Beginning in May 2022, Mpox virus spread rapidly in high-income countries through close human-to-human contact primarily amongst communities of gay, bisexual and men who have sex with men (GBMSM). ...Behavioural change arising from increased knowledge and health warnings may have reduced the rate of transmission and modified Vaccinia-based vaccination is likely to be an effective longer-term intervention. We investigate the UK epidemic presenting 26-week projections using a stochastic discrete-population transmission model which includes GBMSM status, rate of formation of new sexual partnerships, and clique partitioning of the population. The Mpox cases peaked in mid-July; our analysis is that the decline was due to decreased transmission rate per infected individual and infection-induced immunity among GBMSM, especially those with the highest rate of new partners. Vaccination did not cause Mpox incidence to turn over, however, we predict that a rebound in cases due to behaviour reversion was prevented by high-risk group-targeted vaccination.
To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE).
Through inducing Spk inflammation in murine models, leukocyte ...migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction.
Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling.
Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.
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•SARS-CoV-2 Spike protein (Spk) induces acute inflammatory responses in a murine model of peritonitis.•Diminazene aceturate (DIZE) exerts anti-inflammatory effects on Spk-induced inflammation in mice.•DIZE mitigates DNA extracellular traps (DETs) in human leukocytes: neutrophils, monocytes, and macrophages.
In this paper, we provide a retrospective cohort study with patients that have been hospitalized for general or intensive care unit admission due to COVID-19, between March 3 and July 29, 2020, in ...the state of Bahia, Brazil. We aim to correlate those patients' demographics, symptoms and comorbidities, with the risk of mortality from COVID-19, length of hospital stay, and time from diagnosis to definitive outcome. On the basis of a dataset provided by the Health Secretary of the State of Bahia, we selected 3,896 hospitalized patients from a total of 154,868 COVID-19 patients that included non-hospitalized patients and patients with invalid registration in the dataset. Then, we statistically analyzed whether there was a significant correlation between the patient record data and the COVID-19 pandemic, and our main findings reinforced by the use of a multivariable logistic regression were that older age (Odds Ratio OR = 1.03, 95% Confidence Interval CI = 1.03-1.04, p-value (p) <0.001), an initial symptom of shortness of breath (OR = 1.88, 95% CI = 1.60-2.20, p < 0.001), and the presence of comorbidities, mainly chronic kidney disease (OR = 2.41, 95% CI = 1.67-3.48, p < 0.001) are related to an increased risk of mortality from COVID-19. On the other hand, sore throat (OR = 0.74, 95% CI = 0.58-0.95, p = 0.02) and length of hospital stay (OR = 0.96, 95% CI = 0.58-0.95, p < 0.001) are more related to a reduced risk of mortality from COVID-19. Moreover, a multivariable linear regression conducted with statistically significant variables (p < 0.05) showed that age (OR = 0.97, 95% CI = 0.95-0.98, p < 0.001) and time from diagnosis to definitive outcome (OR = 1.67, 95% CI = 1.64-1.71, p < 0.001) are associated with the length of hospital stay.
Summary
Objective
Phenotypes caused by de novo SCN1A pathogenic variants are very variable, ranging from severely affected patients with Dravet syndrome to much milder genetic epilepsy febrile ...seizures plus cases. The most important determinant of disease severity is the type of variant, with variants that cause a complete loss of function of the SCN1A protein (α‐subunit of the neuronal sodium channel Nav1.1) being detected almost exclusively in Dravet syndrome patients. However, even within Dravet syndrome disease severity ranges greatly, and consequently other disease modifiers must exist. A better prediction of disease severity is very much needed in daily practice to improve counseling, stressing the importance of identifying modifying factors in this patient group. We evaluated 128 participants with de novo, pathogenic SCN1A variants to investigate whether mosaicism, caused by postzygotic mutation, is a major modifier in SCN1A‐related epilepsy.
Methods
Mosaicism was investigated by reanalysis of the pathogenic SCN1A variants using single molecule molecular inversion probes and next generation sequencing with high coverage. Allelic ratios of pathogenic variants were used to determine whether mosaicism was likely. Selected mosaic variants were confirmed by droplet digital polymerase chain reaction and sequencing of different tissues. Developmental outcome was classified based on available data on intelligence quotient and school functioning/education.
Results
Mosaicism was present for 7.5% of de novo pathogenic SCN1A variants in symptomatic patients. Mosaic participants were less severely affected than nonmosaic participants if only participants with truncating variants are considered (distribution of developmental outcome scores, Mann‐Whitney U, P = .023).
Significance
Postzygotic mutation is a common phenomenon in SCN1A‐related epilepsies. Participants with mosaicism have on average milder phenotypes, suggesting that mosaicism can be a major modifier of SCN1A‐related diseases. Detection of mosaicism has important implications for genetic counseling and can be achieved by deep sequencing of unique reads.
Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require ...investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion.
A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival.
The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001).
In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.
Parameters of retrieval surgery are meticulously documented in the United Kingdom, where up to 40% of livers are donation after circulatory death (DCD) donations. This retrospective analysis focuses ...on outcomes after transplantation of DCD livers, retrieved by different UK centers between 2011 and 2016. Donor and recipient risk factors and the donor retrieval technique were assessed. A total of 236 DCD livers from 9 retrieval centers with a median UK DCD risk score of 5 (low risk) to 7 points (high risk) were compared. The majority used University of Wisconsin solution for aortic flush with a median hepatectomy time of 27‐44 minutes. The overall liver injury rate appeared relatively high (27.1%) with an observed tendency toward more retrieval injuries from centers performing a quicker hepatectomy. Among all included risk factors, the UK DCD risk score remained the best predictor for overall graft loss in the multivariate analysis (P < 0.001). In high‐risk and futile donor‐recipient combinations, the occurrence of liver retrieval injuries had negative impact on graft survival (P = 0.023). Expectedly, more ischemic cholangiopathies (P = 0.003) were found in livers transplanted with a higher cumulative donor‐recipient risk. Although more biliary complications with subsequent graft loss were found in high‐risk donor‐recipient combinations, the impact of the standardized national retrieval practice on outcomes after DCD liver transplantation was minimal.
Highlights • Second functional characterization of SCN8A mutation in epileptic encephalopathy. • Channel functioning was investigated in neuronal cells. • Protein stability was investigated after ...correction for transcript abundance. • Functional effects of this mutation only partially overlapping with previously described mutation. • Raises discussion about functional mechanism of sodium channels in epileptic encephalopathy.
Dravet syndrome is a severe genetic encephalopathy, caused by pathogenic variants in
Low-grade parental mosaicism occurs in a substantial proportion of families (7%-13%) and has important ...implications for recurrence risks. However, parental mosaicism can remain undetected by methods regularly used in diagnostics. In this study, we use single-molecule molecular inversion probes (smMIP), a technique with high sensitivity for detecting low-grade mosaic variants and high cost-effectiveness, to investigate the incidence of parental mosaicism of
variants in a cohort of 90 families and assess the feasibility of this technique.
Deep sequencing of
was performed using smMIPs. False positive rates for each of the proband's pathogenic variants were determined in 145 unrelated samples. If parents showed corresponding variant alleles at a significantly higher rate than the established noise ratio, mosaicism was confirmed by droplet digital PCR (ddPCR).
Sequence coverage of at least 100× at the location of the corresponding pathogenic variant was reached for 80 parent couples. The variant ratio was significantly higher than the established noise ratio in eight parent couples, of which four (5%) were regarded as true mosaics, based on ddPCR results. The false positive rate of smMIP analysis without ddPCR was therefore 50%. Three of these variants had previously been considered de novo in the proband by Sanger sequencing.
smMIP technology combined withnext generation sequencing (NGS) performs better than Sanger sequencing in the detection of parental mosaicism. Because parental mosaicism has important implications for genetic counselling and recurrence risks, we stress the importance of implementing high-sensitivity NGS-based assays in standard diagnostics.
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