0198: Global and regional echocardiographic strain to assess early phase of hypertrophic cardiomyopathy due to sarcomeric mutations

ObjectiveHypertrophic cardiomyopathy (HCM) is a genetic disease with delayed cardiac expression. Our objective was to characterize global and regional LV myocardial strain by two-dimensional imaging in sarcomeric HCM families and hypothesized that early systolic dysfunction, before hyper-trophic stage, may be diagnosed by this technique.Methods and resultsWe analyzed 81 adults: HCM patients with LV hypertrophy (LVH+, n=38), mutation carriers without LV hypertrophy (LVH/G+, n=20), and normal control subjects (n=23). We calculated global longitudinal strain (GLS), regional peak longitudinal strain and the Echo/TDI score (combination of 3 parameters about remodeling and pulse TDI). Age, sex ratio and body surface area were not significantly different between groups. Maximal 2D wall thickness of left ventricle was 10.1±1.6mm in LVH-/G+and not different from controls (9.9±1.2mm). We observed that LV GLS was not different in LVH-/G+as compared to controls (–21.6%±3.2 vs –23.5%±3.3) but was reduced in HCM patients (–15.3%±4.5) although a normal ejection fraction. Interestingly, regional peak longitudinal strain was similar in LVH-/G+and controls except antero-septo-basal segment strain that was decreased in LVH-/G+as compared to controls (–15.6%±7.2 vs –20.0%±3.9, p=0.025). A cut-off of –16% for abnormal strain of antero-septo-basal segment identified LVH-/G+subjects with a sensitivity of 47% and a specificity of 90%. The Echo/TDI score was different in LVH-/G+as compared to controls (p=0.0008) and sensitivity of previous defined cut-off was 83% for identification of LVH-/G+. All LVH-/G+subjects with abnormal regional strain, except one, had abnormal Echo/TDI score.ConclusionWe observed that regional longitudinal strain, but not global strain, was significantly reduced at early stage of HCM. This tool may be useful for clinical evaluation of relatives in daily practice, but does not provide significant additional information as compared to the Echo/TDI score

Scikit-learn: Machine Learning in Python

International audienceScikit-learn is a Python module integrating a wide range of state-of-the-art machine learning algorithms for medium-scale supervised and unsupervised problems. This package focuses on bringing machine learning to non-specialists using a general-purpose high-level language. Emphasis is put on ease of use, performance, documentation, and API consistency. It has minimal dependencies and is distributed under the simplified BSD license, encouraging its use in both academic and commercial settings. Source code, binaries, and documentation can be downloaded from http://scikit-learn.sourceforge.net

Pathophysiological and diagnostic implications of cardiac biomarkers and antidiuretic hormone release in distinguishing immersion pulmonary edema from decompression sickness

Immersion pulmonary edema (IPE) is a misdiagnosed environmental illness caused by water immersion, cold, and exertion. IPE occurs typically during SCUBA diving, snorkeling, and swimming. IPE is sometimes associated with myocardial injury and/or loss of consciousness in water, which may be fatal. IPE is thought to involve hemodynamic and cardiovascular disturbances, but its pathophysiology remains largely unclear, which makes IPE prevention difficult. This observational study aimed to document IPE pathogenesis and improve diagnostic reliability, including distinguishing in some conditions IPE from decompression sickness (DCS), another diving-related disorder. Thirty-one patients (19 IPE, 12 DCS) treated at the Hyperbaric Medicine Department (Ste-Anne hospital, Toulon, France; July 2013–June 2014) were recruited into the study. Ten healthy divers were recruited as controls. We tested: (i) copeptin, a surrogate marker for antidiuretic hormone and a stress marker; (ii) ischemia-modified albumin, an ischemia/hypoxia marker; (iii) brain-natriuretic peptide (BNP), a marker of heart failure, and (iv) ultrasensitive-cardiac troponin-I (cTnI), a marker of myocardial ischemia. We found that copeptin and cardiac biomarkers were higher in IPE versus DCS and controls: (i) copeptin: 68% of IPE patients had a high level versus 25% of DCS patients (P < 0.05) (mean ± standard-deviation: IPE: 53 ± 61 pmol/L; DCS: 15 ± 17; controls: 6 ± 3; IPE versus DCS or controls: P < 0.05); (ii) ischemia-modified albumin: 68% of IPE patients had a high level versus 16% of DCS patients (P < 0.05) (IPE: 123 ± 25 arbitrary-units; DCS: 84 ± 25; controls: 94 ± 7; IPE versus DCS or controls: P < 0.05); (iii) BNP: 53% of IPE patients had a high level, DCS patients having normal values (P < 0.05) (IPE: 383 ± 394 ng/L; DCS: 37 ± 28; controls: 19 ± 15; IPE versus DCS or controls: P < 0.01); (iv) cTnI: 63% of IPE patients had a high level, DCS patients having normal values (P < 0.05) (IPE: 0.66 ± 1.50 μg/L; DCS: 0.0061 ± 0.0040; controls: 0.0090 ± 0.01; IPE versus DCS or controls: P < 0.01). The combined “BNP-cTnI” levels provided most discrimination: all IPE patients, but none of the DCS patients, had elevated levels of either/both of these markers. We propose that antidiuretic hormone acts together with a myocardial ischemic process to promote IPE. Thus, monitoring of antidiuretic hormone and cardiac biomarkers can help to make a quick and reliable diagnosis of IPE

PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cell

Race-free estimated glomerular filtration rate equation in kidney transplant recipients:development and validation study

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials).PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021.MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P 30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m 2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m 2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P 30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P 30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys.TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.</p

Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage

Study of bone mineral density through pubic CT scans : Methodological approach and its applications to age estimation

L'estimation de l'âge au décès est une étape majeure afin d'établir un profil biologique et permettre une identification reconstructive en anthropologie médico-légale. Ainsi, de nombreuses régions anatomiques ont été étudiées, notamment la symphyse pubienne qui présente un intérêt majeur par sa maturation tardive. Une des méthodes d'évaluation les plus connues est celle de Suchey-Brooks basée sur les caractéristiques morphologiques de la symphyse pubienne. De manière générale, l'os est en remodelage constant, ce qui se traduit notamment par une diminution plus ou moins linéaire de sa densité avec l'âge, en considérant divers facteurs intercurrents. Les progrès en imagerie médicale permettent de mesurer de façon simple, sur des images scanographiques, la densité minérale osseuse (DMO). L'objectif de notre première étude était d'évaluer l'évolution de la DMO en fonction de l'âge, notamment chez des sujets âgés de plus de 40 ans. Nous avons réalisé une étude rétrospective à partir de 88 symphyses pubiennes d'individus masculins et 113 d'individus féminins âgés de plus de 40 ans et ayant bénéficié d'un examen tomodensitométrique dans un hôpital français entre novembre 2017 et avril 2018. Les résultats mettaient en évidence une corrélation négative significative entre la densité osseuse et l'âge pour les deux sexes, associée à d'excellents accords intra- et inter-observateurs concernant l'allocation de la phase de Suchey-Brooks. De plus, une différence significative de densité osseuse entre les stades 6-1 et 6-2 a été observée chez les individus masculins. L'objectif de notre seconde étude était de proposer des équations de régression linéaire afin d'en déduire l'âge chronologique à partir de la densité osseuse, en utilisant les unités Hounsfield (HU) et la densité osseuse moyenne au niveau de la symphyse pubienne. De plus, nous avons évalué la fiabilité de la méthode et exploré la perspective d'utiliser les unités Hounsfield plutôt que la densité osseuse moyenne dans l'estimation de l'âge. Nous avons construit rétrospectivement un échantillon référence de 400 symphyses pubiennes et un échantillon test de 120 symphyses pubiennes. Nous avons mis en évidence des erreurs absolues moyennes homogènes entre les mesures en unités Hounsfield et les densités osseuses moyennes, la plupart inférieures à 10 ans. En outre, nous avons observé une surestimation modérée chez les individus jeunes et une surestimation minime chez les individus plus âgés. Les contributions de notre travail sont les suivantes : au moyen d'une approche méthodologique originale liée à des mesures réalisées sur des scanners de sujets vivants, la DMO, par ses propriétés de reproductibilité et de continuité, pourrait aider à améliorer la précision de l'estimation de l'âge par la méthode de Suchey-Brooks, particulièrement pour les individus âgés (stades 4 à 6). De plus, avec une fiabilité importante, les mesures en unités Hounsfield semblent appropriées pour corréler la densité osseuse avec l'âge d'un individu, notamment en contexte médico-légal. Enfin, les premiers résultats paraissent orienter vers une validation de cette méthode sur des images scanographiques post-mortem de sujets masculins à différents stades de putréfaction.In forensic anthropology, the estimation of age at death is mainly required to establish a biological profile and facilitate individual identification. Thus, many anatomical structures have been studied, such as the pubic symphysis, which is a source of major interest due to its late maturation. One of the most well-known methods of assessment is the Suchey-Brooks (SB) system based on the morphological characteristics of the pubic symphysis. Generally, bony structures are constantly remodeling. This is mainly seen as a more or less linear reduction in density with increasing age, in addition to other intercurrent factors. The progress made in medical imaging enable to easily measure bone mineral density (BMD) on computed tomography (CT) images. The aim of our first study was to test the evolution of BMD according to age, especially for individuals over 40 years old. We retrospectively studied pubic bones from 88 males and 113 females over 40 years of age undergoing clinical multi-slice computed tomography (MSCT) in a French hospital between November 2017 and April 2018. The results revealed a significant negative correlation between BMD and age for males and females with moderate to strong intra- and inter-observer reliabilites of the phase allocation in the SB system. Moreover, a significant difference in BMD between stages 6-1 and 6-2 for males was observed. The aim of our second study was to propose linear regression formulae in order to deduce chronological age from bone density, using both Hounsfield unit (HU) and mean bone density (mBD) values of the pubic symphysis. Moreover, we intended to test the reliability and then to explore the feasibility of using HU instead of mBD values for age estimation. We retrospectively built a reference sample of 400 pubic symphyses using computed tomography at a French hospital and a test sample of 120 pubic symphyses. We highlighted homogeneous mean absolute errors for both HU and mBD values, most of them being less than 10 years. Moreover, we reported a moderate overestimation for younger individuals and a very small underestimation for older individuals. Contributions of our work are as follows : thanks to an original methodological approach based on clinical CT scan measurements, BMD might help to improve the reliability of the SB system by its advantages of being reproducible and continuous, especially for older individuals (stages 4 to 6). Moreover, with a valuable level of reliability, HU measurements seem to be suitable for linking bone density with the age of individuals in forensic practice. Finally, the first results seem to confirm this method from post-mortem CT images of males corpses at different states of decomposition

Étude de la densité minérale osseuse à partir d'examens tomodensitométriques du pubis : approche méthodologique et application à l'estimation de l'âge

L'estimation de l'âge au décès est une étape majeure afin d'établir un profil biologique et permettre une identification reconstructive en anthropologie médico-légale. Ainsi, de nombreuses régions anatomiques ont été étudiées, notamment la symphyse pubienne qui présente un intérêt majeur par sa maturation tardive. Une des méthodes d'évaluation les plus connues est celle de Suchey-Brooks basée sur les caractéristiques morphologiques de la symphyse pubienne. De manière générale, l'os est en remodelage constant, ce qui se traduit notamment par une diminution plus ou moins linéaire de sa densité avec l'âge, en considérant divers facteurs intercurrents. Les progrès en imagerie médicale permettent de mesurer de façon simple, sur des images scanographiques, la densité minérale osseuse (DMO). L'objectif de notre première étude était d'évaluer l'évolution de la DMO en fonction de l'âge, notamment chez des sujets âgés de plus de 40 ans. Nous avons réalisé une étude rétrospective à partir de 88 symphyses pubiennes d'individus masculins et 113 d'individus féminins âgés de plus de 40 ans et ayant bénéficié d'un examen tomodensitométrique dans un hôpital français entre novembre 2017 et avril 2018. Les résultats mettaient en évidence une corrélation négative significative entre la densité osseuse et l'âge pour les deux sexes, associée à d'excellents accords intra- et inter-observateurs concernant l'allocation de la phase de Suchey-Brooks. De plus, une différence significative de densité osseuse entre les stades 6-1 et 6-2 a été observée chez les individus masculins. L'objectif de notre seconde étude était de proposer des équations de régression linéaire afin d'en déduire l'âge chronologique à partir de la densité osseuse, en utilisant les unités Hounsfield (HU) et la densité osseuse moyenne au niveau de la symphyse pubienne. De plus, nous avons évalué la fiabilité de la méthode et exploré la perspective d'utiliser les unités Hounsfield plutôt que la densité osseuse moyenne dans l'estimation de l'âge. Nous avons construit rétrospectivement un échantillon référence de 400 symphyses pubiennes et un échantillon test de 120 symphyses pubiennes. Nous avons mis en évidence des erreurs absolues moyennes homogènes entre les mesures en unités Hounsfield et les densités osseuses moyennes, la plupart inférieures à 10 ans. En outre, nous avons observé une surestimation modérée chez les individus jeunes et une surestimation minime chez les individus plus âgés. Les contributions de notre travail sont les suivantes : au moyen d'une approche méthodologique originale liée à des mesures réalisées sur des scanners de sujets vivants, la DMO, par ses propriétés de reproductibilité et de continuité, pourrait aider à améliorer la précision de l'estimation de l'âge par la méthode de Suchey-Brooks, particulièrement pour les individus âgés (stades 4 à 6). De plus, avec une fiabilité importante, les mesures en unités Hounsfield semblent appropriées pour corréler la densité osseuse avec l'âge d'un individu, notamment en contexte médico-légal. Enfin, les premiers résultats paraissent orienter vers une validation de cette méthode sur des images scanographiques post-mortem de sujets masculins à différents stades de putréfaction.In forensic anthropology, the estimation of age at death is mainly required to establish a biological profile and facilitate individual identification. Thus, many anatomical structures have been studied, such as the pubic symphysis, which is a source of major interest due to its late maturation. One of the most well-known methods of assessment is the Suchey-Brooks (SB) system based on the morphological characteristics of the pubic symphysis. Generally, bony structures are constantly remodeling. This is mainly seen as a more or less linear reduction in density with increasing age, in addition to other intercurrent factors. The progress made in medical imaging enable to easily measure bone mineral density (BMD) on computed tomography (CT) images. The aim of our first study was to test the evolution of BMD according to age, especially for individuals over 40 years old. We retrospectively studied pubic bones from 88 males and 113 females over 40 years of age undergoing clinical multi-slice computed tomography (MSCT) in a French hospital between November 2017 and April 2018. The results revealed a significant negative correlation between BMD and age for males and females with moderate to strong intra- and inter-observer reliabilites of the phase allocation in the SB system. Moreover, a significant difference in BMD between stages 6-1 and 6-2 for males was observed. The aim of our second study was to propose linear regression formulae in order to deduce chronological age from bone density, using both Hounsfield unit (HU) and mean bone density (mBD) values of the pubic symphysis. Moreover, we intended to test the reliability and then to explore the feasibility of using HU instead of mBD values for age estimation. We retrospectively built a reference sample of 400 pubic symphyses using computed tomography at a French hospital and a test sample of 120 pubic symphyses. We highlighted homogeneous mean absolute errors for both HU and mBD values, most of them being less than 10 years. Moreover, we reported a moderate overestimation for younger individuals and a very small underestimation for older individuals. Contributions of our work are as follows : thanks to an original methodological approach based on clinical CT scan measurements, BMD might help to improve the reliability of the SB system by its advantages of being reproducible and continuous, especially for older individuals (stages 4 to 6). Moreover, with a valuable level of reliability, HU measurements seem to be suitable for linking bone density with the age of individuals in forensic practice. Finally, the first results seem to confirm this method from post-mortem CT images of males corpses at different states of decomposition