Increasing hospitalisation of patients with herpes zoster ophthalmicus-an interdisciplinary retrospective analysis.

BACKGROUND: The occurrence of herpes zoster is rising globally. Future trends will be influenced by changes in population demographics and the growing number of patients at risk. Overall this poses a challenge for healthcare systems. METHODS: In our interdisciplinary, single-centre retrospective analysis, we aimed to assess the burden of the disease within the Department of Dermatology and the Eye Centre from the Medical Centre, University of Freiburg from 2009-2022. We obtained data from 3034 cases coded using the ICD-10 B02.x. Patients were characterised by sex, age, year of treatment, and type of treatment (inpatient vs. outpatient). RESULTS: Overall we observed a 200% increase in the number of herpes zoster patients over the 13-year period. Upon closer analysis, this was mainly due to a rise in inpatient treatment for herpes zoster ophthalmicus. CONCLUSIONS: If the incidence of herpes zoster ophthalmicus continues to increase at the current rate the number of hospitalisations of zoster ophthalmicus would double by 2040, assuming guideline-appropriate treatment. Overall, the results show a growing need for inpatient ophthalmological care.

Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease.

Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci (ift80 and ift172) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Xenopus tropicalis Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining-based in silico screen found ttc30a to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. Ttc30a/b transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type-specific manner. These findings have implications for potential therapeutic strategies.

Balancing multiple stakeholder objectives for floodplain reconnection and wetland restoration.

Floodplain reconnection and wetland restoration projects are increasingly implemented to enhance flood resiliency, and these nature-based solutions can also achieve co-benefits of nutrient storage and improved habitats. Considering the multiple and sometimes incompatible objectives of stakeholders for uses of riverside lands, a decision-support tool linked to a hydraulic model would enable planners to simulate floodplain restoration scenarios while also quantifying and assessing the trade-offs between the stakeholder objectives to arrive at optimal restoration designs. We illustrate a simple ranking approach using an n-dimensional objective function to represent key stakeholders engaged in restoration. We applied our approach in a watershed in central Vermont (USA) that has been identified by regional and state-level stakeholders as an important location to mitigate flooding damages but also to improve water quality - all within a context of increasing development pressures on riparian lands and limited financial resources to accomplish restoration. Eleven different floodplain reconnection and wetland restoration modifications were combined in six scenarios and simulated with 2D Hydrologic Engineering Center's River Analysis System (2D HEC-RAS), along with a baseline (no-action) scenario. Only modest attenuation of peak flows for 2-, 25-, 50- and 100-year design storms was achieved by the floodplain restoration scenarios due to the steep setting, and flashy nature of the watershed. Yet, several scenarios of floodplain reconnection projects more than met the necessary annual phosphorus load reductions targeted under a Total Maximum Daily Load implementation plan. Our approach provided planners with a ranking of restoration scenarios that best met multiple stakeholder objectives and allowed effectiveness of alternate design scenarios to be quantified, justified, and visualized to promote consensus decision-making.

Incidence and severity of immune-related hepatitis after dual checkpoint therapy is linked to younger age independent of herpes virus immunity.

BACKGROUND AND AIMS: Dual immune checkpoint blockade (ICB) therapy can result in immune-related-adverse events (irAE) such as ICB-hepatitis. An expansion of effector-memory (TEM) CD4 T cells associated with antiviral immunity against herpesviridae was implicated in ICB-hepatitis. Notably, these memory subsets are frequently associated with age. Here, we sought to understand baseline patient, immune and viral biomarkers associated with the development of ICB-hepatitis to identify currently lacking baseline predictors and test if an expansion of TEM or positive serology against herpesviridae can predict ICB-hepatitis. METHODS: A discovery (n = 39) and validation cohort (n = 67) of patients with advanced melanoma undergoing anti-PD-1&anti-CTLA4 combination therapy (total n = 106) were analyzed for baseline clinical characteristics, occurrence of irAE and oncological outcomes alongside serological status for CMV, EBV and HSV. Immune populations were profiled by high-parametric flow cytometry (n = 29). RESULTS: ICB-hepatitis occurred in 59% of patients within 100 days; 35.9% developed severe (CTCAE 3-4) hepatitis. Incidence of ICB-hepatitis was higher in the younger (< 55y: 85.7%) compared to older (> = 55y: 27.8%) age group (p = 0.0003), occured earlier in younger patients (p < 0.0001). The association of younger age with ICB-Hepatitis was also observed in the validation cohort (p = 0.0486). Incidence of ICB-hepatitis was also associated with additional non-hepatic irAE (p = 0.018), but neither positive IgG serostatus for CMV, EBV or HSV nor TEM subsets despite an association of T cell subsets with age. CONCLUSION: Younger age more accurately predicts ICB-hepatitis after anti-PD-1&anti-CTLA4 checkpoint therapy at baseline compared to herpes virus serology or TEM subsets. Younger patients should be carefully monitored for the development of ICB-hepatitis.

Evaluation of the integrated riparian ecosystem response to future flow regimes on semiarid rivers in Colorado, USA.

Riparian ecosystems are shaped by interactions among streamflow, plants, and physical processes. Sustaining functioning riparian ecosystems in the face of climate change, growing human demands for water, and increasing water scarcity requires improved understanding of the sensitivity of riparian ecosystems to shifts in flow regimes and associated adaptive management strategies. We applied projected future flow regimes to an ecogeomorphic model of riparian and channel response to evaluate these interactions. We tested the hypothesis that components of the riparian ecosystem vary in their vulnerabilities to shifts in flow attributes and that changes in the representation of functional groups of plants result from interactions between ecological and physical drivers. Using the Yampa and Green Rivers in northwestern Colorado as our test system, we investigated ecogeomorphic response to (1) synthetic flow regimes representing continuous changes from baseline flows; and (2) future flow scenarios that incorporate changing climate, demand, and water-resource projects. For this region, we showed that riparian plant presence, composition, and cover are highly sensitive to the high flows that occur early in the growing season, but that shifts to low flows are also important, especially for determining the functional diversity of a riparian community. Future flow regimes are likely to induce vegetation encroachment on lower channel surfaces and to increase plant cover, which will be dominated by fewer functional groups. In particular, we predict a decrease in some mesic plants (shrubs and tall herbs) and an increase in presence and cover of late-seral, xeric shrubs, most of which are non-native species. Managing for high flows that occur early in the growing season must complement maintenance of adequate baseflows to maintain ecosystem functioning in the face of hydrologic alterations induced by climate change and human water demand.

Improving flood hazard datasets using a low-complexity, probabilistic floodplain mapping approach.

As runoff patterns shift with a changing climate, it is critical to effectively communicate current and future flood risks, yet existing flood hazard maps are insufficient. Modifying, extending, or updating flood inundation extents is difficult, especially over large scales, because traditional floodplain mapping approaches are data and resource intensive. Low-complexity floodplain mapping techniques are promising alternatives, but their simplistic representation of process falls short of capturing inundation patterns in all situations or settings. To address these needs and deficiencies, we formalize and extend the functionality of the Height Above Nearest Drainage (i.e., HAND) floodplain mapping approach into the probHAND model by incorporating an uncertainty analysis. With publicly available datasets, the probHAND model can produce probabilistic floodplain maps for large areas relatively rapidly. We describe the modeling approach and then provide an example application in the Lake Champlain Basin, Vermont, USA. Uncertainties translate to on-the-ground changes to inundated areas, or floodplain widths, in the study area by an average of 40%. We found that the spatial extent of probable inundation captured the distribution of observed and modeled flood extents well, suggesting that low-complexity models may be sufficient for representing inundation extents in support of flood risk and conservation mapping applications, especially when uncertainties in parameter inputs and process simplifications are accounted for. To improve the accuracy of flood hazard datasets, we recommend investing limited resources in accurate topographic datasets and improved flood frequency analyses. Such investments will have the greatest impact on decreasing model output variability, therefore increasing the certainty of flood inundation extents.