Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response 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.

Identifying Medical Diagnoses and Treatable Diseases by Image-Based Deep Learning.

The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.

Sublethal necroptosis signaling promotes inflammation and liver cancer.

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.

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.).

Aridity is expressed in river topography globally.

It has long been suggested that climate shapes land surface topography through interactions between rainfall, runoff and erosion in drainage basins1-4. The longitudinal profile of a river (elevation versus distance downstream) is a key morphological attribute that reflects the history of drainage basin evolution, so its form should be diagnostic of the regional expression of climate and its interaction with the land surface5-9. However, both detecting climatic signatures in longitudinal profiles and deciphering the climatic mechanisms of their development have been challenging, owing to the lack of relevant global data and to the variable effects of tectonics, lithology, land surface properties and human activities10,11. Here we present a global dataset of 333,502 river longitudinal profiles, and use it to explore differences in overall profile shape (concavity) across climate zones. We show that river profiles are systematically straighter with increasing aridity. Through simple numerical modelling, we demonstrate that these global patterns in longitudinal profile shape can be explained by hydrological controls that reflect rainfall-runoff regimes in different climate zones. The most important of these is the downstream rate of change in streamflow, independent of the area of the drainage basin. Our results illustrate that river topography expresses a signature of aridity, suggesting that climate is a first-order control on the evolution of the drainage basin.

Lethal trap created by adaptive evolutionary response to an exotic resource.

Global transport of organisms by humans provides novel resources to wild species, which often respond maladaptively. Native herbivorous insects have been killed feeding on toxic exotic plants, which acted as 'ecological traps'1-4. We document a novel 'eco-evolutionary trap' stemming from the opposite effect; that is, high fitness on an exotic resource despite lack of adaptation to it. Plantago lanceolata was introduced to western North America by cattle-ranching. Feeding on this exotic plant released a large, isolated population of the native butterfly Euphydryas editha from a longstanding trade-off between maternal fecundity and offspring mortality. Because of this release-and despite a reduced insect developmental rate when feeding on this exotic-Plantago immediately supported higher larval survival than did the insects' traditional host, Collinsia parviflora 5 . Previous work from the 1980s documented an evolving preference for Plantago by ovipositing adults 6 . We predicted that if this trend continued the insects could endanger themselves, because the availability of Plantago to butterflies is controlled by humans, who change land management practices faster than butterflies evolve 6 . Here we report the fulfilment of this prediction. The butterflies abandoned Collinsia and evolved total dependence on Plantago. The trap was set. In 2005, humans withdrew their cattle, springing the trap. Grasses grew around the Plantago, cooling the thermophilic insects, which then went extinct. This local extinction could have been prevented if the population had retained partial use of Collinsia, which occupied drier microhabitats unaffected by cattle removal. The flush of grasses abated quickly, rendering the meadow once again suitable for Euphydryas feeding on either host, but no butterflies were observed from 2008 to 2012. In 2013-2014, the site was naturally recolonized by Euphydryas feeding exclusively on Collinsia, returning the system to its starting point and setting the stage for a repeat of the anthropogenic evolutionary cycle.

Groundwater dependence of riparian woodlands and the disrupting effect of anthropogenically altered streamflow.

Riparian ecosystems fundamentally depend on groundwater, especially in dryland regions, yet their water requirements and sources are rarely considered in water resource management decisions. Until recently, technological limitations and data gaps have hindered assessment of groundwater influences on riparian ecosystem health at the spatial and temporal scales relevant to policy and management. Here, we analyze Sentinel-2-derived normalized difference vegetation index (NDVI; n = 5,335,472 observations), field-based groundwater elevation (n = 32,051 observations), and streamflow alteration data for riparian woodland communities (n = 22,153 polygons) over a 5-y period (2015 to 2020) across California. We find that riparian woodlands exhibit a stress response to deeper groundwater, as evidenced by concurrent declines in greenness represented by NDVI. Furthermore, we find greater seasonal coupling of canopy greenness to groundwater for vegetation along streams with natural flow regimes in comparison with anthropogenically altered streams, particularly in the most water-limited regions. These patterns suggest that many riparian woodlands in California are subsidized by water management practices. Riparian woodland communities rely on naturally variable groundwater and streamflow components to sustain key ecological processes, such as recruitment and succession. Altered flow regimes, which stabilize streamflow throughout the year and artificially enhance water supplies to riparian vegetation in the dry season, disrupt the seasonal cycles of abiotic drivers to which these Mediterranean forests are adapted. Consequently, our analysis suggests that many riparian ecosystems have become reliant on anthropogenically altered flow regimes, making them more vulnerable and less resilient to rapid hydrologic change, potentially leading to future riparian forest loss across increasingly stressed dryland regions.

Biochemical interactions between the Atm1-like transporter from Novosphingobium aromaticivorans and heavy metals.

Novosphingobium aromaticivorans has the ability to survive in harsh environments by virtue of its suite of iron-containing oxygenases that biodegrade an astonishing array of aromatic compounds. It is also resistant to heavy metals through Atm1, an ATP-binding cassette protein that mediates active efflux of heavy metals conjugated to glutathione. However, Atm1 orthologues in higher organisms have been implicated in the intracellular transport of organic iron complexes. Our hypothesis suggests that the ability of Atm1 to remove heavy metals is related to the need for regulated iron handling in N. aromaticivorans to support high oxygenase activity. Here we provide the first data demonstrating a direct interaction between an iron-porphyrin compound (hemin) and NaAtm1. Hemin displayed considerably higher binding affinity and lower EC50 to stimulate ATP hydrolysis by Atm1 than Ag-GSH, GSSG or GSH, established substrates of the transporter. Co-incubation of NaAtm1 and hemin with Ag-GSH in ATPase assays revealed a non-competitive interaction, indicating distinct binding sites on NaAtm1 and this property was reinforced using molecular docking analysis. Our data suggests that NaAtm1 has considerable versatility in transporting organic conjugates of metals and that this versatility enables it to play roles in detoxification processes for toxic metals and in homeostasis of iron. The ability to play these distinct roles is enabled by the plasticity of the substrate binding site within the central cavity of NaAtm1.

Preoperative Evaluation of Thyroid Cancer: A Review of Current Best Practices.

OBJECTIVE: The incidence of thyroid cancer has significantly increased in recent decades. Although most thyroid cancers are small and carry an excellent prognosis, a subset of patients present with advanced thyroid cancer, which is associated with increased rates of morbidity and mortality. The management of thyroid cancer requires a thoughtful individualized approach to optimize oncologic outcomes and minimize morbidity associated with treatment. Because endocrinologists usually play a key role in the initial diagnosis and evaluation of thyroid cancers, a thorough understanding of the critical components of the preoperative evaluation facilitates the development of a timely and comprehensive management plan. The following review outlines considerations in the preoperative evaluation of patients with thyroid cancer. METHODS: A clinical review based on current literature was generated by a multidisciplinary author panel. RESULTS: A review of considerations in the preoperative evaluation of thyroid cancer is provided. The topic areas include initial clinical evaluation, imaging modalities, cytologic evaluation, and the evolving role of mutational testing. Special considerations in the management of advanced thyroid cancer are discussed. CONCLUSION: Thorough and thoughtful preoperative evaluation is critical for formulating an appropriate treatment strategy in the management of thyroid cancer.

PHASE 2 RANDOMIZED STUDY (ORION-1) OF A NOVEL, BIODEGRADABLE DEXAMETHASONE IMPLANT (AR-1105) FOR THE TREATMENT OF MACULAR EDEMA DUE TO CENTRAL OR BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: AR-1105 is a novel biodegradable sustained-release dexamethasone implant designed to deliver 6-month durability. This Phase 2 study evaluated two AR-1105 formulations with different release profiles in patients with macular edema due to retinal vein occlusion. METHODS: Patients received a single intravitreal injection with 340 µg dexamethasone. In the initial phase, five patients received clinical formulation (CF) 1. In the randomized phase, 44 patients were randomized 1:1 to CF1 or CF2. The follow-up was 6 months. Patients had vision loss due to macular edema diagnosed ≥9 (central retinal vein occlusion) or ≥12 months (branch retinal vein occlusion) before screening, and could be treatment-naive or -experienced (if received prior steroids, must have demonstrated response). RESULTS: Both formulations improved vision and reduced retinal thickening from baseline across all visits. At Month 6, mean changes in best-corrected visual acuity were +4.3 and +8.0 letters, and mean changes in central subfield thickness were -93 µm and -211 µm in CF1 and CF2 randomized patients, respectively. Most common adverse events were reduced visual acuity, worsening macular edema, conjunctival hemorrhage, and increased intraocular pressure. No patients required surgery or laser for intraocular pressure control. CONCLUSION: Both formulations were well tolerated and demonstrated clinically meaningful and sustained improvements in vision and retinal thickening in patients with retinal vein occlusion with longstanding edema.

Three-Year Safety and Efficacy of the 0.19-mg Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: The PALADIN Study.

PURPOSE: To assess the long-term safety and efficacy of the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (Iluvien; Alimera Sciences, Inc) in patients with diabetic macular edema (DME). DESIGN: Three-year, phase 4, nonrandomized, open-label observational study. PARTICIPANTS: Patients with DME who previously received corticosteroid treatment without a clinically significant rise in intraocular pressure (IOP; all eyes, n = 202 eyes of 159 patients; 36-month completion, n = 94 eyes). METHODS: A prospective, observational study in which patients received a 0.19-mg FAc intravitreal implant at baseline and then were observed for safety-, visual-, anatomic-, and treatment burden-related outcomes for up to 36 months. MAIN OUTCOME MEASURES: Primary safety outcomes included changes in IOP and interventions to manage IOP elevations. Secondary outcomes included changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), and adjunctive DME treatment frequency RESULTS: At 36 months after FAc implantation, study eyes showed a mean CST change of -60.69 µm (P < 0.0001) and a mean BCVA change of +3.61 letters (P = 0.0222) compared with baseline. Overall median treatment frequency decreased from 3.4 treatments/year in the 36 months before FAc implantation to 1 treatment/year in the 36 months after FAc implant, a treatment burden reduction of 70.5%. Furthermore, among the group that completed 36 months of treatment (n = 94 eyes), 25.53% of eyes remained rescue free through 36 months. Mean IOP remained stable throughout the study, and IOP increases to more than 30 mmHg occurred in 10.89% of eyes. Intraocular pressure-related procedures were infrequent, with a surgical rate of 2.97%, with 1.49% attributable to steroid use (vs. surgeries attributable primarily to neovascular glaucoma). In addition, an IOP response of < 25 mmHg after the steroid challenge predicted that 96.92% of eyes would have a similar outcome to 0.19-mg FAc implant at the last visit. Intraocular pressure increases that did occur were manageable with standard treatments (n = 202 eyes). CONCLUSIONS: In patients with DME, the 0.19-mg FAc implant provided improved visual outcomes and reduced treatment burden compared with previous treatments while maintaining a favorable safety profile.

Local groundwater decline exacerbates response of dryland riparian woodlands to climatic drought.

Dryland riparian woodlands are considered to be locally buffered from droughts by shallow and stable groundwater levels. However, climate change is causing more frequent and severe drought events, accompanied by warmer temperatures, collectively threatening the persistence of these groundwater dependent ecosystems through a combination of increasing evaporative demand and decreasing groundwater supply. We conducted a dendro-isotopic analysis of radial growth and seasonal (semi-annual) carbon isotope discrimination (Δ13 C) to investigate the response of riparian cottonwood stands to the unprecedented California-wide drought from 2012 to 2019, along the largest remaining free-flowing river in Southern California. Our goals were to identify principal drivers and indicators of drought stress for dryland riparian woodlands, determine their thresholds of tolerance to hydroclimatic stressors, and ultimately assess their vulnerability to climate change. Riparian trees were highly responsive to drought conditions along the river, exhibiting suppressed growth and strong stomatal closure (inferred from reduced Δ13 C) during peak drought years. However, patterns of radial growth and Δ13 C were quite variable among sites that differed in climatic conditions and rate of groundwater decline. We show that the rate of groundwater decline, as opposed to climate factors, was the primary driver of site differences in drought stress, and trees showed greater sensitivity to temperature at sites subjected to faster groundwater decline. Across sites, higher correlation between radial growth and Δ13 C for individual trees, and higher inter-correlation of Δ13 C among trees were indicative of greater drought stress. Trees showed a threshold of tolerance to groundwater decline at 0.5 m year-1 beyond which drought stress became increasingly evident and severe. For sites that exceeded this threshold, peak physiological stress occurred when total groundwater recession exceeded ~3 m. These findings indicate that drought-induced groundwater decline associated with more extreme droughts is a primary threat to dryland riparian woodlands and increases their susceptibility to projected warmer temperatures.

Brolucizumab 12- and 16-Week Fixed Dosing Potential in Neovascular AMD: A post hoc Evaluation of Data from the HAWK and HARRIER Trials.

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.

Suprachoroidal triamcinolone acetonide versus rescue therapies for the treatment of uveitic macular oedema: A post hoc analysis of PEACHTREE.

BACKGROUND: This post hoc analysis compared the efficacy and safety of suprachoroidally administered triamcinolone acetonide (CLS-TA) to other commonly available treatments for non-infectious uveitis. METHODS: Results from the PEACHTREE study were compared between subjects randomised to CLS-TA not requiring rescue therapy and those subjects randomised to control, who subsequently required rescue therapy. Endpoints included best corrected visual acuity (BCVA), central subfield thickness (CST), treatment emergent adverse events and intraocular pressure (IOP) related safety findings. RESULTS: In this analysis, there were 83 unrescued CLS-TA subjects and 46 rescued control subjects. At Week 24, 51.9% of the unrescued CLS-TA subjects gained ≥15 letters in BCVA, compared to 37.0% of the rescued control subjects (p = 0.115). Unrescued CLS-TA subjects showed a mean gain of 15.7 versus 10.9 letters in rescued control subjects (p = 0.080). A significantly greater mean reduction in CST was observed for unrescued CLS-TA subjects versus rescued control subjects (174.0 and 148.5 µm; p = 0.040). Of unrescued CLS-TA subjects, 4.9% experienced IOP elevations ≥30 mm Hg at any visit versus 10.9% of rescued control subjects. Further, use of IOP-lowering medications appeared lower in unrescued CLS-TA subjects versus rescued control subjects (7.2% vs. 13.0%). There were no IOP-lowering surgical interventions in either group. CONCLUSION: CLS-TA subjects experienced significantly greater reduction in CST and tended towards greater improvement in BCVA, compared with rescued control subjects. Suprachoroidally administered CLS-TA showed a lower incidence of IOP-related safety findings.

Preference Provides a Plethora of Problems (Don't Panic).

This review was solicited as an autobiography. The "problems" in my title have two meanings. First, they were professional difficulties caused by my decision to study oviposition preferences of butterflies that were not susceptible to traditional preference-testing designs. Until I provided video, my claim that the butterflies duplicate natural post-alighting host-assessment behavior when placed on hosts by hand was not credible, and the preference-testing technique that I had developed elicited skepticism, anger, and derision. The second meaning of "problems" is scientific. Insect preference comes with complex dimensionality that interacts with host acceptability. Part Two of this review describes how my group's work in this area has revealed unexpected axes of variation in plant-insect interactions-axes capable of frustrating attempts to derive unequivocal conclusions from apparently sensible experimental designs. The possibility that these complexities are lurking should be kept in mind as preference and performance experiments are devised.

Colonizations cause diversification of host preferences: A mechanism explaining increased generalization at range boundaries expanding under climate change.

As species' poleward range limits expand under climate change, generalists are expected to be better colonists than specialists, extending their ranges faster. This effect of specialization on range shifts has been shown, but so has the reverse cause-effect: in a global meta-analysis of butterfly diets, it was range expansions themselves that caused increases in population-level diet breadth. What could drive this unexpected process? We provide a novel behavioral mechanism by showing that, in a butterfly with extensive ecotypic variation, Edith's checkerspot, diet breadths increased after colonization events as diversification of individual host preferences pulled novel hosts into population diets. Subsequently, populations that persisted reverted toward monophagy. We draw together three lines of evidence from long-term studies of 15 independently evolving populations. First, direct observations showed a significant increase in specialization across decades: in recent censuses, eight populations used fewer host genera than in the 1980s while none used more. Second, behavioral preference-testing experiments showed that extinctions and recolonizations at two sites were followed, at first by diversification of heritable preference ranks and increases in diet breadth, and subsequently by homogenization of preferences and contractions of diet breadth. Third, we found a significant negative association in the 1980s between population-level diet breadth and genetic diversity. Populations with fewer mtDNA haplotypes had broader diets, extending to 3-4 host genera, while those with higher haplotype diversity were more specialized. We infer that diet breadth had increased in younger, recently colonized populations. Preference diversification after colonization events, whether caused by (cryptic) host shifts or by release of cryptic genetic variation after population bottlenecks, provides a mechanism for known effects of range shifts on diet specialization. Our results explain how colonizations at expanding range margins have increased population-level diet breadths, and predict that increasing specialization should accompany population persistence as current range edges become range interiors.

Impact of a specialty trained billing team on an academic otolaryngology practice.

PURPOSE: To determine how the incorporation of specialty specific training for coders within a focused billing team affected revenue, efficiency, time to reimbursement, and physician satisfaction in an academic otolaryngology practice. MATERIALS AND METHODS: Our academic otolaryngology department recently implemented a new billing system, which incorporated additional training in otolaryngology surgical procedures for medical coders. A mixed model analysis of variance was used to compare billing outcomes for the 6 months before and 6 months after this new approach was initiated. The following metrics were analyzed: Current Procedural Terminology codes, total charges, time between services rendered and billing submission, and time to reimbursement. A survey of department physicians assessing satisfaction with the system was reviewed. RESULTS: There were 4087 Current Procedural Terminology codes included in the analysis. In comparing the periods before and after implementation of the new system, statistically significant decreases were found in the mean number of days to coding completion (19.3 to 12.0, respectively, p < 0.001), days to posting of charges (27.0 to 15.2, p < 0.001), days to final reimbursement (54.5 to 27.2, p < 0.001), and days to closure of form (179.2 to 76.6, p < 0.001). Physician satisfaction with communication and coder feedback increased from 36% to 64% after initiation of the new program. CONCLUSIONS: The implementation of additional specialty training for medical coders in the otolaryngology department of a large medical system was associated with improved revenue cycle efficiency. Additionally, this model appears to improve physician satisfaction and confidence with the coding system.

Evaluation of Strain Transition Properties between Cast-In Fibre Bragg Gratings and Cast Aluminium during Uniaxial Straining.

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.