The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to... Show moreThe genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease. Show less
Helmi, M.; Wilde, R. de; Jansen, J.; Geerts, B.; Berg, P. van den; Versteegh, M.; ... ; Groeneveld, A. 2012
Patients in the intensive care unit (ICU) and in the peri-operative phase are dependent on physicians and nurses for their fluid intake. Volume status optimization is required to maximize oxygen... Show morePatients in the intensive care unit (ICU) and in the peri-operative phase are dependent on physicians and nurses for their fluid intake. Volume status optimization is required to maximize oxygen delivery to vital organs. Unnecessary fluid administration can, however, lead to general and pulmonary oedema, cardiac failure, infections, prolonged hospitalization and death. Besides signs like skin turgor, diuresis and skin colour, hemodynamic measurements like central venous pressure (CVP) and mean arterial pressure (MAP) are most often used for hemodynamic management. These parameters, however, often fail to accurately predict the response of a patient to fluid loading. Cardiac output (CO) is the amount of blood pumped through the circulation by the heart per minute. The general conception is that an increase in cardiac output will improve perfusion of vital organs. Increased flow might also imply improved oxygen delivery to the tissues. This is the basis of the fluid loading responsiveness strategy (FLR). This strategy aims to prevent fluid overloading by an accurate prediction of the response in cardiac output to fluid loading. Arthur Guyton__s work provided an important step forward to the determination of volume status directly. Together with the shape of cardiac output function curve, dimensions of the vascular system, blood viscosity and mean systemic filling pressure (MSFP) can be considered as a primary determinant of venous return and thus cardiac output. Ultimately, MSFP can be used to calculate stressed volume and, hence, quantify effective volume status in a specific patient. In this thesis, we review literature on fluid loading responsiveness research, we try to assess the impact of literature on hemodynamic management in Dutch ICU__s, we discuss a novel method to assess mean systemic filling pressure and last we discuss studies performed to assess the reliability of several challenges to predict FLR; +10 cmH2O PEEP, the fluid challenge, passive leg raising, the respiratory ventilator manoeuvre and the measurement of baseline MSFP. The manoeuvres are aimed at determining the working point of the circulation on the Frank- Starling curve. It is assumed that when the patient is on the ascending portion of the Frank- Starling curve an (auto)transfusion will increase cardiac output. Show less
Geerts, B.; Wilde, R. de; Aarts, L.; Jansen, J. 2011
