Are cuffless devices challenged enough? Design of a validation protocol for ambulatory blood pressure monitors at the wrist: the case of the Aktiia Bracelet.

The US and European guidelines for the diagnosis and management of hypertension recommend the introduction of systematic home and night Blood Pressure (BP) monitoring. Fully-automated wearable devices can address the needs of patients and clinicians by improving comfort while achieving measurement accuracy. Often located at the wrist and based on indirect BP measurements, these devices must address the challenges of ambulatory scenarios. New validation strategies are needed, but little guidance has been published so far.In this work, we propose an experimental protocol for the validation of cuffless wrist BP monitors that addresses ambulatory environment challenges in a controlled experimental setting. The protocol assesses the robustness of the measurement for different body postures, the ability of the device to track BP changes, and its ability to deal with hydrostatic pressure changes induced by different arm heights.Performance testing using Aktiia Bracelet is provided as an illustration. The results of this pilot study indicate that the Aktiia Bracelet can generate accurate BP estimates for sitting and lying positions and is not affected by hydrostatic pressure perturbations.Clinical Relevance- Automated cuffless BP monitoring is opening a new chapter in the way patients are being diagnosed and managed. This paper provides a guidance on how to assess the clinical utility of such devices when used in different body positions.

Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C.

The limb girdle and congenital muscular dystrophies (LGMD and CMD) are characterized by skeletal muscle weakness and dystrophic muscle changes. The onset of symptoms in CMD is within the first few months of life, whereas in LGMD they can occur in late childhood, adolescence or adult life. We have recently demonstrated that the fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C), characterized by the inability to walk, leg muscle hypertrophy and a secondary deficiency of laminin alpha2 and alpha-dystroglycan. Both MDC1C and LGMD2I map to an identical region on chromosome 19q13.3. To investigate whether these are allelic disorders, we undertook mutation analysis of FKRP in 25 potential LGMD2I families, including some with a severe and early onset phenotype. Mutations were identified in individuals from 17 families. A variable reduction of alpha-dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin alpha2 either by immunocytochemistry or western blotting. Unexpectedly, affected individuals from 15 families had an identical C826A (Leu276Ileu) mutation, including five that were homozygous for this change. Linkage analysis identified at least two possible haplotypes in linkage disequilibrium with this mutation. Patients with the C826A change had the clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C. The spectrum of LGMD2I phenotypes ranged from infants with an early presentation and a Duchenne-like disease course including cardiomyopathy, to milder phenotypes compatible with a favourable long-term outcome.

Prenatal molecular cytogenetic diagnosis of partial tetrasomy 10p due to neocentromere formation in an inversion duplication analphoid marker chromosome.

Neocentromeres are fully functional centromeres found on rearranged or marker chromosomes that have separated from endogenous centromeres. Neocentromeres often result in partial tri- or tetrasomy because their formation confers mitotic stability to acentric chromosome fragments that would normally be lost. We describe the prenatal identification and characterization of a de novo supernumerary marker chromosome (SMC) containing a neocentromere in a 20-wk fetus by the combined use of comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). GTG-banding of fetal metaphases revealed a 47,XY,+mar karyotype in 100% of cultured amniocytes; parental karyotypes were both normal. Although sequential tricolor FISH using chromosome-specific painting probes identified a chromosome 10 origin of the marker, a complete panel of chromosome-specific centromeric satellite DNA probes failed to hybridize to any portion of the marker. The presence of a neocentromere on the marker chromosome was confirmed by the absence of hybridization of an all-human-centromere alpha-satellite DNA probe, which hybridizes to all normal centromeres, and the presence of centromere protein (CENP)-C, which is associated specifically with active kinetochores. Based on CGH analysis and FISH with a chromosome 10p subtelomeric probe, the marker was found to be an inversion duplication of the distal portion of chromosome 10p. Thus, the proband's karyotype was 47,XY,+inv dup(10)(pter-->p14 approximately 15::p14 approximately 15-->neo-->pter), which is the first report of partial tetrasomy 10p resulting from an analphoid marker chromosome with a neocentromere. This study illustrates the use of several molecular strategies in distinguishing centric alphoid markers from neocentric analphoid markers.

Mosaicism with a normal cell line and an unbalanced structural rearrangement.

Mosaicism with a normal cell line (N) and an unbalanced autosomal structural rearrangement (UASR) is rare. This report describes a case of a newborn female with a karyotype of 46,XX,der(4)t(4;15)(q35;q22)/46,XX. Molecular cytogenetic analysis confirmed the origin of the derivative chromosome 4. Here we discuss this case as well as other cases of mosaic karyotypes involving N/UASR.

Prenatal diagnosis of low level trisomy 15 mosaicism: review of the literature.

Low level chromosome mosaicism found at amniocentesis is problematic for clinicians and patients. We report prenatal diagnosis of a fetus with a rare karyotype of 47,XX, + 15/46,XX. Second trimester amniocentesis was performed for advanced maternal age. Fetal ultrasound revealed a hypoplastic right ventricle and intrauterine growth retardation (IUGR). The rest of the fetal anatomy was within normal limits. A mosaic karyotype of 47,XX, + 15/46,XX was observed. The couple interrupted the pregnancy at 19 weeks by dilation and suction evacuation. Careful evaluation of multiple pieces of fetal parts and placenta revealed one abnormal finding: a single umbilical artery. Cytogenetic metaphase and fluorescent in situ hybridization (FISH) interphase analyses of cells from fetal lung, heart, placenta, and skin revealed the presence of the trisomic line in all tissues. Molecular analysis demonstrated that the origin of the extra chromosome 15 was maternal, the error most likely occurred in meiosis I and the diploid line was of biparental inheritance. This case report discusses the associated findings in this fetus and reviews the literature describing other cases of mosaic trisomy 15.

Congenital vocal cord paralysis with possible autosomal recessive inheritance: case report and review of the literature.

We describe an infant with congenital vocal cord paralysis born to consanguineous parents. While autosomal dominant and X-linked inheritance have been previously reported in this condition, we conclude that the degree of parental consanguinity in this case strongly suggests autosomal recessive inheritance. Although we cannot exclude X-linked inheritance, evidence from animal studies demonstrates autosomal recessive inheritance and provides a possible molecular basis for congenital vocal cord paralysis.

Prenatal detection of monosomy 21 mosaicism.

We report a case of chromosomal mosaicism for monosomy 21 revealed in amniotic fluid cell culture. Ultrasound examination at 19 weeks' gestation showed in utero growth retardation and a complex cardiac malformation. A repeated amniocentesis confirmed the presence of monosomy 21 mosaicism. In view of the sonographically detected fetal abnormalities, termination of pregnancy was elected.

Enzyme augmentation in moderate to life-threatening Gaucher disease.

Gaucher disease type 1 (GD type 1) is the most prevalent lysosomal storage disease and has its highest frequency in the Ashkenazi Jewish population. Deficiency of the enzyme, acid beta-glucosidase, results in the deposition of glucocerebroside primarily in macrophages. The accumulation of such "Gaucher cells" leads to visceromegaly, hepatic and bone marrow dysfunction, hypersplenism, and bony disease. Eleven GD type 1 patients, ages 4-52 y, with moderate to life-threatening manifestations, received 6-12 mo of enzyme augmentation with a macrophage-targeted acid beta-glucosidase preparation. Within 6 mo, substantial increases in Hb levels (mean = +30%) and platelet counts (mean = +39%) were observed. Hepatic and splenic volumes decreased by approximately 20% (range = 3-35%) and approximately 35% (20-52%), respectively. Hematologic and hepatic volume improvements were similar in the splenectomized (n = 4) and nonsplenectomized (n = 7) patient groups. In this patient population, no major differences were observed in the hematologic and visceral improvements with enzyme doses of 30, 50, or 60 IU/kg administered every 2 wk. Normal levels of acid beta-glucosidase activity were present in hepatic autopsy samples from one patient 11 d after enzyme infusion. In comparison, exogenous activity was absent from brain and lung specimens of the same patient. High levels (approximately 10-fold normal) were present in bone marrow samples from two patients obtained at 1 and 11 d after infusions. These studies demonstrate biochemical and clinical improvements by targeted enzyme augmentation in GD type 1, even in far advanced, life-threatening involvement.(ABSTRACT TRUNCATED AT 250 WORDS)