Ayalacrockett7340
Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in
in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in
and the genotypes causative for PCL.
Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in NDUFV2 in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in NDUFV2 and the genotypes causative for PCL.
Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (
) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Telaprevir Here, we describe the prevalence of rare variants in
in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.
Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.
PTVs in
were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in
were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in
. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.
Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of
PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.
Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of KCNH1-related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain.
Pathogenic
variants are a frequent cause of developmental and epileptic encephalopathy.
We recruited 13 adults (between 18 years and 45 years of age) with
encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.
While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individncern.Ubiquitin protein ligase E3 component n-recognin 5 (UBR5) has been identified as an oncogene in diverse cancers; however, whether its expression was associated with radiosensitivities of non-small cell lung cancer (NSCLC) cells remains unclear. Expression levels of UBR5 in NSCLC tissues and cell lines were examined by immunohistochemical staining and western blotting. Colony formation assay, CCK-8 cell viability assay, flow cytometry, and caspase-3 activity assay were performed to evaluate the radiosensitization of UBR5 knockdown in NSCLC cells, and the underlying mechanism in vitro was also investigated. UBR5 was highly expressed in NSCLC tissues, and its high expression was associated with the poor prognosis in 50 patients with NSCLC. After X-ray irradiation, the protein expression levels of UBR5 were also increased in NSCLC cells. UBR5 inhibition enhanced the radiosensitivity of NSCLC cells by inhibiting the cell viability and inducing apoptosis. Further investigation indicated that UBR5 knockdown-mediated radiosensitization involved the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Knockdown of UBR5 radiosensitizes NSCLC cells via the inactivation of the PI3K/AKT signal, which provided a novel therapeutic target for NSCLC radiosensitization.
To evaluate whether baseline and changes in cardiovascular health (CVH) were related to incident atrial fibrillation (AF) risk in the elderly population.
From the Korea National Health Insurance Service-Senior cohort, we included 208 598 participants without prior AF (median age 70 (IQR 66-74) years; 90 916 (43.6%) men) who underwent national health check-ups between 1 January 2005 and 31 December 2012. Using the six metrics of the American Heart Association, participants were categorised as having low, moderate and high CVH.
Over a median follow-up of 7.2 years, 7818 cases of incident AF occurred. In multivariable analysis, moderate (HR 0.90; 95% CI 0.86 to 0.94) and high (HR 0.81; 95% CI 0.73 to 0.91) CVH status at baseline were associated with a lower risk of incident AF. However, in 109 695 participants with changes in CVH between the first and second check-ups, the direction of change in CVH scores showed no consistent association with future AF incidence. In newly diagnosed participants with AF, the incidence of the composite outcome (stroke, major bleeding and all-cause death) decreased with every 1-point increase in the baseline CVH score (HR 0.94; 95% CI 0.89 to 0.99).
In the general elderly population, better baseline CVH metrics were associated with lower incident AF risk. In participants with newly diagnosed AF, better CVH was also associated with lower incidence of future composite outcomes. However, the direction of change in CVH status within 2 years showed an inconsistent influence on incident AF risk.
In the general elderly population, better baseline CVH metrics were associated with lower incident AF risk. In participants with newly diagnosed AF, better CVH was also associated with lower incidence of future composite outcomes. However, the direction of change in CVH status within 2 years showed an inconsistent influence on incident AF risk.Cardiogenic shock (CS) remains the leading cause of death in patients hospitalised with acute myocardial infarction with mortality as high as 40%-50% prior to hospital discharge. The failure of inotropic therapy to maintain adequate perfusion and to prevent irreversible end-organ failure has led to attempts to improve outcomes by mechanical circulatory support (MCS) devices. Axial flow ventricular assist devices, namely Impella, are an attractive therapeutic option due to their positive haemodynamic benefits and ease of use. Despite clear beneficial haemodynamic effects, which should significantly impact on the pathophysiology of CS, there are currently no clear data to support their use in the reduction of clinical end points such as cardiac death. This review summarises and critically evaluates the current scientific evidence for the use of axial flow ventricular assist devices and highlights gaps in our understanding. Given such gaps, a consensus multidisciplinary approach, predicated on emphasising timely diagnosis and appropriate use of MCS, is vital to ensure that the right patient is paired with the right device at the right time.
The novel coronavirus (SARS-CoV-2) is a global pandemic. The lack of protective vaccine or treatment led most of the countries to follow the flattening of the infection curve with social isolation measures. There is evidence that socioeconomic inequalities have been shaping the COVID-19 burden among low and middle-income countries. This study described what sociodemographic and socioeconomic factors were associated with the greatest risk of COVID-19 infection and mortality and how did the importance of key neighbourhood-level socioeconomic factors change over time during the early stages of the pandemic in the Rio de Janeiro municipality, Brazil.
We linked socioeconomic attributes to confirmed cases and deaths from COVID-19 and computed age-standardised incidence and mortality rates by domains such as age, gender, crowding, education, income and race/ethnicity.
The evidence suggests that although age-standardised incidence rates were higher in wealthy neighbourhoods, age-standardised mortality rates were higher in deprived areas during the first 2 months of the pandemic. The age-standardised mortality rates were also higher in males, and in areas with a predominance of people of colour, which are disproportionately represented in more vulnerable groups. The population also presented COVID-19 'rejuvenation', that is, people became risk group younger than in developed countries.
We conclude that there is a strong health gradient for COVID-19 death risk during the early stages of the pandemic. COVID-19 cases continued to move towards the urban periphery and to more vulnerable communities, threatening the health system functioning and increasing the health gradient.
We conclude that there is a strong health gradient for COVID-19 death risk during the early stages of the pandemic. COVID-19 cases continued to move towards the urban periphery and to more vulnerable communities, threatening the health system functioning and increasing the health gradient.
Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in moderate CKD but have not been studied in kidney failure. The study objective is to determine the effectiveness and safety of prasugrel and ticagrelor in kidney failure.
This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all patients on dialysis who received a drug-eluting stent and were alive at 90 days after stent implantation. Inverse probability-weighted Cox proportional hazard models were used. Weights were estimated with propensity scores for multiple treatments.
This cohort included 6648 patients on clopidogrel, 621 on prasugrel, and 449 on ticagrelor. A total of 3279 primary composite (cardiovascular death, myocardial infarction, or stroke) and 2120 clinically relevant bleeding events were observed. The incidence of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke at 12 months was similar across the three treatment groups. The absolute event rate in the unweighted cohort was 144 events per 100 patient-years for clopidogrel, 126 for prasugrel, and 161 for ticagrelor.
