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The tree-ring lab at BOKU University, Vienna, Austria has been sampling and dating by means of dendrochronology in the eastern part of Austria since 1996. Among other objects, the roof constructions of 982 historical buildings were analysed, resulting in 13 916 samples. The time span extends from the oldest roof truss at a church in Salzburg, dated to 1135, to the youngest in Vienna, dated to 1997. The aim of present paper is to provide an overview of the findings on historical roof constructions in Austria based on data collected over the last 27 years. Out of the total sample elements, 69.0% were made out of Norway spruce, followed by silver fir with 19.6%. All other species played a minor role: pine (5.0%), larch (3.6%), oak (2.7%), followed by a few elements made of stone pine, elm, beech, and poplar. The proportion of wood species reflects the significant influence of alpine regions. Within the city of Vienna, where all building timber was rafted, the amount of spruce wood is 72.3%. There were no clear visible changes in the wood species share over time. Along with dendro-dating, building historians have been analyzing the typology of roof trusses and the changes within time. It was possible to see clear alterations from simple rafter constructions to huge multi-level constructions with standing and sometimes hanging columns and roof constructions with lying posts (in the plane of the rafters) that transition back to constructions with standing columns.

This study presents a new stable oxygen isotope chronology, covering the years 800–2000 AD, constructed using modern and subfossil wood derived from trees growing around Lake Schwarzensee in Austria. The climatic signal imparted in the chronology is conditioned mainly by the direct influence of environmental factors on the isotopic signature of source water, which in turn is regulated by evaporation and condensation mechanisms. The second driver of stable oxygen isotope is the physiological response of trees to changing weather conditions, most importantly rates of transpiration. The chronology of stable oxygen isotopes corresponds well with both temperature (r = 0.485; p < 0.05) and total precipitation (r = −0.548; p < 0.05) during the growing season (May–September). This mixed signal results from the fact that the relationship between the content of stable oxygen isotopes and the influence of climate is multifactorial. Moreover, the effect exerted by meteorological conditions on stable isotope ratio changes over time. This is most probably linked to interannual variation in climatic and environmental factors.

The impacts of climate change in forests are often cascading, affecting plant growth, plant performance but often also rendering trees susceptible to insect pathogen attack. Potentially these insect infestations could have a greater impact on the forest’s carbon sequestration potential, than the direct climate effects on plant growth and forestry production. Regional and context-specific responses to a changing climate are expected: In regions where forest productivity is constrained by low temperatures, such as high altitudes, growth is likely to increase as temperatures rise, whilst in regions with limited water availability, a decline in growth is predicted as a result of more frequent and prolonged droughts and/or changing precipitation patterns.Norway spruce is high-yielding, easy to manage and has a number of economic advantages over broadleaf production. Spruce is economically the most important and common tree species in Austria, making up over 50% the Austrian forestry area. Area-wide planting throughout Austria was supported for decades, which often led to planting in regions where the production risk for spruce was and remains high and where active management does not necessarily cover costs. This legacy of this planting policy means that stands are often still planted on sites, where the trees are close to the limit of suitability. Spruce has shallow roots and less access to deeper soil moisture, so it is particularly susceptible to drought stress. Trees that suffer from changing site conditions are likely to be more susceptible to disease and insect infestation than trees that are not exposed to additional site stresses. In an effort to identify sites that have suffered from drought in the past and that are vulnerable to possible pest infestations, a method to predict bark beetle susceptibility is being developed, based on stable isotope signatures in tree rings. Specifically, we will test whether the stable isotope data (¹³C,¹⁸O) in the tree rings can provide an accurate archive of information about past climate variability and physiological responses to environmental and geomorphological conditions: These data can provide historical insights into water status, in particular soil water availability and use, temperature and water consumption of individual trees. They can be correlated with detailed archived weather and precipitation data as well as easily measured parameters such as canopy temperature or spectral data. We will present our approach and the first results, which are based on samples from the Austrian forest inventory and complemented with samples from additional bark-beetle infested areas.

While numerous correlational studies on the impact of climatic variation on tree ring formation consider plant functional traits, masting cycles and stochastic disturbances, the role of soil properties is frequently neglected due to insufficient data availability. Using a homogenous dataset of increment cores collected in mature stands at 1562 different forest sites with detailed plot specific climate, stand and soil information in the province of Styria in Austria we are focusing on the role of soil water storage (plant available water capacity – AWC) and soil nutrient status on tree ring formation. The study area covers a wide altitudinal and climate gradient with mean annual temperatures ranging from 2.1°C to 10.2°C and mean annual precipitation ranging from 695 mm to 2024 mm. Generalized Additive Mixed Models (GAMM) for annual tree ring width over 38 years (1980 to 2018) were fitted for six tree species (Abies alba, Fagus Sylvatica, Larix decidua, Picea abies, Pinus sylvestris, Quercus robur/petrea). Individual tree characteristics, stand attributes, general site characteristics (terrain information calculated from high resolution ALS), downscaled climate information in high temporal resolution, and soil information were used as independent variables. Soil data was derived from a morphological description of 80 cm soil pits dug on each corresponding forest site. Via pedo-transfer-functions (using functions available from the literature as well as derived from laboratory analyses of approximately 25% of the pits), soil characteristics such as AWC and soil nutrient status were calculated.In a two-step procedure, we first developed a general tree growth model, including solely tree and stand attributes (e.g. age, competition) and general site specific information available in high spatial resolution (e.g. slope, aspect, irradiance, mean annual temperature, precipitation). Subsequently, we added soil attributes to the model and checked for their effect on model parameters. AWC and soil nutrient status do have significant influence on tree ring formation when added to the tree ring model. However, this effect varies amongst tree species. The results are consistent with tree species specific traits as available from literature: E.g. deep rooting species like Quercus benefit more from high water storage capacity than shallow rooting Picea abies; the effect of soil nutrient status is most pronounced for Fagus sylvatica, which has high nutritional requirements and more negligible for Pinus sylvestris, with low nutritional requirements. As soil formation itself depends upon geological substrate, landform and climate, the improvement of model quality when adding additional soil information is moderate.

Species continuity under the harsh climatic conditions of the boreal forest requires trees to ensure the functioning of two main life processes, namely growth and reproduction. However, species survival becomes a challenge when environmental conditions become unstable and reach the taxa’s ecological tolerance limit. Survival in an unstable environment is possible through the concurring processes of phenotypic plasticity and local adaptation; each process has its advantages and shortcomings. Local adaptation allows attaining the best possible fitness under conditions of limited gene flow and strong directional selection, leading to specific adaptations to the local environment; however, there is a risk of maladaptation when conditions suddenly change. In turn, phenotypic plasticity provides trees an advantage when weather events change rapidly and enables a response expressed by the production of different phenotypes by the same genotype. However, this process is expensive in terms of costs in maintenance and causes developmental instability within the individual. Boreal trees utilize both processes as reflected in variations in their functional traits within the same species. In this chapter, we address the main life processes, presenting the variability of functional traits of flowering and seed production, xylem conductivity, bud and cambium phenology, as well as transpiration and photosynthesis, as a consequence of the interaction of genotype and environment. We describe the practical consequences of a variation in functional traits, as expressed in chemical and mechanical wood properties. Finally, we outline applications and perspectives for managing boreal forests in a context of heterogeneous and changing environmental conditions.

The website oldestwoodenobjects.net serves as a platform for the scientific community to collect, display and share early traces of wood utilization. It also serves educational purposes, to teach a wide audience about how multifunctional and durable wood can be, when wisely used. The collection of objects is large and diverse, ranging from simple tools for hunting, like spears, to musical instruments of the high culture, such as violins. The first means of transport, dugout canoes or early infrastructure, like water wells, are remarkably old. Due to weathering, early buildings or constructions are poorly or only partially preserved. But some sacred buildings that are still in use today have an impressive age. At the time of writing this manuscript, a total of 211 prehistoric and historic wooden objects from around the globe were gathered and can be compared at the online application. The oldest item on the list is from 300 000 years before present. To continue expanding the database, the community is encouraged to contribute new entries.

Wooden shingles have been known in Europe and other regions worldwide for several thousands of years. They are usually split, and according to handicraft rules, as well as historical literature, a split surface has many advantages. It is more flexible, more elastic, stronger, and less exposed to cupping than a sawn surface because no fibers have been cut. It also follows wood rays; it is more durable than a sawn surface because cut fibers absorb more moisture, creating good conditions for fungal growth. However, because sawing is the main procedure for dividing logs into timber, sawn boards are currently used for roofing. The short life span of such roofing has often been discussed by craftsmen. In this study, a 37-year-old roofing was evaluated to determine the important parameters of high-durability sawn boards. Results showed that the presence of juvenile wood, fiber deviations, and knots reduced the durability of these boards. Therefore, sawn boards of the same wood quality as split shingles may have the same durability.

Michael Grabner,1 Julja Burchard,2 Chi Nguyen,3 Haechung Chung,4 Nilesh Gangan,3 J Jay Boniface,2 John AF Zupancic,5 Eric Stanek1 1Scientific Affairs, HealthCore, Inc., Wilmington, DE, USA; 2Research and Development, Sera Prognostics, Salt Lake City, UT, USA; 3Health Economics and Outcomes Research, HealthCore, Inc., Wilmington, DE, USA; 4Research Operations, HealthCore, Inc., Wilmington, DE, USA; 5Department of Neonatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USACorrespondence: Michael GrabnerScientific Affairs, HealthCore, Inc., 123 Justison St, Suite 200, Wilmington, DE, 19801, USATel +1 302-230-2000Email mgrabner@healthcore.comBackground: Preterm birth (PTB) carries increased risk of short- and long-term health problems as well as higher healthcare costs. Current strategies using clinically accepted maternal risk factors (prior PTB, short cervix) can only identify a minority of singleton PTBs.Objective: We modeled the cost-effectiveness of a risk-screening-and-treat strategy versus usual care for commercially insured pregnant US women without clinically accepted PTB risk factors. The risk-screening-and-treat strategy included use of a novel PTB prognostic blood test (PreTRM®) in the 19th– 20th week of pregnancy, followed by treatment with a combined regimen of multi-component high-intensity-case-management and pharmacologic interventions for the remainder of the pregnancy for women assessed as higher-risk by the test, and usual care in women without higher risk.Methods: We built a cost-effectiveness model using a combined decision-tree/Markov approach and a US payer perspective. We modeled 1-week cycles of pregnancy from week 19 to birth (preterm or term) and assessed costs throughout the pregnancy, and further to 12-months post-delivery in mothers and 30-months in infants. PTB rates and costs were based on > 40,000 mothers and infants from the HealthCore Integrated Research Database® with birth events in 2016. Estimates of test performance, treatment effectiveness, and other model inputs were derived from published literature.Results: In the base case, the risk-screening-and-treat strategy dominated usual care with an estimated 870 fewer PTBs (20% reduction) and $54 million less in total cost ($863 net savings per pregnant woman). Reductions were projected for neonatal intensive care admissions (10%), overall length-of-stay (7%), and births < 32 weeks (33%). Treatment effectiveness had the strongest influence on cost-effectiveness estimates. The risk-screening-and-treat strategy remained dominant in the majority of probabilistic sensitivity analysis simulations and model scenarios.Conclusion: Use of a novel prognostic test during pregnancy to identify women at risk of PTB combined with evidence-based treatment is estimated to reduce total costs while preventing PTBs and their consequences.Keywords: preterm birth, cost effectiveness, progesterone, prognostic test

The Vienna Hofburg is a large complex of buildings of unique historic importance with historical wooden constructions from the 13th to the 20th century. Within its wooden roof constructions, rafting wedges were found, which proves that the timber used did not originate in the surroundings of Vienna but had to be transported to the city. An ascertainment of these residual traces in eleven wings of the Hofburg building was made; five different types (within two main groups) of rafting wedges and withies (softened twigs that can be used like short ropes to tie trunks together) were defined: (1) simple flat wedges, driven into the fresh wood; (2) round or squared wedges, with or without withies driven into bored wholes. It was not possible to trace back the origin of the construction timber by means of that typology. However, the combination of dendroprovenancing and historic records found in archives led to first results.

Wood in Austria has been an indispensable source of energy, but also, a crucial building material. In the field of dendroarchaeology the timeline between raw material harvest and finalisation of a wooden construction is a crucial piece of puzzle in understanding building history. This paper aims to provide an overview on historical timber supply in Austria by examining the felling and debarking methods, as recorded in old literature and, from the visible evidence on beams in wooden constructions. Historically, depending on the size and location of a building, a small or extended supply chain of timber was required. These generally consisted of logs travelling via streams and rivers, and possibly beforehand passing through sluices and log slides, being skidded by horses and oxen, and being moved by manpower on sleighs, or simply on the forest floor. The seasonal working steps of the logging process included felling, debranching, debarking, cutting to length, and the start of the transportation process. Debarking was a specific focus in this investigation, as the appearance of bast (the inner bark of trees from which ropes were made) or even bark residues on the waney edge (outermost growth ring underneath the bark), may provide a clue to the felling time of year. These indications of the cutting season have been noticed during dendrochronological sampling of beams in historical buildings. Improved knowledge of them may contribute to future research of these buildings.

Wood is one of the most important sustainable natural resources. Throughout centuries, large cities as well as regions of very high wood demand (for example, areas of salt production and iron processing) had to be supplied with wood for building and burning. One of the largest forests in Austria can be found in the National Park covering the range of mountains called “Limestone Alps.” Within this region, a wide network of dams was set up to transport single logs (“Holztrift”). Due to the dendrochronological dating of the surviving dams, regional chronologies spanning a length of almost 600 years for Norway spruce, Silver fir and European larch were set up. These chronologies serve as the background for dendro-provenancing timber. Dendro-provenancing checks the similarities between samples and different regional chronologies. The highest statistical figures give hints of the origins of the wood. Archival analyses show that many logs were transported to Vienna as rafts. For example, in 1865, more than 1504 rafts arrived in Vienna, all from different origins. The logs were used as building material as well as for burning. Further archival analyses showed that logs from this region were also used for building the roof of the Hofburg Castle in Vienna. Several hundred samples from the roof construction were dendrochronologically dated and used for dendro-provenancing. The origin of the logs was confirmed to be the wider region of the Northern alpine foothills. This meant that rafts from the rivers Alm and Traun as well as from the rivers Steyr and Enns had floated down to Vienna.

Introduction Global prevalence estimates for chronic kidney disease (CKD) in rheumatoid arthritis (RA) vary. This study assessed real-world prevalence estimates of renal impairment, based on estimated glomerular filtration rate (eGFR), among commercially insured patients with RA in the United States (US). Methods In this retrospective cohort study, we used administrative claims data from the HealthCore Integrated Research Database (HIRD®) between January 2013 and December 2018. Adult patients with ≥ 2 claims for RA and ≥ 2 serum creatinine (SCr) measurements ≥ 90 days apart on or after the index date were included. eGFR was calculated per the Modification of Diet in Renal Disease equation. Prevalence of eGFR-based renal impairment was estimated for the overall RA population and for two subgroups: patients on advanced therapies (biologic disease-modifying antirheumatic drugs/tofacitinib) and patients stratified based on health plan types. Results Among 128,062 patients with ≥ 2 RA claims, 42,173 had qualifying SCr measurements, 16,197 were on advanced RA therapies, and 4911 had Medicare Advantage or Supplemental plus Part D coverage. For the overall population and the subgroup on advanced therapies, mild renal impairment was observed in 52% and 51%, moderate renal impairment in 9% and 7%, and severe renal impairment in 0.5% and 0.3% of patients, respectively. Moderate and severe renal impairment was more prevalent in the Medicare Advantage/Supplemental plus Part D population compared to the commercial coverage population. Conclusions Approximately 7–10% of commercially insured adult patients in the US with RA had moderate or severe renal impairment. Assessment of renal function is an important consideration for safe treatment.

Aim To compare 6‐month adherence, persistence and treatment patterns among patients initiating once‐weekly glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), dulaglutide versus semaglutide, and dulaglutide versus exenatide BCise, using claims from the HealthCore Integrated Research Database. Materials and methods Patients aged ≥18 years, with type 2 diabetes, ≥1 claim for dulaglutide, semaglutide or exenatide BCise during the index period February 2018 to December 2018 (index date = earliest GLP‐1RA fill date), no claim for GLP‐1RAs in the 6‐month pre‐index period, and continuous enrolment 6 months pre‐ and post‐index were included. Dulaglutide users were propensity‐matched 1:1 to semaglutide users (3852 pairs) or exenatide BCise users (1879 pairs). The proportions of adherent (proportion of days covered ≥80%) patients were compared using chi‐squared tests. Persistence, measured as days to discontinuation, was analysed using a Cox regression model. Results Matched cohorts (dulaglutide:semaglutide and dulagutide:exenatide BCise) were balanced in baseline characteristics and the mean age was 54 and 55 years, respectively, with approximately 51% and 49% women, respectively. At 6 months, significantly more dulaglutide users were adherent than semaglutide (59.7% vs. 42.7%; P

Background As real-world data resources expand and improve, there will increasingly be opportunities to study the effectiveness of interventions. There is a need to ensure that study designs explore potential sources of bias and either acknowledge or mitigate them, in order to improve the accuracy of findings. The objective of this study was to understand newly approved drug utilization patterns in real-world clinical settings over time. Methods This retrospective study included three sources of real-world data (claims, electronic health records, and recoded data from a quality care program) collected from patients diagnosed with gastric cancer who initiated therapy with either trastuzumab or ramucirumab. Linear regression was used to investigate trends in the use of these drugs for the care of patients with gastric cancer over time from Food and Drug Administration (FDA) approval. Results Eligible patients (n=1700) had consistent demographic and clinical characteristics over time. After regulatory approval, trastuzumab was used in later lines of therapy and then shifted to earlier lines (p=0.002), while ramucirumab utilization remained consistent over time after FDA approval (p=0.49). Ramucirumab augmentation, defined as the addition of the drug after initiation of a line of therapy, decreased over time (p=0.03), and trastuzumab augmentation remained consistent over time (p=0.58). Conclusion Since treatment effectiveness may change across lines of treatment, bias may arise if there are changes in the use of the drug (such as line migration) during the time period of analysis using real-world data.

Objective A survey of US adults with type 2 diabetes mellitus was conducted to better understand patients' insulin initiation experiences and treatment persistence behaviors. Research design and methods Participants were recruited from consumer panels and grouped by basal insulin treatment pattern: continuers (no gap of ≥7 days within 6 months of initiation); interrupters (gap ≥7 days, resumed treatment); discontinuers (stopped for ≥7 days, not resumed). A quota of approximately 50 respondents per persistence category was set. Results A total of 154 respondents (52 continuers, 52 interrupters, 50 discontinuers) completed the survey. Mean age was 51.4 years; 51.9% male. Continuers were more likely to report their views being considered during initiation, and less likely to report a sense of failure. Concerns included insulin dependence (64.3% agree/strongly agree), frequent blood glucose monitoring (55.2%), costs/ability to pay (53.9%), fears of or mistakes during self-injection (52.6%), and weight gain (52.6%). Continuers were motivated by benefits of insulin therapy; experienced or potential side effects were notable factors for interruption/discontinuation. Healthcare provider instruction was indicated as a reason for continuing, stopping, and restarting therapy. Conclusion Benefits of basal insulin therapy motivated continuers while side effects impacted interruption/discontinuation. Persistence on basal insulin is often influenced by provider actions. Earlier provider intervention upon signs of treatment discontinuation may promote persistence.

Objective Choosing chemotherapy for metastatic colorectal cancer (mCRC) requires balancing clinical effectiveness and risk of complications. This study characterized real-world inpatient/emergency department (ED) hospitalizations during first-line chemotherapy among individuals with mCRC. Methods This retrospective cohort study used data from medical and pharmacy claims. All patients had mCRC with ≥1 claim for ≥1 of the 5 most frequently utilized first-line chemotherapy agents (fluorouracil, oxaliplatin, bevacizumab, irinotecan, capecitabine). The main outcome was all-cause hospitalizations (inpatient or ED setting) identified from claims via ICD-9/10-CM coding from index date until 30 days after the end of first-line chemotherapy or last available data. Results A total of 717 individuals (mean age 55 years; 58% male; ECOG 0/1/2+/missing in 44%/39%/6%/11%; median follow-up 116 days) met study criteria. Thirty-four distinct chemotherapy regimens were used. Overall, 40% of patients had ≥1 hospitalization (n=285; total 415 hospitalizations); 12% (n=85) had ≥2 hospitalizations. The median time to first hospitalization was 52 days; median inpatient length of stay was 4 days; infections/neutropenia (21%) and bowel-related complications (17%) were the most common issues associated with inpatient hospitalizations. In univariate analyses, insurance plan type, geographical location, ECOG, and renal disease were associated with hospitalization. In multivariable analyses, ECOG ≥1 was associated with a 67% increase (p

This study presents a new chronometric method for the dating of wood. The clock used is the chemical breakdown of specific parts, such as the acetyl groups of the hemicelluloses. The presented prediction models cover a maximum of 3000 years and include old living trees, construction wood and cold waterlogged wood. Any other preservation conditions are not covered by these models. Under these conditions, abiotic factors dominate and the contribution of microbial decay is negligible. This is a pre-requisite for the application of the present models. Brittle parts of the wood cannot be dated. Infrared spectroscopy was applied to detect the molecular changes over time. Currently, four models are available for Norway spruce, European larch, oak, and silver fir.

This study aimed to assess treatment patterns and frequency of inadequate response associated with advanced therapy initiation among patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in the USA.Adult patients with AS or PsA who initiated advanced therapy were identified from the HealthCore Integrated Research Database®. Inadequate response to advanced therapies (tumour necrosis factor inhibitors [TNFi] and non-TNFi biologics) was identified using a claims-based algorithm. Factors influencing inadequate response were assessed using multivariable logistic regression.In total, 646 patients with AS, and 1433 patients with PsA were evaluated. Among patients with AS (mean age, 43 years; male, 58%), 93% patients initiated TNFi, and 69% of patients had inadequate response. In patients with PsA (mean age, 49 years; male, 47%), 67% initiated TNFi, and 77% had inadequate response. Low adherence was the main predictor of inadequate response in patients with AS (56%) and PsA (63%). Inadequate responders were more likely to be female (odds ratio [OR] 2.05 for AS and 1.37 for PsA). Prior exposure to TNFi was associated with 3.89- and 2.14-fold greater odds of inadequate response in both AS and PsA patients, respectively, while patients using methotrexate were less likely to have inadequate response (OR 0.48 for AS and 0.72 for PsA; all p 0.05).Over 69% of patients with AS and 77% of patients with PsA had inadequate response to their index advanced therapy during 1 year after initiation. Health plan claims data appear useful to classify inadequate responders in AS and PsA. Key Points • Estimating inadequate response to advanced therapies and identifying factors associated with this outcome using claims data could improve treatment outcomes in AS and PsA. • In a sample of commercially insured US patients, over 69% of patients with AS and 77% of patients with PsA had inadequate response to their index advanced therapy during 1 year after initiation. Patient characteristics such as sex and prior therapy use were predictive of inadequate response to advanced therapies. • Health plan claims data appear useful to classify inadequate responders in AS and PsA and identify factors associated with this outcome.

Summary–Stable isotope abundances convey valuable information about plant physiological processes and underlying environmental controls. Central gaps in our mechanistic understanding of hydrogen isotope abundances impede their widespread application within the plant and biogeosciences.–To address these gaps, we analysed intramolecular deuterium abundances in glucose of Pinus nigra extracted from an annually resolved tree-ring series (1961 to 1995).–We found fractionation signals (i.e., temporal variability in deuterium abundance) at glucose H1 and H2 introduced by closely related metabolic processes. Regression analysis indicates that these signals (and thus metabolism) respond to drought and atmospheric CO2 concentration beyond a response change point. They explain ≈60% of the whole-molecule deuterium variability. Altered metabolism is associated with below-average yet not exceptionally low growth.–We propose the signals are introduced at the leaf-level by changes in sucrose-to-starch carbon partitioning and anaplerotic carbon flux into the Calvin-Benson cycle. In conclusion, metabolism can be the main driver of hydrogen isotope variation in plant glucose.

To describe clinical characteristics and treatment outcomes for early or late initiation of dulaglutide therapy in patients with type 2 diabetes.This retrospective, claims-based analysis evaluated adults with type 2 diabetes, ≥1 claim for dulaglutide 0.75 mg or 1.5 mg once-weekly injection (between November 2014 and August 2019), and no prior use of glucagon-like peptide 1 receptor agonists or insulin. Cohorts were defined based on the number of oral antidiabetic drug (OAD) classes used within the 24-month baseline period before dulaglutide therapy initiation: 1 OAD, 2 OADs, or ≥3 OADs. The number of OAD classes used before dulaglutide therapy initiation served as a proxy for timing of initiation, with a higher number of OAD classes indicating a longer duration of T2D. Baseline demographic and clinical characteristics were compared across each cohort. Six-month follow-up outcomes, including change in glycosylated hemoglobin (HbAThe study population consisted of 18,121 patients across the 1 OAD (n = 4822), 2 OADs (n = 6293), and ≥3 OADs (n = 7006) cohorts. Mean age at baseline was 54.7 years. Males were more prevalent in the ≥3 OADs cohort. Most patients (67%-70%) initiated treatment with dulaglutide 0.75 mg. Dose escalation to 1.5 mg was uncommon (15%-20%) but trended higher in the ≥3 OAD cohort. Adherence to dulaglutide at 6-month follow-up (61%-67%) increased with higher baseline OAD use. The HbACohorts of dulaglutide therapy initiators, defined by prior OAD use as a proxy of timing of initiation, differed in their baseline characteristics and short-term follow-up outcomes. Earlier dulaglutide therapy initiation was associated with lower mean HbA

Judith J Stephenson,1 Jonathon Colby Gable,2 Rebekah Zincavage,1 Gregory L Price,2 Collin Churchill,2 Emily Zhu,2 Keri Stenger,2 Mukul Singhal,1 Bal Nepal,1 Michael Grabner,1 Michael J Fisch,3 David Debono,4 Amy R Geschwender,5 Gebra Cuyun Carter2 1HealthCore, Inc., Wilmington, DE, USA; 2Eli Lilly and Company, Indianapolis, IN, USA; 3AIM Specialty Health, Chicago, IL, USA; 4Anthem, Inc., Indianapolis, IN, USA; 5SWOG Cancer Research Network, San Antonio, TX, USACorrespondence: Judith J Stephenson Tel +1 302-547-5770Email JStephenson@healthcore.comPurpose: To describe patients’ perspectives on the use of and potential challenges and barriers with adherence/persistence to cyclin-dependent kinase 4 and 6 inhibitors (CDK4& 6i’s) to treat metastatic breast cancer (MBC).Methods: This qualitative study consisted of 60-minute semi-structured telephone interviews with patients with MBC in the US who were either current or recent CDK4& 6i users, identified from administrative claims of survey-eligible commercial and Medicare Advantage patients in the HealthCore Integrated Research Database between November 1, 2018 and November 1, 2019. Patients were recruited by email and/or mailed letter. The 60-minute telephone interviews were conducted by a trained facilitator using a study-developed interview discussion guide that included topics impacting treatment choice and adherence/persistence. Interviews were audio-recorded, transcribed, and thematically analyzed.Results: All 462 eligible patients were sent a recruitment email and/or letter to which 36 patients responded, consented to participate, and met study inclusion criteria; 25 patients scheduled interviews, and 24 completed them. Study participants were predominately white, non-Hispanic (96%) with a mean age of 59.5 years. Participants reported a largely positive experience and mentioned very few adherence/persistence issues. They further reported appreciating the ease and convenience of oral oncolytics, coped with side effects, had strong medical and social support, and experienced few cost issues.Conclusion: The few adherence/persistence issues reported by participants contrasts with other findings of suboptimal oral oncolytic use. Interview themes indicated several factors that likely contributed to the lack of adherence/persistence issues: trusted relationship with oncologist, belief in importance of medication, positive medication views, strong medical and social support, and minimal personal drug cost. Future research should focus on whether and how much these factors impact adherence/persistence in more diverse populations. If adherence/persistence issues are identified in these populations, then it would be appropriate to study the development of interventions that target factors associated with better adherence/persistence.Keywords: oral oncolytics, patient perspective, semi-structured interviews, adherence, persistence, CDK4& 6i users

Introduction Levothyroxine monotherapy (Synthroid® or multiple generic levothyroxine [GL] formulations) is standard treatment for hypothyroidism. Our objective was to compare effectiveness (as measured by achievement of thyroid-stimulating hormone [TSH] levels) and economic outcomes of Synthroid vs. any one of multiple GLs in patients with hypothyroidism. Methods Data for this retrospective cohort study were obtained from the HealthCore Integrated Research Database®. All study patients had ≥ 2 claims between 1 January 2006 and 31 December 2017 with ICD-9/10-CM diagnosis codes for hypothyroidism; were persistent users of Synthroid vs. any GL; and had ≥ 1 TSH laboratory result during 12-month follow-up. Patients were divided into one of two cohorts based on index medication and were 1:1 matched using propensity scores. The primary outcome was the proportion of patients with last TSH laboratory result during follow-up within the reference range (0.3–4.12 mIU/L). Secondary outcomes included all-cause and hypothyroidism-related healthcare resource utilization (HCRU) and costs. Results After propensity score matching, the Synthroid and GL cohorts each contained 18,382 patients. At follow-up, significantly more patients receiving Synthroid were in the TSH reference range vs. GL (78.5% vs. 77.2%, respectively, p = 0.002). HCRU and costs were broadly similar between the cohorts in terms of all-cause inpatient hospitalizations, emergency department visits, outpatient services, and pharmacy fills. Irrespective of index medication, patients with TSH within the reference range had significantly lower hypothyroidism-related medical and total costs compared to those outside the range. Conclusions This real-world data study showed Synthroid was associated with better TSH target achievement vs. GL in a US managed care population. Achieving TSH goals may provide substantial economic value by reducing hypothyroidism-related HCRU and costs. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01969-3.

This retrospective, observational study assessed glycemic control over a 6-month follow-up among patient cohorts with T2D who initiated dulaglutide (DU) 0.75 mg or 1.5 mg following use of either 1, 2 or 3+ oral antihyperglycemic drugs (OAD) during the 24-month pre-index period. This analysis used US claims data from the HealthCore Integrated Research Database (HIRD®) between November 2012 and February 2020 (index date=earliest DU fill between November 2014 and August 2019). Patients ≥18 years old with T2D, ≥1 pharmacy claim for OAD during the pre-index period, continuous enrollment from 24 months pre-index to 6 months post-index date, and ≥1 A1C result within both 6 months pre- and 6 months post-index were included. There were differences in patient characteristics between the cohorts with significant trends (*see figure) of increasing age, comorbidity index scores and pre-index A1C seen with increasing number of prior OADs. Early initiation of DU, proxied by initiation after 1 OAD, resulted in an A1C reduction of 1.39%, and reductions of 1.30% and 1.01% in the 2 OAD and 3+ OAD cohorts, respectively (figure). Greater A1C reductions were observed across subgroups with higher pre-index A1C in each OAD cohort. In this real-world study, a clinically relevant reduction in A1C was seen within 6 months across all cohorts defined by the timing of initiation of DU, with increasing trend of A1C reduction seen with fewer number of prior OADs. Disclosure M. Hoog: Employee; Self; Eli Lilly and Company, Lilly Diabetes, Stock/Shareholder; Self; Abbott, Eli Lilly and Company, PPD. J. L. Smith: Employee; Self; HealthCore, Other Relationship; Self; Eli Lilly and Company. M. Yu: Employee; Self; Lilly Diabetes, Employee; Spouse/Partner; LifeLabs, Stock/Shareholder; Self; Lilly Diabetes, Stock/Shareholder; Spouse/Partner; Lilly Diabetes. J. Peleshok: Employee; Self; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. M. Grabner: Other Relationship; Self; Eli Lilly and Company.

Coping with discomfort and the uncertainties of daily adjustments are prominent challenges confronting individuals with type 2 diabetes mellitus (T2DM) who require multiple daily injections (MDI) of insulin. For this growing population, wearable, disposable devices capable of delivering consistent and sustained doses of basal-bolus therapy may help to alleviate concerns and improve outcomes. However, studies on the comparative effectiveness of new, innovative delivery systems versus MDI on insulin requirements, glycemic control, and health care costs are sparse.To examine glycemic control, insulin use, and diabetes medication costs for users of the V-Go Wearable Insulin Delivery device compared with MDI insulin therapy among individuals with T2DM in a commercially insured population in the United States.This retrospective cohort study queried administrative claims data from the HealthCore Integrated Research Database from July 1, 2011, through July 31, 2017. Cohorts included individuals with T2DM aged 21-80 years either newly initiating V-Go or using MDI for basal/bolus insulin. The date of earliest claim for V-Go prescription fill or for bolus insulin was defined as the index date, depending on the cohort. Previous insulin therapy was required in both cohorts. Baseline hemoglobin A1c (A1c) values were identified during the 6 months before and 15 days after the index date; results closest to 12 months after the index date were selected as follow-up. Insulin use and diabetes medication cost data were examined during the 6 months baseline and the second half of the 1-year follow-up. V-Go and MDI users were 1:1 matched on baseline insulin exposure, A1c level, and other characteristics of interest. Univariate and multivariate tests were used to compare follow-up outcomes.Matched cohorts included 118 well-balanced pairs (mean age: 56 years; mean baseline A1c: 9.2%). During follow-up, both cohorts experienced improvements in glycemic control relative to baseline (% with A1c ≤ 9%, baseline/follow-up: V-Go 49/69,This study was the first to evaluate clinical and economic outcomes associated with the use of V-Go for up to a 1-year follow-up period. Relative to MDI users, V-Go users had similar glycemic control but lower insulin use and lower diabetes medication costs during follow-up. V-Go therapy may provide an opportunity to improve quality measures more cost-effectively in people with T2DM who require basal-bolus therapy.This study was funded by Valeritas. Nguyen is an employee of Valeritas. Zhou, Grabner, Barron, and Quimbo are employees of HealthCore, which received funding for this study from Valeritas. Raval was an employee of HealthCore at the time the study was conducted. Partial findings from this study were presented at the International Society of Pharmacoeconomics and Outcomes Research 23rd Annual International Meeting; May 19-23, 2018; Baltimore, MD; and the 54th European Association for the Study of Diabetes Annual Meeting; October 1-5, 2018; Berlin, Germany.

Aim The aim was to decipher Europe‐wide spatio‐temporal patterns of forest growth dynamics and their associations with carbon isotope fractionation processes inferred from tree rings as modulated by climate warming. Location Europe and North Africa (30‒70° N, 10° W‒35° E). Time period 1901‒2003. Major taxa studied Temperate and Euro‐Siberian trees. Methods We characterize changes in the relationship between tree growth and carbon isotope fractionation over the 20th century using a European network consisting of 20 site chronologies. Using indexed tree‐ring widths (TRWi), we assess shifts in the temporal coherence of radial growth across sites (synchrony) for five forest ecosystems (Atlantic, boreal, cold continental, Mediterranean and temperate). We also examine whether TRWi shows variable coupling with leaf‐level gas exchange, inferred from indexed carbon isotope discrimination of tree‐ring cellulose (Δ13Ci). Results We find spatial autocorrelation for TRWi and Δ13Ci extending over a maximum of 1,000 km among forest stands. However, growth synchrony is not uniform across Europe, but increases along a latitudinal gradient concurrent with decreasing temperature and evapotranspiration. Latitudinal relationships between TRWi and Δ13Ci (changing from negative to positive southwards) point to drought impairing carbon uptake via stomatal regulation for water saving occurring at forests below 60° N in continental Europe. An increase in forest growth synchrony over the 20th century together with increasingly positive relationships between TRWi and Δ13Ci indicate intensifying impacts of drought on tree performance. These effects are noticeable in drought‐prone biomes (Mediterranean, temperate and cold continental). Main conclusions At the turn of this century, convergence in growth synchrony across European forest ecosystems is coupled with coordinated warming‐induced effects of drought on leaf physiology and tree growth spreading northwards. Such a tendency towards exacerbated moisture‐sensitive growth and physiology could override positive effects of enhanced leaf intercellular CO2 concentrations, possibly resulting in Europe‐wide declines of forest carbon gain in the coming decades. Spanish Government, Grant/Award Number: AGL2015‐68274 ‐C3 ‐3‐R; Sixth Framework Programme, Grant/AwardNumber: EVK2‐2001 ‐00237; Seventh Framework Programme, Grant/AwardNumber: COST ‐STSM ‐ECOST ‐STSM ‐FP1304‐140915‐066395 and ERANET‐Mundus program (Grant agreement 20112573)

Aims To evaluate adherence, persistence, glycaemic control and costs at 12‐month follow‐up for patients initiating dulaglutide versus liraglutide or exenatide once weekly. Materials and methods The present retrospective observational claims study included patients with type 2 diabetes (T2D) and ≥ 1 pharmacy claim for dulaglutide, liraglutide or exenatide once weekly from the HealthCore Integrated Research Database. Adherence was defined as proportion of days covered ≥80%, and persistence was measured by time to discontinuation of index therapy. Change from baseline in glycated haemoglobin (HbA1c) concentration was assessed in a subset with pre‐ and post‐index HbA1c results. Propensity scores were used to match the cohorts. Results The baseline characteristics were balanced for the matched cohorts, dulaglutide versus liraglutide (n = 2471) and dulaglutide versus exenatide once weekly (n = 1891). Among those initiating dulaglutide there was a significantly higher proportion of adherent patients compared with the groups initiating liraglutide (51.2% vs. 38.2%; P