify gene expression programs responding to sugar feeding, including downregulation of ribosome biogenesis genes, known targets of Myc. Clockwork orange (CWO), a component of the circadian clock, is found to be a mediator of this repressive response and to be necessary for survival on a high-sugar diet. CWO expression is directly activated by Mondo-Mlx, and it counteracts Myc through repression of its gene expression and through binding to overlapping genomic regions. CWO mouse ortholog BHLHE41 has a conserved role in repressing ribosome biogenesis genes in primary hepatocytes. Collectively, our data uncover a cross-talk between conserved gene regulatory circuits balancing the activities of anabolic pathways to maintain homeostasis during sugar feeding.
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Proteínas de Drosophila , Proteínas Repressoras , Ribossomos , Açúcares , Animais , Camundongos , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Ribossomos/metabolismo , Açúcares/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Repressoras/metabolismoRESUMO
BACKGROUND: Cardiovascular magnetic resonance (CMR) imaging during supine exercise at (sub)maximal oxygen consumption (VO2 ) offers unique diagnostic insights. However, maximal VO2 is not achievable in the supine position and standardizing submaximal exercise intensities remains challenging. Using heart rate or workload could be a viable option to translate VO2 -based submaximal exercise intensities. AIM: To translate submaximal exercise intensities upright cycling exercise (UCE) to supine push-pull exercise (SPPE), by comparing heart rate or workload determined during UCE, with heart rate and workload during SPPE at similar exercise intensities. METHODS AND RESULTS: Sixteen healthy young adults (20.4 ± 2.2 years; 8 female) underwent cardiopulmonary UCE and SPPE testing [mean ± standard deviation maximal VO2 : 3.2 ± 0.6 vs. 5 ± 0.3 L min-1 , p < 0.001 and median (interquartile range) of the maximum workload: 310 (244, 361) vs. 98 (98, 100), p < 0.001, respectively]. Heart rate at 40% and 60% of maximal VO2 , as determined by UCE, showed low bias (-3 and 0 bpm, respectively) and wide limits of agreement (±26 and ±28 bpm, respectively), in Bland-Altman analysis. VO2 /Workload relation was exponential and less efficient during SPPE compared to UCE. Generalized estimated equation analysis predicted model-based mean workload during SPPE, with acceptable 95% confidence interval. CONCLUSION: Heart rate during UCE at submaximal exercise intensities can reasonably well be used to for SPPE in healthy subjects. Using workload, an ergometer specific, model-based mean can be used to determine exercise intensities during SPPE. Individual variations in response to posture and movement change are high. During clinical interpretation of exercise CMR, individual exercise intensity has to be considered.
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Ciclismo , Exercício Físico , Humanos , Feminino , Espectroscopia de Ressonância MagnéticaRESUMO
Several studies have previously investigated the effects of sticky mittens training on reaching and grasping development. However, recent critique casted doubts on the robustness of the motor effect of this training. The current study presents a pre-registered report that aimed to generalize these effects to Swedish infants. Three-month-old infants N = 96, 51 females, mostly White middle class in Uppsala, received daily, parent-led sticky mittens or observational training for 2 weeks or no training in 2019. Reaching and grasping abilities were assessed before and after training, using motion tracking and a 4-step reaching task. Sticky mittens training did not facilitate successful reaching. These results indicate that beneficial motor effects of sticky mittens training did not generalize to this sample.
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Força da Mão , Lactente , Feminino , Humanos , SuéciaRESUMO
BACKGROUND: There is a need for a validated simple Dutch paediatric activity scale. The purpose was to translate and transculturally validate the Dutch Hospital for Special Surgery Paediatric Functional Activity Brief Scale (HSS Pedi-FABS) questionnaire in healthy children and adolescents. METHODS: The original HSS Pedi-FABS was translated forward and backward and was transculturally adapted after performing a pilot study among children and professionals. The final version of the Dutch HSS Pedi-FABS was validated in healthy children and adolescents aged 10 to 18 years old. Children who had any condition or injury limiting their normal physical activity were excluded. The interval between the first questionnaire T0 (HSS Pedi-FABS, Physical Activity Questionnaire for children or adolescents (PAQ-C/A) and Tegner activity scale) and the second questionnaire T1 (HSS Pedi-FABS) was 2 weeks. Construct validity, interpretability and reliability were evaluated. Content validity was evaluated through cognitive interviews among a smaller group of children and through a questionnaire among professionals. RESULTS: To evaluate content validity, 9 children and adolescents were interviewed, and 30 professionals were consulted. Content validity among professionals showed a relevance of less than 85% for most items on construct. However, content validity among children was good with a 92% score for item relevance. Readability was scored at a reading level of 11- to 12-year-olds. The validation group consisted of 110 healthy children and adolescents (mean age of 13.9 years ±2.6). Construct validity was considered good as 8 out of 10 hypotheses were confirmed. The Dutch HSS Pedi-FABS showed no floor or ceiling effect. Analysis of the internal consistency in the validation group resulted in a Cronbach's alpha of 0.82. Test-retest reliability was evaluated among 69 children and adolescents and revealed an Intraclass Correlation Coefficient (ICC) of 0.76. CONCLUSION: The Dutch HSS Pedi-FABS showed good psychometric properties in a healthy Dutch paediatric and adolescent population. Limitations of the current Dutch HSS Pedi-FABS are content validity on construct of items reported by professionals.
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Exercício Físico , Nível de Saúde , Adolescente , Criança , Hospitais , Humanos , Projetos Piloto , Reprodutibilidade dos TestesRESUMO
BACKGROUND: The number of interventions is lower, and the level of satisfaction is higher among women who receive midwife-led primary care from one or two midwives, compared to more midwives. This suggests that midwives in small-sized practices practice more women-centred. This has yet to be explored. OBJECTIVE: To examine pregnant women's perceptions, of the interpersonal action component of woman-centred care by primary care midwives, working in different sized practices. METHODS: A cross-sectional study using the Client Centred Care Questionnaire (CCCQ), administered during the third trimester of pregnancy among Dutch women receiving midwife-led primary care from midwives organised in small-sized practices (1-2 midwives), medium-sized (3-4 midwives) and large-sized practices (≥5 midwives). A Welch ANOVA with post hoc Bonferroni correction was performed to examine the differences. RESULTS: 553 completed questionnaires were received from 91 small-sized practices/104 women, 98 medium-sized practices/258 women and 65 large-sized practices/191 women. The overall sum scores varied between 57-72 on a minimum/maximum scoring range of 15-75. Women reported significantly higher woman-centred care scores of midwives in small-sized practices (score 70.7) compared with midwives in medium-sized practices (score 63.6) (p<.001) and large-sized practices (score 57.9) (p<.001), showing a large effect (d .88; d 1.56). Women reported statistically significant higher woman-centred care scores of midwives in medium-sized practices compared with large-sized practices (p<.001), showing a medium effect (d .69). CONCLUSION: There is a significant variance in woman-centred care based on women's perceptions of woman-midwife interactions in primary care midwifery, with highest scores reported by women receiving care from a maximum of two midwives. Although the CCCQ scores of all practices are relatively high, the significant differences in favour of small-sized practices may contribute to moving woman-centred care practice from 'good' to 'excellent' practice.
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Relações Interpessoais , Tocologia/métodos , Enfermeiros Obstétricos/psicologia , Assistência Centrada no Paciente , Gestantes/psicologia , Adulto , Estudos Transversais , Feminino , Humanos , Países Baixos , Gravidez , Atenção Primária à Saúde , Inquéritos e QuestionáriosRESUMO
Introduction: Physical activity is associated with many physiological and psychological health benefits across the lifespan. Children with a chronic disease often have lower levels of daily physical activity, and a decreased exercise capacity compared to healthy peers. In order to learn more about limitations for physical activity, we investigate children with four different chronic diseases: children with a Fontan circulation, children with Broncho Pulmonary Dysplasia (BPD), Pompe disease and inflammatory bowel disease (IBD). Each of these diseases is likely to interfere with physical activity in a different way. Knowing the specific limitations for physical activity would make it possible to target these, and increase physical activity by a personalized intervention. The aim of this study is to first investigate limitations for physical activity in children with various chronic diseases. Secondly, to measure the effects of a tailored exercise intervention, possibly including a personalized dietary advice and/or psychological counseling, on exercise capacity, endurance, quality of life, fatigue, fear for exercise, safety, muscle strength, physical activity levels, energy balance, and body composition. Methods and Analysis: This randomized crossover trial will aim to include 72 children, aged 6-18 years, with one of the following diagnosis: a Fontan circulation, BPD, Pompe disease and IBD. Eligible patients will participate in the 12-week tailored exercise intervention and are either randomized to start with a control period or start with the intervention. The tailored 12-week exercise interventions, possibly including a personalized dietary advice and/or psychological counseling, will be designed based on the found limitations for physical activity in each disease group during baseline measurements by the Rotterdam Exercise Team. Effects of the tailored training interventions will be measured on the following endpoints: exercise capacity (measured by cardiopulmonary exercise test), endurance, physical activity levels, muscle strength, quality of life, fatigue, fear for exercise, disease activity, cardiac function (in children with a Fontan circulation), energy balance, and body composition. Ethics and Dissemination: Conducted according to the Declaration of Helsinki and Good Clinical Practice. Medical-ethical approval was obtained. Trial Registration Number: NL8181, https://www.trialregister.nl/trial/8181.
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Almost two decades ago, the sticky mittens paradigm was demonstrated as a way to train reaching and grasping behaviors in pre-reaching infants, and consequently improve visual attentional abilities. In that first study, Needham and colleagues fitted 3-month-old infants with Velcro loop-covered mittens and allowed them to interact with Velcro hook-covered toys over the course of 2 weeks. In this review, we scrutinize the 17 studies that have followed those first sticky mittens results in regards to the motor, social perception, and visual attentional domains. Furthermore, we discuss the proposed mechanisms of the sticky mittens training. Current evidence strongly suggests that sticky mittens training facilitates social perception, which is consistent with prior correlational work showing links between action production and action perception. However, studies targeting motor and visual attentional abilities have too diverse results to warrant firm conclusions. We conclude that future research should focus on uncovering if there is a connection between sticky mittens training and motor behavior.
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Atenção , Força da Mão , Humanos , Lactente , Jogos e Brinquedos , Percepção SocialAssuntos
Cisto Epidérmico/genética , Regulação da Expressão Gênica , Locos de Características Quantitativas/genética , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Cisto Epidérmico/patologia , Feminino , Humanos , Imuno-Histoquímica , Região de Controle de Locus Gênico/genética , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos BN , Sensibilidade e EspecificidadeRESUMO
The importance of vigilance within organizations working with high-risk biological material receives increasing attention. However, an in-depth and comprehensive tool, dedicated to increase awareness of potential risks and to assess an organization's current biosecurity vulnerabilities, has not been available yet. We developed the "Biosecurity Vulnerability Scan," a web tool that identifies biosecurity gaps in an organization based on eight biosecurity pillars of good practice. Although the tool aims primarily to assist biosafety and biosecurity officers, it can also be useful to researchers working with dangerous pathogens, their principal investigators, management, or those responsible for security issues in the life sciences. Results are only stored locally and are provided in an "overview report," which includes information on relevant risks and control measures. This can support well-substantiated decision-making on strengthening biosecurity measures within a specific organization. With this article, we aim to support institutes to increase their overall security resilience and to improve institutional biosecurity in particular by providing practical recommendations. The Biosecurity Vulnerability Scan is available at www.biosecurityvulnerabilityscan.nl.
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This review provides a historical overview of the inception and development of bioinformatics research in the Netherlands. Rooted in theoretical biology by foundational figures such as Paulien Hogeweg (at Utrecht University since the 1970s), the developments leading to organizational structures supporting a relatively large Dutch bioinformatics community will be reviewed. We will show that the most valuable resource that we have built over these years is the close-knit national expert community that is well engaged in basic and translational life science research programmes. The Dutch bioinformatics community is accustomed to facing the ever-changing landscape of data challenges and working towards solutions together. In addition, this community is the stable factor on the road towards sustainability, especially in times where existing funding models are challenged and change rapidly.
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Redes Comunitárias , Biologia Computacional/métodos , Biologia Computacional/organização & administração , Análise de Sequência de DNA/normas , Pesquisa Translacional Biomédica , Humanos , Países BaixosRESUMO
Abdullahi, Y, Coetzee, B, and van den Berg, L. Relationships between results of an internal and external match load determining method in male, singles badminton players. J Strength Cond Res 33(4): 1111-1118, 2019-The purpose of study was to determine relationships between results of an internal and external match load determining method. Twenty-one players who participated in selected badminton championships during the 2014/2015 season served as subjects. The heart rate (HR) values and global positioning system (GPS) data of each player were obtained using a fix Polar HR Transmitter Belt and MinimaxX GPS device. Moderate significant Spearman's rank correlations were found between HR and absolute duration (r = 0.43 at a low intensity [LI] and 0.44 at a high intensity [HI]), distance covered (r = 0.42 at a HI), and player load (r = 0.44 at a HI). Results also revealed an opposite trend for external and internal measures of load, as the average relative HR value was found to be the highest for the HI zone (54.1%) compared with the relative measures of external load where average values (1.29-9.89%) were the lowest for the HI zone. In conclusion, our findings show that results of an internal and external badminton match load determining method are more related to each other in the HI zone than other zones and that the strength of relationships depend on the duration of activities that are performed in especially LI and HI zones. Overall, trivial to moderate relationships between results of an internal and external match load determining method in male, singles badminton players reaffirm the conclusions of others that these constructs measure distinctly different demands and should therefore be measured concurrently to fully understand the true requirements of badminton match play.
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Frequência Cardíaca , Esforço Físico/fisiologia , Esportes com Raquete/fisiologia , Acelerometria , Adulto , Sistemas de Informação Geográfica , Humanos , Masculino , Fatores de Tempo , Adulto JovemRESUMO
This study examines how salience and a center bias drive infants' first fixation while looking at complex scenes. Adults are known to have a strong center bias, their first point of gaze is nearly always in the center of the scene. The center bias is likely to be a strategic bias, as looking towards the center minimizes the distance to other parts of the scene and important objects are often located at the center. In an experimental design varying salience regions of scenes and start positions we examined infants' (Nâ¯=â¯48, Ageâ¯=â¯5-20-month-olds) first fixation after scene onset. The pre-registered hypothesis that infants also have a center bias while looking at real-world scenes was confirmed. The strength of the center bias is correlated with the saliency distribution such that the bias is weaker when the strongest salience is peripheral rather central. In the absence of clear salient regions there still was a strong center bias. These results suggests there is a competition between stimulus-driven factors and a center bias in steering attention from a young age onwards.
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Viés , Movimentos Oculares/fisiologia , Fixação Ocular/fisiologia , Percepção Visual/fisiologia , Adolescente , Atenção , Feminino , Humanos , Lactente , Masculino , Reconhecimento Visual de Modelos/fisiologia , Adulto JovemRESUMO
INTRODUCTION: Laboratory biosecurity is of continuously growing interest due to increasing concerns about deliberate misuse of biological materials and emerging biological risks. These risks continue to be magnified by globalization, the rapid pace of scientific development, and dual-use technologies. Worldwide laboratory capacities are expanding, which calls for concrete actions to improve laboratory biosafety and biosecurity practices to protect researchers and the community. Hence, laboratories require comprehensive biorisk management programs to minimize the risk of accidental and deliberate release of infectious biological materials. OBJECTIVE: Malaysia has prioritized the concern of national biosecurity and aims to consolidate laboratory biosecurity performance to detect and prevent the deliberate release of biological agents. METHODS: Two 3-day workshops were organized over the course of four months in which Malaysia collaborated with The Netherlands. This bilateral engagement aimed to integrate biosecurity practices in their national biorisk management programs, and resulted into a comprehensive biosecurity checklist for laboratory assessment and monitoring. RESULTS: This biosecurity checklist is based on Malaysian and Dutch expert opinions and national and international guidelines and regulations. The biosecurity checklist is a survey-driven tool that consists of a set of concrete questions for each key biosecurity area, which are discussion points for assessment. CONCLUSION: We display a practical biosecurity checklist for laboratory assessment and monitoring. Although the presented checklist was the template for the specific Malaysia checklist, it could serve as a template for other countries.
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Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
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Desequilíbrio Alélico , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Sistemas CRISPR-Cas , Aberrações Cromossômicas , Cromossomos Humanos Par 8 , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Dinamarca , Perfilação da Expressão Gênica , Genômica , Genótipo , Humanos , Perda de Heterozigosidade , Repetições de Microssatélites , Fenótipo , Mutação Puntual , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do GenomaRESUMO
Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.