11 research outputs found
Predicting the immediate impact of national lockdown on neovascular age-related macular degeneration and associated visual morbidity: an INSIGHT Health Data Research Hub for Eye Health report
OBJECTIVE: Predicting the impact of neovascular age-related macular degeneration (nAMD) service disruption on visual outcomes following national lockdown in the UK to contain SARS-CoV-2. METHODS AND ANALYSIS: This retrospective cohort study includes deidentified data from 2229 UK patients from the INSIGHT Health Data Research digital hub. We forecasted the number of treatment-naïve nAMD patients requiring anti-vascular endothelial growth factor (anti-VEGF) initiation during UK lockdown (16 March 2020 through 31 July 2020) at Moorfields Eye Hospital (MEH) and University Hospitals Birmingham (UHB). Best-measured visual acuity (VA) changes without anti-VEGF therapy were predicted using post hoc analysis of Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD trial sham-control arm data (n=238). RESULTS: At our centres, 376 patients were predicted to require anti-VEGF initiation during lockdown (MEH: 325; UHB: 51). Without treatment, mean VA was projected to decline after 12 months. The proportion of eyes in the MEH cohort predicted to maintain the key positive visual outcome of ≥70 ETDRS letters (Snellen equivalent 6/12) fell from 25.5% at baseline to 5.8% at 12 months (UHB: 9.8%-7.8%). Similarly, eyes with VA <25 ETDRS letters (6/96) were predicted to increase from 4.3% to 14.2% at MEH (UHB: 5.9%-7.8%) after 12 months without treatment. CONCLUSIONS: Here, we demonstrate how combining data from a recently founded national digital health data repository with historical industry-funded clinical trial data can enhance predictive modelling in nAMD. The demonstrated detrimental effects of prolonged treatment delay should incentivise healthcare providers to support nAMD patients accessing care in safe environments. TRIAL REGISTRATION NUMBER: NCT00056836
Human and mouse essentiality screens as a resource for disease gene discovery
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery
Predicting the immediate impact of national lockdown on neovascular age-related macular degeneration and associated visual morbidity: an INSIGHT Health Data Research Hub for Eye Health report.
OBJECTIVE
Predicting the impact of neovascular age-related macular degeneration (nAMD) service disruption on visual outcomes following national lockdown in the UK to contain SARS-CoV-2.
METHODS AND ANALYSIS
This retrospective cohort study includes deidentified data from 2229 UK patients from the INSIGHT Health Data Research digital hub. We forecasted the number of treatment-naïve nAMD patients requiring anti-vascular endothelial growth factor (anti-VEGF) initiation during UK lockdown (16 March 2020 through 31 July 2020) at Moorfields Eye Hospital (MEH) and University Hospitals Birmingham (UHB). Best-measured visual acuity (VA) changes without anti-VEGF therapy were predicted using post hoc analysis of Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD trial sham-control arm data (n=238).
RESULTS
At our centres, 376 patients were predicted to require anti-VEGF initiation during lockdown (MEH: 325; UHB: 51). Without treatment, mean VA was projected to decline after 12 months. The proportion of eyes in the MEH cohort predicted to maintain the key positive visual outcome of ≥70 ETDRS letters (Snellen equivalent 6/12) fell from 25.5% at baseline to 5.8% at 12 months (UHB: 9.8%-7.8%). Similarly, eyes with VA <25 ETDRS letters (6/96) were predicted to increase from 4.3% to 14.2% at MEH (UHB: 5.9%-7.8%) after 12 months without treatment.
CONCLUSIONS
Here, we demonstrate how combining data from a recently founded national digital health data repository with historical industry-funded clinical trial data can enhance predictive modelling in nAMD. The demonstrated detrimental effects of prolonged treatment delay should incentivise healthcare providers to support nAMD patients accessing care in safe environments.
TRIAL REGISTRATION NUMBER
NCT00056836
Folic Acid Supplementation Is Suboptimal in a National Cohort of Older Veterans Receiving Low Dose Oral Methotrexate
Co-prescription of folic acid in patients receiving low dose oral methotrexate is recommended because it reduces adverse events and prolongs the use of methotrexate (MTX). However, little is known about how often new users of methotrexate are co-prescribed folic acid, and what factors are associated with its use. We aimed to determine the prevalence, predictors of, and persistence of folic acid use in a population-based cohort of MTX users with rheumatic diseases.Using a national, administrative database of patients seen through the Veterans Health Administration (VHA) that included pharmacy and laboratory data, we performed an observational cohort study of veterans over 65 years old who were new users of MTX. We used log-binomial regression to identify independent predictors of folic acid use and Kaplan Meyer survival analysis to examine persistence of folic acid over time.We studied 2467 incident users of MTX. 27% of patients were not prescribed folic acid through the VHA pharmacy within 30 days of MTX initiation. Patients who did not see a rheumatologist were 23% less likely to receive folic acid compared to patients who did have a rheumatologist visit during the baseline period (RR (95% CI) 0.77 (0.72, 0.82). These results remained unchanged even after adjusting for demographic, clinical, and other factors (adjusted RR (95% CI) 0.78 (0.74, 0.85)). After 20 months, only 50% of patients continued to receive folic acid.In a nationwide VHA cohort of new users of oral MTX, many patients did not receive folic acid or discontinued it over time. Rheumatologists were more likely to prescribe folic acid than other providers. These data highlight the need to improve patient safety for users of methotrexate by standardizing workflows for folic acid supplementation
Colorectal cancer in patients seen at the teaching hospitals of Guadeloupe and Martinique: discrepancies, similarities in clinicopathological features, and p53 status
Selenorhodamine Photosensitizers for Photodynamic Therapy of P-Glycoprotein-Expressing Cancer Cells
Nkx6.1 Controls a Gene Regulatory Network Required for Establishing and Maintaining Pancreatic Beta Cell Identity
Science goals and mission architecture of the Europa Lander mission concept
© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Hand, K., Phillips, C., Murray, A., Garvin, J., Maize, E., Gibbs, R., Reeves, G., San Martin, A., Tan-Wang, G., Krajewski, J., Hurst, K., Crum, R., Kennedy, B., McElrath, T., Gallon, J., Sabahi, D., Thurman, S., Goldstein, B., Estabrook, P., Lee, S. W., Dooley, J. A., Brinckerhoff, W. B., Edgett, K. S., German, C. R., Hoehler, T. M., Hörst, S. M., Lunine, J. I., Paranicas, C., Nealson, K., Smith, D. E., Templeton, A. S., Russell, M. J., Schmidt, B., Christner, B., Ehlmann, B., Hayes, A., Rhoden, A., Willis, P., Yingst, R. A., Craft, K., Cameron, M. E., Nordheim, T., Pitesky, J., Scully, J., Hofgartner, J., Sell, S. W., Barltrop, K. J., Izraelevitz, J., Brandon, E. J., Seong, J., Jones, J.-P., Pasalic, J., Billings, K. J., Ruiz, J. P., Bugga, R. V., Graham, D., Arenas, L. A., Takeyama, D., Drummond, M., Aghazarian, H., Andersen, A. J., Andersen, K. B., Anderson, E. W., Babuscia, A., Backes, P. G., Bailey, E. S., Balentine, D., Ballard, C. G., Berisford, D. F., Bhandari, P., Blackwood, K., Bolotin, G. S., Bovre, E. A., Bowkett, J., Boykins, K. T., Bramble, M. S., Brice, T. M., Briggs, P., Brinkman, A. P., Brooks, S. M., Buffington, B. B., Burns, B., Cable, M. L., Campagnola, S., Cangahuala, L. A., Carr, G. A., Casani, J. R., Chahat, N. E., Chamberlain-Simon, B. K., Cheng, Y., Chien, S. A., Cook, B. T., Cooper, M., DiNicola, M., Clement, B., Dean, Z., Cullimore, E. A., Curtis, A. G., Croix, J-P. de la, Pasquale, P. Di, Dodd, E. M., Dubord, L. A., Edlund, J. A., Ellyin, R., Emanuel, B., Foster, J. T., Ganino, A. J., Garner, G. J., Gibson, M. T., Gildner, M., Glazebrook, K. J., Greco, M. E., Green, W. M., Hatch, S. J., Hetzel, M. M., Hoey, W. A., Hofmann, A. E., Ionasescu, R., Jain, A., Jasper, J. D., Johannesen, J. R., Johnson, G. K., Jun, I., Katake, A. B., Kim-Castet, S. Y., Kim, D. I., Kim, W., Klonicki, E. F., Kobeissi, B., Kobie, B. D., Kochocki, J., Kokorowski, M., Kosberg, J. A., Kriechbaum, K., Kulkarni, T. P., Lam, R. L., Landau, D. F., Lattimore, M. A., Laubach, S. L., Lawler, C. R., Lim, G., Lin, J. Y., Litwin, T. E., Lo, M. W., Logan, C. A., Maghasoudi, E., Mandrake, L., Marchetti, Y., Marteau, E., Maxwell, K. A., Namee, J. B. Mc, Mcintyre, O., Meacham, M., Melko, J. P., Mueller, J., Muliere, D. A., Mysore, A., Nash, J., Ono, H., Parker, J. M., Perkins, R. C., Petropoulos, A. E., Gaut, A., Gomez, M. Y. Piette, Casillas, R. P., Preudhomme, M., Pyrzak, G., Rapinchuk, J., Ratliff, J. M., Ray, T. L., Roberts, E. T., Roffo, K., Roth, D. C., Russino, J. A., Schmidt, T. M., Schoppers, M. J., Senent, J. S., Serricchio, F., Sheldon, D. J., Shiraishi, L. R., Shirvanian, J., Siegel, K. J., Singh, G., Sirota, A. R., Skulsky, E. D., Stehly, J. S., Strange, N. J., Stevens, S. U., Sunada, E. T., Tepsuporn, S. P., Tosi, L. P. C., Trawny, N., Uchenik, I., Verma, V., Volpe, R. A., Wagner, C. T., Wang, D., Willson, R. G., Wolff, J. L., Wong, A. T., Zimmer, A. K., Sukhatme, K. G., Bago, K. A., Chen, Y., Deardorff, A. M., Kuch, R. S., Lim, C., Syvertson, M. L., Arakaki, G. A., Avila, A., DeBruin, K. J., Frick, A., Harris, J. R., Heverly, M. C., Kawata, J. M., Kim, S.-K., Kipp, D. M., Murphy, J., Smith, M. W., Spaulding, M. D., Thakker, R., Warner, N. Z., Yahnker, C. R., Young, M. E., Magner, T., Adams, D., Bedini, P., Mehr, L., Sheldon, C., Vernon, S., Bailey, V., Briere, M., Butler, M., Davis, A., Ensor, S., Gannon, M., Haapala-Chalk, A., Hartka, T., Holdridge, M., Hong, A., Hunt, J., Iskow, J., Kahler, F., Murray, K., Napolillo, D., Norkus, M., Pfisterer, R., Porter, J., Roth, D., Schwartz, P., Wolfarth, L., Cardiff, E. H., Davis, A., Grob, E. W., Adam, J. R., Betts, E., Norwood, J., Heller, M. M., Voskuilen, T., Sakievich, P., Gray, L., Hansen, D. J., Irick, K. W., Hewson, J. C., Lamb, J., Stacy, S. C., Brotherton, C. M., Tappan, A. S., Benally, D., Thigpen, H., Ortiz, E., Sandoval, D., Ison, A. M., Warren, M., Stromberg, P. G., Thelen, P. M., Blasy, B., Nandy, P., Haddad, A. W., Trujillo, L. B., Wiseley, T. H., Bell, S. A., Teske, N. P., Post, C., Torres-Castro, L., Grosso, C. Wasiolek, M. Science goals and mission architecture of the Europa Lander mission concept. The Planetary Science Journal, 3(1), (2022): 22, https://doi.org/10.3847/psj/ac4493.Europa is a premier target for advancing both planetary science and astrobiology, as well as for opening a new window into the burgeoning field of comparative oceanography. The potentially habitable subsurface ocean of Europa may harbor life, and the globally young and comparatively thin ice shell of Europa may contain biosignatures that are readily accessible to a surface lander. Europa's icy shell also offers the opportunity to study tectonics and geologic cycles across a range of mechanisms and compositions. Here we detail the goals and mission architecture of the Europa Lander mission concept, as developed from 2015 through 2020. The science was developed by the 2016 Europa Lander Science Definition Team (SDT), and the mission architecture was developed by the preproject engineering team, in close collaboration with the SDT. In 2017 and 2018, the mission concept passed its mission concept review and delta-mission concept review, respectively. Since that time, the preproject has been advancing the technologies, and developing the hardware and software, needed to retire risks associated with technology, science, cost, and schedule.K.P.H., C.B.P., E.M., and all authors affiliated with the Jet Propulsion Laboratory carried out this research at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (grant No. 80NM0018D0004). J.I.L. was the David Baltimore Distinguished Visiting Scientist during the preparation of the SDT report. JPL/Caltech2021
Same data, different analysts: variation in effect sizes due to analytical decisions in ecology and evolutionary biology
Gould E, Fraser H, Parker T, et al. Same data, different analysts: variation in effect sizes due to analytical decisions in ecology and evolutionary biology. 2023.Although variation in effect sizes and predicted values among studies of similar phenomena is inevitable, such variation far exceeds what might be produced by sampling error alone. One possible explanation for variation among results is differences among researchers in the decisions they make regarding statistical analyses. A growing array of studies has explored this analytical variability in different (mostly social science) fields, and has found substantial variability among results, despite analysts having the same data and research question. We implemented an analogous study in ecology and evolutionary biology, fields in which there have been no empirical exploration of the variation in effect sizes or model predictions generated by the analytical decisions of different researchers. We used two unpublished datasets, one from evolutionary ecology (blue tit, Cyanistes caeruleus, to compare sibling number and nestling growth) and one from conservation ecology (Eucalyptus, to compare grass cover and tree seedling recruitment), and the project leaders recruited 174 analyst teams, comprising 246 analysts, to investigate the answers to prespecified research questions. Analyses conducted by these teams yielded 141 usable effects for the blue tit dataset, and 85 usable effects for the Eucalyptus dataset. We found substantial heterogeneity among results for both datasets, although the patterns of variation differed between them. For the blue tit analyses, the average effect was convincingly negative, with less growth for nestlings living with more siblings, but there was near continuous variation in effect size from large negative effects to effects near zero, and even effects crossing the traditional threshold of statistical significance in the opposite direction. In contrast, the average relationship between grass cover and Eucalyptus seedling number was only slightly negative and not convincingly different from zero, and most effects ranged from weakly negative to weakly positive, with about a third of effects crossing the traditional threshold of significance in one direction or the other. However, there were also several striking outliers in the Eucalyptus dataset, with effects far from zero. For both datasets, we found substantial variation in the variable selection and random effects structures among analyses, as well as in the ratings of the analytical methods by peer reviewers, but we found no strong relationship between any of these and deviation from the meta-analytic mean. In other words, analyses with results that were far from the mean were no more or less likely to have dissimilar variable sets, use random effects in their models, or receive poor peer reviews than those analyses that found results that were close to the mean. The existence of substantial variability among analysis outcomes raises important questions about how ecologists and evolutionary biologists should interpret published results, and how they should conduct analyses in the future