No free lunch for avoiding clustering vulnerabilities in distributed systems.

Emergent design failures are ubiquitous in complex systems, and often arise when system elements cluster. Approaches to systematically reduce clustering could improve a design's resilience, but reducing clustering is difficult if it is driven by collective interactions among design elements. Here, we use techniques from statistical physics to identify mechanisms by which spatial clusters of design elements emerge in complex systems modelled by heterogeneous networks. We find that, in addition to naive, attraction-driven clustering, heterogeneous networks can exhibit emergent, repulsion-driven clustering. We draw quantitative connections between our results on a model system in naval engineering to entropy-driven phenomena in nanoscale self-assembly, and give a general argument that the clustering phenomena we observe should arise in many distributed systems. We identify circumstances under which generic design problems will exhibit trade-offs between clustering and uncertainty in design objectives, and we present a framework to identify and quantify trade-offs to manage clustering vulnerabilities.

Neighborhood-scale lead (Pb) speciation in Akron, Ohio (USA) soils: primary sources, post-deposition diagenesis, and high concentrations of labile Pb.

Lead (Pb) poses a significant risk to infants and children through exposure to contaminated soil and dust. However, there is a lack of information on Pb speciation and distribution at the neighborhood-scale. This work aimed to determine: (1) the distribution of acid-extractable (labile) Pb and other metals ([M]AE) in two neighborhoods in Akron, Ohio (USA) (Summit Lake and West Akron; n = 82 samples); and (2) Pb speciation and potential sources. Total metal concentration ([M]T) and [M]AE was strongly correlated for Pb and Zn (R2 of 0.66 and 0.55, respectively), corresponding to 35% and 33% acid-extractability. Lead and Zn exhibited a strong positive correlation with each other (R2 = 0.56 for MT and 0.68 for MAE). Three types of Pb-bearing phases were observed by electron microscopy: (1) galena (PbS)-like (5-10 µm); (2) paint chip residuals (10-20 µm); and (3) Pb-bearing Fe-oxides (20 µm). Isotope ratio values for PbAE were 1.159 to 1.245 for 206Pb/207Pb, and 1.999 to 2.098 for 208Pb/206Pb, and there was a statistically significant difference between the two neighborhoods (p = 0.010 for 206Pb/207Pb and p = 0.009 for 208Pb/206Pb). Paint and petrol are the dominant sources of Pb, with some from coal and fly ash. Lead speciation and distribution is variable and reflects a complex relationship between the input of primary sources and post-deposition transformations. This work highlights the importance of community science collaborations to expand the reach of soil sampling and establish areas most at risk based on neighborhood-dependent Pb speciation and distribution for targeted remediation.

It's time to consider the Arcellinida shell as a weapon.

The shells of testate amoebae are morphologically diverse and persistent in the environment. Accordingly, the examination of the morphology and composition of shells became a standard tool in ecological, palaeoecological, and evolutionary studies. However, so far the function of the shell remains poorly understood and, although based on limited evidence, the shell was considered as a defense mechanism. Based on recent evidence, we propose that the shell of arcellinid testate amoebae is a crucial component facilitating the amoebae's attack of large prey. Accordingly, the shell is not purely protective, but must be considered also as a weapon. This change in perspective opens up numerous new avenues in protistology and will lead to a substantial change in ecological, palaeoecological, and evolutionary research.

Effectiveness and safety of recombinant zoster vaccine: A review of real-world evidence.

The recombinant zoster vaccine (RZV) was licensed in the US for prevention of herpes zoster (HZ) in 2017. We conducted a literature search (January 1, 2017-August 1, 2023) using PubMed, Embase, and Scopus to consolidate the real-world evidence related to RZV. Overall, RZV effectiveness against HZ was high across the studied populations in real-world settings, including adults aged ≥ 50 years and patients aged ≥ 18 years with immunodeficiency or immunosuppression. Effectiveness was higher with two doses versus one dose, especially in elderly people and immunocompromised individuals. The safety profile of RZV was broadly consistent with that established in clinical trials. RZV does not appear to increase the risk of disease flares in patients with immune-mediated diseases. Approximately two-thirds of individuals received a second RZV dose within 2-6 months after the first dose. Collectively, RZV effectiveness against HZ was high, and these real-world studies reaffirm its favorable benefit-risk profile.

What is the context?Herpes zoster is a common and painful rash that develops following reactivation of latent (meaning silent or dormant) varicella zoster virus, which is the virus that causes the common childhood illness chickenpox. The recombinant zoster vaccine (RZV) was first approved for the prevention of herpes zoster in the USA and Canada in 2017 and has since been approved in the European Union and various other countries. The approval was based on the results of large clinical trials. Since its launch over 5 years ago, evidence for RZV use in real-world settings has been collected; the benefits of real-world studies include large sample sizes, more diverse populations, and the ability to identify rare side effects.What is new?We provide a review of real-world studies, which have shown that RZV is effective across the studied populations, including in adults aged 50 years and above and in patients with immunodeficiencies (i.e., those who have a decreased ability to fight infections or other diseases) or receiving immunosuppressive therapies (treatments that lower the activity of the body's immune system). The safety profile of RZV in real-world studies was generally consistent with that seen in clinical trials.What is the impact?These studies show the effectiveness and well-tolerated safety profile of RZV in real-world settings.

Burden of Herpes Zoster Among Patients with Psoriasis in the United States.

INTRODUCTION: Patients with psoriasis (PsO) are at increased risk of herpes zoster (HZ), but recent data on the incidence of HZ among patients with PsO and the impact of HZ on healthcare resource use (HRU) and costs for patients with PsO have not been described. METHODS: This retrospective, longitudinal, cohort study estimated HZ incidence in cohorts of adults with vs without PsO (PsO + vs PsO-) and HRU and costs among those with PsO, with vs without HZ (PsO + /HZ + vs PsO + /HZ-) using Optum's de-identified Clinformatics Data Mart Database during 2015-2020. Patients with psoriatic arthritis were excluded from all four cohorts. Comparisons between cohorts used generalized linear models to adjust outcomes based on various baseline characteristics. RESULTS: The incidence rate of HZ was significantly higher in the PsO + (n = 144,115) vs PsO- (n = 23,837,237) cohorts at 11.35 vs 7.67 per 1000 patient-years; adjusted incidence rate ratio (aIRR): 1.21, 95% confidence interval (CI): 1.16-1.25. HRU (outpatient, emergency department, and inpatient) was significantly higher in the PsO + /HZ + (n = 1859) vs PsO + /HZ- (n = 78,664) cohorts during 1 month and 3 months after HZ diagnosis (e.g., outpatient visits during month: 2.83 vs 1.30 per patient; aIRR: 1.96; 95% CI 1.86-2.06). Mean all-cause costs were also significantly higher in the PsO + /HZ + vs PsO + /HZ- cohort during both month ($5020 vs $2715 per patient; adjusted cost difference: $1390; 95% CI $842-$1964) and 3 months ($12,305 vs $8256; adjusted cost difference: $1422; 95% CI $280-$2889) after HZ diagnosis. CONCLUSION: These findings show the increased incidence of HZ among patients with PsO and the clinical and economic burdens of HZ in this population. Considering the high prevalence of PsO, insights into the impact of HZ in these patients provide valuable evidence to inform clinical decision-making.

Psoriasis is an inflammatory condition that causes flaky, scaly skin. Herpes zoster (shingles) causes a painful rash, usually on the abdomen. However, recent data on the proportion of patients with psoriasis who develop herpes zoster is lacking. Furthermore, little is known about the healthcare resources that are used or the costs of care for patients with psoriasis who develop herpes zoster. We found that patients with psoriasis were 21% more likely to have herpes zoster than patients without psoriasis. Among patients with psoriasis, those who developed herpes zoster had twice as many doctor's visits, 3 times as many emergency department visits, and twice as many inpatient hospital stays during the month after a herpes zoster diagnosis as patients without herpes zoster. This resulted in an additional cost of $1390 per patient with psoriasis and herpes zoster compared with those with psoriasis but without herpes zoster. Overall, patients with psoriasis are at increased risk of developing herpes zoster and the healthcare resource use and associated cost of treating herpes zoster in patients with psoriasis is substantial.

Impact of chronic fibrosing interstitial lung disease on healthcare use: association between fvc decline and inpatient hospitalization.

BACKGROUND: Many types of interstitial lung diseases (ILDs) may transition to progressive chronic-fibrosing ILDs with rapid lung function decline and a negative survival prognosis. In real-world clinical settings, forced vital capacity (FVC) measures demonstrating progressive decline may be linked to negative outcomes, including increased risks of costly healthcare resource utilization (HRU). Thus, we assessed the relationship between rate of decline in lung function and an increase in HRU, specifically inpatient hospitalization, among patients with chronic fibrosing ILD. METHODS: This study utilized electronic health records from 01-Oct-2015 to 31-Oct-2019. Eligible patients (≥ 18 years old) had ≥ 2 fibrosing ILD diagnosis codes, clinical activity for ≥ 15 months, and ≥ 2 FVC tests occurring 6 months apart. Patients with missing demographic data, IPF, or use of nintedanib or pirfenidone were excluded. Two groups were defined by relative change in percent of predicted FVC (FVC% pred) from baseline to 6 months: significant decline (≥ 10%) vs. marginal decline/stable FVC (decrease < 10% or increase). The primary outcome was defined as the occurrence of an inpatient hospitalization 6 months after the first FVC value. Descriptive and multivariable analysis was conducted to examine the impact of FVC decline on occurrence of inpatient hospitalization. RESULTS: The sample included 566 patients: 13% (n = 75) with significant decline and 87% (n = 491) with marginal decline/stable FVC; their mean age (SD) was 65 (13.7) years and 56% were female. Autoimmune diagnoses were observed among 40% of patients with significant decline, and 27% with marginal decline/stable FVC. The significant decline group had better lung function at baseline than the marginal/stable group. For patients with FVC% <80% at baseline, reduction of FVC% ≥10% was associated with significantly increased odds of an inpatient hospitalization (odds ratio [OR] 2.85; confidence interval [CI] 1.17, 6.94 [p = 0.021]). CONCLUSION: Decline in FVC% ≥10% was associated with increased odds of inpatient hospitalization among patients with reduced lung function at baseline. These findings support the importance of preserving lung function among patients with fibrosing ILD.

The potential impact of increased recombinant zoster vaccine coverage on the burden of herpes zoster among adults aged 50-59 years.

INTRODUCTION: Recombinant zoster vaccine (RZV) is recommended in the US for prevention of herpes zoster (HZ) in adults aged ≥50 years. Vaccination rates remain suboptimal for adults 50-59 years compared with adults ≥50 years overall. The objective of this study was to model changes in outcomes associated with improved RZV vaccination coverage in US adults 50-59 years. METHODS: A multicohort Markov model compared a scenario using real-world vaccination coverage for US adults 50-59 years in 2020 versus scenarios assuming higher coverage. Outcomes, based on a lifetime horizon, included HZ cases and complications avoided, quality-adjusted life-years (QALY), and costs. Model inputs included HZ epidemiology, RZV vaccine efficacy, coverage, adverse events, and costs, based on published literature and US sources. Some inputs were updated from previous models, including real-world estimates of RZV coverage, series completion, and reflecting longer-term data on waning of vaccine efficacy. The model utilized a cohort size of 42,756,488 individuals based on the 2020 US population census. RESULTS: The model projected that increasing RZV coverage in adults 50-59 years from 7.3 % to 14.6 % (to coverage for adults 60-64 years in 2020) would avoid an additional 504,468 HZ cases, 42,077 postherpetic neuralgia cases, and 56,247 cases of other HZ-associated complications. The increase in vaccine coverage would result in higher vaccination-related costs of $1,172,411,566, but the avoided HZ cases and complications would be expected to result in direct cost savings of $721,973,386 and indirect cost savings of $593,497,480 from avoided productivity loss. Overall, a gain of 5,230 discounted QALYs and cost savings of $143,059,299 from a societal perspective would be realized. CONCLUSION: Modestly higher RZV coverage in US adults 50-59 years could reduce the clinical burden associated with HZ and may result in societal cost savings. These findings demonstrate the potential value of increasing RZV vaccination in this population.

Unlocking foraminiferal genetic diversity on estuarine mudflats with eDNA metabarcoding.

Environmental biomonitoring is a prerequisite for efficient evaluation and remediation of ecosystem degradation due to anthropogenic pressure or climate change. Estuaries are key habitats subject to multiple anthropogenic and natural stressors. Due to these multiple stressors, the detection of anthropogenic pressure is challenging. The fact that abundant natural stressors often lead to negative quality assessments has been coined the "estuarine quality paradox". To solve this issue, the application of molecular approaches with successful bioindicators like foraminifera is promising. However, sampling protocols, molecular procedures and data analyses need to be validated before such tools can be routinely applied. We conducted an environmental DNA survey of estuarine mudflats along the French Atlantic coast, using a metabarcoding approach targeting foraminifera. Our results demonstrate that estuarine environments have only a few active OTUs dominating the community composition and a large stock of dormant or propagule stages. This last genetic diversity components constitute an important reservoir, with different species which can potentially develop in response to the temporal variability of the multiple stressors. In fact, different OTUs were dominant in the studied estuaries. Our statistical model shows that the physical and chemical characteristics of the sediment and the climatic conditions explain only 43 % of the community composition variance. This suggests that other, less easily quantifiable factors, such as the history and use of the estuaries or the ecological drift could play an important role as well. Environmental DNA biomonitoring opens new perspectives to better characterize the genetic diversity in estuaries.

Economic and Clinical Burden of Herpes Zoster Among Patients With Inflammatory Bowel Disease in the United States.

Background: Patients with ulcerative colitis (UC) or Crohn's disease (CD) are at increased risk of herpes zoster (HZ); however, relevant cost and healthcare resource utilization (HCRU) data are limited. Methods: We estimated HCRU (hospitalization, emergency department [ED], and outpatient visits) and costs in patients with UC or CD, with and without HZ, using administrative claims data (October 2015-February 2020). HCRU and costs (2020 US dollars) were compared at 1 month, 1 quarter, and 1 year after the index date, using propensity score adjustment and generalized linear models. Results: In total, 20 948 patients were included: UC+/HZ+ (n = 431), UC+/HZ- (n = 10 285), CD+/HZ+ (n = 435), and CD+/HZ- (n = 9797). Patients with HZ had higher all-cause HCRU rates and all-cause total healthcare costs relative to those without HZ. In the first month, adjusted incidence rate ratios (aIRRs) for hospitalizations and ED visits for patients with UC and HZ compared with UC alone were 2.87 (95% confidence interval [CI], 1.93-4.27) and 2.66 (95% CI,1.74-4.05), respectively; for those with CD and HZ, aIRRs were 3.34 (95% CI, 2.38-4.70) and 3.31 (95% CI, 2.32-4.71), respectively, compared with CD alone (all P < .001). Adjusted cost differences in UC and CD cohorts with HZ over the first month were $2189 and $3774, respectively, chiefly driven by higher inpatient costs. The incremental impact on HCRU and costs in cohorts with HZ predominantly occurred during the first quarter following diagnosis. Conclusions: HZ is associated with increased HCRU and costs in patients with UC and CD, especially shortly after diagnosis.

Clinical and Economic Burden of Herpes Zoster in Patients with Rheumatoid Arthritis: A Retrospective Cohort Study Using Administrative Claims.

OBJECTIVE: To estimate the incremental healthcare resource utilization (HRU) and cost burden posed by herpes zoster (HZ) in adult patients with rheumatoid arthritis (RA) in the United States. METHODS: A retrospective cohort study was conducted using an administrative claims database containing commercial and Medicare Advantage with Part D data, between October 2015 and February 2020. Patients with RA and HZ (RA+/HZ+) or RA without HZ (RA+/HZ-) were identified based on diagnosis codes and relevant medications. Outcomes measured included HRU and medical, pharmacy, and total costs at month 1, quarter 1, and year 1 after the index date (HZ diagnosis for RA+/HZ+ cohort, randomly assigned for RA+/HZ- cohort). Generalized linear models incorporating propensity scores and other covariates were used to estimate differences in outcomes between cohorts. RESULTS: A total of 1866 patients from the RA+/HZ+ cohort and 38,846 patients from the RA+/HZ- cohort were included. Hospitalizations and emergency department visits occurred more frequently in the RA+/HZ+ than the RA+/HZ- cohort, especially in the month after HZ diagnosis (adjusted incidence rate ratio [95% confidence interval (CI)] for hospitalizations: 3.4 [2.8; 4.2]; emergency department visits: 3.7 [3.0; 4.4]). Total costs were also higher in the month after HZ diagnosis (mean adjusted cost difference [95% CI]: $3404 [$2089; $4779]), with cost differences driven by increased medical costs ($2677 [$1692; $3670]). CONCLUSIONS: These findings highlight the high economic burden of HZ among individuals with RA in the United States. Strategies to reduce the risk of HZ in patients with RA (such as vaccination) may serve to reduce this burden. Video abstract.

Incidence and risk of herpes zoster in patients with ulcerative colitis and Crohn's disease in the USA.

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of herpes zoster (HZ). We evaluated the incidence of HZ in ulcerative colitis (UC) and Crohn's disease (CD) patients and compared this with HZ incidence in a non-IBD population. Methods: We conducted a retrospective cohort study (GSK study identifier: VEO-000043) of adults aged ≥18 years with UC and CD and without IBD who were identified from claims recorded in a US healthcare database between October 2015 and February 2020. Crude HZ incidence rates/1,000 person-years (PY) were calculated, and comparisons of HZ incidence rates between UC or CD and non-IBD cohorts were made using adjusted generalized linear models. Results: The study population comprised a total of 29,928 UC, 25,959 CD, and 11,839,329 non-IBD patients. Crude overall HZ incidence rates were 13.64/1,000 PY (UC), 15.94/1,000 PY (CD), and 7.95/1,000 PY (non-IBD). UC and CD patients had increased HZ incidence rates, with adjusted incidence rate ratios of 1.35 (95% confidence interval [CI], 1.26-1.44) and 1.66 (95% CI, 1.56-1.77), respectively, compared with non-IBD patients. Stratified analysis indicated increased relative rates of HZ in progressively younger age strata in the UC and CD patients compared with non-IBD patients. HZ incidence rates were higher in UC and CD patients who had previously received thiopurines or methotrexate, TNF-inhibitors, or corticosteroids than in UC and CD patients who did not take those medicines. Conclusion: UC and CD patients had increased HZ incidence rates compared with patients without IBD, demonstrating the importance of HZ prevention in IBD patients.

Through the eDNA looking glass: Responses of fjord benthic foraminiferal communities to contrasting environmental conditions.

The health of coastal marine environments is severely declining with global changes. Proxies, such as those based on microeukaryote communities, can record biodiversity and ecosystem responses. However, conventional studies rely on microscopic observations of limited taxonomic range and size fraction, missing putatively ecologically informative community components. Here, we tested molecular tools to survey foraminiferal biodiversity in a fjord system (Sweden) on spatial and temporal scales: Alpha and beta diversity responses to natural and anthropogenic environmental trends were assessed and variability of foraminiferal environmental DNA (eDNA) compared to morphology-based data. The identification of eDNA-obtained taxonomic units was aided by single-cell barcoding. Our study revealed wide diversity, including typical morphospecies recognized in the fjords, and so-far unrecognized taxa. DNA extraction method impacted community composition outputs significantly. DNA extractions of 10 g sediment more reliably represented present diversity than of 0.5-g samples and, thus, are preferred for environmental assessments in this region. Alpha- and beta diversity of 10-g extracts correlated with bottom-water salinity similar to morpho-assemblage diversity changes. Sub-annual environmental variability resolved only partially, indicating damped sensitivity of foraminiferal communities on short timescales using established metabarcoding techniques. Systematically addressing the current limitations of morphology-based and metabarcoding studies may strongly improve future biodiversity and environmental assessments.

Incidence of Herpes Zoster in Patients With Rheumatoid Arthritis in the United States: A Retrospective Cohort Study.

OBJECTIVE: To estimate the incidence of herpes zoster (HZ) in patients with rheumatoid arthritis (RA) compared with the general population in the USA. METHODS: This retrospective, longitudinal cohort study used data from an administrative claims database containing both commercial and Medicare Advantage Part D data, with a data period from October 2015 to February 2020. Patients were aged ≥ 18 years and divided into 2 cohorts: patients with RA and patients without RA. Diagnosis and procedure codes were used to identify HZ cases and calculate incidence rates (IRs) of HZ in the 2 cohorts. Data were stratified by age group (ie, 18-49, 18-29, 30-39, 40-49, 50-64, and ≥ 65 yrs) and RA therapy type. IR ratios (IRRs), adjusted by cohort baseline characteristics, were estimated using generalized linear models to compare the incidence of HZ between cohorts. RESULTS: The overall IR of HZ was higher in the RA cohort (21.5 per 1000 person-years [PY]; N = 67,650) than in the non-RA cohort (7.6 per 1000 PY; N = 11,401,743). The highest IRs in both cohorts were observed in the age group of ≥ 65 yrs (23.4 and 11.4 per 1000 PY in the RA cohort and non-RA cohort, respectively). The overall adjusted IRR of HZ was 1.93 (95% CI 1.87-1.99, P < 0.001) for the RA cohort compared with the non-RA cohort. In the RA cohort, the highest IRs by medication class were observed in patients using corticosteroids and those using Janus kinase inhibitors. CONCLUSION: These results highlight the increased incidence of HZ in patients with RA.

A needle in a haystack: A new metabarcoding approach to survey diversity at the species level of Arcellinida (Amoebozoa: Tubulinea).

Environmental DNA-based diversity studies have increased in popularity with the development of high throughput sequencing technologies. This permits the potential simultaneous retrieval of vast amounts of molecular data from many different organisms and species, thus contributing to a wide range of biological disciplines. Environmental DNA protocols designed for protists often focused on the highly conserved small subunit of the ribosome gene, that does not permit species-level assignments. On the other hand, eDNA protocols aiming at species-level assignments allow a fine level ecological resolution and reproducible results. These protocols are currently applied to organisms living in marine and shallow lotic freshwater ecosystems, often in a bioindication purpose. Therefore, in this study, we present a species-level eDNA protocol designed to explore diversity of Arcellinida (Amoebozoa: Tubulinea) testate amoebae taxa that is based on mitochondrial cytochrome oxidase subunit I (COI). These organisms are widespread in lentic water bodies and soil ecosystems. We applied this protocol to 42 samples from peatlands, estuaries and soil environments, recovering all the infraorders in Glutinoconcha (with COI data), except for Hyalospheniformes. Our results revealed an unsuspected diversity in morphologically homogeneous groups such as Cylindrothecina, Excentrostoma or Sphaerothecina. With this protocol we expect to revolutionize the design of modern distributional Arcellinida surveys. Our approach involves a rapid and cost-effective analysis of testate amoeba diversity living in contrasted ecosystems. Therefore, the order Arcellinida has the potential to be established as a model group for a wide range of theoretical and applied studies.

A Modified Murine Heterotopic Heart Transplant Protocol Matching Contemporary Standards of Aseptic Technique, Anesthesia, and Analgesia.

The development of experimental models of cardiac transplantation in animals has contributed to many advances in the fields of immunology and solid organ transplantation. While the heterotopic vascularized murine cardiac transplantation model was initially utilized in studies of graft rejection using combinations of mismatched inbred mouse strains, access to genetically modified strains and therapeutic modalities can provide powerful new preclinical insights. Fundamentally, the surgical methodology for this technique has not changed since its development, especially with respect to important factors such as aseptic technique, anesthesia, and analgesia, which make material impacts on postsurgical morbidity and mortality. Additionally, improvements in perioperative management are expected to provide improvements in both animal welfare and experimental outcomes. This paper reports upon a protocol developed in collaboration with a subject matter expert in veterinary anesthesia and describes the surgical technique with an emphasis on perioperative management. Additionally, we discuss the implications of these refinements and provide details on troubleshooting critical surgical steps for this procedure.

Burden of illness in progressive fibrosing interstitial lung disease.

BACKGROUND: Progressive fibrosing interstitial lung disease (ILD) is a relatively new clinical concept describing a variety of ILDs characterized by progressive pulmonary fibrosis with associated lung function decline and worsening chest imaging. Little is known about health care resource utilization (HCRU) and costs associated with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF). This study analyzed the adjusted HCRU and cost burden among patients with incident non-IPF progressive fibrosing ILD vs matched patients with incident fibrosing ILD that had not yet progressed. METHODS: This was a retrospective study of insured US adults newly diagnosed with non-IPF fibrosing ILD from October 2016 to June 2019, conducted using administrative claims data from the Optum Research Database. Progressive disease was identified using claims-based proxies comprising health care utilization associated with management of progressive fibrosing ILD. Patients in the progressive population were 1:1 propensity score matched to not-yet-progressed patients on the basis of baseline demographic and clinical characteristics. All-cause HCRU and health care costs were presented as weighted per-patient-per-month (PPPM) measures to account for variable follow-up. Differences in study outcomes between matched cohorts were evaluated using Z-tests for continuous measures and Rao-Scott tests for binary measures. RESULTS: The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with not-yet-progressed fibrosing ILD. Mean (SD) weighted PPPM counts of follow-up health care encounters were significantly higher for the progressive vs not-yet-progressed cohort: ambulatory visits, 4.2 (3.6) vs 3.1 (3.3); emergency department visits, 0.3 (0.5) vs 0.1 (0.3); and inpatient (IP) stays, 0.1 (0.2) vs 0.0 (0.1) (P < 0.001 for all). Among patients with an IP stay, those with progressive disease had more inpatient days than those with not-yet-progressed disease (mean [SD] 1.6 [2.4] days vs 1.0 [1.3] days, P < 0.001). Mean weighted PPPM (SD) all-cause health care costs were also significantly higher for progressive vs not-yet-progressed patients, including total costs ($4,382 [$9,597] vs $2,243 [$4,162], P < 0.001), medical costs ($3,662 [$9,150] vs $1,627 [$3,524], P < 0.001), and pharmacy costs ($720 [$2,097] vs $616 [$2,070], P = 0.002). The difference in medical costs between cohorts was driven primarily by higher inpatient costs for progressive vs not-yet-progressed patients ($1,729 [$7,557] vs $523 [$2,118], P < 0.001). CONCLUSIONS: Progressive fibrosing ILD carries a substantial economic and health care burden. Among patients with incident non-IPF fibrosing ILD, all-cause HCRU and costs were significantly higher for those with a progressive phenotype than for matched patients whose disease had not yet progressed. The cost differential was driven primarily by hospitalizations, which were longer and more frequent for the progressive cohort. Disclosures: This work was funded by Boehringer Ingelheim Pharmaceuticals, Inc. Drs Conoscenti and Shetty are employees of Boehringer Ingelheim (BI). Dr Singer was an employee of BI at the time the study was conducted. Dr Brown was a paid consultant for BI for this study. Dr Bengtson, Ms Anderson, and Dr Brekke are employees of Optum, which was contracted by BI to conduct the study. Medical writing assistance was provided by Yvette Edmonds, PhD (Optum), and was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc.

Care patterns of patients with chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype.

BACKGROUND: Interstitial lung diseases (ILDs) include a variety of parenchymal lung diseases. The most common types of ILDs are idiopathic pulmonary fibrosis (IPF), autoimmune ILDs and hypersensitivity pneumonitis (HP). There is limited real world data on care patterns of patients with chronic fibrosing ILDs with a progressive phenotype other than IPF. Therefore, the aim of this study is to describe care patterns in these patients. METHODS: This retrospective cohort study used claims data from 2015 to 2019 from the Optum Research Database. The study population included adults (≥ 18 years old) with at least two diagnosis codes for fibrosing ILD during the identification period (1OCT2016 to 31DEC2018). A claim-based algorithm for disease progression was used to identify patients likely to have a progressive fibrotic phenotype using progression proxies during the identification period. Index date was the first day of progression proxy identification after fibrosing ILD diagnosis. Patients were required to have continuous enrollment for 12 months before (baseline) and after (follow-up) index date. Patients with an IPF diagnosis were excluded. Descriptive statistics were used to describe the patient population and care patterns. RESULTS: 11,204 patients were included in the study. Mean age of the patient population was 72.7 years, and 54.5% were female. Unclassified ILDs (48.0%), HP (25.2%) and autoimmune ILDs (16.0%) were the most common ILD types. Other respiratory conditions were prevalent among patients including chronic obstructive pulmonary disease (COPD) (58.9%), obstructive sleep apnea (OSA) (25.0%) and pulmonary hypertension (9.8%). During baseline, 65.3% of all patients had at least one pulmonology visit, this proportion was higher during follow-up, at 70.6%. Baseline and follow-up use for HRCT were 39.9% and 48.8%, and for pulmonary function tests were 43.7% and 48.5% respectively. Use of adrenal corticosteroids was higher during follow-up than during baseline (62.5% vs. 58.0%). Anti-inflammatory and immunosuppressive medication classes were filled by a higher percentage of patients during follow-up than during baseline. CONCLUSIONS: Comprehensive testing is essential for diagnosis of a progressive phenotype condition, but diagnostic tests were underutilized. Patients with this condition frequently were prescribed anti-inflammatory and immunosuppressive medications.

Discrepancies between prokaryotes and eukaryotes need to be considered in soil DNA-based studies.

Metabarcoding approaches are exponentially increasing our understanding of soil biodiversity, with a major focus on the bacterial part of the microbiome. Part of the soil diversity are also eukaryotes that include fungi, algae, protists and Metazoa. Nowadays, soil eukaryotes are targeted with the same approaches developed for bacteria and archaea (prokaryotes). However, fundamental differences exist between domains. After providing a short historical overview of the developments of metabarcoding applied to environmental microbiology, we compile the most important differences between domains that prevent direct method transfers between prokaryotic and eukaryotic soil metabarcoding approaches, currently dominated by short-read sequencing. These include the existence of divergent diversity concepts and the variations in eukaryotic morphology that affect sampling and DNA extraction. Furthermore, eukaryotes experienced much more variable evolutionary rates than prokaryotes, which prevent capturing the entire eukaryotic diversity in a soil with a single amplification protocol fit for short-read sequencing. In the final part we focus on future potentials for optimization of eukaryotic metabarcoding that include superior possibility of functionally characterizing eukaryotes and to extend the current information obtained, such as by adding a real quantitative component. This review should optimize future metabarcoding approaches targeting soil eukaryotes and kickstart this promising research direction.

Impact of timing of nintedanib initiation among patients newly diagnosed with idiopathic pulmonary fibrosis.

AIMS: While nintedanib treatment has been shown to slow the progression of idiopathic pulmonary fibrosis (IPF) in patients across varying levels of lung function, the effect of treatment timing on outcomes has not been examined. We assessed hospitalization risk and medical costs among patients with IPF based on the timing of nintedanib initiation after IPF diagnosis. MATERIALS AND METHODS: This retrospective administrative claims study included data from 04/01/2014-09/30/2019 for patients aged ≥40 years who initiated nintedanib within 1 year of IPF diagnosis. Patients were assigned to study cohorts based on the time from IPF diagnosis to nintedanib initiation. All-cause hospitalization and all-cause medical costs were modeled using marginal structural models including inverse probability weights to adjust for both baseline and time-varying characteristics. RESULTS: Of 11,195 patients diagnosed with IPF during the identification period, 449 met the study selection criteria (mean age 72.3 years, 68% male, mean follow-up time 13.3 months). Adjusted hospitalization risk and medical costs both varied significantly by the timing of nintedanib initiation (p < .001 and p = .020, respectively). Adjusted weighted hospitalization risk was higher among untreated vs. treated patients in months 2-3, months 4-6, and months 7-12 after diagnosis (hazard ratio [95% CI] 1.97 [1.09-3.56], p = .026; 2.62 [1.22-5.63], p = .014; and 5.57 [2.31-13.45], p < .001, respectively). Medical costs were 69% higher for patients initiating treatment in months 2-3 vs. month 1 (cost ratio [95% CI] 1.69 [1.20-2.38], p = .003). LIMITATIONS: Disease severity could not be assessed because clinical data were unavailable; however, proxies such as oxygen use were included to adjust for between-cohort differences in disease severity. CONCLUSIONS: Patients who initiate nintedanib promptly after IPF diagnosis may have reduced hospitalization risk and medical costs compared with those who start treatment later. Additional studies are warranted to improve understanding of the impact of prompt antifibrotic therapy on patient outcomes.