67 research outputs found
Auxological tools for following growth in extreme short stature and for evaluating growth promoting interventions
Growth charts are inevitable tools for following children in clinical practice and also when evaluating growth promoting therapy. Growth is a concern especially for families to children of extreme short stature such as in skeletal dysplasias but evaluations of growth pattern with changes in height position is complicated when height develops far below normal population range. Height gain from growth hormone therapy is variable for short stature conditions without aberrant growth hormone secretion such as in Turner syndrome. This makes it difficult to communicate realistic adult height estimates to concerned families.
The first part of this PhD project used semi-longitudinal data from 4,375 measuring occasions to construct growth and body proportion references for achondroplasia and to describe these in relation to normal population references. Typical for achondroplasia, tempo in head size was increased attaining final size earlier than normal. Height was at the same time compromised with major loss in height position during the first years of life, due to limited growth capacity of the legs. At adult ages, leg length was half of that in normal population and arm span almost 35 percent lower than normal contributing to severely reduced area of personal access. Pronounced body disproportions distort the BMI-value in achondroplasia, which is why specific BMI charts were constructed.
Clinical achondroplasia charts were developed to support surveillance of these children and, as short stature matrix, possibly also for other children with severe short stature for which syndrome-specific charts are missing. The usability of these achondroplasia charts were tested by illustrating growth pattern of selected skeletal dysplasias.
Obtained achondroplasia references for height, sitting height, leg length and arm span might contribute to a better understanding of the effect of FGFR3 signalling on growth and will also be inevitable tools for evaluation of novel treatments.
In the second part, variability in response to growth hormone therapy was studied by dividing a sample of 455 girls with Turner syndrome, reported in the Swedish National Register for growth hormone treatment of children and adolescents, into good and poor response based on the distribution of total height gain from treatment. As age at treatment initiation was distributed over almost entire growth period, the sample was further grouped into those with treatment start during normally prepubertal and pubertal ages. Differences of clinical relevance were higher mid-parental height, higher GH dose at 12 months of treatment and improved body proportions in the younger good response group; and younger age and shorter height position at treatment initiation and higher GH dose in the older good response group. These findings could possibly be influenced by subgroups identified in graphic presentations. Initial height gain from treatment did not necessarily translate into better total height gain neither in younger or older poor groups. In contrast to previous claims, early initiation of growth hormone treatment per se did often not result in better total height gain
Eigenstate resolved infrared and millimeter-wave-infrared double resonance spectroscopy of methylamine in the N-H stretch Ărst overtone region
The eigenstate resolved, near-infrared spectrum of methylamine, has been measured at 5 MHz CH 3 NH 2 , resolution in the region near 6615 cm~1 using a molecular-beam laser spectrometer with optothermal detection. Part of the spectrum of the NH (symmetric stretch Ărst overtone) has been assigned by applying 2l 1 a millimeter-waveĂinfrared double resonance technique. The spectra are very fractionated by intramolecular vibrational energy redistribution with an observed density of states between 20 and 30 states per cm~1 which is about four times the density of vibrational states calculated in the harmonic approximation. The coupling between the bright states and the bath is found to be rather strong (0.1 cm~1), and the lifetime for the redistribution is determined to be 3 ps for the vibration. 2l
Impact of body mass index on relapse in children with acute lymphoblastic leukemia treated according to Nordic treatment protocols
Objectives High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols. Method In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0-17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut-offs: underweight, = 30 kg/m(2). Results In Cox multivariate regression analyses, an increased risk of relapse was observed in children aged 10-17.9 years with unhealthy BMI at diagnosis (underweight hazard ratio HR: 2.90 [95% confidence interval: 1.24-6.78],P = .01; overweight, HR: 1.95 [1.11-3.43],P = .02, and obese HR: 4.32 [95% 2.08-8.97],P <.001), compared to children with healthy weight. BMI had no impact on relapse in children under 10 years of age. Conclusion High BMI, and especially obesity at diagnosis, is an independent adverse prognostic factor for relapse in older children with ALL.Peer reviewe
Bedaquiline and clofazimine resistance in Mycobacterium tuberculosis: an in-vitro and in-silico data analysis
Background: Bedaquiline is a core drug for the treatment of multidrug-resistant tuberculosis; however, the understanding of resistance mechanisms is poor, which is hampering rapid molecular diagnostics. Some bedaquiline-resistant mutants are also cross-resistant to clofazimine. To decipher bedaquiline and clofazimine resistance determinants, we combined experimental evolution, protein modelling, genome sequencing, and phenotypic data. Methods: For this in-vitro and in-silico data analysis, we used a novel in-vitro evolutionary model using subinhibitory drug concentrations to select bedaquiline-resistant and clofazimine-resistant mutants. We determined bedaquiline and clofazimine minimum inhibitory concentrations and did Illumina and PacBio sequencing to characterise selected mutants and establish a mutation catalogue. This catalogue also includes phenotypic and genotypic data of a global collection of more than 14 000 clinical Mycobacterium tuberculosis complex isolates, and publicly available data. We investigated variants implicated in bedaquiline resistance by protein modelling and dynamic simulations. Findings: We discerned 265 genomic variants implicated in bedaquiline resistance, with 250 (94%) variants affecting the transcriptional repressor (Rv0678) of the MmpS5âMmpL5 efflux system. We identified 40 new variants in vitro, and a new bedaquiline resistance mechanism caused by a large-scale genomic rearrangement. Additionally, we identified in vitro 15 (7%) of 208 mutations found in clinical bedaquiline-resistant isolates. From our in-vitro work, we detected 14 (16%) of 88 mutations so far identified as being associated with clofazimine resistance and also seen in clinically resistant strains, and catalogued 35 new mutations. Structural modelling of Rv0678 showed four major mechanisms of bedaquiline resistance: impaired DNA binding, reduction in protein stability, disruption of protein dimerisation, and alteration in affinity for its fatty acid ligand. Interpretation: Our findings advance the understanding of drug resistance mechanisms in M tuberculosis complex strains. We have established an extended mutation catalogue, comprising variants implicated in resistance and susceptibility to bedaquiline and clofazimine. Our data emphasise that genotypic testing can delineate clinical isolates with borderline phenotypes, which is essential for the design of effective treatments. Funding: Leibniz ScienceCampus Evolutionary Medicine of the Lung, Deutsche Forschungsgemeinschaft, Research Training Group 2501 TransEvo, Rhodes Trust, Stanford University Medical Scientist Training Program, National Institute for Health and Care Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Bill & Melinda Gates Foundation, Wellcome Trust, and Marie SkĆodowska-Curie Actions
Operationalizing multimorbidity and autonomy for health services research in aging populations - the OMAHA study
<p>Abstract</p> <p>Background</p> <p>As part of a Berlin-based research consortium on health in old age, the OMAHA (Operationalizing Multimorbidity and Autonomy for Health Services Research in Aging Populations) study aims to develop a conceptual framework and a set of standardized instruments and indicators for continuous monitoring of multimorbidity and associated health care needs in the population 65 years and older.</p> <p>Methods/Design</p> <p>OMAHA is a longitudinal epidemiological study including a comprehensive assessment at baseline and at 12-month follow-up as well as brief intermediate telephone interviews at 6 and 18 months. In order to evaluate different sampling procedures and modes of data collection, the study is conducted in two different population-based samples of men and women aged 65 years and older. A geographically defined sample was recruited from an age and sex stratified random sample from the register of residents in Berlin-Mitte (Berlin OMAHA study cohort, n = 299) for assessment by face-to-face interview and examination. A larger nationwide sample (German OMAHA study cohort, n = 730) was recruited for assessment by telephone interview among participants in previous German Telephone Health Surveys. In both cohorts, we successfully applied a multi-dimensional set of instruments to assess multimorbidity, functional disability in daily life, autonomy, quality of life (QoL), health care services utilization, personal and social resources as well as socio-demographic and biographical context variables. Response rates considerably varied between the Berlin and German OMAHA study cohorts (22.8% vs. 59.7%), whereas completeness of follow-up at month 12 was comparably high in both cohorts (82.9% vs. 81.2%).</p> <p>Discussion</p> <p>The OMAHA study offers a wide spectrum of data concerning health, functioning, social involvement, psychological well-being, and cognitive capacity in community-dwelling older people in Germany. Results from the study will add to methodological and content-specific discourses on human resources for maintaining quality of life and autonomy throughout old age, even in the face of multiple health complaints.</p
Complete response to gemtuzumab ozogamicin in a patient with refractory mast cell leukemia
Mast cell (MC) leukemia (MCL) is a subtype of systemic mastocytosis (SM) defined by the World Health Organization as â©Ÿ 20% of MCs in the bone marrow (BM) aspirate, with (leukemic variant) or without (aleukemic variant) â©Ÿ 10% of MCs in peripheral blood (PB). The European/American Consensus Group on Mastocytosis has recently proposed a new subclassification of MCL that distinguishes acute vs chronic MCL based on the presence vs absence of organ damage, respectively.Peer Reviewe
Growth reference charts for children with hypochondroplasia
Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18âyears. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16âyears. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials
Diagnostic performance of the AID line probe assay in the detection of Mycobacterium tuberculosis and drug resistance in Romanian patients with presumed TB.
BACKGROUND: The AID line probe assay has shown promising evaluation data on the detection of Mycobacterium tuberculosis as well as 1st- and 2nd-line drug resistance, using isolates and selected clinical samples in previous studies.
METHODS: The diagnostic performance of three AID-modules (AID INH/RIF, AID FQ/EMB and AID AG) was analyzed in sputum samples from patients with presumed tuberculosis against culture methods and phenotypic drug resistance as reference standards.Results59 patients had culture-confirmed tuberculosis. All AID modules showed moderate sensitivity (46/59, 78.0%, 65.3-87.7) and very good specificity (100%, 95.5%, 93.7%). There was a high proportion of invalid tests, resulting in 32.6%, 78.3% and 19.6% of 46 AID-positive tuberculosis cases, who could not be assessed for drug resistance by the AID INH/RIF-, AID FQ/EM- and AID AG-module, respectively. A small number of patients showed drug resistance by reference standards: Three MDR-TB cases plus three, one and one patients with resistance to streptomycin, fluoroquinolones and aminoglycosides, respectively. The AID-assay detected all MDR-TB cases, two of three streptomycin-resistant TB cases, one of one of fluoroquinolone-resistant and missed one aminoglycoside-resistant TB case.
DISCUSSION: The high proportion of invalid results precludes the use of the AID-assay from direct sputum-based tuberculosis and drug-resistance testing
Changes in body mass index during treatment of childhood acute lymphoblastic leukemia with the Nordic ALL2008 protocol
Funding Information: Christina Egnell is supported by funding from the Swedish Childhood Cancer Foundation (Barncancerfonden, grant numbers TJ2018â0093; PR2019â0075; TJ2019â0048). This work is part of the Danish nationâwide research program Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by the Danish Cancer Society (Râ257âA14720) and the Danish Childhood Cancer Foundation (2019â5934 and 2020â5769). Publisher Copyright: © 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.Objectives: Children with acute lymphoblastic leukemia (ALL) have a tendency to gain weight during treatment. As overweight and obesity associate with health problems, prophylactic interventions are warranted. Therefore, it is important to identify the children most prone to gain weight. Methods: Patients aged 2.0â17.9 years at ALL diagnosis were identified from the NOPHO ALL2008 registry. Registry data was complemented with height and weight at the end of therapy from questionnaires. Body mass index (BMI) was classified according to international age- and sex-adjusted International Obesity Task Force BMI cut-offs. BMI values were transformed into standard deviation scores (SDS) to calculate the difference in BMISDS during treatment. Results: Data on BMI change were available for 765 children. Overweight and obesity doubled during treatment: 9.7% were overweight and 2.1% obese at diagnosis and 21.8% and 5.4% at the end of therapy, respectively. The mean BMISDS change was +0.64. Younger (2.0â5.9 years) and healthy weight children were most prone to become overweight (mean change in BMI SDS +0.85 and + 0.65, respectively). Conclusions: Younger children (2.0â5.9 years) with healthy weight at diagnosis were most prone to becoming overweight and therefore are an important group to target while considering interventions.Peer reviewe
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