COVID-19 mortality,excess mortality,deaths per million and infection fatality ratio,Belgium, 9 March 2020 to 28 June 2020

BackgroundCOVID-19 mortality, excess mortality, deaths per million population (DPM), infection fatality ratio (IFR) and case fatality ratio (CFR) are reported and compared for many countries globally. These measures may appear objective, however, they should be interpreted with caution.AimWe examined reported COVID-19-related mortality in Belgium from 9 March 2020 to 28 June 2020, placing it against the background of excess mortality and compared the DPM and IFR between countries and within subgroups.MethodsThe relation between COVID-19-related mortality and excess mortality was evaluated by comparing COVID-19 mortality and the difference between observed and weekly average predictions of all-cause mortality. DPM were evaluated using demographic data of the Belgian population. The number of infections was estimated by a stochastic compartmental model. The IFR was estimated using a delay distribution between infection and death.ResultsIn the study period, 9,621 COVID-19-related deaths were reported, which is close to the excess mortality estimated using weekly averages (8,985 deaths). This translates to 837 DPM and an IFR of 1.5% in the general population. Both DPM and IFR increase with age and are substantially larger in the nursing home population.DiscussionDuring the first pandemic wave, Belgium had no discrepancy between COVID-19-related mortality and excess mortality. In light of this close agreement, it is useful to consider the DPM and IFR, which are both age, sex, and nursing home population-dependent. Comparison of COVID-19 mortality between countries should rather be based on excess mortality than on COVID-19-related mortality.     

Biasing human epidermal growth factor receptor 4 (HER4) tyrosine kinase signaling with antibodies: Induction of cell death by antibody‐dependent HER4 intracellular domain trafficking

Human epidermal growth factor receptor 4 (HER4) isoforms have oncogenic or tumor suppressor functions depending on their susceptibility to proteolytic cleavage and HER4 intracellular domain (4ICD) translocation. Here, we report that the neuregulin 1 (NRG1) tumor suppressor mechanism through the HER4 JMa/CYT1 isoform can be mimicked by the agonist anti‐HER4 Ab C6. Neuregulin 1 induced cleavage of poly(ADP‐ribose) polymerase (PARP) and sub‐G₁ DNA fragmentation, and also reduced the metabolic activity of HER3^?/HER4⁺ cervical (C‐33A) and ovarian (COV318) cancer cells. This effect was confirmed in HER4 JMa/CYT1‐, but not JMa/CYT2‐transfected BT549 triple‐negative breast cancer cells. Neuregulin 1 favored 4ICD cleavage and retention in mitochondria in JMa/CYT1‐transfected BT549 cells, leading to reactive oxygen species (ROS) production through mitochondrial depolarization. Similarly, the anti‐HER4 Ab C6, which binds to a conformational epitope located on a.a. 575‐592 and 605‐620 of HER4 domain IV, induced 4ICD cleavage and retention in mitochondria, and mimicked NRG1‐mediated effects on PARP cleavage, ROS production, and mitochondrial membrane depolarization in cancer cells. In vivo, C6 reduced growth of COV434 and HCC1187 tumor cell xenografts in nude mice. Biasing 4ICD trafficking to mitochondria with anti‐HER4 Abs to mimic NRG1 suppressor functions could be an alternative anticancer strategy.     

Functional evaluation of polyarylamide fibers for use in a prosthesis for anterior cruciate ligament replacement in the sheep

In order to evaluate the potential use of polyarylamide fibers as a prosthetic material for ligament replacement, resected sheep anterior cruciate ligaments were replaced by braided devices routed through a tibial tunnel and over the top of the lateral femoral condyle. Twelve sheep were used and sacrificed between 3 and 12 months. The tissue response to the implant was evaluated histologically. Morphologic features of the fibers and the abraded particles were measured by image analysis. Simultaneously, the tensile properties as well as the creep and fatigue properties of non-implanted prostheses were measured under laboratory conditions. It was shown that the polyarylamide fibers exhibited high strength, a high modulus, but low fatigue abrasion properties. At autopsy, 1 prosthesis was broken, 6 had frayed and 5 were intact. There was no adverse tissue response to the intact fibers. Inflammation was always linked to the presence of polymeric particles. A large bony ingrowth in the tibial tunnel through the prostheses strands was observed. There was no material resorption throughout the experiment. Polyarylamide fibers appear to be a suitable material for ligament replacement provided that abrasion against bone can be avoided.     

LEUCOVORIN AND MAXIMUM TOLERATED DOSE TOXICITY OF METHOTREXATE IN RATS

High-dose methotrexate (HD-MTX) is widely used in combination chemotherapy and can be handled without life-threatening toxicity in combination with leucovorin (LV) rescue. However, in an experimental animal modelfortesting of short-term HD-MTX effects in anesthetized rats, the authors previously demonstrated intolerable toxicity and death within a few hours in some animals. Serum levels were below levels routinely found in patients on HD-MTX treatment. This study was aimed at disclosure of possible mechanisms for acute toxicity of MTX in rats. The previously determined maximum tolerated dose of 5 g/kg MTX was used as the test dose. The animals that died showed sudden reduction in heart rate and blood pressure. LV, 1 g/kg infused immediately prior to MTX, changed MTX elimination kinetics, but did not change the acute toxicity. The data of this study together with additional evidence obtained in the experimental model, suggest that MTX acute toxicity may not be related to its antiproliferative effect, but rather to perturbation of endothelial cell and platelet function.     

Stargardt disease: towards developing a model to predict phenotype

Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype–phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype–phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families.     

Experiences of the implementation of clinical practice guidelines – interviews with nurse managers and nurses in hospital care

Scand J Caring Sci; 2010; 24; 514–522
Experiences of the implementation of clinical practice guidelines – interviews with nurse managers and nurses in hospital care The implementation of clinical practice guidelines (CPGs) has become an increasingly common element of clinical care, but little qualitative research has been conducted in real‐life clinical settings. The aim was to elucidate experiences and factors of importance for the implementation of CPGs in hospital care. Twenty interviews were conducted, audio‐taped and transcribed verbatim. A manifest and latent content analysis was performed to interpret the text. A system of subcategories related to five categories and one overall theme were developed. The data reveal that the implementation of CPGs is continuous processes of creating reliable and tenable routines that involve all staff members and expect to lead to better and safer patient care as well as to increased knowledge and confidence among staff. The process is initiated by internal or external demands and represents a way to keep abreast of knowledge development. Several factors facilitate the implementation and have an influence on the use and compliance with CPGs. To increase support for and willingness to use the CPG, it appears important to involve all staffs in the implementation process as well as to follow up and give feedback continuously to staff and management. It seems necessary to evaluate the process to supervise compliance with CPGs and to balance priorities and costs. Evaluation can also demonstrate importance of the application.     

Comparative expression of the psoriasin (S100A7) and S100C genes in breast carcinoma and co-localization to human chromosome 1q21-q22

Using differential screening of a breast cancer cDNA library, we isolated a cDNA encoding the psoriasin (S100A7) protein, previously identified in psoriatic epidermis. In the present study, we demonstrate that the psoriasin gene is expressed in breast cancer cell lines and in cancer cells of some breast carcinomas but not in any non-cancerous tissues examined, except skin. Another S100 gene, S100C, which we co-localized with the psoriasin gene to human chromosome Iq21-q22, was found to be expressed in most tissues and cell lines evaluated. These findings add support to the concept that the S100 genes clustered in human chromosome Iq21-q22 are individually controlled and that some of them may be involved in the regulation of cell transformation and/or differentiation.