Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease.

Immune protection following either vaccination or infection with SARS-CoV-2 is thought to decrease over time. We designed a retrospective study, conducted at Leumit Health Services in Israel, to determine the kinetics of SARS-CoV-2 IgG antibodies following administration of two doses of BNT162b2 vaccine, or SARS-CoV-2 infection in unvaccinated individuals. Antibody titers were measured between 31 January 2021, and 31 July 2021 in two mutually exclusive groups: (i) vaccinated individuals who received two doses of BNT162b2 vaccine and had no history of previous infection with COVID-19 and (ii) SARS-CoV-2 convalescents who had not received the vaccine. A total of 2653 individuals fully vaccinated by two doses of vaccine during the study period and 4361 convalescent patients were included. Higher SARS-CoV-2 IgG antibody titers were observed in vaccinated individuals (median 1581 AU/mL IQR [533.8–5644.6]) after the second vaccination than in convalescent individuals (median 355.3 AU/mL IQR [141.2–998.7]; p < 0.001). In vaccinated subjects, antibody titers decreased by up to 38% each subsequent month while in convalescents they decreased by less than 5% per month. Six months after BNT162b2 vaccination 16.1% subjects had antibody levels below the seropositivity threshold of <50 AU/mL, while only 10.8% of convalescent patients were below <50 AU/mL threshold after 9 months from SARS-CoV-2 infection. This study demonstrates individuals who received the Pfizer-BioNTech mRNA vaccine have different kinetics of antibody levels compared to patients who had been infected with the SARS-CoV-2 virus, with higher initial levels but a much faster exponential decrease in the first group.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver. Our aim was to understand the molecular mechanisms linking liver regeneration under chronic inflammation to hepatic tumorigenesis. Mdr2-KO mice, a model of inflammation-associated cancer, underwent partial hepatectomy (PHx), which led to enhanced hepatocarcinogenesis. Moreover, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage-response machinery and increased genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis, cell-cycle arrest, and senescence and suggest their involvement in tumor growth acceleration subsequent to PHx. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic inflammation escape senescence and apoptosis and reenter the cell cycle, triggering the enhanced tumorigenesis. Thus, we clarify the immediate and long-term contributions of the DNA damage response to HCC development and recurrence. hepatocellular carcinoma | MRI | MDR2 -/-mice | genomic instability

Background-The independent association between elevated triglycerides and all-cause mortality among patients with established coronary heart disease is controversial. The aim of this study was to investigate this association in a large cohort of patients with proven coronary heart disease. Methods and Results-The study cohort comprised 15 355 patients who were screened for the Bezafibrate Infarction Prevention (BIP) trial. Twenty-two-year mortality data were obtained from the national registry. Patients were divided into 5 groups according to strata of fasting serum triglycerides: (1) low-normal triglycerides (<100 mg/dL); (2) highnormal triglycerides (100-149 mg/dL); (3) borderline hypertriglyceridemia triglycerides (150-199 mg/dL); (4) moderate hypertriglyceridemia triglycerides (200-499 mg/dL); (5) severe hypertriglyceridemia triglycerides (≥500 mg/dL). Ageand sex-adjusted survival was 41% in the low-normal triglycerides group than 37%, 36%, 35%, and 25% in groups with progressively higher triglycerides (P<0.001). In an adjusted Cox-regression for various covariates including high-density lipoprotein cholesterol, each 1 unit of natural logarithm (Ln) triglycerides elevation was associated with a corresponding 6% (P=0.016) increased risk of 22-year all-cause mortality. The 22-year mortality risk for patients with severe hypertriglyceridemia was increased by 68% when compared with patients with low-normal triglycerides (P<0.001). Conclusions-In patients with established coronary heart disease, higher triglycerides levels are independently associated with increased 22-year mortality. Even in patients with triglycerides of 100 to 149 mg/dL, the elevated risk for death could be detected than in patients with lower triglycerides levels, whereas severe hypertriglyceridemia denotes a population with particularly increased mortality risk. (Circ Cardiovasc Qual Outcomes. 2016;9:100-108.

Arthrogryposis multiplex congenita (AMC) is a group of disorders characterized by congenital joint contractures caused by reduced fetal movements. AMC has an incidence of 1 in 3000 newborns and is genetically heterogeneous. We describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterized by bilateral clubfoot, decreased fetal movements, delay in motor milestones, then progressive motor decline after the first decade. Genome-wide linkage analysis revealed a single locus on chromosome 6q25 with Z(max) = 3.55 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Homozygous A to G nucleotide substitution of the conserved AG splice acceptor site at the junction of intron 136 and exon 137 of the SYNE-1 gene was found in patients. This mutation results in an aberrant retention of intron 136 of SYNE-1 RNA leading to premature stop codons and the lack of the C-terminal transmembrane domain KASH of nesprin-1, the SYNE-1 gene product. Mice lacking the KASH domain of nesprin-1 display a myopathic phenotype similar to that observed in patients. Altogether, these data strongly suggest that the splice site mutation of SYNE-1 gene found in the family is responsible for AMC. Recent reports have shown that mutations of the SYNE-1 gene might be responsible for autosomal recessive adult onset cerebellar ataxia. These data indicate that mutations of nesprin-1 which interacts with lamin A/C may lead to at least two distinct human disease phenotypes, myopathic or neurological, a feature similar to that found in laminopathies.

Background and AimsmicroRNAs (miRNAs) are small noncoding RNAs that regulate cognate mRNAs post-transcriptionally. miRNAs have been implicated in regulating gene expression in embryonic developmental processes, including proliferation and differentiation. The liver is a multifunctional organ, which undergoes rapid changes during the developmental period and relies on tightly-regulated gene expression. Little is known regarding the complex expression patterns of both mRNAs and miRNAs during the early stages of human liver development, and the role of miRNAs in the regulation of this process has not been studied. The aim of this work was to study the impact of miRNAs on gene expression during early human liver development.MethodsGlobal gene and miRNA expression were profiled in adult and in 9–12w human embryonic livers, using high-density microarrays and quantitative RT-PCR.ResultsEmbryonic liver samples exhibited a gene expression profile that differentiated upon progression in the developmental process, and revealed multiple regulated genes. miRNA expression profiling revealed four major expression patterns that correlated with the known function of regulated miRNAs. Comparison of the expression of the most regulated miRNAs to that of their putative targets using a novel algorithm revealed a significant anti-correlation for several miRNAs, and identified the most active miRNAs in embryonic and in adult liver. Furthermore, our algorithm facilitated the identification of TGFβ-R1 as a novel target gene of let-7.ConclusionsOur results uncover multiple regulated miRNAs and genes throughout human liver development, and our algorithm assists in identification of novel miRNA targets with potential roles in liver development.

BACKGROUND Smokers are generally more susceptible to infectious respiratory diseases and are at higher risk of developing severe complications from these infections. Conflicting reports exist regarding the impact of smoking on the risk of Coronavirus disease 2019 (COVID-19) infection. METHODS We carried out a population-based study among over 3,000,000 adult members of Clalit Health Services, the largest health provider in Israel. Since the beginning of the disease outbreak, 114,545 individuals underwent RT-PCR testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and 4.0% had positive results. We performed a case-control study among patients who underwent SARS-CoV-2 testing, to assess the impact of smoking on infection incidence and severity. Individuals with positive tests were matched in a 1:5 ratio to individuals tested negative, of the same sex, age, and ethnicity/religion. Conditional logistic regressions were performed to evaluate odds ratios for current and previous smoking on the risk of testing positive. Multivariable logistic regressions were performed among patients infected with COVID-19 to estimate the association between smoking and fatal or severe disease requiring ventilation. Regressions were performed with and without adjustment for preexisting medical conditions. RESULTS In the matched cohort, current smokers (9.8%) were significantly less prevalent among members tested positive compared to the general population, and to matched members tested negative (19.4%, P<0.001). Current smoking was associated with significantly reduced odds ratio (OR) for testing positive OR=0.457 (95% confidence interval (CI) 0.407-0.514). Among patients tested positive, there was no evidence of significantly increased risk of developing severe or fatal disease. CONCLUSION The risk of infection by COVID-19 appears to be reduced by half among current smokers. This intriguing finding may reveal unique infection mechanisms present for COVID-19 which may be targeted to combat the disease and reduce its infection rate.

Objectives To determine whether time elapsed since the second injection of the Pfizer-BioNTech BNT162b2 mRNA vaccine was significantly associated with the risk of covid-19 infection after vaccination in people who received two vaccine injections. Design Test negative design study. Setting Electronic health records of a large state mandated healthcare organisation, Israel. Participants Adults aged ≥18 years who had received a reverse transcription polymerase chain reaction (RT-PCR) test between 15 May 2021 and 17 September 2021, at least three weeks after their second vaccine injection, had not received a third vaccine injection, and had no history of covid-19 infection. Main outcome measures Positive result for the RT-PCR test. Individuals who tested positive for SARS-CoV-2 and controls were matched for week of testing, age category, and demographic group (ultra-orthodox Jews, individuals of Arab ancestry, and the general population). Conditional logistic regression was adjusted for age, sex, socioeconomic status, and comorbid conditions. Results 83 057 adults received an RT-PCR test for SARS-CoV-2 during the study period and 9.6% had a positive result. Time elapsed since the vaccine injection was significantly longer in individuals who tested positive (P<0.001). Adjusted odds ratio for infection at time intervals >90 days since vaccination were significantly increased compared with the reference of <90 days: 2.37 (95% confidence interval 1.67 to 3.36) for 90-119 days, 2.66 (1.94 to 3.66) for 120-149 days, 2.82 (2.07 to 3.84) for 150-179 days, and 2.82 (2.07 to 3.85) for ≥180 days (P<0.001 for each 30 day interval). Conclusions In this large population of adults tested for SARS-CoV-2 by RT-PCR after two doses of mRNA BNT162b2 vaccine, a gradual increase in the risk of infection was seen for individuals who received their second vaccine dose after at least 90 days.