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Objective: Examine the impact of a primary care-embedded clinical pharmacist-led intervention (UCMyRx) on hemoglobin A1C and blood pressure control, relative to usual care, among patients with Type 2 diabetes (TD2) and Medicaid, in a large healthcare system. Methods: We used data extracted from the Electronic Health Records system and a Difference-In-Differences study design with a 2:1 propensity-matched comparison group to evaluate the impact of UCMyRx on HbA1c and systolic blood pressure among patients with TD2 and Medicaid, relative to usual care. Results: Having at least one UCMyRx clinical pharmacist visit was associated with a significant reduction in HbA1c; (-.27%, P-value= .03) but no impact on SBP. We do not find differential UCMyRx effects on HbA1c or SBP among the subpopulations with baseline HbA1C ≥9% or SBP ≥150 mmHg, respectively. In Charlson Comorbidity Index (CCI)-stratified analyses we found stronger UCMyRx effects on HbA1C (-.47%, P-value< .02) among the CCI tercile with the lowest comorbidity score (CC1 ≤ 5). Significant UCMyRx effects are only observed among the subpopulation of Medicaid beneficiaries without Medicare (-.35%, P-value= .02). Conclusions: The UCMyRx intervention is a useful strategy for improving HbA1c control among patients with TD2 and Medicaid.

Abstract: The combination of taxa and size classes of phytoplankton that coexist at any location affects the structure of the marine food web and the magnitude of carbon fluxes to the deep ocean. But what controls the patterns of this community structure across environmental gradients remains unclear. Here, we focus on the North East Pacific Transition Zone, a ~ 10° region of latitude straddling warm, nutrient‐poor subtropical and cold, nutrient‐rich subpolar gyres. Data from three cruises to the region revealed intricate patterns of phytoplankton community structure: poleward increases in the number of cell size classes; increasing biomass of picoeukaryotes and diatoms; decreases in diazotrophs and Prochlorococcus; and both increases and decreases in Synechococcus. These patterns can only be partially explained by existing theories. Using data, theory, and numerical simulations, we show that the patterns of plankton distributions across the transition zone are the result of gradients in nutrient supply rates, which control a range of complex biotic interactions. We examine how interactions such as size‐specific grazing, multiple trophic strategies, shared grazing between several phytoplankton size classes and heterotrophic bacteria, and competition for multiple resources can individually explain aspects of the observed community structure. However, it is the combination of all these interactions together that is needed to explain the bulk compositional patterns in phytoplankton across the North East Pacific Transition Zone. The synthesis of multiple mechanisms is essential for us to begin to understand the shaping of community structure over large environmental gradients.

Abstract Understanding the causes of the ~90 ppmv atmospheric CO2 swings between glacial and interglacial climates is an important open challenge in paleoclimate research. Although the regularity of the glacial-interglacial cycles hints at a single driving mechanism, Earth System models require many independent physical and biological processes to explain the full observed CO2 signal. Here we show that biologically sequestered carbon in the ocean can explain an atmospheric CO2 change of 75 ± 40 ppmv, based on a mass balance calculation using published carbon isotopic measurements. An analysis of the carbon isotopic signatures of different water masses indicates similar regenerated carbon inventories at the Last Glacial Maximum and during the Holocene, requiring that the change in carbon storage was dominated by disequilibrium. We attribute the inferred change in carbon disequilibrium to expansion of sea-ice or change in the overturning circulation.

ImportanceAmong patients with type 2 diabetes (T2D), Hispanic individuals are more likely than non-Hispanic White individuals to develop diabetes-related complications.ObjectiveTo examine the association of a pharmacist-led intervention (UCMyRx) with hemoglobin A1c (HbA1c) and systolic blood pressure (SBP) among Hispanic patients with T2D.Design, setting, and participantsThis quality improvement study used electronic health record data and a difference-in-differences study design to evaluate the association of UCMyRx exposure with changes in HbA1c concentration and SBP among Hispanic patients with T2D, relative to usual care, at University of California, Los Angeles primary care clinics between February and April of 2023. The study population included patients with an International Classification of Diseases, Ninth Revision/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of T2D, self-reporting Hispanic ethnicity, age 18 years or older, with 1 or more visits with a UCMyRx pharmacist (treatment) or 2 or more visits, 2 or more years apart, during the study window (comparison). Additionally, patients had to have the following observations during the study window (March 2, 2013-December 31, 2018): (1) a HbA1c 8% or higher, anywhere between 365 days before and 14 days after the index date (date of the first UCMyRx visit or a randomly generated index date) and a follow-up HbA1c measure within 120 to 365 days after the index date (n = 396) and/or (2) a SBP 140 mm Hg or higher between 365 days before and 14 days after the index date, and a follow-up SBP measure within 120 to 450 days after the index date (n = 795).ExposurePharmacists review laboratory results/vital signs, perform medication reconciliation, and develop personally tailored interventions to address adherence barriers and increase guideline-concordant care.Main outcomes and measuresPre- to post-index date changes in HbA1c and SBP.ResultsOf the 931 unique patients with T2D analyzed, the mean (SD) age was 64 (14.1) years, and 552 (59.3%) were female. In adjusted analyses, having 1 or more UCMyRx visits was associated with a reduction in HbA1c concentration (β = -0.46%; 95% CI, -0.84% to -0.07%) but no change in SBP (β = -1.71 mm Hg; 95% CI, -4.00 to 0.58 mm Hg).Conclusions and relevanceIn this quality improvement study of UCMyRx among Hispanic patients with T2D, a negative association was observed between UCMyRx exposure and HbA1c concentration but not SBP. Pharmacist-led intervention may be a strategy for improving outcomes among Hispanic patients with T2D.

Abstract Logjams create an upstream backwater of deepened, slower water, locally reducing bed shear stress. We compared hydraulic impact of logjam series across 37 geomorphically diverse reaches of mountain streams observed over 11 years in the US Southern Rockies. To enable reach‐scale comparison of logjam structure and spacing, we identified the modeled best‐fit effective resistance coefficient minimizing difference between outflow exiting a 1D channel with logjams present, and the same model channel with elevated channel resistance. Effective resistance increased with ratio of jam upstream depth to depth without a logjam, ratio of backwater length to average spacing, and decreased for randomly distributed jams due to close spacing, which reduced backwater impact. An analytic approximation and boundaries for region of relative spacing with steepest increase in effective resistance are provided. Our results can assist in targeting interventions to areas where hydraulic impact is greatest, providing value for money in nature‐based solution design.

ObjectiveWe aimed to develop a distributed, immutable, and highly available cross-cloud blockchain system to facilitate federated data analysis activities among multiple institutions.Materials and methodsWe preprocessed 9166 COVID-19 Structured Query Language (SQL) code, summary statistics, and user activity logs, from the GitHub repository of the Reliable Response Data Discovery for COVID-19 (R2D2) Consortium. The repository collected local summary statistics from participating institutions and aggregated the global result to a COVID-19-related clinical query, previously posted by clinicians on a website. We developed both on-chain and off-chain components to store/query these activity logs and their associated queries/results on a blockchain for immutability, transparency, and high availability of research communication. We measured run-time efficiency of contract deployment, network transactions, and confirmed the accuracy of recorded logs compared to a centralized baseline solution.ResultsThe smart contract deployment took 4.5 s on an average. The time to record an activity log on blockchain was slightly over 2 s, versus 5-9 s for baseline. For querying, each query took on an average less than 0.4 s on blockchain, versus around 2.1 s for baseline.DiscussionThe low deployment, recording, and querying times confirm the feasibility of our cross-cloud, blockchain-based federated data analysis system. We have yet to evaluate the system on a larger network with multiple nodes per cloud, to consider how to accommodate a surge in activities, and to investigate methods to lower querying time as the blockchain grows.ConclusionBlockchain technology can be used to support federated data analysis among multiple institutions.

The starting point for this study is the simulation study of Metcalfe et al. (2018) which suggested that retention times of the order of 10 h are required for natural flood management storage features to have a maximum effect on large flow peaks. A analysis of the celerity characteristics for some log jams at Tebay Gill, Cumbria (upland UK), suggests that the impacts of storage in slowing the celerities is only of the order of minutes. An analysis of storage-discharge dynamics based on observations at 4 jams reveals that the dynamics of storages can be represented with time constants of between 3 and 213 min, still well short of those required to maximise the effects for larger flood flows. That is not to say that there will not be reduction in flood peaks for smaller events, only that for large events the effects will be limited. A spreadsheet tool for retention times has been developed to help in the design of new schemes that is freely available.

Abstract Photosynthesis fuels primary production at the base of marine food webs. Yet, in many surface ocean ecosystems, diel-driven primary production is tightly coupled to daily loss. This tight coupling raises the question: which top-down drivers predominate in maintaining persistently stable picocyanobacterial populations over longer time scales? Motivated by high-frequency surface water measurements taken in the North Pacific Subtropical Gyre (NPSG), we developed multitrophic models to investigate bottom-up and top-down mechanisms underlying the balanced control of Prochlorococcus populations. We find that incorporating photosynthetic growth with viral- and predator-induced mortality is sufficient to recapitulate daily oscillations of Prochlorococcus abundances with baseline community abundances. In doing so, we infer that grazers in this environment function as the predominant top-down factor despite high standing viral particle densities. The model-data fits also reveal the ecological relevance of light-dependent viral traits and non-canonical factors to cellular loss. Finally, we leverage sensitivity analyses to demonstrate how variation in life history traits across distinct oceanic contexts, including variation in viral adsorption and grazer clearance rates, can transform the quantitative and even qualitative importance of top-down controls in shaping Prochlorococcus population dynamics.

Abstract Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, and can be observed during the prodromal phase of Parkinson’s disease (PD). However, the mechanism underlying these pathophysiological changes remains to be elucidated. Mutations in vacuolar protein sorting 35 (VPS35) and leucine-rich repeat kinase 2 (LRRK2) both lead to autosomal dominant PD, and VPS35 and LRRK2 may physically interact to govern the trafficking of synaptic cargos within the endo-lysosomal network in a kinase-dependent manner. To better understand the functional role of VPS35 and LRRK2 on dopamine physiology, we examined Vps35 haploinsufficient (Haplo) and Vps35 p.D620N knock-in (VKI) mice and how their behavior, dopamine kinetics and biochemistry are influenced by LRRK2 kinase inhibitors. We found Vps35 p.D620N significantly elevates LRRK2-mediated phosphorylation of Rab10, Rab12 and Rab29. In contrast, Vps35 haploinsufficiency reduces phosphorylation of Rab12. While striatal dopamine transporter (DAT) expression and function is similarly impaired in both VKI and Haplo mice, that physiology is normalized in VKI by treatment with the LRRK2 kinase inhibitor, MLi-2. As a corollary, VKI animals show a significant increase in amphetamine induced hyperlocomotion, compared to Haplo mice, that is also abolished by MLi-2. Taken together, these data show Vps35 p.D620N confers a gain-of-function with respect to LRRK2 kinase activity, and that VPS35 and LRRK2 functionally interact to regulate DAT function and striatal dopamine transmission.

We investigated the host status of harvest-ready green Persian lime, Citrus x latifolia Tan. (Rutaceae), to Oriental fruit fly (Bactrocera dorsalis [Hendel]) and Mediterranean fruit fly (Ceratitis capitata [Wiedemann]) (Diptera: Tephritidae) using laboratory and field studies. In forced-infestation small cage exposures (using 25 × 25 × 25 cm screened cages with 50 gravid females) and large olfactometer cage tests (using 2.9 × 2.9 × 2.5 m walk-in screened cages with 100 gravid females), punctured limes were infested by Oriental fruit fly and Mediterranean fruit fly at low rates compared to papaya controls, whereas undamaged intact fruit was not infested. Field collection and packing of 45,958 commercial export-grade fruit and subsequent incubation to look for natural infestation resulted in no emergence of fruit flies. Forced infestation studies in the field using sleeve cages to enclose fruit with a high density of fruit flies (50 gravid females) on the tree also showed no infestation. Commercial export-grade Persian lime fruit should be considered a conditional nonhost for Oriental fruit fly and Mediterranean fruit fly.

Remote sensing observations from satellites and global biogeochemical models have combined to revolutionize the study of ocean biogeochemical cycling, but comparing the two data streams to each other and across time remains challenging due to the strong spatial-temporal structuring of the ocean. Here, we show that the Wasserstein distance provides a powerful metric for harnessing these structured datasets for better marine ecosystem and climate predictions. The Wasserstein distance complements commonly used point-wise difference methods such as the root-mean-squared error, by quantifying differences in terms of spatial displacement in addition to magnitude. As a test case, we consider chlorophyll (a key indicator of phytoplankton biomass) in the northeast Pacific Ocean, obtained from model simulations, in situ measurements, and satellite observations. We focus on two main applications: (i) comparing model predictions with satellite observations, and (ii) temporal evolution of chlorophyll both seasonally and over longer time frames. The Wasserstein distance successfully isolates temporal and depth variability and quantifies shifts in biogeochemical province boundaries. It also exposes relevant temporal trends in satellite chlorophyll consistent with climate change predictions. Our study shows that optimal transport vectors underlying the Wasserstein distance provide a novel visualization tool for testing models and better understanding temporal dynamics in the ocean.

Abstract Follett et al. (2020, https://doi.org/10.1029/2020gl089346) demonstrated that a large wood jam can be modeled as a porous obstruction with momentum loss proportional to the number, size, and packing density of the logs and jam length. Poppema and Wüthrich (2024, https://doi.org/10.1029/2023gl106348) incorporated uniform flow Froude number, broadening the scope of our work. Here, we demonstrate that Froude number can be directly introduced to equations in the main body of Follett et al. (2020, https://doi.org/10.1029/2020gl089346), without requiring uniform flow. Based on this, we show that a managed increase in upstream depth is possible for conditions below a critical discharge, in which equilibrium upstream depth over uniformly distributed jams can be adjusted with inter‐jam spacing. This design could retain water in low flow conditions, allowing jams to act independently above critical discharge. Finally, we suggest that log orientation can be included in our model by varying both drag coefficient and frontal area perpendicular to the flow.

Aquatic ecologists are integrating mixotrophic plankton – here defined as microorganisms with photosynthetic and phagotrophic capacity – into their understanding of marine food webs and biogeochemical cycles. Understanding mixotroph temporal and spatial distributions, as well as the environmental conditions under which they flourish, is imperative to understanding their impact on trophic transfer and biogeochemical cycling. Mixotrophs are hypothesized to outcompete strict photoautotrophs and heterotrophs when either light or nutrients are limiting, but testing this hypothesis has been hindered by the challenge of identifying and quantifying mixotrophs in the field. Using field observations from a multi-decadal northern North Atlantic dataset, we calculated the proportion of organisms that are considered mixotrophs within individual microplankton samples. We also calculated a “trophic index” that represents the relative proportions of photoautotrophs (phytoplankton), mixotrophs, and heterotrophs (microzooplankton) in each sample. We found that the proportion of mixotrophs was positively correlated with temperature, and negatively with either light or inorganic nutrient concentration. This proportion was highest during summertime thermal stratification and nutrient limitation, and lowest during the North Atlantic spring bloom period. Between 1958 and 2015, changes in the proportion of mixotrophs coincided with changes in the Atlantic Multi-decadal Oscillation (AMO), was highest when the AMO was positive, and showed a significant uninterrupted increase in offshore regions from 1992-2015. This study provides an empirical foundation for future experimental, time series, and modeling studies of aquatic mixotrophs.

Abstract Families are under increasing stress from the rising cost of raising children, especially single-parent households and those where both parents work. Lack of paid family leave and dependable child [...]

Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development.

Global biogeochemical ocean models are invaluable tools to examine how physical, chemical, and biological processes interact in the ocean. Satellite-derived ocean color properties, on the other hand, provide observations of the surface ocean, with unprecedented coverage and resolution. Advances in our understanding of marine ecosystems and biogeochemistry are strengthened by the combined use of these resources, together with sparse in situ data. Recent modeling advances allow the simulation of the spectral properties of phytoplankton and remote sensing reflectances, bringing model outputs closer to the kind of data that ocean color satellites can provide. However, comparisons between model outputs and analogous satellite products (e.g., chlorophyll a) remain problematic. Most evaluations are based on point-by-point comparisons in space and time, where spuriously large errors can occur from small spatial and temporal mismatches, whereas global statistics provide no information on how well a model resolves processes at regional scales. Here, we employ a unique suite of methodologies, the Probability Density Functions to Evaluate Models (PDFEM), which generate a robust comparison of these resources. The probability density functions of physical and biological properties of Longhurst's provinces are compared to evaluate how well a model resolves related processes. Differences in the distributions of chlorophyll a concentration (mg m−3) provide information on matches and mismatches between models and observations. In particular, mismatches help isolate regional sources of discrepancy, which can lead to improving both simulations and satellite algorithms. Furthermore, the use of radiative transfer in the model to mimic remotely sensed products facilitates model–observation comparisons of optical properties of the ocean.

BackgroundA common complaint in older adults is trouble with their memory, especially for new information. Current knowledge about normal aging and changes in memory identify a divide between memory tasks that are unaffected by aging and those that are. Among the unaffected are recognition tasks. These memory tasks rely on accessing well-known information, often include environmental support, and tend to be automatic. Negative age effects on memory are often observed at both encoding and during recall. Older adults often have difficulty with recall tasks, particularly those that require effortful self-initiated processing, episodic memory, and retention of information about contextual cues. Research in memory for music in healthy aging suggests a skill-invariance hypothesis: that age effects dominate when general-purpose cognitive mechanisms are needed to perform the musical task at hand, while experience effects dominate when music-specific knowledge is needed to perform the task [1].AimsThe goals of this pair of studies were to investigate the effects of age and familiarity on musical memory in the context of real pieces of music, and to compare a live concert experimental setting with a lab-based experimental setting.MethodParticipants' task was to click a button (or press the spacebar) when they heard the target theme in three pieces of music. One was Mozart's Eine Kleine Nachtmusik and the others were original pieces commissioned for this study, one tonal and one atonal. Participants heard the relevant theme three times before listening to a piece of music. The music was performed by the Newfoundland Symphony Orchestra; participants either attended the concert, or watched a recording of the concert in the lab. Participants also completed two short cognitive tests and filled out a questionnaire collecting demographic information and a hearing abilities self-assessment.ResultsWe find a significant effect of familiarity and setting but not of age or musical training on recognition performance as measured by d'. More specifically, performance is best for the familiar, tonal piece, moderate for the unfamiliar tonal piece and worst for the unfamiliar atonal piece. Performance was better in the live setting than the lab setting.ConclusionsThe absence of an age effect provides encouraging evidence that music's diverse cues may encourage cognitive scaffolding, in turn improving encoding and subsequent recognition. Better performance in an ecological versus lab setting supports the expansion of ecological studies in the field.

Managing annual row crops on marginally productive croplands can be environmentally unsustainable and result in variable economic returns. Incorporating perennial bioenergy feedstocks into marginally productive cropland can engender ecosystem services and enhance climate resiliency while also diversifying farm incomes. We use one of the oldest bioenergy-specific field experiments in North America to evaluate economically and environmentally sustainable management practices for growing perennial grasses on marginal cropland. This long-term field trial called 9804 was established in 1998 in eastern Nebraska and compared the productivity and sustainability of corn (Zea mays L.)—both corn grain and corn stover—and switchgrass (Panicum virgatum L.) bioenergy systems under different harvest strategies and nitrogen (N) fertilizer rates. This experiment demonstrated that switchgrass, compared to corn, is a reliable and sustainable bioenergy feedstock. This experiment has been a catalyst for other bioenergy projects which have also expanded our understanding of growing and managing bioenergy feedstocks on marginal cropland. We (1) synthesize research from this long-term experiment and (2) provide perspective concerning both the knowledge gained from this experiment and knowledge gaps and how to fill them as well as the role switchgrass will play in the future of bioenergy.

Background: The risks of osteoporosis and breast cancer are increasing in elderly women. Bisphosphonates and denosumab are recommended for treatment of osteoporosis. They have different and overlapping pharmacodynamics and previous studies have shown conflicting results regarding their risk association with breast cancer. We intend to further look into this issue through a comparative study. Methods: Electronic health records of 91,626 women older than 50 years with no previous history of malignancy and no nonbreast cancer during follow-up were retrieved from southern California and retrospectively analyzed using univariate, bivariate, and log-rank tests. Medication use, breast cancer risk, and associated demographic and clinical history were assessed. Results: Over an average of 3.6 years follow-up, the breast cancer relative risks (RRs) counted after 365 days of latency are 1.12 (95% confidence interval [CI]: 0.64-1.97) for denosumab ever users and 0.37 (95% CI: 0.21-0.66) for bisphosphonates ever users, when covariates are comparable. The significant difference is supported by the Log-rank test (p = 0.0004). Excluding statins coprescribers, the breast cancer RR is 1.31 (0.71, 2.43) in denosumab group and 0.26 (0.11, 0.62) in bisphosphonates group. There is a reduced RR in statins ever users (0.47, 95% CI: 0.38-0.58), and the breast cancer risk difference is not significant between concomitant denosumab/statins and bisphosphonates/statins ever users with RR 0.65 (0.16, 2.58) versus 0.55 (0.26, 1.16), p = 0.692. Conclusions: Our data support an association of lower breast cancer risk with bisphosphonates use in elderly women. We did not observe a lower breast cancer risk in denosumab group; however, our data revealed a potential lower breast cancer risk in denosumab users with concurrent statins use and this requires further study.

ObjectiveTo utilize, in an individual and institutional privacy-preserving manner, electronic health record (EHR) data from 202 hospitals by analyzing answers to COVID-19-related questions and posting these answers online.Materials and methodsWe developed a distributed, federated network of 12 health systems that harmonized their EHRs and submitted aggregate answers to consortia questions posted at https://www.covid19questions.org. Our consortium developed processes and implemented distributed algorithms to produce answers to a variety of questions. We were able to generate counts, descriptive statistics, and build a multivariate, iterative regression model without centralizing individual-level data.ResultsOur public website contains answers to various clinical questions, a web form for users to ask questions in natural language, and a list of items that are currently pending responses. The results show, for example, that patients who were taking angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, within the year before admission, had lower unadjusted in-hospital mortality rates. We also showed that, when adjusted for, age, sex, and ethnicity were not significantly associated with mortality. We demonstrated that it is possible to answer questions about COVID-19 using EHR data from systems that have different policies and must follow various regulations, without moving data out of their health systems.Discussion and conclusionsWe present an alternative or a complement to centralized COVID-19 registries of EHR data. We can use multivariate distributed logistic regression on observations recorded in the process of care to generate results without transferring individual-level data outside the health systems.

ObjectiveThe Consortium for Clinical Characterization of COVID-19 by EHR (4CE) is an international collaboration addressing coronavirus disease 2019 (COVID-19) with federated analyses of electronic health record (EHR) data. We sought to develop and validate a computable phenotype for COVID-19 severity.Materials and methodsTwelve 4CE sites participated. First, we developed an EHR-based severity phenotype consisting of 6 code classes, and we validated it on patient hospitalization data from the 12 4CE clinical sites against the outcomes of intensive care unit (ICU) admission and/or death. We also piloted an alternative machine learning approach and compared selected predictors of severity with the 4CE phenotype at 1 site.ResultsThe full 4CE severity phenotype had pooled sensitivity of 0.73 and specificity 0.83 for the combined outcome of ICU admission and/or death. The sensitivity of individual code categories for acuity had high variability-up to 0.65 across sites. At one pilot site, the expert-derived phenotype had mean area under the curve of 0.903 (95% confidence interval, 0.886-0.921), compared with an area under the curve of 0.956 (95% confidence interval, 0.952-0.959) for the machine learning approach. Billing codes were poor proxies of ICU admission, with as low as 49% precision and recall compared with chart review.DiscussionWe developed a severity phenotype using 6 code classes that proved resilient to coding variability across international institutions. In contrast, machine learning approaches may overfit hospital-specific orders. Manual chart review revealed discrepancies even in the gold-standard outcomes, possibly owing to heterogeneous pandemic conditions.ConclusionsWe developed an EHR-based severity phenotype for COVID-19 in hospitalized patients and validated it at 12 international sites.

ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.