Individualized versus Standardized Risk Assessment in Patients at High Risk for Adverse Drug Reactions (The IDrug Randomized Controlled Trial)–Never Change a Running System?

The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95%CI 1.02–2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95%CI 1.05–3.76]), and not significant on DOAC treatment (OR 1.52 [95%CI 0.63–3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance

Educating the Next Generation of Pharmacogenomics Experts: Global Educational Needs and Concepts

Personalised Therapeutic

The geodynamic and limnological evolution of Balkan Lake Ohrid, possibly the oldest extant lake in Europe

Studies of the upper 447 m of the DEEP site sediment succession from central Lake Ohrid, Balkan Peninsula, North Macedonia and Albania provided important insights into the regional climate history and evolutionary dynamics since permanent lacustrine conditions established at 1.36 million years ago (Ma). This paper focuses on the entire 584-m-long DEEP sediment succession and a comparison to a 197-m-long sediment succession from the Pestani site ~5 km to the east in the lake, where drilling ended close to the bedrock, to unravel the earliest history of Lake Ohrid and its basin development. 26Al/10Be dating of clasts from the base of the DEEP sediment succession implies that the sedimentation in the modern basin started at c. 2 Ma. Geophysical, sedimentological and micropalaeontological data allow for chronological information to be transposed from the DEEP to the Pestani succession. Fluvial conditions, slack water conditions, peat formation and/or complete desiccation prevailed at the DEEP and Pestani sites until 1.36 and 1.21 Ma, respectively, before a larger lake extended over both sites. Activation of karst aquifers to the east probably by tectonic activity and a potential existence of neighbouring Lake Prespa supported filling of Lake Ohrid. The lake deepened gradually, with a relatively constant vertical displacement rate of ~0.2 mm a−1 between the central and the eastern lateral basin and with greater water depth presumably during interglacial periods. Although the dynamic environment characterized by local processes and the fragmentary chronology of the basal sediment successions from both sites hamper palaeoclimatic significance prior to the existence of a larger lake, the new data provide an unprecedented and detailed picture of the geodynamic evolution of the basin and lake that is Europe’s presumed oldest extant freshwater lake

Mediterranean winter rainfall in phase with African monsoons during the past 1.36 million years

Mediterranean climates are characterized by strong seasonal contrasts between dry summers and wet winters. Changes in winter rainfall are critical for regional socioeconomic development, but are difficult to simulate accurately1 and reconstruct on Quaternary timescales. This is partly because regional hydroclimate records that cover multiple glacial–interglacial cycles2,3 with different orbital geometries, global ice volume and atmospheric greenhouse gas concentrations are scarce. Moreover, the underlying mechanisms of change and their persistence remain unexplored. Here we show that, over the past 1.36 million years, wet winters in the northcentral Mediterranean tend to occur with high contrasts in local, seasonal insolation and a vigorous African summer monsoon. Our proxy time series from Lake Ohrid on the Balkan Peninsula, together with a 784,000-year transient climate model hindcast, suggest that increased sea surface temperatures amplify local cyclone development and refuel North Atlantic low-pressure systems that enter the Mediterranean during phases of low continental ice volume and high concentrations of atmospheric greenhouse gases. A comparison with modern reanalysis data shows that current drivers of the amount of rainfall in the Mediterranean share some similarities to those that drive the reconstructed increases in precipitation. Our data cover multiple insolation maxima and are therefore an important benchmark for testing climate model performance

The geodynamic and limnological evolution of Balkan Lake Ohrid, possibly the oldest extant lake in Europe

Studies of the upper 447 m of the DEEP site sediment succession from central Lake Ohrid, Balkan Peninsula, North Macedonia and Albania provided important insights into the regional climate history and evolutionary dynamics since permanent lacustrine conditions established at 1.36 million years ago (Ma). This paper focuses on the entire 584-m-long DEEP sediment succession and a comparison to a 197-m-long sediment succession from the Pestani site ~5 km to the east in the lake, where drilling ended close to the bedrock, to unravel the earliest history of Lake Ohrid and its basin development. 26Al/10Be dating of clasts from the base of the DEEP sediment succession implies that the sedimentation in the modern basin started at c. 2 Ma. Geophysical, sedimentological and micropalaeontological data allow for chronological information to be transposed from the DEEP to the Pestani succession. Fluvial conditions, slack water conditions, peat formation and/or complete desiccation prevailed at the DEEP and Pestani sites until 1.36 and 1.21 Ma, respectively, before a larger lake extended over both sites. Activation of karst aquifers to the east probably by tectonic activity and a potential existence of neighbouring Lake Prespa supported filling of Lake Ohrid. The lake deepened gradually, with a relatively constant vertical displacement rate of ~0.2 mm a−1 between the central and the eastern lateral basin and with greater water depth presumably during interglacial periods. Although the dynamic environment characterized by local processes and the fragmentary chronology of the basal sediment successions from both sites hamper palaeoclimatic significance prior to the existence of a larger lake, the new data provide an unprecedented and detailed picture of the geodynamic evolution of the basin and lake that is Europe’s presumed oldest extant freshwater lake

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity