IntroductionPatients submitted to a Fontan operation sustain a lifelong state of reduced cardiac output and increased venous pressure potentially inducing premature aging. We hypothesize that Fontan ...patients, despite their young age, resemble more elderly patients compared to age-matched controls.MethodsAt a tertiary care center, we evaluated 17 Fontan patients who had a recent abdominal CT scan for Fontan associated liver disease follow-up. Psoas muscle area (PMA), a recognized marker of frailty, was measured on the axial plane at the level of L4. The distributions of PMA scores were compared between Fontan and 1) patients undergoing a transcatheter aortic valve replacement (TAVR); and 2) an age-matched healthy cohort, separately with Kruskal-Wallis test.ResultsThe Fontan group comprised six males and 11 females aged 19-40. The proportions of systemic left ventricle and heterotaxy syndrome were 82% and 18% respectively in females and 33% and 33% respectively in males. The TAVR cohort included 241 males and 184 females aged 70-99. The healthy cohort enrolled 59 males and 66 females age-matched to the Fontan group. Among the Fontan patients, median and interquartile range of PMA were 18.1, 14.85-21.12 cm2 in females and 23.41, 22.25-30.21 cm2 in males. The comparison between the groups for males (Panel A) and females (Panel B) are illustrated in the Figure.ConclusionsMales Fontan appear to have reduced muscle mass that resembles more patients who are candidates for TAVR than aged-matched controls, an observation that, interestingly, was not seen in females in this small well-characterized cohort. To our knowledge, this is the first study to document a direct comparison of Fontan patients to other subgroups illustrating a mismatch between chronological and biological age in Fontan. Further studies are needed to elucidate the possible protective effect of female sex.
To identify genetic markers associated with late treatment-related skeletal morbidity in survivors of childhood acute lymphoblastic leukemia (ALL).
To this end, we measured the association between ...reduction in bone mineral density or vertebral fractures prevalence and variants from 1039 genes derived through whole exome sequencing in 242 childhood ALL survivors. Top-ranking variants were confirmed through genotyping, and further explored with stratified analyses and multivariable models.
The minor allele of rs1944294 in
gene was associated with bone geometrical parameter, trabecular cross-sectional area (p = 0.001). The association was modulated by radiation therapy (p = 0.001) and post-treatment time (p = 0.0002).
The variant in
gene is a potential novel risk factor of bone morbidity in survivors of childhood ALL.
Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child ...development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors.
Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers.
We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models.
Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616
=0.0002 (Pmax) and rs41270041
,
=0.02 (Fmax)) and two rare ones located in the
gene
=0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (
≤0.02).
Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the
and
genes, which could lead to personalized prevention strategies in childhood ALL survivors.
Background: Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable ...period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors. Purpose: Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers. Patients and methods: We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through wholeexome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models. Results: Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616DUOX2, P=0.0002 (Pmax) and rs41270041ADAMTS4, P=0.02 (Fmax)) and two rare ones located in the ALOX15 gene (P=0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (P<0.02). Conclusion: Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the DUOX2, ADAMTS4 and ALOX15 genes, which could lead to personalized prevention strategies in childhood ALL survivors. Keywords: acute lymphoblastic leukemia, late adverse effects, skeletal muscle deficit, genetic association study, whole exome sequencing
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