Iminodiacetic-phosphoramidates as metabolic prototypes for diversifying nucleic acid polymerization in vivo

Previous studies in our laboratory proved that certain functional groups are able to mimic the pyrophosphate moiety and act as leaving groups in the enzymatic polymerization of deoxyribonucleic acids by HIV-1 reverse transcriptase. When the potential leaving group possesses two carboxylic acid moieties linked to the nucleoside via a phosphoramidate bond, it is efficiently recognized by this error-prone enzyme, resulting in nucleotide incorporation into DNA. Here, we present a new efficient alternative leaving group, iminodiacetic acid, which displays enhanced kinetics and an enhanced elongation capacity compared to previous results obtained with amino acid deoxyadenosine phosphoramidates. Iminodiacetic acid phosphoramidate of deoxyadenosine monophosphate (IDA-dAMP) is processed by HIV-1 RT as a substrate for single nucleotide incorporation and displays a typical Michaelis–Menten kinetic profile. This novel substrate also proved to be successful in primer strand elongation of a seven-base template overhang. Modelling of this new substrate in the active site of the enzyme revealed that the interactions formed between the triphosphate moiety, magnesium ions and enzyme's residues could be different from those of the natural triphosphate substrate and is likely to involve additional amino acid residues. Preliminary testing for a potential metabolic accessibility lets us to envision its possible use in an orthogonal system for nucleic acid synthesis that would not influence or be influenced by genetic information from the outside

Overweight, Obesity and Underweight Is Associated with Adverse Psychosocial and Physical Health Outcomes among 7-Year-Old Children: The 'Be Active, Eat Right' Study

Background:Limited studies have reported on associations between overweight, and physical and psychosocial health outcomes among younger children. This study evaluates associations between overweight, obesity and underweight in 5-year-old children, and parent-reported health outcomes at age 7 years.Methods:Data were used from the 'Be active, eat right' study. Height and weight were measured at 5 and 7 years. Parents reported on child physical and psychosocial health outcomes (e.g. respiratory symptoms, general health, happiness, insecurity and adverse treatment). Regression models, adjusted for potential confounders, were fitted to predict health outcomes at age 7 years.Results:The baseline study sample consisted of 2,372 children mean age 5.8 (SD 0.4) years; 6.2% overweight, 1.6% obese and 15.0% underweight. Based on parent-report, overweight, obese and underweight children had an odds ratio (OR) of 5.70 (95% CI: 4.10 to 7.92), 35.34 (95% CI: 19.16; 65.17) and 1.39 (95% CI: 1.05 to 1.84), respectively, for being treated adversely compared to normal weight children. Compared to children with a low stable body mass index (BMI), parents of children with a high stable BMI reported their child to have an OR of 3.87 (95% CI: 1.75 to 8.54) for visiting the general practitioner once or more, an OR of 15.94 (95% CI: 10.75 to 23.64) for being treated adversely, and an OR of 16.35 (95% CI: 11.08 to 24.36) for feeling insecure.Conclusion:This study shows that overweight, obesity and underweight at 5 years of age is associated with more parent-reported adverse treatment of the child. Qualitative research examining underlying mechanisms is recommended. Healthcare providers should be aware of the possible adverse effects of childhood overweight and also relative underweight, and provide parents and children with appropriate counseling

Energy In/Out of Place

This book, and the online workshop that preceded it, are attempts to intensify the sense of place within our scholarship and in our scholarly practices. They are formed from the efforts of five research teams examining energy cultures in five different locations around the world. Team members weren’t necessarily experts on their given places, but many were bound to these sites through time, kith, and kin

Care management for Type 2 diabetes in the United States: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>This systematic review and meta-analysis aims at assessing the composition and performance of care management models evaluated in the last decade and their impact on patient important outcomes.</p> <p>Methods</p> <p>A comprehensive literature search of electronic bibliographic databases was performed to identify care management trials in type 2 diabetes. Random effects meta-analysis was used when feasible to pool outcome measures.</p> <p>Results</p> <p>Fifty-two studies were eligible. Most commonly reported were surrogate outcomes (such as HbA1c and LDL), followed by process measures (clinic visit or testing frequency). Less frequently reported were quality of life, patient satisfaction, self-care, and healthcare utilization. Most care management modalities were carved out from primary care. Meta-analysis demonstrated a statistically significant but trivial reduction of HbA1c (weighted difference in means -0.21%, 95% confidence interval -0.40 to -0.03, p < .03) and LDL-cholesterol (weighted difference in means -3.38 mg/dL, 95% confidence interval -6.27 to -0.49, p < .02).</p> <p>Conclusions</p> <p>Most care management programs for patients with type 2 diabetes are 'carved-out', accomplish limited effects on metabolic outcomes, and have unknown effects on patient important outcomes. Comparative effectiveness research of different models of care management is needed to inform the design of medical homes for patients with chronic conditions.</p

National laboratory-based surveillance system for antimicrobial resistance: a successful tool to support the control of antimicrobial resistance in the Netherlands

An important cornerstone in the control of antimicrobial resistance (AMR) is a well-designed quantitative system for the surveillance of spread and temporal trends in AMR. Since 2008, the Dutch national AMR surveillance system, based on routine data from medical microbiological laboratories (MMLs), has developed into a successful tool to support the control of AMR in the Netherlands. It provides background information for policy making in public health and healthcare services, supports development of empirical antibiotic therapy guidelines and facilitates in-depth research. In addition, participation of the MMLs in the national AMR surveillance network has contributed to sharing of knowledge and quality improvement. A future improvement will be the implementation of a new semantic standard together with standardised data transfer, which will reduce errors in data handling and enable a more real-time surveillance. Furthermore, the

Molecular characteristics of carbapenemase-producing Enterobacterales in the Netherlands; results of the 2014–2018 national laboratory surveillance

Objectives: Carbapenem resistance mediated by mobile genetic elements has emerged worldwide and has become a major public health threat. To gain insight into the molecular epidemiology of carbapenem resistance in The Netherlands, Dutch medical microbiology laboratories are requested to submit suspected carbapenemase-producing Enterobacterales (CPE) to the National Institute for Public Health and the Environment as part of a national surveillance system. Methods: Meropenem MICs and species identification were confirmed by E-test and MALDI-TOF and carbapenemase production was assessed by the Carbapenem Inactivation Method. Of all submitted CPE, one species/carbapenemase gene combination per person per year was subjected to next-generation sequencing (NGS). Results: In total, 1838 unique isolates were received between 2014 and 2018, of which 892 were unique CPE isolates with NGS data available. The predominant CPE species were Klebsiella pneumoniae (n = 388, 43%), Escherichia coli (n = 264, 30%) and Enterobacter cloacae complex (n = 116, 13%). Various carbapenemase alleles of the same carbapenemase gene resulted in different susceptibilities to meropenem and this effect varied between species. Analyses of NGS data showed variation of prevalence of carbapenemase alleles over time with blaOXA-48 being predominant (38%, 336/892), followed by blaNDM-1 (16%, 145/892). For the first time in the Netherlands, blaOXA-181, blaOXA-232 and blaVIM-4 were detected. The genetic background of K. pneumoniae and E. coli isolates was highly diverse. Conclusions: The CPE population in the Netherlands is diverse, suggesting multiple introductions. The predominant carbapenemase alleles are blaOXA-48 and blaNDM-1. There was a clear association between species, carbapenemase allele and susceptibility to meropenem

La force musculaire et son évaluation chez l’enfant infirme moteur cérébral

La faiblesse musculaire est un facteur déterminant de la symptomatologie de l’enfant infirme moteur cérébral. Il est important de la détecter de façon précise afin de la prendre en considération dans les programmes de rééducation. Pour mesurer la force musculaire nous disposons actuellement d’un large choix d’outils. Le testing musculaire donne une mesure rapide, mais son principal inconvénient est sa subjectivité. Il est surtout valable pour les valeurs comprises entre 0 et 3 points sur 5. Les dynamomètres fournissent des valeurs objectives et quantifiables. Ils sont faciles à utiliser, cependant les procédures d’utilisation, le positionnement sans ou avec l’influence de la gravité, la stabilisation ou non de l’articulation, l’expérience de l’examinateur sont responsables d’une source non négligeable d’erreurs dont il faut tenir compte dans le suivi des programmes d’entraînement musculaire. Les appareils d’isocinétisme sont considérés comme des appareils de référence donnant des mesures fiables, cependant leur utilisation clinique est limitée. Toutes ces méthodes requièrent un niveau optimal de participation de l’enfant et un bon contrôle moteur. La présence de spasticité ou de rétractions peut perturber la qualité de la mesure. Par ailleurs, un gain de force après une rééducation ciblée a certainement des répercussions sur les activités de l’enfant mais n’est pas le seul élément à prendre en compte pour réduire les incapacités.The muscular weakness is a determining factor in the cerebral palsy symptoms. Muscle strength should be evaluated as objectively as possible to improve the quality of diagnosis and treatment. To measure the muscle strength, we have at the present time a wide choice of tools. The most common and easy method is manual muscle testing, but its main inconvenience is its subjectivity. The manual muscle testing seems to be more appropriate for assigning grades 0 to 3 over 5. Hand held dynamometers give objective and quantifiable values. They are easy to use however the procedures, the positioning of the limb segment without or with the influence of the gravity, the stabilization or not of the joint, the experience of the clinician are responsible for a important errors of measurement which it is necessary to take into account in the follow-up of the programs of muscular training. The isokinetic testing machines are considered as golden standard, they offer a good stabilization of the patient, accurate end repeatable measurement and no examiner bias. Their clinical uses are limited due the lack of portability and the time required doing the measurements. All of these methods need an optimal level of the child participation and a good motor control. The spasticity and the contractures may interfere in the quality of the measurement. In the rehabilitation filed even if the strength improvement is important to reduce the disability, activity-based intervention are also necessary for reducing activity limitation in children with cerebral palsy

Clinical evaluation in pediatric orthopedic practice: What should the general practitioner know? [Examen clinique en orthopédie pédiatrique: Ce que le médecin généraliste doit savoir]

L’orthopédie pédiatrique est de nos jours une spécialité à part entière, qui se distingue de l’orthopédie adulte tant par ses pathologies que par son approche clinique. Cet article décrit l’examen clinique orthopédique « global » tel qu’il est réalisé par les auteurs dans leur pratique quotidienne, en mettant l’accent sur les aspects plus pertinents pour le médecin généraliste, l’objectif étant que ce dernier sache distinguer le normal du pathologique. Seule l’évaluation clinique de l’enfant ayant acquis la marche est décrite, selon une chronologie permettant de gagner progressivement la confiance de l’enfant