Drug therapy - a challenge in primary care.

Introduction: Drug therapy in primary care is a broad field, with two areas previously identified as particularly challenging: treatment of the elderly and prescription of antibiotics against uncomplicated upper respiratory tract infections (URTIs). General practitioners’ (GPs’) attitudes and adherence to evidence-based treatment guidelines might be influenced by different interventions and need to be studied. Objectives: 1. To study different intervention models that might influence GPs’ adherence to treatment guidelines. 2. To describe GPs’ attitudes towards locally developed treatment guidelines. Methods: (Paper I) Systematic medication reviews by pharmacists were performed in a randomised controlled study of 369 elderly patients living in the community or nursing homes, who were using the multi-dose drug dispensing (MDD) system. Drug lists were assessed before and after the intervention with a focus on potentially inappropriate medications (PIMs). (Paper II) A retrospective analysis of medication lists was conducted in the same patient sample, with a focus on fall risk-increasing drugs (FRIDs), orthostatic drugs (ODs) and falls. (Paper III) A randomised controlled study was performed using two questionnaire-based behaviour change interventions aimed at reducing prescription of antibiotics against URTIs in primary care. (Paper IV) A qualitative study was performed using focus group interviews to assess GPs’ attitudes towards evidence-based local treatment guidelines. Results: Papers I and II: Systematic medication reviews by pharmacists reduced the number of patients taking PIMs and the total number of drugs these patients were taking, but not the number of patients taking more than three psychotropic drugs. A significant proportion (87%) of the study sample was taking FRIDs and ODs. Numbers of FRIDs were associated with the total number of drugs and with severe falls. There was no association between numbers of ODs and occurrence of severe falls. Paper III: There was a significant decrease in the antibiotic prescribing rate in one of the two intervention groups compared to the control group in patients 0-6 years, but no differences between the groups in patients of all ages. Paper IV: Trust in evidence-based recommendations and patient safety were found to be key factors in prescribing, as was the patient-doctor encounter, with emphasis on informing the patient. The GPs all experienced a lack of time to self-inform, difficulties managing patients with multiple prescribers and direct-to-consumer drug industry information. Cost containment was perceived as both a barrier and a motivator for adherence to guidelines. Conclusion: Multi-professional assessment of patient’s drug list and questionnaire-based behaviour change interventions might be feasible methods to improve quality of drug treatment in primary care and need to be studied further. GPs found trust in evidence-based guidelines and patient safety to be essential in drug prescribing

Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein

Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2´ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice expressing human ACE2 against infection when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

A first update on mapping the human genetic architecture of COVID-19

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