Improving the clinico-radiological association in neurological diseases

Despite the key role of magnetic resonance imaging (MRI) in the diagnosis and monitoring of multiple sclerosis (MS) and cerebral small vessel disease (SVD), the association between clinical and radiological disease manifestations is often only moderate, limiting the use of MRI-derived markers in the clinical routine or as endpoints in clinical trials. In the projects conducted as part of this thesis, we addressed this clinico-radiological gap using two different approaches. Lesion-symptom association: In two voxel-based lesion-symptom mapping studies, we aimed at strengthening lesion-symptom associations by identifying strategic lesion locations. Lesion mapping was performed in two large cohorts: a dataset of 2348 relapsing-remitting MS patients, and a population-based cohort of 1017 elderly subjects. T2-weighted lesion masks were anatomically aligned and a voxel-based statistical approach to relate lesion location to different clinical rating scales was implemented. In the MS lesion mapping, significant associations between white matter (WM) lesion location and several clinical scores were found in periventricular areas. Such lesion clusters appear to be associated with impairment of different physical and cognitive abilities, probably because they affect commissural and long projection fibers. In the SVD lesion mapping, the same WM fibers and the caudate nucleus were identified to significantly relate to the subjects’ cerebrovascular risk profiles, while no other locations were found to be associated with cognitive impairment. Atrophy-symptom association: With the construction of an anatomical physical phantom, we aimed at addressing reliability and robustness of atrophy-symptom associations through the provision of a “ground truth” for atrophy quantification. The built phantom prototype is composed of agar gels doped with MRI and computed tomography (CT) contrast agents, which realistically mimic T1 relaxation times of WM and grey matter (GM) and showing distinguishable attenuation coefficients using CT. Moreover, due to the design of anatomically simulated molds, both WM and GM are characterized by shapes comparable to the human counterpart. In a proof-of-principle study, the designed phantom was used to validate automatic brain tissue quantification by two popular software tools, where “ground truth” volumes were derived from high-resolution CT scans. In general, results from the same software yielded reliable and robust results across scans, while results across software were highly variable reaching volume differences of up to 8%

Molecular risk assessment of BIG 1-98 participants by expression profiling using RNA from archival tissue

The purpose of the work reported here is to test reliable molecular profiles using routinely processed formalin-fixed paraffin-embedded (FFPE) tissues from participants of the clinical trial BIG 1-98 with a median follow-up of 60 months

Simulating rewetting events in intermittent rivers and ephemeral streams: A global analysis of leached nutrients and organic matter

Climate change and human pressures are changing the global distribution and the ex‐ tent of intermittent rivers and ephemeral streams (IRES), which comprise half of the global river network area. IRES are characterized by periods of flow cessation, during which channel substrates accumulate and undergo physico‐chemical changes (precon‐ ditioning), and periods of flow resumption, when these substrates are rewetted and release pulses of dissolved nutrients and organic matter (OM). However, there are no estimates of the amounts and quality of leached substances, nor is there information on the underlying environmental constraints operating at the global scale. We experi‐ mentally simulated, under standard laboratory conditions, rewetting of leaves, river‐ bed sediments, and epilithic biofilms collected during the dry phase across 205 IRES from five major climate zones. We determined the amounts and qualitative character‐ istics of the leached nutrients and OM, and estimated their areal fluxes from riverbeds. In addition, we evaluated the variance in leachate characteristics in relation to selected environmental variables and substrate characteristics. We found that sediments, due to their large quantities within riverbeds, contribute most to the overall flux of dis‐ solved substances during rewetting events (56%–98%), and that flux rates distinctly differ among climate zones. Dissolved organic carbon, phenolics, and nitrate contrib‐ uted most to the areal fluxes. The largest amounts of leached substances were found in the continental climate zone, coinciding with the lowest potential bioavailability of the leached OM. The opposite pattern was found in the arid zone. Environmental vari‐ ables expected to be modified under climate change (i.e. potential evapotranspiration, aridity, dry period duration, land use) were correlated with the amount of leached sub‐ stances, with the strongest relationship found for sediments. These results show that the role of IRES should be accounted for in global biogeochemical cycles, especially because prevalence of IRES will increase due to increasing severity of drying event

Intent to Be Vaccinated against COVID-19 in Victoria, Australia

Background: High vaccine uptake requires strong public support, acceptance, and willingness. Methods: A longitudinal cohort study gathered survey data every four weeks between 1 October 2020 and 9 November 2021 in Victoria, Australia. Data were analysed for 686 participants aged 18 years and older. Results: Vaccine intention in our cohort increased from 60% in October 2020 to 99% in November 2021. Vaccine intention increased in all demographics, but longitudinal trends in vaccine intention differed by age, employment as a healthcare worker, presence of children in the household, and highest qualification attained. Acceptance of vaccine mandates increased from 50% in October 2020 to 71% in November 2021. Acceptance of vaccine mandates increased in all age groups except 18–25 years; acceptance also varied by gender and highest qualification attained. The main reasons for not intending to be vaccinated included safety concerns, including blood clots, and vaccine efficacy. Conclusion: COVID-19 vaccination campaigns should be informed by understanding of the sociodemographic drivers of vaccine acceptance to enable socially and culturally relevant guidance and ensure equitable vaccine coverage. Vaccination policies should be applied judiciously to avoid polarisation

An Overview of Cell-Based Assay Platforms for the Solute Carrier Family of Transporters

The solute carrier (SLC) superfamily represents the biggest family of transporters with important roles in health and disease. Despite being attractive and druggable targets, the majority of SLCs remains understudied. One major hurdle in research on SLCs is the lack of tools, such as cell-based assays to investigate their biological role and for drug discovery. Another challenge is the disperse and anecdotal information on assay strategies that are suitable for SLCs. This review provides a comprehensive overview of state-of-the-art cellular assay technologies for SLC research and discusses relevant SLC characteristics enabling the choice of an optimal assay technology. The Innovative Medicines Initiative consortium RESOLUTE intends to accelerate research on SLCs by providing the scientific community with high-quality reagents, assay technologies and data sets, and to ultimately unlock SLCs for drug discovery

Simulating rewetting events in intermittent rivers and ephemeral streams: A global analysis of leached nutrients and organic matter

Climate change and human pressures are changing the global distribution and the ex‐ tent of intermittent rivers and ephemeral streams (IRES), which comprise half of the global river network area. IRES are characterized by periods of flow cessation, during which channel substrates accumulate and undergo physico‐chemical changes (precon‐ ditioning), and periods of flow resumption, when these substrates are rewetted and release pulses of dissolved nutrients and organic matter (OM). However, there are no estimates of the amounts and quality of leached substances, nor is there information on the underlying environmental constraints operating at the global scale. We experi‐ mentally simulated, under standard laboratory conditions, rewetting of leaves, river‐ bed sediments, and epilithic biofilms collected during the dry phase across 205 IRES from five major climate zones. We determined the amounts and qualitative character‐ istics of the leached nutrients and OM, and estimated their areal fluxes from riverbeds. In addition, we evaluated the variance in leachate characteristics in relation to selected environmental variables and substrate characteristics. We found that sediments, due to their large quantities within riverbeds, contribute most to the overall flux of dis‐ solved substances during rewetting events (56%–98%), and that flux rates distinctly differ among climate zones. Dissolved organic carbon, phenolics, and nitrate contrib‐ uted most to the areal fluxes. The largest amounts of leached substances were found in the continental climate zone, coinciding with the lowest potential bioavailability of the leached OM. The opposite pattern was found in the arid zone. Environmental vari‐ ables expected to be modified under climate change (i.e. potential evapotranspiration, aridity, dry period duration, land use) were correlated with the amount of leached sub‐ stances, with the strongest relationship found for sediments. These results show that the role of IRES should be accounted for in global biogeochemical cycles, especially because prevalence of IRES will increase due to increasing severity of drying event