Changing characteristics over time of individuals receiving COVID-19 vaccines in Denmark: A population-based descriptive study of vaccine uptake.

AIMS: The Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake and characteristics of COVID-19 vaccine recipients in Denmark. METHODS: Using nationwide healthcare registries, we identified all Danish residents ⩾5 years of age who received at least one dose of a COVID-19 vaccine from 27 December 2020-29 January 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups and vaccination priority groups, and described characteristics of vaccine recipients during two-month-intervals and in vaccination priority groups. RESULTS: By 29 January 2022, 88%, 86% and 64% of Danish residents ⩾5 years (n=5,562,008) had received a first, second and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84%). Uptake ranged from 48% in 5-11-year-olds to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs 3.7-4.6% in later periods) and diabetes (9.3-12% vs 0.91-2.4% in later periods). CONCLUSIONS: We document substantial changes over time in, for example, age, sex and medical history of COVID-19 vaccine recipients. Though these results are related to the differential vaccine rollout in Denmark, similar findings are probable in other countries and should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Primary care visits can reduce the risk of potentially avoidable hospitalizations among persons with diabetes in France.

BACKGROUND: Diabetes is a frequent chronic condition, which can lead to costly complications if not managed well in the primary care setting. Potentially avoidable hospitalizations (PAH) are considered as an indirect measure of primary care. However, the association between primary care use and PAH in diabetic patients has not been investigated in France. METHODS: We investigate the association between primary care indicators and PAH at an individual level among persons with diabetes in a population-based cohort study on the French national health insurance database (EGB sample). PAH occurrence in 2013 was modeled as a function of primary care use and access, health status and socio-economic indicators over the exposure period 2011-12 using a cause-specific hazards model with death as a competing event. RESULTS: We included 25 293 diabetics in our cohort, among which 385 (1.5%) experienced at least 1 PAH in 2013. After adjustment on health status indicators, primary care use had a protective effect against PAH. Diabetic patients who had seen a general practitioner (GP) 10-14 times had a reduced hazard of PAH compared to less frequent encounters (HR=0.49, P<0.001). The effect size decreased when the number of encounters increased, suggesting a remaining confounding effect of health status. CONCLUSIONS: For the first time in France, this study shows a protective effect of the number of GP encounters against PAH at an individual level and highlights the importance of a frequent monitoring of diabetic patients in the primary care setting to prevent PAH occurrence.

Mining electronic health records: towards better research applications and clinical care.

Clinical data describing the phenotypes and treatment of patients represents an underused data source that has much greater research potential than is currently realized. Mining of electronic health records (EHRs) has the potential for establishing new patient-stratification principles and for revealing unknown disease correlations. Integrating EHR data with genetic data will also give a finer understanding of genotype-phenotype relationships. However, a broad range of ethical, legal and technical reasons currently hinder the systematic deposition of these data in EHRs and their mining. Here, we consider the potential for furthering medical research and clinical care using EHR data and the challenges that must be overcome before this is a reality.

Sudden Sensorineural Hearing Loss Following Immunization With BNT162b2 or mRNA-1273: A Danish Population-Based Cohort Study.

OBJECTIVE: To compare the occurrence of sudden sensorineural hearing loss following immunization with BNT162b2 (Comirnaty®; Pfizer BioNTech) or mRNA-1273 (Spikevax®; Moderna) to the occurrence among unvaccinated individuals. STUDY DESIGN: Cohort study. SETTING: Nationwide Danish health care registers comprised all Danish residents living in Denmark on October 1, 2020, who were 18 years or older or turned 18 in 2021. METHODS: We compared the occurrence of sudden sensorineural hearing loss following immunization with BNT162b2 (Comirnaty®; Pfizer BioNTech) or mRNA-1273 (Spikevax®; Moderna) (first, second, or third dose) against unvaccinated person time. Secondary outcomes were a first-ever hospital diagnosis of vestibular neuritis and a hearing examination, by an ear-nose-throat (ENT) specialist, followed by a prescription of moderate to high-dose prednisolone. RESULTS: BNT162b2 or mRNA-1273 vaccine was not associated with an increased risk of receiving a discharge diagnosis of sudden sensorineural hearing loss (adjusted hazard ratio [HR]: 0.99, confidence interval [CI]: 0.59-1.64) or vestibular neuritis (adjusted HR: 0.94, CI: 0.69-1.24). We found a slightly increased risk (adjusted HR: 1.40, CI, 1.08-1.81) of initiating moderate to high-dose oral prednisolone following a visit to an ENT specialist within 21 days from receiving a messenger RNA (mRNA)-based Covid-19 vaccine. CONCLUSION: Our findings do not suggest an increased risk of sudden sensorineural hearing loss or vestibular neuritis following mRNA-based COVID-19 vaccination. mRNA-Covid-19 vaccination may be associated with a small excess risk of a visit to an ENT specialist visit followed by a prescription of moderate to high doses of prednisolone.

Using electronic patient records to discover disease correlations and stratify patient cohorts.

Electronic patient records remain a rather unexplored, but potentially rich data source for discovering correlations between diseases. We describe a general approach for gathering phenotypic descriptions of patients from medical records in a systematic and non-cohort dependent manner. By extracting phenotype information from the free-text in such records we demonstrate that we can extend the information contained in the structured record data, and use it for producing fine-grained patient stratification and disease co-occurrence statistics. The approach uses a dictionary based on the International Classification of Disease ontology and is therefore in principle language independent. As a use case we show how records from a Danish psychiatric hospital lead to the identification of disease correlations, which subsequently can be mapped to systems biology frameworks.

A Wnt oscillator model for somitogenesis.

We propose a model for the segmentation clock in vertebrate somitogenesis, based on the Wnt signaling pathway. The core of the model is a negative feedback loop centered around the Axin2 protein. Axin2 is activated by beta-catenin, which in turn is degraded by a complex of GSK3beta and Axin2. The model produces oscillatory states of the involved constituents with typical time periods of a few hours (ultradian oscillations). The oscillations are robust to changes in parameter values and are often spiky, where low concentration values of beta-catenin are interrupted by sharp peaks. Necessary for the oscillations is the saturated degradation of Axin2. Somite formation in chick and mouse embryos is controlled by a spatial Wnt gradient which we introduce in the model through a time-dependent decrease in Wnt3a ligand level. We find that the oscillations disappear as the ligand concentration decreases, in agreement with observations on embryos.

Proteomic profiling of human colon cancer cells treated with the histone deacetylase inhibitor belinostat.

The anticancer drug belinostat is a hydroxamate histone deacetylase inhibitor that has shown significant antitumour activity in various tumour models and also in clinical trials. In this study, we utilized a proteomic approach in order to evaluate the effect of this drug on protein expression in the human colon cancer cell line HCT116. Protein extracts from untreated HCT116 cells, and cells grown for 24 h in the presence of 1 and 10 muM belinostat were analysed by 2-D gel electrophoresis. Proteins were visualized by colloidal Coomassie blue staining and quantitative analysis of gel images revealed 45 unique differentially expressed proteins that were identified by LC-MSMS analysis. Among these proteins, of particular interest are the downregulated proteins nucleophosmin and stratifin, and the upregulated proteins nucleolin, gelsolin, heterogeneous nuclear ribonucleoprotein K, annexin 1, and HSP90B that all were related to the proto-oncogene proteins p53, Myc, activator protein 1, and c-fos protein. The modulation of these proteins is consistent with the observations that belinostat is able to inhibit clonogenic cell growth of HCT116 cells and the biological role of these proteins will be discussed.

Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase.

BACKGROUND: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) are promising cancer drugs currently in clinical trials in oncology, including APO866, CHS-828 and the CHS-828 prodrug EB1627/GMX1777, but cancer cell resistance to these drugs has not been studied in detail. METHODS: Here, we introduce an analogue of CHS-828 called TP201565 with increased potency in cellular assays. Further, we describe and characterize a panel of cell lines with acquired stable resistance towards several NAMPT inhibitors of 18 to 20,000 fold compared to their parental cell lines. RESULTS: We find that 4 out of 5 of the resistant sublines display mutations of NAMPT located in the vicinity of the active site or in the dimer interface of NAMPT. Furthermore, we show that these mutations are responsible for the resistance observed. All the resistant cell lines formed xenograft tumours in vivo. Also, we confirm CHS-828 and TP201565 as competitive inhibitors of NAMPT through docking studies and by NAMPT precipitation from cellular lysate by an analogue of TP201565 linked to sepharose. The NAMPT precipitation could be inhibited by addition of APO866. CONCLUSION: We found that CHS-828 and TP201565 are competitive inhibitors of NAMPT and that acquired resistance towards NAMPT inhibitors can be expected primarily to be caused by mutations in NAMPT.

Characterization of resistance to a recombinant hexameric Fas-ligand (APO010) in human cancer cell lines.

Multiple myeloma remains a hard-to-treat cancer as all patients eventually progress because of drug resistance. Thus, there is a need for novel and non-cross-resistant treatment options, and we aimed to address this issue by introducing a new immuno-oncology drug (APO010) in multiple myeloma treatment. APO010 is a hexameric Fas-ligand that mimics cytotoxic T-lymphocyte signaling through the Fas-receptor to induce apoptosis. APO010 is currently in clinical trials with multiple myeloma patients. Thus, an understanding of the mechanisms contributing to resistance to APO010 will be essential for future clinical studies with APO010, and it might be possible to develop strategies to circumvent this resistance. We developed APO010-resistant variants of human multiple myeloma cell lines (LP1, MOLP-8, and KMS-12-BM) and a human Burkitt's lymphoma cell line (Raji) by exposing the cells to gradually increasing concentrations of APO010 over a period of 6-12 months. The resistant cell lines were characterized on the basis of immunocytochemistry, Fas-receptor protein expression, mRNA expression analysis, and pathway analysis. APO010-resistant cell lines exhibited a 4- to 520-fold increase in resistance to APO010 and still remained sensitive to other chemotherapeutics. Downregulation of the Fas-receptor protein expression was observed in all resistant cell lines. mRNA expression analysis of the resistant versus parental cell lines confirmed a significant alteration in FAS expression between sensitive and resistant cell lines (p = 0.03), while pathway analysis revealed alterations in mRNA signaling pathways of Fas. On the basis of the pre-clinical data obtained, it can be concluded that downregulation of Fas-receptor can mediate resistance to APO010.