SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection

Is there a crisis in nursing retention in New South Wales?

Background: There is a severe shortage of nurses in Australia. Policy makers and researchers are especially concerned that retention levels of nurses in the health workforce have worsened over the last decade. There are also concerns that rapidly growing private sector hospitals are attracting qualified nurses away from the public sector. To date no systematic analysis of trends in nursing retention rates over time has been conducted due to the lack of consistent panel data. Results: A 1.4 percentage point improvement in retention has led to a 10% increase in the overall supply of nurses in NSW. There has also been a substantial aging of the workforce, due to greater retention and an increase in mature age entrants. The improvement in retention is found in all types of premises and is largest in nursing homes. There is a substantial amount of year to year movement in and out of the workforce and across premises. The shortage of nurses in public hospitals is due to a slowdown in entry rather than competition from the rapidly growing private sector hospitals. Policy Implications: The finding of an improvement (rather than a worsening) in retention suggests that additional improvements may be difficult to achieve as further retention must involve individuals more and more dissatisfied with nursing relative to other opportunities. Hence policies targeting entry such as increased places in nursing programs and additional subsidies for training costs may be more effective in dealing with the workforce shortage. This is also the case for shortages in public sector hospitals as retention in nursing is found to be relatively high in this sector. However, the large amount of year to year movements across nursing jobs, especially among the younger nurses, also suggests that policies aimed at reducing job switches and increasing the number who return to nursing should also be pursued. More research is needed in understanding the relative importance of detailed working conditions and the problems associated with combining family responsibilities and nursing jobs. © 2008 Doiron et al; licensee BioMed Central Ltd

Reproducibility of quantitative F-18-3'-deoxy-3'-fluorothymidine measurements using positron emission tomography

Positron emission tomography (PET) using F-18-3'-deoxy-3'-fluorothymidine ([F-18]FLT) allows noninvasive monitoring of tumour proliferation. For serial imaging in individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative [F-18]FLT measurements. Nine patients with non-small-cell lung cancer (NSCLC) and six with head-and-neck cancer (HNC) underwent [F-18]FLT PET twice within 7 days prior to therapy. The maximum pixel value (SUVmax) and a threshold defined volume (SUV41%) were defined for all delineated lesions. The plasma to tumour transfer constant (K-i) was estimated using both Patlak graphical analysis and nonlinear regression (NLR). NLR was also used to estimate k(3), which, at least in theory, selectively reflects thymidine kinase 1 activity. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. All primary tumours and > 90% of clinically suspected locoregional metastases could be delineated. In total, 24 lesions were defined. NLR-derived K-i, Patlak-derived K-i, SUV41% and SUVmax showed excellent reproducibility with ICCs of 0.92, 0.95, 0.98 and 0.93, and SDs of 16%, 12%, 7% and 11%, respectively. Reproducibility was poor for k(3) with an ICC of 0.43 and SD of 38%. Quantitative [F-18]FLT measurements are reproducible in both NSCLC and HNC patients. When monitoring response in individual patients, changes of more than 15% in SUV41%, 20-25% in SUVmax and Patlak-derived K-i, and 32% in NLR3k-derived K-i are likely to represent treatment effect

The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians

BACKGROUND: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. METHODS: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. RESULTS: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84–1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Phase II study of capecitabine and mitomycin C as first-line treatment in patients with advanced colorectal cancer

This study was designed to assess the safety and efficacy of capecitabine and mitomycin C (MMC) in previously untreated patients with advanced colorectal cancer (CRC). Patients received capecitabine 2500 mg m2 day 1, orally divided in two doses of 1250 mg m-2 in the morning and evening for 14 days every 21 days and MMC 7 mg m-2 (maximum total dose 14 mg) as an intravenous bolus every 6 weeks for a total of four courses. The median age was 70 years (range 24–85) and the majority of patients (86.9%) were of performance status 1/2. The most common metastatic site was liver. In all, 84 patients were assessable for response. The overall response rate was 38% (95% CI: 27.7–49.3) and a further 33.3% of patients achieved stable disease over 12 weeks. There was good symptom resolution ranging from 64 to 86%. Grade 3/4 toxicity was as follows: hand–foot syndrome 19.7%; diarrhoea 10%; neutropenia 2.4%; infection 2.3%. Capecitabine and MMC have shown encouraging activity with a favourable toxicity profile, a convenient administration schedule, and could be considered for patients deemed unsuitable for oxaliplatin and irinotecan combinations.S Rao, D Cunningham, T Price, M E Hill, P J Ross, N Tebbutt, A R Norman, J Oates and P Shellit

Imaging with non-FDG PET tracers: outlook for current clinical applications

Apart from the historical and clinical relevance of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG), various other new tracers are gaining a remarkable place in functional imaging. Their contribution to clinical decision-making is irreplaceable in several disciplines. In this brief review we aimed to describe the main non-FDG PET tracers based on their clinical relevance and application for patient care

Age at menarche in Canada: results from the National Longitudinal Survey of Children & Youth

<p>Abstract</p> <p>Background</p> <p>Given the downward trend in age at menarche and its implications for the reproductive health and wellbeing of women, little is known about menarcheal age in Canada. Most Canadian studies are only representative of specific populations. The present study, therefore, aims to assess the distribution of age at menarche for Canadian girls and explore its variation across socio-economic and demographic factors.</p> <p>Methods</p> <p>The analysis of the study was based on all female respondents aged 14 to 17 years during Cycle 4 (2000/2001) of the National Longitudinal Survey of Children & Youth (NLSCY). The main outcome was age at menarche assessed as the month and year of the occurrence of the first menstrual cycle. Kaplan Meier was used to estimate the mean and median of age at menarche. Chi-square test was used to assess the differences in early, average and later maturers across the different levels of socio-economic and demographic variables. Bootstrapping was performed to account for the complex sampling design.</p> <p>Results</p> <p>The total number of girls analyzed in this study was 1,403 weighted to represent 601,911 Canadian girls. The estimated mean and median of age at menarche was 12.72 years (standard deviation = 1.05) and 12.67 years, respectively. The proportions of early (< 11.53 years), average (≥11.53 years and ≤13.91 years) and late maturers (> 13.91 years) were 14.6% (95% confidence interval (CI): 11.92-17.35), 68.0% (95% CI: 63.82-72.17) and 17.4% (95% CI: 14.10-20.63), respectively. Variations across the menarcheal groups were statistically significant for the province of residence, household income and family type.</p> <p>Conclusion</p> <p>The findings of the study pave the way for future Canadian research. More studies are warranted to understand menarcheal age in terms of its variation across the provinces, the secular trend over time and its potential predictors.</p

Krüppel-like Factor 4 Regulates Intestinal Epithelial Cell Morphology and Polarity

Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that plays a vital role in regulating cell lineage differentiation during development and maintaining epithelial homeostasis in the intestine. In normal intestine, KLF4 is predominantly expressed in the differentiated epithelial cells. It has been identified as a tumor suppressor in colorectal cancer. KLF4 knockout mice demonstrated a decrease in number of goblet cells in the colon, and conditional ablation of KLF4 from the intestinal epithelium led to altered epithelial homeostasis. However, the role of KLF4 in differentiated intestinal cells and colon cancer cells, as well as the mechanism by which it regulates homeostasis and represses tumorigenesis in the intestine is not well understood. In our study, KLF4 was partially depleted in the differentiated intestinal epithelial cells by a tamoxifen-inducible Cre recombinase. We found a significant increase in the number of goblet cells in the KLF4-deleted small intestine, suggesting that KLF4 is not only required for goblet cell differentiation, but also required for maintaining goblet cell numbers through its function in inhibiting cell proliferation. The number and position of Paneth cells also changed. This is consistent with the KLF4 knockout study using villin-Cre [1]. Through immunohistochemistry (IHC) staining and statistical analysis, we found that a stem cell and/or tuft cell marker, DCAMKL1, and a proliferation marker, Ki67, are affected by KLF4 depletion, while an enteroendocrine cell marker, neurotensin (NT), was not affected. In addition, we found KLF4 depletion altered the morphology and polarity of the intestinal epithelial cells. Using a three-dimensional (3D) intestinal epithelial cyst formation assay, we found that KLF4 is essential for cell polarity and crypt-cyst formation in human colon cancer cells. These findings suggest that, as a tumor suppressor in colorectal cancer, KLF4 affects intestinal epithelial cell morphology by regulating proliferation, differentiation and polarity of the cells

Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[18F]-Fluoro-L-Thymidine ([18F]FLT) Positron Emission Tomography (PET)

Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[$^{18}F$]-fluoro-L-thymidine ([$^{18}F$]FLT) and 2-[$^{18}F$]-fluoro-2-deoxy-D-glucose ([$^{18}F$]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [$^{18}F$]FLT uptake after only two days of treatment, [$^{18}F$]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [$^{18}F$]FLT PET but not [$^{18}F$]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [$^{18}F$]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [$^{18}F$]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [$^{18}F$]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [$^{18}F$]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC