Abstract Background Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural ...history studies of LMNA -associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain. Objectives This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype. Methods The incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined. Results The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death. Conclusions LMNA -related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.
Background and Objectives
Since the advent of AIDS, men who have sex with men (MSM) have often been deferred from blood donation. In France, quarantine plasma donation by MSM donors with the same ...deferral rules as for other donors was introduced in July 2016 and continued up to March 2022. At this time, MSM‐specific deferral criteria were lifted for all blood or plasma donation. The donor deferral, as well as rate of infectious markers in plasma donors who would have been otherwise deferred for MSM activity, was evaluated and compared with those of the other donors during the same time period from June 2016 to March 2022.
Results
A total of 8843 MSM donors made 12,250 plasma donation applications. The overall deferral rate was very high (75.2%), mainly due to the absence of apheresis capacity at the donation site. The deferral criteria for sexual risk were present in 12.1% of MSM donors compared with 1.0% in other plasma and blood donors (p < 0.001). Overall, 994 MSM donors made 2880 plasma donations. Of these, one donation was HIV positive (34.7 vs. 0.6/105 donations by other donors, relative risk RR: 61.0 95% confidence interval CI: 8.5–437.7), one was HBV positive (34.7 vs. 4.5/105, RR: 7.7 95% CI: 1.1–54.6) and none were HCV positive (0 vs. 2.4/105). Additionally, 21 donations were syphilis positive (729.2 vs. 10.7/105, RR: 67.9 95% CI: 44.2–104.4). A post hoc analysis of eligible MSM donors who were unable to donate plasma due to logistic constraints yielded similar findings.
Conclusion
Plasma donation by donors who would have been otherwise deferred for MSM activity was associated with both an increased deferral rate for sexual risk and an increased rate of infectious markers, notably syphilis.
Abstract
Background and Objectives
Data from 21 years (2000–2020) of haemovigilance were used to assess human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) ...incidence rates in repeat blood donors and the occurrence of transfusion‐transmitted (TT) viral infections.
Materials and Methods
Blood donors who converted for HIV, HCV or HBV markers within serial three‐year analysis periods were included. Epidemiological and virological data were retrieved from the national epidemiological donor database and were supplemented with information on blood components and the infection status of recipients of the previous negative donation (D.N‐1) of donors who seroconverted.
Results
Incidence rates declined from 1.27 to 0.35/100,000 person‐years for HIV, from 0.59 to 0.19 for HCV and from 1.66 to 0.18 for HBV. Risk factors and lookback for 232 HIV, 90 HCV and 74 HBV seroconversions were investigated. The main risk factor identified at post‐donation interview was having sex with men (47.8% of males) for HIV and a sexual risk for HCV (30.6%) and HBV (37.1%). The viral loads and sequences were retrospectively tested in 191 HIV, 74 HCV and 62 HBV D.N‐1 archived samples. Six (five HBV and one HIV‐1) were positive all low viral loads. Two recipients were infected by red blood cells from two HBV seroconverting donors before the introduction of HBV‐nucleic acid testing.
Conclusion
HIV, HCV and HBV incidence rates in blood donors declined over the two past decades in France. There is a very small risk of a blood component that tests negative entering the blood supply resulting in TT infections, especially after introduction of molecular assays in donor screening.
Hepatitis B virus (HBV) infection is the most frequent viral infection found in blood donors (BDs) in France. We analyzed the epidemiological and sero-molecular data on HBV infection gathered over ...the past two decades by the French haemovigilance surveillance network, blood screening laboratories, and the national reference center for transfusion infectious risks (NRC). Between 2000 and 2020, 6149 of the 58,160,984 donations (1.06/10,000) tested HBV positive, 98% of them from first-time blood donors (FTBDs). In addition, 2212 (0.0071%) of the 30,977,753 donations screened for HBV DNA tested DNA positive, of which 25 (1.1%) were positive only for this marker. HBV prevalence decreased by 2.8-fold and the residual risk for transfusion-transmitted HBV infection decreased 13-fold and was divided by 13. The major risk factor for HBV infection was the origin of donors (endemic country, 66.5%), followed by parenteral exposure (10.7%). In the whole HBV-positive BD population, genotype D was predominant (41.8%), followed by genotypes A (26.2%) and E (20.4%), reflecting the geographical origin of donors. The low and decreasing prevalence and incidence of HBV infection in French BDs, coupled with a screening strategy using three HBV markers (HBsAg, anti-HBc and DNA), ensures a high level of blood safety, further reinforced by the implementation of pathogen-reduction measures.
Background and Objectives
The risk of a blood donation contaminated with hepatitis E virus (HEV) entering the blood supply before introducing universal HEV‐RNA screening in France was estimated to ...assess the benefit of such a measure.
Materials and Methods
The results of selective HEV nucleic acid testing (HEV‐NAT) performed in mini pool of six plasma donations between 2018 and 2020 were extrapolated to the whole blood donor (BD) population after adjustment on three variables: regional establishment, sex and age group.
Results
Among the 246,285 plasma donations collected from 172,635 BDs tested for HEV‐RNA, 248 (10.1/10,000) were positive. The extrapolation to all BDs led to an estimated rate of 5.9/10,000 donations (95% confidence interval CI: 4.5–7.4) which would be positive to HEV‐RNA and a prevalence of 9.9/10,000 BDs (95% CI: 7.5–12.3). This prevalence was 4.4 times higher in males than females (16.8/10,000 vs. 3.8/10,000, p < 10−4). The highest prevalence was observed in males in the 30–39 age group (20.5/10,000) and the lowest in females in the 50–70 age group (2.8/10,000).
Conclusion
The risk of an HEV‐RNA‐positive donation entering the blood supply was estimated at 1 in 1682 donations. This risk does not translate directly to the risk of HEV transfusion transmission, which mainly depends on the total number of viral particles in the transfused blood component and the sensitivity of NAT.
Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC ...pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index‐patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non‐compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease‐causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in‐frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non‐compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause ...remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing.
WES was performed in 22 patients, all without a mutation identified in desmosomal genes. Putative pathogenic variants were screened in 96 candidate genes associated with other cardiomyopathies/channelopathies. The sequencing coverage depth of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 exons was compared to the mean coverage distribution to detect large insertions/deletions. All suspected deletions were verified by real-time qPCR, Multiplex-Ligation-dependent-Probe-Amplification (MLPA) and cGH-Array. MLPA was performed in 50 additional gene-negative probands.
Coverage-depth analysis from the 22 WES data identified two large heterozygous PKP2 deletions: one from exon 1 to 14 and one restricted to exon 4, confirmed by qPCR and MLPA. MLPA identified 2 additional PKP2 deletions (exon 1-7 and exon 1-14) in 50 additional probands confirming a significant frequency of large PKP2 deletions (5.7%) in gene-negative ARVC/D. Putative pathogenic heterozygous variants in EYA4, RBM20, PSEN1, and COX15 were identified in 4 unrelated probands.
A rather high frequency (5.7%) of large PKP2 deletions, undetectable by Sanger sequencing, was detected as the cause of ARVC/D. Coverage-depth analysis through next-generation sequencing appears accurate to detect large deletions at the same time than conventional putative mutations in desmosomal and cardiomyopathy-associated genes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Objectives
Implementing a ferritin testing policy for whole blood (WB) donors may prevent iron deficiency (ID, ferritin <26 ng/mL) and anaemia, but may induce donation losses. As part ...of a national prevention plan in France, we aimed to estimate its impact on ID, anaemias and WB donations among donors at high risk of ID.
Materials and Methods
A micro‐simulation model was developed to evaluate different scenarios compared to the current situation without ferritin testing as a reference scenario. The following scenarios were simulated: a minimum scenario with a 6‐month deferral for donors with absent iron store (AIS, ferritinemia <15 ng/ml), a main scenario with additional delayed invitations for donors with ferritinemia 15–25 ng/ml and a supplementation scenario with additional iron supplementation for 50% of the donors with AIS.
Results
In the main scenario, 52,699 WB donations per year were estimated to be lost after 1 year (−8%), falling to 27,687 (−4.7%) after 5 years. IDs and anaemias were reduced by 13.6% and 29.3%, respectively, after 1 year. The supplementation scenario increased the number of prevented IDs and anaemias to 24.1% and 35.4%, respectively, after 1 year, and halved the number of anaemias at 5 years. The latter scenario also had the least impact on the number of donations (−3.2% after 5 years).
Conclusion
A ferritin testing policy resulting in delayed donations for ID donors is effective in reducing IDs and anaemias, but significantly impacts the number of donations, thereby posing a self‐sufficiency challenge.
Left ventricular non‐compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. ...The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias.
Fifty‐two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes.
Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub‐phenotype of cardiomyopathy.
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