Aims
Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and ...clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM.
Methods and results
We retrieved PubMed/Medline literature on genotype–phenotype associations in patients with DCM and mutations in
LMNA
,
PLN
,
RBM20, MYBPC3, MYH7, TNNT2
and
TNNI3
. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Together, 48 studies with 8097 patients were included. Furthermore, we reviewed recent studies investigating genotype-phenotype associations in DCM patients with
TTN
mutations. The average frequency of mutations in the investigated genes was between 1 and 5 %. The mean age of DCM onset was the beginning of the fifth decade for all genes. Heart transplantation (HTx) rate was highest in
LMNA
mutation carriers (27 %), while
RBM20
mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 73 % of DCM patients with
LMNA
mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in
PLN
mutation carriers. The frequency of ventricular arrhythmia in DCM patients with
LMNA
(50 %) and
PLN
(43 %) mutations was significantly higher. The penetrance of DCM phenotype in subjects with
TTN
truncating variants increased with age and reached 100 % by age of 70.
Conclusion
A pooled analysis of available genotype-phenotype data shows a higher prevalence of sudden cardiac death (SCD), cardiac transplantation, or ventricular arrhythmias in
LMNA
and
PLN
mutation carriers compared to sarcomeric gene mutations. This study will further support the clinical interpretation of genetic findings.
Novel considerations are presented on the physics, apparatus and accelerator designs for a future, luminous, energy frontier electron-hadron (
eh
) scattering experiment at the LHC in the thirties ...for which key physics topics and their relation to the hadron-hadron HL-LHC physics programme are discussed. Demands are derived set by these physics topics on the design of the LHeC detector, a corresponding update of which is described. Optimisations on the accelerator design, especially the interaction region (IR), are presented. Initial accelerator considerations indicate that a common IR is possible to be built which alternately could serve
eh
and
hh
collisions while other experiments would stay on
hh
in either condition. A forward-backward symmetrised option of the LHeC detector is sketched which would permit extending the LHeC physics programme to also include aspects of hadron-hadron physics. The vision of a joint
eh
and
hh
physics experiment is shown to open new prospects for solving fundamental problems of high energy heavy-ion physics including the partonic structure of nuclei and the emergence of hydrodynamics in quantum field theory while the genuine TeV scale DIS physics is of unprecedented rank.
We investigate on time evolution of envelopes and emittance of bunched beams in photo-injectors. We carry out a detailed beam dynamic study with focus on calculations of space charge forces. We take ...the average of the forces over the whole ensemble of particles. This results in space charge coefficients that are largely independent of the bunch distribution. By implementing these coefficients in the beam envelope equations we find a set of modified equations as a model for describing the evolution of the bunch envelope. Our equations crucially decrease the consumed time in particle-in-cell codes for designing today’s photo-injectors. The feasibility and accuracy of the model have been benchmarked against the simulation results from existing particle-in-cell codes with very good agreement. We apply our model for the design of the ultra-short bunch photo-injector of the AWAKE experiment. Moreover, by using assumption of linear external fields we develop the governing equations of the bunch emittances in photo-injectors. These equations allow us to partly quantitatively and partly qualitatively study the effects of external and space charge fields on emittance growth phenomena.
Purpose
According to the European Public Health Authority guidance for ending isolation in the context of COVID-19, a convalescent healthcare worker (HCW) can end their isolation at home and resume ...work upon clinical improvement and two negative RT-PCR tests from respiratory specimens obtained at 24-h intervals at least 8 days after the onset of symptoms. However, convalescent HCWs may shed SARS-CoV-2 viral RNA for prolonged periods.
Methods
40 healthy HCWs off work because of ongoing positive RT-PCR results in combined nasopharyngeal (NP) and oropharyngeal (OP) swabs following SARS-CoV-2 infection were invited to participate in this study. These HCWs had been in self-isolation because of a PCR-confirmed SARS-CoV-2 infection. NP and OP swabs as well as a blood sample were collected from each participant. RT-PCR and virus isolation was performed with each swab sample and serum neutralization test as well as two different ELISA tests were performed on all serum samples.
Results
No viable virions could be detected in any of 29 nasopharyngeal and 29 oropharyngeal swabs taken from 15 long-time carriers. We found SARSCoV- 2 RNA in 14/29 nasopharyngeal and 10/29 oropharyngeal swabs obtained from screening 15 HCWs with previous COVID-19 up to 55 days after symptom onset. Six (40%) of the 15 initially positive HCWs converted to negative and later reverted to positive again according to their medical records. All but one HCW, a healthy volunteer banned from work, showed the presence of neutralizing antibodies in concomitantly taken blood samples. Late threshold cycle (Ct) values in RT-PCR mean 37.4; median 37.3; range 30.8–41.7 and the lack of virus growth in cell culture indicate that despite the positive PCR results no infectivity remained.
Conclusion
We recommend lifting isolation if the RT-PCR Ct-value of a naso- or oropharyngeal swab sample is over 30. Positive results obtained from genes targeted with Ct-values > 30 correspond to non-viable/noninfectious particles that are still detected by RT-PCR. In case of Ct-values lower than 30, a blood sample from the patient should be tested for the presence of neutralizing antibodies. If positive, non-infectiousness can also be assumed.
Nairobi sheep disease virus/Ganjam virus M D, Baron; B, Holzer
Revue scientifique et technique (International Office of Epizootics)
34, Številka:
2
Journal Article
Recenzirano
Nairobi sheep disease virus (NSDV) is a tick-borne virus which causes a severe disease in sheep and goats, and has been responsible for several outbreaks of disease in East Africa. The virus is also ...found in the Indian subcontinent, where it is known as Ganjam virus. The virus only spreads through the feeding of competent infected ticks, and is therefore limited in its geographic distribution by the distribution of those ticks, Rhipicephalus appendiculata in Africa and Haemaphysalis intermedia in India. Animals bred in endemic areas do not normally develop disease, and the impact is therefore primarily on animals being moved for trade or breeding purposes. The disease caused by NSDV has similarities to several other ruminant diseases, and laboratory diagnosis is necessary for confirmation. There are published methods for diagnosis based on polymerase chain reaction, for virus growth in cell culture and for other simple diagnostic tests, though none has been commercialised. There is no established vaccine against NSDV, although cell-culture attenuated strains have been developed which show promise and could be put into field trials if it were deemed necessary. The virus is closely related to Crimean-Congo haemorrhagic fever virus, and studies on NSDV may therefore be useful in understanding this important human pathogen.
Several new accelerator projects are being studied at CERN in a broad energy range from atomic to Tera scale level. The beam energy as well as the beam quality requirements raise the need for new ...future acceleration concepts to achieve more efficient accelerating structures and / or more compact devices. The article gives a number of examples of the studies, the beam parameters that are foreseen in the different projects and their proposed technical layout.
A
bstract
A search for the
K
+
→
π
+
X
decay, where
X
is a long-lived feebly interacting particle, is performed through an interpretation of the
K
+
→
π
+
ν
ν
¯
analysis of data collected in 2017 by ...the NA62 experiment at CERN. Two ranges of
X
masses, 0–110 MeV
/c
2
and 154–260 MeV
/c
2
, and lifetimes above 100 ps are considered. The limits set on the branching ratio, BR(
K
+
→
π
+
X
), are competitive with previously reported searches in the first mass range, and improve on current limits in the second mass range by more than an order of magnitude.
The condition dependence of sexually selected traits is an important assumption of sexual selection theory. Several laboratory studies have documented a positive relationship between food ...availability, body condition, and sexual display. However, these studies might not reflect the resource allocation between body maintenance, reserves, and the sexually selected trait under natural conditions. Further, the effect of condition-dependent signaling on female mate choice has hardly been investigated experimentally in the field. We therefore investigated the effect of food availability on body condition, calling behavior, and sexual attractiveness of male field crickets, Gryllus campestris, under field conditions. Food availability was manipulated for individual males by supplementing food in a confined area close to the burrow. Food-supplemented males showed a significant increase in body condition, whereas the opposite was found in the control males. Males receiving extra food called more frequently, whereas the calling-song characteristics were not affected by the treatment. Further, food-supplemented males attracted more females than did control males, and their higher attractiveness was partly explained by their superior calling rate. Our study thus indicates condition-dependent signaling as an important determinant of the sexual attractiveness of males to females under natural condition.
The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non‐coding RNAs. Besides this dynamic regulation, a large part ...of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome‐wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients (n = 50) with dilated cardiomyopathy (DCM), 80,635 non‐protein‐coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non‐coding RNAs and 1,756 protein‐coding transcripts. 65.3% of the SV‐eQTLs do not harbor a significant SNV‐eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein‐coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SVs in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SVs explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike.
Synopsis
In a multi‐omics analysis, structural variants in dilated cardiomyopathy (DCM) patients have been detected that are associated with altered gene expression. Besides regulatory genomic elements, also non‐coding RNAs have been identified as possible new players in the molecular homeostasis in the heart.
Germline structural variants in DCM patients are distributed evenly over the genome, with 3.7 times more deletions than insertions.
Cis regulatory effects of structural variants can be linked to distinct protein coding and non‐coding transcripts.
Cardiac SV‐eQTLs are mainly heart specific compared to peripheral blood and may explain up to 7.5% of transcript variation.
Whole genome sequencing seems indispensable when studying the human cardiac transcriptome to avoid larger bias due to otherwise undetected SVs.
In a multi‐omics analysis, structural variants in dilated cardiomyopathy patients have been detected that are associated with altered gene expression. Besides regulatory genomic elements, also non‐coding RNAs have been identified as possible new players in the molecular homeostasis in the heart.
PDF
