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Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation.Significance:Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia.This article is highlighted in the In This Issue feature, p. 2221

Supplementary Figure from Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Intravitreally injected anti-vascular endothelial growth factor (anti-VEGF) agents are first-line treatment for neovascular age-related macular degeneration (nAMD). Phase 3 trials demonstrated non-inferiority of anti-VEGF therapy with brolucizumab compared with aflibercept in best corrected visual acuity (BCVA) gains, with superior anatomical outcomes after brolucizumab. The purpose of the review was to summarize real-world efficacy and safety data on brolucizumab in patients with nAMD. The review protocol was registered with PROSPERO (ID: CRD42021290530). We conducted systematic searches in Embase, Medline and key ophthalmology congress websites (19 October 2021). Original reports of efficacy and/or safety in patients receiving brolucizumab to treat nAMD in clinical practice were eligible. The descriptive summary includes reports describing at least 10 brolucizumab-treated eyes. In total, 2907 brolucizumab-treated eyes from 26 studies were included. Outcomes were available for treatment-naive eyes (six studies), eyes switched to brolucizumab from other anti-VEGFs (16 studies), and/or treatment-naive and switch eyes combined (eight studies). Follow-up time points ranged from 4 weeks to 1 year post-brolucizumab initiation. For BCVA, significant improvements compared with brolucizumab initiation were reported in four of six studies in treatment-naive eyes (mean BCVA improvement, range: +3.7 to +11.9 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and in three of 12 studies in switch eyes (range: +9.0 to +15 ETDRS letters) (all p

Erosion is directly tied to landscape evolution through the relationship between sediment flux and vertical lowering of the land surface. Therefore, the analysis of erosion rates across the planet measured over different temporal domains may provide perspectives on the drivers and processes of land surface change over various timescales. Different metrics are commonly used to quantify erosion (or denudation) over timescales of <101 years (suspended sediment flux) and 103–106 years (cosmogenic radionuclides), meaning that reconciling potentially contrasting rates at these timescales at any location is challenging. Studies over the last several decades into erosion rates and their controls have yielded valuable insights into geomorphic processes and landforms over time and space, but many are focused at local or regional scales. Gaps remain in understanding large-scale patterns and exogenous drivers (climatic, anthropogenic, tectonic) of erosion across the globe. Here we leverage the expanding availability and coverage of cosmogenic-derived erosion data and historical archives of suspended sediment yield to explore these controls more broadly and place them in the context of classical geomorphic theory. We make the following findings in this paper: (1) there are relationships between both long- and short-term erosion rates and mean annual precipitation, as well as aridity, similar to that proposed in classic geomorphic literature on erosion; (2) agricultural activities have apparently increased short-term erosion rates, outpacing natural drivers; (3) short-term erosion rates exceed long-term rates in all climatic regions except in mid- and high latitudes, where long-terms rates are higher due to the influence of repeated glacial cycles; and (4) tectonically active margins have generally higher long-term erosion rates and apparently lower rainfall thresholds for erosion which potentially arise due to steeper slopes and associated landslides, overcoming vegetative root reinforcement. These results highlight the complex interplay of external controls on land surface processes and reinforce the view that timescale of observation may reveal different erosion rates and principal controls.

Immune checkpoint blockade therapy has revolutionized cancer care, including the treatment of advanced metastatic disease. However, most patients derive little or no clinical benefit from these therapies and many cancer types are notoriously non-responsive. Motivated by (1) the correlation between tumor neoantigen abundance and anti-tumor immunity and (2) that most cancers are characterized by widespread dysregulation of RNA processing, we reasoned that pharmacologic modulation of RNA splicing might increase cancer cell immunogenicity via the generation of splicing-derived neoantigens. We demonstrated that two compounds which modulate RNA splicing via distinct mechanisms, inhibited tumor growth and enhanced response to immune checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Critical for their clinical translatability, therapeutic doses of splicing inhibitors were non-toxic, tolerated by the host immune system, and did not affect T cell activation, proliferation, and anti-cancer killing activities. Mechanistically, splicing modulation induced stereotyped, dose-dependent “splicing failure” — dramatic intron retention, alternative exon skipping, etc. — that was consistent across multiple mouse and human tumor types. By combining RNA-seq-based peptide predictions and mass spectrometry of the MHC I-bound immunopeptidome, we identified drug-induced, splicing-derived peptides that promote the expansion of antigen-specific CD8+ T cells and trigger anti-tumor T cell responses in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic. Citation Format: James D. Thomas, Sydney X. Lu, Emma De Neef, Erich Sabio, Benoit Rousseau, Mathieu Gigoux, David A. Knorr, Benjamin Greenbaum, Yuval Elhanati, Simon J. Hogg, Andrew Chow, Arnab Ghosh, Abigail Xie, Dmitriy Zamarin, Daniel Cui, Caroline Erickson, Michael Singer, Hana Cho, Eric Wang, Bin Lu, Benjamin H. Durham, Harshal Shah, Diego Chowell, Austin M. Gabel, Yudao Shen, Jing Liu, Jian Jin, Matthew C. Rhodes, Richard E. Taylor, Henrik Molina, Jedd D. Wolchok, Taha Merghoub, Luis A. Diaz Jr, Omar Abdel-Wahab, Robert K. Bradley. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5742.

Background Primary hyperparathyroidism (PHPT) is one of the known causes of secondary osteoporosis. PHPT is associated with increased bone turnover, low bone density and quality; but there have been conflicting results on the risk of fractures. There is limited information on the effects of age, gender, and ethnicity on fracture risk in PHPT. Objective To determine the prevalence of vertebral fractures (VFx) and associated risk factors in patients with PHPT Design: Retrospective cross-sectional study Setting: Academic medical center in a community setting Main outcome measured: 1) Bone mineral density (BMD), and T- and Z-scores of the lumbar spine (LS). 2) Vertebral morphometry was assessed using the Genant method to identify asymptomatic vertebral fractures (VFx) on CT spine images. 3) Biochemical measurements included serum PTH, Creatinine (Cr) and Calcium (Ca). Results In this retrospective study of consecutive 560 PHPT patients verified by surgery [447 women with a median age of 62y; 362 Caucasians (65%), 142 African Americans (AA, 25%) and 22 unspecified race (10%)] were included. Prevalence of VFx was 13% (n=75), other sites 15% (n=84), wrist fractures 3% (n=16) and hip fractures 1% (n=6). Fracture prevalence at all sites was higher in women, but significant only for VFx (71% vs 29%, p=0.04). In subgroup analysis by age (above or below 50y) and gender, there was no significant difference in LS BMD, T- or Z-score values, serum PTH, Ca and Cr in patients with and without VFx. In subgroup analysis by ethnicity: i) prevalence of all fractures was higher in Caucasians compared to AA and others ii) mean serum PTH (±SD) level was significantly higher in AA vs Caucasian patients with VFx (190 ± 124 vs 121 ± 57 pg/mL, p=0.03) and iii) no significant differences were noted in LS BMD, T-or Z-scores, serum Ca and Cr in patients with VFx. In multivariate analysis (age, serum Ca, PTH >100, and LS BMD) to predict risk of VFx in all patients, only age [OR 1.07, CI 1.03-1.11) and serum Ca [OR 1.7, CI 1.03–2.79] were significant factors. In women, multivariate analysis identified increasing age to be the only significant risk factor to predict risk of VFx. [OR 1.107, CI 1.03-1.12]. Conclusion Vertebral fractures (VFx) is more prevalent in comparison to wrist and hip fractures in patients with PHPT. Serum PTH is significantly higher in African American PHPT patients with VFx. Increasing age and serum calcium ≥11.1 mg/dL are significant predictors of VFx in PHPT patients. Presentation: Saturday, June 11, 2022 12:42 p.m. - 12:47 p.m., Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Land use and land cover change significantly influence regional energy budgets, and hydrological and biogeochemical cycles which may occur from both anthropogenic and natural disturbances. Likewise, vegetation may also respond dynamically to climate. In the past decades, the Horn of Africa has been hit by several droughts and heatwaves causing severe economic, environmental, and social damage. To evaluate and mitigate such impacts, it is necessary to establish and quantify the linkage between land cover change and regional climate. This study presents an observational analysis of recent (2001–2019) historical changes in land cover and land use and their relation to climate in the Horn of Africa. Firstly, we evaluate changes in land cover using the Moderate Resolution Imaging Spectrometer (MODIS) dataset. Results indicate steady expansion of grasslands (net gain is 1.2% of total area) and an opposite pattern for open shrublands during the period 2001–2016. Importantly, deforestation of evergreen broadleaf forest (0.3% of the total area) is also noticeable in continuous fractional vegetation cover (FVC) analysis. Next, the Global Database of Historical Yields (GDHY) is explored to identify the yield trends for two main cereals: maize and wheat. Wheat yield shows increasing trends in the northern and southern parts, while maize yields increase in Ethiopia and mildly decrease in Kenya. To quantify the adverse impact of drought on yields, three drought indices are used: (a) Standardized Precipitation Evapotranspiration Index (SPEI), (b) self-calibrating Palmer Drought Severity Index (scPDSI), and (c) Standard Evapotranspiration Deficit Index (SEDI). The analysis identifies SPEI12 as arguably the best performing drought index for monitoring and forecasting impacts on yields in this region. Finally, a Conditional Spectral Granger Causality (CSGC) algorithm is employed for understanding the influence of climate variability on vegetation dynamics. Although the influence of climatic factors (i.e., precipitation, temperature, and solar energy radiation) on vegetation dynamics is heterogeneous, given the wide spectrum of climate regimes in the region, an overall increased influence of temperature on vegetation dynamics is revealed. In conclusion, the observational evidence indicates that climate plays an important role as a driver of both crop and natural vegetation change in the Horn of Africa.

Reservoirs play a vital role in the supply and management of water resources around the world. In Great Britain, reservoir operations are largely determined by the local water company, and there is very little national-scale information available to quantify their impact on river flows. Consequently, large-scale hydrological modelling and data analyses often focus on ‘natural’ or ‘near-natural’ catchments. To support the long-term resilience of water supply and the environment under changing climate and demand, it is essential that we understand where, when and how reservoirs are leading to deviations from a natural flow regime. This will help inform and validate advancements in the large-scale simulation of reservoir-impacted catchments, as well as deepening our understanding of how reservoir operations influence streamflow behaviour.Due to the age and location of reservoirs across Great Britain, there is a distinct lack of upstream or pre-construction flow timeseries. As a result, we cannot use standard approaches – such as indicators of hydrological alteration- which base analysis on the pre-and-post construction flow regimes. To fill this gap, we define a suite of hydrological signatures and compare observed streamflow timeseries from 1980- 2015 across 166 reservoir catchments and 112 near-natural catchments in Great Britain. We use signatures, characterizing the water balance, flow duration curve and low flow regime, to identify differences in streamflow between these two groups of catchments, and attribute alterations to upstream reservoir operation. We find that gauges with a reservoir upstream are more likely to induce runoff deficits exceeding total PET, and that routine reservoir releases lead to plateaus in the flow duration curve. By defining two new reservoir-based catchment descriptors, our results show that the degree of flow regulation at a gauge depends on the upstream storage capacity and the contributing area of upstream reservoirs. Such descriptors begin to identify thresholds below which the influence of reservoirs is indistinguishable, and help to characterise the extent of reservoir influence across Great Britain.This analysis highlights groups of reservoir-impacted catchments which cannot be represented by a natural regime. It is in these locations that advancements in large-scale hydrological modelling are crucial for water resource simulation, and that the influence of reservoir operations on the flow regime must be accounted for.

Early warning of drought conditions can help protect lives and livelihoods, especially in dry regions of subsistence agriculture and pastoralism. Regions such as the Horn of Africa Drylands (HAD) may benefit from advance warning of changes to available water supplies, as rural communities make critical decisions about planting and moving livestock at particular points in time. However whilst the regionally-mandated seasonal forecast for HAD provides information on rainfall totals, it does not quantify expected impacts on water balance components such as soil moisture and groundwater storage. This latter information may be more useful to rural communities who rely on groundwater for water resources for humans and livestock, and soil moisture for crop growth. These hydrological quantities can typically be estimated with hydrological models, but in drylands the processes governing water partitioning are complex and largely unrepresented in most existing regional and global hydrological models. Here we leverage the capability of a dryland-specific hydrological model (DRYP) to produce rainfall-driven water security forecasts for HAD. DRYP incorporates spatially varying rainfall and evaporative demand, dynamic surface-groundwater interactions, ephemeral flow through channels and focused groundwater recharge. We employ DRYP in a pilot application to produce seasonal forecasts of soil moisture and groundwater recharge for a large catchment within the HAD. We use the objective seasonal forecasts provided by the IGAD Climate Prediction and Application Centre (ICPAC) and disseminated within the Greater Horn of Africa Climate Outlook Forum (GHACOF). Methodological approaches to integrate DRYP with the regional climate outlook disseminated by ICPAC are described, along with evaluation of potential skill of these new water security forecasts for the regional pilot catchment. Finally, we describe and update on an active forecast pilot activity, where water security forecasts for the current rainfall season (March-May 2022) have been co-produced with ICPAC and disseminated to stakeholders in February 2022 as part of the GHACOF event, now publicly available via the ICPAC East Africa Hazards Watch platform, under the EU H2020-funded DOWN2EARTH project. Co-design activity arising from recent stakeholder workshops will be described.

The Horn of Africa drylands (HAD) are highly vulnerable to hydroclimatic extremes, with droughts and floods frequently leading to famines, crop losses, and significant humanitarian crises. However, development of robust mitigation measures has been hindered by the lack of understanding of the drivers of the two main rainfall seasons in the region: the long (March–May) and short (October–December) rains. In particular, the inter-annual variability of the long rains has been subject of much debate; a significant amount of research has attempted to diagnose the drivers of the observed decline in the long rains. Given the ecological and socio-economic importance of the two rain seasons for the HAD region, understanding the major moisture sources and their variability in both space and time is essential. Such an analysis can help disentangle the causes of temporal variability in rainfall, especially the long rains, improve forecasts, and build ecosystem and community resilience against hydroclimatic extremes.To trace the origin of rainfall over the HAD region, we use global simulations of the FLEXPART version 9.01, forced with the ERA-Interim reanalysis for a period of 37 years (1980–2016). The FLEXPART outputs include the properties of the air parcels at 3-hourly time steps, which are then post-processed to identify the source regions of rainfall using the Heat and Moisture Tracking Framework (HAMSTER v1.2.0) described by Keune et al. (2021). Using this framework, we first trace the rainfall occurring over the HAD region during the long and short rain seasons to their terrestrial and oceanic sources spatially. Then, we track the changes in the contributions of ocean and land evaporation to HAD rainfall in time over the 37-year period. Preliminary results show that around 80% of HAD rainfall originates from Indian Ocean evaporation, for both seasons. For both seasons the contribution of evaporation from land is relatively low compared to the oceanic contribution. For the long rains, a similar amount of moisture originates from recycling (local) and remote sources (10.9% and 10.5% respectively). On the other hand the short rains show a larger proportion of local recycling (13.8%) relative to remote land evaporation (9.4%). The larger contribution of remote land sources for the long rains arises from the Indian subcontinent and Southeast Asia. Further, we shed light on the trends and anomalies in source regions for the two rain seasons, with particular focus on the anomalies in moisture sources that are characteristic of extreme dry and wet conditions.References:Keune, J., Schumacher, D. L., and Miralles, D. G.: A holistic framework to estimate the origins of atmospheric moisture and heat using a Lagrangian model, Geosci. Model Dev. Discuss. [preprint], in review, 2021.

BACKGROUND: Covalent (irreversible) Bruton’s tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell–receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.)

Purpose To compare patterns of choroidal venous drainage in eyes with pachychoroid disease to those of healthy subjects using ultra-widefield indocyanine green angiography (UWF ICGA). Methods Patients with pachychoroid disease and healthy controls were recruited at two referral centers. UWF ICGA images were used to evaluate the proportion of the postequatorial fundus drained by major vortex vein systems in each quadrant and to study the incidence and topography of choroidal vascular hyperpermeability (CVH) and intervortex venous anastomoses. Widefield swept-source optical coherence tomography (SS-OCT) was used to evaluate choroidal thickness at the posterior pole in eyes with pachychoroid disease. Results Fifty-two pachychoroid eyes and 26 healthy eyes were evaluated. Eyes with pachychoroid disease showed a significant within-subject variance in the proportion of the postequatorial fundus drained by each vortex vein system (range, 4.1%–48.1%; P < 0.0001) that was not seen in controls (range, 17.3%–31.7%; P = 0.11). CVH was present in all pachychoroid disease eyes and three of 26 controls. Intervortex venous anastomoses were present in 46 of 52 pachychoroid disease eyes and nine of 26 control eyes. Vortex vein systems with large drainage areas showed greater density of CVH spots. SS-OCT demonstrated asymmetric choroidal drainage in the macula of 59% of pachychoroid eyes. CVH and intervortex venous anastomoses were more prominent in areas showing maximal choroidal thickness. Conclusions In eyes with pachychoroid disease, imbalanced choroidal venous drainage with congestion of specific vortex vein systems may contribute to a state of choroidal venous insufficiency characterized by regional choroidal thickening, CVH and remodeling of venous drainage routes.

Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation. Significance: Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia. This article is highlighted in the In This Issue feature, p. 2221

Introduction: This post hoc analysis applies a fixed dosing stratification approach to patient-level brolucizumab data from the phase III HAWK and HARRIER trials to determine the proportion of patients who would have been assigned to fixed dosing regimens with treatment intervals of 8, 12, or 16 weeks (q8w, q12w, or q16w) based on the presence/absence of disease activity (DA) following the loading phase. The analysis also simulates central subfield thickness (CSFT) data to estimate the anatomical outcomes if the patients had been thus assigned. Of note, the limitations of this analysis include the post hoc nature of the work and the inability to directly compare HAWK and HARRIER with TENAYA and LUCERNE due to the differences in design. Design: This study was a post hoc modelling analysis of patient-level data. Methods: Using patient-level data from HAWK and HARRIER, patients (n = 730) were allocated to a fixed q16w, q12w, or q8w regimen based on assessment of DA at weeks 16 and 20. Two definitions of DA were used: DA 1, based on a phase II study of faricimab, and DA 2, a definition derived from common clinical consideration including visual acuity and anatomical changes. CSFT simulations were performed using a pharmacokinetic/pharmacodynamic model describing CSFT response to anti-VEGF treatment. Outcome measures were modelled patient allocation to fixed regimens and mean CSFT reduction. Results: Using DA definitions 1 and 2, respectively, 78% and 76% of patients in the brolucizumab arm were allocated to a greater than or equal to q12w regimen, and 56% and 52% were allocated to a q16w regimen. Mean reduction in CSFT was similar between the two study drugs with both DA definition assumptions. Conclusions: This analysis demonstrates the potential durability of action and effectiveness of brolucizumab.

Introduction The evolution of the paramedic role over recent years has changed dramatically, with an increased emphasis on treating more patients in the community rather than conveying to hospitals unnecessarily. Paramedics see and treat a diverse range of patients from acute events to chronic conditions, many patients have co-morbidities and polypharmacy in an aging population. Thus, the modern paramedic must be equipped with holistic clinical skills over a wide variety of specialties. Multi-disciplinary working in hospices is well established but does not typically include paramedicine. Paramedicine has changed in recent years extending beyond the typical emergency response model to encompass community paramedicine with paramedics working in primary care but the role within hospices is still to be developed. Method Paramedics draw on a multitude of skill sets from symptom management, physical assessment, signposting, referrals and many more, and are adept at talking and communicating with people in the very worst of situations showing empathy and care, a baseline for all palliative care. My role as a paramedic in the hospice team is to conduct assessments, using my experience of visiting patients within the community and deciding on a course of action/referral or input required. Outcomes Mountbatten Isle of Wight has seen two paramedics integrate well with the community palliative care team. Paramedics have been able to give IV infusions to patients within their homes to help avoid clinical environments. Paramedics have extensive patient assessment and diagnostic skillsets and these have been added to by in-house training on catheterisation/advance care planning and end-of-life care supplementing the care provided by nursing staff within the community team. Conclusion The role of the paramedic within hospice community teams is still in its infancy. We know that hospice services work differently across the country and therefore there are no hard and fast rules for what a paramedic may do.

To compare the outcomes of brolucizumab versus aflibercept in patients with neovascular age-related macular degeneration with early residual fluid in the HAWK and HARRIER studies.Post hoc analysis using pooled data from the phase 3 studies HAWK (NCT02307682) and HARRIER (NCT02434328).The early residual fluid cohort for this post hoc analysis consisted of patients treated with either brolucizumab 6 mg (n = 730 patients) or aflibercept 2 mg (n = 729 patients) and who had the presence of intraretinal fluid (IRF), subretinal fluid (SRF), or both verified by spectral-domain OCT at the week 12 clinic visit.After 3 initial monthly doses, patients treated with brolucizumab received injections every 12 weeks (q12w) or every 8 weeks (q8w), depending on the neovascular age-related macular degeneration disease activity, whereas patients treated with aflibercept received fixed q8w dosing.The mean change in best-corrected visual acuity and central subfield thickness (CST) from the baseline to that at weeks 48 and 96, the proportion of patients treated with brolucizumab remaining on q12w dosing to week 96, and the change in fluid status at weeks 48 and 96.All analyses were based on 149 of 730 (20.4%) patients treated with brolucizumab and 217 of 729 (29.8%) patients treated with aflibercept with spectral-domain OCT-verified IRF, SRF, or both at their week 12 visit. The best-corrected visual acuity improvements from baseline at weeks 48 and 96 were numerically better for brolucizumab than for aflibercept (least square mean [standard error] 7.9 ± 1.1 vs. 4.6 ± 0.9 and 7.4 ± 1.3 vs. 2.9 ± 1.1 letters, respectively). The CST reductions from baseline at weeks 48 and 96 were consistently greater with brolucizumab than with aflibercept (least square mean [standard error], μm: -194.9 ± 13.7 vs. -123.9 ± 11.3; and -201.1 ± 14.5 vs. -134.2 ± 12.0, respectively). At weeks 48 and 96, patients treated with brolucizumab had a 40.4% and 31.3% probability of remaining on q12w dosing intervals, respectively. Fewer patients treated with brolucizumab had remaining IRF, SRF, or both at weeks 48 and 96 than patients treated with aflibercept (59.1% vs. 75.1% and 49.0% vs. 60.4%, respectively).In patients with early residual fluid, defined as spectral-domain OCT-verified IRF, SRF, or both at the week 12 clinic visit, brolucizumab resolved the early residual fluid and reduced CST more effectively than aflibercept, resulting in greater best-corrected visual acuity improvements through week 96 of anti-VEGF treatment.

Current testing methods are capable of measuring strain near the surface on structural parts, for example by using strain gauges. However, stress peaks often occur within the material and can only be approximated. An alternative strain measurement incorporates fibre-optical strain sensors (Fiber Bragg Gratings, FBG) which are able to determine strains within the material. The principle has already been verified by using embedded FBGs in tensile specimens. The transition area between fibre and aluminium, however, is not yet properly investigated. Therefore, strains in tensile specimens containing FBGs were measured by neutron diffraction in gauge volumes of two different sizes around the Bragg grating. As a result, it is possible to identify and decouple elastic and plastic strains affecting the FBGs and to transfer the findings into a fully descriptive FE-model of the strain transition area.We thus accomplished closing the gap between the external load and internal straining obtained from cast-in FBG and generating valuable information about the mechanisms within the strain transition area.It was found that the porosity within the casting has a significant impact on the stiffness of the tensile specimen, the generation of excess microscopic tensions and thus the formation of permanent plastic strains, which are well recognized by the FBG. The knowledge that FBG as internal strain sensors function just as well as common external strain sensors will now allow for the application of FBG in actual structural parts and measurements under real load conditions. In the future, applications for long-term monitoring of cast parts will also be enabled and are currently under development.

The topology of fluvial networks has long been studied, with Horton's laws describing relationships between stream order, stream density, and stream length often cited as fundamental governing principles of drainage basin development. Building upon these principles, small scale studies have identified patterns of self-similarity in drainage networks in the continental USA, suggesting that to some extent, river networks self-organise in a scale invariant manner. More stringent measures of self-similarity have also been developed, which quantify the fractal nature of side branching structures in fluvial networks. Using such metrics, studies have identified similarities between leaf vein structures and fluvial networks, and have identified a potential climatic signature in North American river topology.The appeal of such techniques over traditional methods of channel analysis using topographic data is that in self-similar networks, the precise location of channel heads is unimportant, allowing analysis to be performed at unprecedented scales, and in locations where data quality is limited. Here, we attempt to reconcile these two suites of techniques to understand the potential and limitations of network topology as an indicator of broader landscape dynamics. We achieve this through the analysis of fluvial networks extracted at a global scale from the Shuttle Radar Topography Mission dataset alongside other global earth observation data.

Background: Obesity increases risk of diabetes, heart disease and cancer; a healthy weight reduces these risks, however weight loss efforts are prone to failure. Developing methods to promote weight loss maintenance is an important public health goal. We report on weight loss maintenance in individuals who followed a nutrient-dense, plant-rich (NDPR) diet. NDPR guidelines focus on increasing micronutrient density and avoidance of processed, highly palatable foods. Methods: Patients of a private family medical practice and members of a NDPR diet internet community (2273) completed an online survey providing information on length of time following a NDPR diet and body weight at several time points. Results: In respondents with pre-diet BMI ≥ 25 who had been following a NDPR diet for at least 2 years, those who reported adhering to NDPR guidelines in at least 80% of meals lost significantly more weight than those reporting lower adherence. Weight lost during year 1 was maintained at 2 and 3 years, and in respondents with initial BMI in the obese range (≥ 30), those losses were significantly greater in respondents who reported at least 80% adherence compared to 50-79% (56 lb. vs. 34 lb.) at 3 years. Between 1 year and 3 years, a low rate (19%) of weight regain ( ≥ 5 lb.) was reported among respondents 80-100% adherent to NDPR guidelines. Conclusions: Weight loss and maintenance for a period of 3 years was observed in this self-selected group, and respondents who reported 80-100% adherence lost significantly more weight than those who reported 50-79% adherence to NDPR guidelines. Individuals achieved substantially greater weight loss than that commonly observed in weight loss intervention studies. An intervention study, which would provide further insight into the influence of the NDPR guidelines on weight loss and maintenance, is warranted.

Purpose: To evaluate the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg in the treatment of patients with diabetic macular edema (DME).Design: Two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols were conducted. Data were pooled for analysis.Participants: Patients (n = 1048) with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of ≥300 μm by optical coherence tomography.Methods: Patients were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for patients treated at month 36) at ≤40 scheduled visits. Patients who met retreatment eligibility criteria could be retreated no more often than every 6 months.Main Outcome Measures: The predefined primary efficacy endpoint for the United States Food and Drug Administration was achievement of ≥15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP).Results: Mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (−111.6 μm) and DEX implant 0.35 mg (−107.9 μm) than sham (−41.9 μm; P < 0.001). Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy.Conclusions: The DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA. The safety profile was acceptable and consistent with previous reports.

The Dharma Planet Survey (DPS) aims to monitor about 150 nearby very bright FGKM dwarfs (within 50 pc) during 2016$-$2020 for low-mass planet detection and characterization using the TOU very high resolution optical spectrograph (R$\approx$100,000, 380-900nm). TOU was initially mounted to the 2-m Automatic Spectroscopic Telescope at Fairborn Observatory in 2013-2015 to conduct a pilot survey, then moved to the dedicated 50-inch automatic telescope on Mt. Lemmon in 2016 to launch the survey. Here we report the first planet detection from DPS, a super-Earth candidate orbiting a bright K dwarf star, HD 26965. It is the second brightest star ($V=4.4$ mag) on the sky with a super-Earth candidate. The planet candidate has a mass of 8.47$\pm0.47M_{\rm Earth}$, period of $42.38\pm0.01$ d, and eccentricity of $0.04^{+0.05}_{-0.03}$. This RV signal was independently detected by Diaz et al. (2018), but they could not confirm if the signal is from a planet or from stellar activity. The orbital period of the planet is close to the rotation period of the star (39$-$44.5 d) measured from stellar activity indicators. Our high precision photometric campaign and line bisector analysis of this star do not find any significant variations at the orbital period. Stellar RV jitters modeled from star spots and convection inhibition are also not strong enough to explain the RV signal detected. After further comparing RV data from the star's active magnetic phase and quiet magnetic phase, we conclude that the RV signal is due to planetary-reflex motion and not stellar activity., 13 pages, 17 figures, Accepted for publication in MNRAS