Effects of water flow and ocean acidification on oxygen and pH gradients in coral boundary layer.

Reef-building corals live in highly hydrodynamic environments, where water flow largely controls the complex chemical microenvironments surrounding them-the concentration boundary layer (CBL). The CBL may be key to alleviate ocean acidification (OA) effects on coral colonies by partially isolating them. However, OA effects on coral CBL remain poorly understood, particularly under different flow velocities. Here, we investigated these effects on the reef-building corals Acropora cytherea, Pocillopora verrucosa, and Porites cylindrica. We preconditioned corals to a control (pH 8.0) and OA (pH 7.8) treatment for four months and tested how low flow (2 cm s-1) and moderate flow (6 cm s-1) affected O2 and H+ CBL traits (thickness, surface concentrations, and flux) inside a unidirectional-flow chamber. We found that CBL traits differed between species and flow velocities. Under OA, traits remained generally stable across flows, except surface pH. In all species, the H+ CBL was thin and led to lower surface pH. Still, low flow thickened H+ CBLs and increased light elevation of surface pH. In general, our findings reveal a weak to null OA modulation of the CBL. Moreover, the OA-buffering capacity by the H+ CBL may be limited in coral species, though low flow could enhance CBL sheltering.

Chronic effects of exposure to polyethylene microplastics may be mitigated at the expense of growth and photosynthesis in reef-building corals.

The causes of the physiological effects of microplastic pollution, potentially harming reef-building corals, are unclear. Reasons might include increased energy demands for handling particles and immune reactions. This study is among the first assessing the effects of long-term microplastic exposure on coral physiology at realistic concentrations (200 polyethylene particles L-1). The coral species Acropora muricata, Pocillopora verrucosa, Porites lutea, and Heliopora coerulea were exposed to microplastics for 11 months, and energy reserves, metabolites, growth, and photosymbiont state were analyzed. Results showed an overall low impact on coral physiology, yet species-specific effects occurred. Specifically, H. coerulea exhibited reduced growth, P. lutea and A. muricata showed changes in photosynthetic efficiency, and A. muricata variations in taurine levels. These findings suggest that corals may possess compensatory mechanisms mitigating the effects of microplastics. However, realistic microplastic concentrations only occasionally affected corals. Yet, corals exposed to increasing pollution scenarios will likely experience more negative impacts.

Characteristics of Users and New Initiators of Single- and Multiple-Inhaler Triple Therapy for Chronic Obstructive Pulmonary Disease in Germany.

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany. Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period. Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period. Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.

Triple therapy (a combination of three different respiratory inhaled medications) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience repeated short-term symptom flare-ups when taking dual therapy (a combination of two different respiratory medications). Previously, patients had to take triple therapy using two or three separate inhalers. More recently, single-inhaler triple therapies have been developed, meaning patients can take all three different medications at the same time via one single inhaler. This study assessed the characteristics of patients who were already receiving triple therapy, or who started triple therapy (either via multiple inhalers or a single inhaler), in Germany between January 2015 and December 2019. In total, 18,630 patients who were already receiving triple therapy during the study period, and 2932 patients who newly started using triple therapy were included. The study reported that more than two-thirds of included patients had experienced at least one flare-up of COPD symptoms in the 2 years before starting triple therapy. Most patients had also received another therapy for COPD before starting triple therapy. A small proportion of patients started taking triple therapy after receiving no other therapy for COPD in the previous 2 years. The results of the study suggest that triple therapy for COPD in Germany is most often used in accordance with recommendations (patients already receiving therapy and experiencing repeated symptom flare-ups).

Real-world evidence of treatment patterns and survival of metastatic gastric cancer patients in Germany.

BACKGROUND: Patients with metastatic gastric cancer (mGC) have poor prognosis. This real-world study aimed to describe treatment regimens and survival of mGC patients. METHODS: A retrospective analysis was conducted using anonymized German claims data (AOK PLUS) covering a period from 2010 to 2021. The study population included newly diagnosed mGC cases identified from 2011 to 2020. The index date was defined as the first diagnosis of metastasis on or after gastric cancer diagnosis. Therapy regimens were identified based on inpatient and outpatient data, and subsequently stratified by line of treatment. Survival analyses were conducted using the Kaplan-Meier method. RESULTS: The cohort consisted of 5,278 mGC incident cases (mean age: 72.7 years; male: 61.9%). Nearly half of the incident cases received mGC-related treatment (49.8%). Treated patients were more often male, younger, and had fewer comorbidities compared to untreated patients. Of the 2,629 mGC patients who started the first line of treatment (1LOT), 32.8% switched to 2LOT, and 10.2% reached 3LOT. Longer survival time was observed among disease-specific treated cases compared with untreated cases (median real-world overall survival (rwOS): 12.7 months [95%CI 12.1 - 13.3 months] vs. 3.7 months [95%CI 3.4 - 4.0 months]). CONCLUSION: Systemic therapy was not received in almost half of the mGC patients. In those patients, a very short median rwOS was observed. Treatment patterns were generally in line with the guideline recommendations, however, therapy switching rates and poor prognosis indicate high unmet needs also in the treated population.

Healthcare resource utilization and associated costs in patients with metastatic urothelial carcinoma: a real-world analysis using German claims data.

AIMS: This retrospective claims data study characterized real-world treatment patterns, healthcare resource utilization (HCRU), and costs in patients with metastatic urothelial carcinoma (mUC) in Germany. MATERIALS AND METHODS: Continuously insured adults with incident mUC diagnosis (=index; ICD-10: C65-C68/C77-C79) in 2015-2019 were identified from two German claims databases. Patients who received first-line (1 L) treatment within 12 months of index were divided into three mutually exclusive sub-cohorts: platinum-based chemotherapy (PB-CT), non-PB-CT, and immunotherapy (IO). Patient characteristics were assessed during a 24-month baseline period; treatments, HCRU, and costs (of the health insurance fund) per patient-year (ppy) were described during 12-month follow-up. RESULTS: We identified 3,226 patients with mUC (mean age, 73.8 years; male, 70.8%; mean Elixhauser Comorbidity Index, 17.6); 1,286 (39.9%) received 1 L treatment within 12 months of index. Of these, 825 (64.2%) received PB-CT, 322 (25.0%) non-PB-CT, and 139 (10.8%) IO. On average, treated patients had 5.1 hospitalizations ppy. Most UC-related hospitalizations ppy were observed in the PB-CT cohort (5.8), followed by the non-PB-CT (4.2) and IO (2.3) cohorts. Mean UC-related hospitalization costs ppy were €22,218 in the treated cohort, €24,294 in PB-CT, €19,079 in IO, and €18,530 in non-PB-CT cohorts. Cancer-related prescription costs ppy averaged €6,323 in treated patients, and €25,955 in IO, €4,318 in non-PB-CT, and €4,270 in PB-CT cohorts. LIMITATIONS: We recognized limitations in our study's sample selection due to unavailable mUC disease status data. We addressed this through an upstream feasibility study conducted in consultation with clinical experts to determine a suitable proxy. Proxies were also used to delineate treatment lines, switches, and discontinuations due to data absence. Furthermore, due to data restrictions, collective dataset analysis was not possible, prompting a meta-analysis for pooled results. CONCLUSIONS: The study shows that mUC is associated with significant HCRU and costs across different types of 1 L systemic therapy.

Treatment patterns and clinical outcomes in metastatic urothelial carcinoma: a German retrospective real-world analysis.

Aim: This study assessed real-world treatment in patients with metastatic urothelial carcinoma (mUC) in Germany. Materials & methods: Patients diagnosed with mUC from 2015 to 2019 were identified in two claims databases: AOK PLUS and GWQ. Results: 3226 patients with mUC were analyzed; 1286 (39.9%) received systemic treatment within 12 months of diagnosis (platinum-based chemotherapy: 64.2%). Factors associated with receiving treatment were: younger age, male sex, less comorbidity and recent diagnosis. In AOK PLUS and GWQ populations, unadjusted median overall survival (interquartile range) from diagnosis in treated patients was 13.7 (6.8-32.9) and 13.8 (7.1-41.7) months, and in untreated patients was 3.0 (1.2-10.8) and 3.6 (1.2-18.8) months, respectively. Conclusion: A significant proportion of patients with mUC in Germany receive no systemic treatment.

What is this article about? This article reports the results from a study in Germany between 2015 and 2019 that investigated how advanced bladder cancer that has spread to other organs was treated and how long people lived after diagnosis. The study looked at systemic therapies, which means treatments that affect the entire body.What were the results? Only 40% of people diagnosed with advanced bladder cancer received systemic treatment within the first 12 months. Of those who did receive systemic treatment, the majority received combination therapy that included a chemotherapy drug containing platinum (64%). Systemic treatment was more likely to be given to people who were younger, less sick, male, or more recently diagnosed. After 12 months, 56% of treated people were still alive, compared with 26% of people without treatment. On average, people who received systemic treatment lived for about 14 months, while people without systemic treatment lived for only 3 to 4 months.What do the results of the study mean? Many people with advanced bladder cancer in Germany do not receive systemic treatment. People who receive treatment are likely to live longer than those who do not receive treatment.

Epidemiology and Real-World Treatment of Incident Diffuse Large B-cell Lymphoma (DLBCL): A German Claims Data Analysis.

INTRODUCTION: The objective of this study was to investigate the prevalence, incidence, and treatment patterns (treatment regimens, switches, duration) for diffuse large B-cell lymphoma (DLBCL) in a real-world setting. METHODS: This was a retrospective German claims data analysis of patients with DLBCL diagnosed between January 1, 2012, and December 31, 2020. The prevalence and cumulative incidence of DLBCL were found for 2019/2020. Line of treatment  (LOT) and treatment setting from first DLBCL diagnosis to end of follow-up were described. Kaplan-Meier overall survival (OS) estimates since DLBCL diagnosis and start of treatment lines were calculated. RESULTS: Overall, 2633 incident DLBCL cases were identified (median age 75 years, 51% male). Of these, 2119 patients received at least one DLBCL-related treatment (LOT1), and 1567 patients died during follow-up. In 2019/2020, the prevalence and cumulative incidence of DLBCL was 34.8/36.7 per 100,000 patients and 14.0/12.7 per 100,000 patients, respectively. For LOT1, 1922 patients were given a chemotherapy-based regimen (1530 with CD20 antibodies). A total of 403 patients were administered a second line (LOT2), of which 183 patients received a CD20 antibody-containing chemotherapy regimen and 100 patients received stem cell transplantation or chimeric antigen receptor (CAR)-T therapy. Of the 136 LOT3+ treatments, 74 were chemotherapy regimens (54 with CD20 antibodies) and 18 were kinase inhibitors. The median time between treatment lines was less than 6 months. Among patients with at least LOT2, approximately 50% received more than one LOT during the first year after diagnosis. Approximately 25% of treated patients died within 6 months of treatment initiation. Of the 2633 included patients, the median OS from diagnosis was 31.0 months (treated patients: 46.8 months, untreated patients: 3.0 months). CONCLUSIONS: Despite advances in the field, high unmet medical need in DLBCL remains. The treatment landscape is very heterogeneous, particularly in second- or later-line treatments, with few patients receiving potentially curative treatment beyond the first line. Treatment for DLBCL, particularly for transplant-ineligible patients, remains challenging.

Common types of microdebris affect the physiology of reef-building corals.

Marine debris, particularly microdebris (< 1 mm) poses a potential threat to marine life, including reef-building corals. While previous research has mainly focused on the impact of single polymer microplastics, the effects of natural microdebris, composed of a mixture of materials, have not been explored. Therefore, this study aimed to assess the effects of different microdebris, originating from major sources of pollution, on reef-building corals. For this, we exposed two scleractinian coral species, Pocillopora verrucosa and Stylophora pistillata, known to frequently ingest microplastics, to four types of microdebris in an 8-week laboratory experiment: fragmented environmental plastic debris, artificial fibers from clothing, residues from the automobile sector consisting of tire wear, brake abrasion, and varnish flakes, a single polymer microplastic treatment consisting of polyethylene particles, and a microdebris-free control treatment. Specifically, we (I) compared the effects of the different microdebris on coral growth, necrosis, and photosynthesis, (II) investigated the difference between the microdebris mixtures and the exposure to the single polymer treatment, and (III) identified potential mechanisms causing species-specific effects by contrasting the feeding responses of the two coral species on microdebris and natural food. We show that the fibers and tire wear had the strongest effects on coral physiology, with P. verrucosa being more affected than S. pistillata. Both species showed increased volume growth in response to the microdebris treatments, accompanied by decreased calcification in P. verrucosa. Photosynthetic efficiency of the symbionts was enhanced in both species. The species-specific physiological responses might be attributed to feeding reactions, with P. verrucosa responding significantly more often to microdebris than S. pistillata. These findings highlight the effect of different microdebris on coral physiology and the need for future studies to use particle mixtures to better mimic naturally occurring microdebris and assess its effect on corals in more detail.

Fifth mass extinction event triggered the diversification of the largest family of freshwater gastropods (Caenogastropoda: Truncatelloidea: Hydrobiidae).

The fifth mass extinction event (MEE) at the Cretaceous-Palaeogene (K-Pg) boundary 66 million years ago (Ma) led to massive species loss but also triggered the diversification of higher taxa. Five models have been proposed depending on whether this diversification occurred before, during or after the K-Pg boundary and the rate of species accumulation. While the effects of the K-Pg MEE on vertebrate evolution are relatively well understood, the impact on invertebrates, particularly in freshwater ecosystems, remains controversial. One example is the hyperdiverse Hydrobiidae-the most species-rich family of freshwater gastropods. Whereas some studies place its origin in the Jurassic or even Carboniferous, most fossil records postdate the K-Pg event. We therefore used robustly time-calibrated multi-locus phylogenies of >400 species representing >100 hydrobiid genera to unravel its evolutionary history and patterns of diversification. We found that the family started diversifying shortly after the K-Pg boundary (∼60 Ma; 95% highest posterior density 52-69 Ma). Lineage richness gradually increased to the present and phylogenetic diversity until ∼25 Ma. These findings suggest that diversification was not initially driven by ecological opportunity. Combining the two criteria of timing and rate of diversification, a soft-explosive diversification model of aquatic vertebrates best fits the patterns observed. We also show that most higher hydrobiid taxa (i.e. subfamilies) diversified from the Middle Oligocene to Middle Miocene (i.e. 12-28 Ma). Two of the 15 major clades delimited are described here as new subfamilies (i.e. Bullaregiinae n. subfam. and Pontobelgrandiellinae n. subfam.), whose members are restricted to subterranean waters. Our results are an important contribution to understanding how the fifth MEE has shaped evolution and patterns of biodiversity in continental aquatic systems. Given the high extinction risks faced by many hydrobiids today, they also emphasise the need to study the biodiversity of vulnerable ecosystems.

Association between treatment and improvements in overall survival of patients with advanced/metastatic non-small cell lung cancer since 2011: A study in the United States, Canada, and Germany using retrospective real-world databases.

BACKGROUND: This study aimed to describe treatment patterns and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) in three countries between 2011 and 2020. METHODS: Three databases (US, Canada, Germany) were used to identify incident aNSCLC patients. OS was assessed from the date of incident aNSCLC diagnosis and, for patients who received at least a first line of therapy (1LOT), from the date of 1LOT initiation. In multivariable analyses, we analyzed the influence of index year and type of prescribed treatment on OS. FINDINGS: We included 51,318 patients with an incident aNSCLC diagnosis. The percentage of patients treated with a 1LOT differed substantially between countries, whereas the number of patients receiving immunotherapies/targeted treatments increased over time in all three countries. Median OS from the date of incident diagnosis was 9.9 months in the United States vs. 4.1 months in Canada. When measured from the start of 1LOT, patients had a median OS of 10.7 months in the United States, 10.9 months in Canada, and 10.9 months in Germany. OS from the start of 1LOT improved in all three countries from 2011 to 2020 by approximately 3 to 4 months. CONCLUSIONS: Observed continuous improvement in OS among patients receiving at least a 1LOT from 2011 to 2020 was likely driven by improved care and changes in the treatment landscape. The difference in the proportion of patients receiving a 1LOT in the observed countries requires further investigation.

Real-world treatment patterns in patients initiating third-line therapy for relapsed or refractory multiple myeloma in Germany, Italy, the United Kingdom, France, and Spain.

OBJECTIVES: To retrospectively analyze real-world treatment patterns in patients with relapsed/refractory multiple myeloma (RRMM) who initiated third-line treatment in Europe. METHODS: German and Italian administrative claims data were sourced from the German AOK PLUS health insurance fund and Italian local health units (2016-2020). Data for the United Kingdom (UK), France, and Spain were sourced from medical chart reviews (MCRs) from 2016 to 2018 (historical) and 2019 to 2021 (new) using electronic case report forms. RESULTS: Across all countries, immunomodulatory imide drug (IMiD)-based regimens were prominent in the third-line setting. From 2016 to 2020, lenalidomide-dexamethasone was most common in Italy (18.0%) and Germany (12.7%). From 2019 to 2021, the most common regimen was ixazomib-lenalidomide-dexamethasone (67.5%) in the UK, pomalidomide-dexamethasone (17.1%) in France, and daratumumab-bortezomib-dexamethasone (15.0%) in Spain. In the historical data (2016-2018), third-line lenalidomide- and pomalidomide-dexamethasone doublet use across the UK (>47%), France (>46%), and Spain (>33%) was high. From historical to new, triplet use increased in Spain (>19% to >60%) as did anti-CD38 agent use in France (15.1% to 51.9%) and Spain (19.7% to 42.1%). CONCLUSIONS: From 2016 to 2021, third-line regimens were mostly IMiD based. The MCR data demonstrated evolving treatment choices from 2016 to 2018 and 2019 to 2021, providing insights into uptake of novel agents and current RRMM European clinical practice.

Feeding responses of reef-building corals provide species- and concentration-dependent risk assessment of microplastic.

The negative impacts of microplastic on reef-building corals are often attributed to the feeding responses to these particles. Although reactions to and ingestion of microplastic are frequently reported, a quantitative comparison to natural particles and of the factors influencing these responses is largely missing. Thus, this study aims to compare the feeding rates of corals to microplastic and natural particles, considering factors influencing these responses. Specifically, we I) studied the feeding responses of corals to microplastic, natural food, and non-food particles, II) examined the influence of biotic factors (i.e., biofilm on the particles and presence of natural food), III) evaluated species-specific differences in feeding responses to microplastic particles, and IV) applied a toxicodynamic model for species- and concentration-dependent risk assessments. We assessed the feeding responses of 11 coral species, spanning different life-history strategies and growth forms in experimental feeding trials. The results showed that the feeding responses of corals to microplastic differ from those to naturally occurring particles. Reactions to microplastic and natural food occurred equally often, while sand was more frequently rejected. Yet, the ingestion process was much more selective, and microplastic was ingested less frequently than natural food. The presence of a biofilm and natural food had activating effects on the feeding behavior of the corals on microplastic. Generally, coral species that exhibit a higher degree of heterotrophic feeding also reacted more often to microplastic. The species- and concentration-dependent toxicodynamic risk model built on these data reveals that most tested coral species are unlikely to be at risk under present environmental concentration levels. However, highly heterotrophic feeders, such as Blastomussa merleti, or generally vulnerable species, such as Pocillopora verrucosa, need special consideration. These findings help to better evaluate the responses of corals to microplastic and their risk in an increasingly polluted ocean.

Claims-based algorithm to estimate the Expanded Disability Status Scale for multiple sclerosis in a German health insurance fund: a validation study using patient medical records.

Background: The Expanded Disability Status Scale (EDSS) quantifies disability and measures disease progression in multiple sclerosis (MS), however is not available in administrative claims databases. Objectives: To develop a claims-based algorithm for deriving EDSS and validate it against a clinical dataset capturing true EDSS values from medical records. Methods: We built a unique linked dataset combining claims data from the German AOK PLUS sickness fund and medical records from the Multiple Sclerosis Management System 3D (MSDS3D). Data were deterministically linked based on insurance numbers. We used 69 MS-related diagnostic indicators recorded with ICD-10-GM codes within 3 months before and after recorded true EDSS measures to estimate a claims-based EDSS proxy (pEDSS). Predictive performance of the pEDSS was assessed as an eight-fold (EDSS 1.0-7.0, ≥8.0), three-fold (EDSS 1.0-3.0, 4.0-5.0, ≥6.0), and binary classifier (EDSS <6.0, ≥6.0). For each classifier, predictive performance measures were determined, and overall performance was summarized using a macro F1-score. Finally, we implemented the algorithm to determine pEDSS among an overall cohort of patients with MS in AOK PLUS, who were alive and insured 12 months prior to and after index diagnosis. Results: We recruited 100 people with MS insured by AOK PLUS who had ≥1 EDSS measure in MSDS3D between 01/10/2015 and 30/06/2019 (620 measurements overall). Patients had a mean rescaled EDSS of 3.2 and pEDSS of 3.0. The pEDSS deviated from the true EDSS by 1.2 points, resulting in a mean squared error of prediction of 2.6. For the eight-fold classifier, the macro F1-score of 0.25 indicated low overall predictive performance. Broader severity groupings were better performing, with the three-fold and binary classifiers for severe disability achieving a F1-score of 0.68 and 0.84, respectively. In the overall AOK PLUS cohort (3,756 patients, 71.9% female, mean 51.9 years), older patients, patients with progressive forms of MS and those with higher comorbidity burden showed higher pEDSS. Conclusion: Generally, EDSS was underestimated by the algorithm as mild-to-moderate symptoms were poorly captured in claims across all functional systems. While the proxy-based approach using claims data may not allow for granular description of MS disability, broader severity groupings show good predictive performance.

Liver disease epidemiology and burden in patients with alterations in plasma protein metabolism: German retrospective insurance claims analysis.

BACKGROUND: Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism (APPM). AIM: To understand the prevalence, burden and progression of liver disease in patients with APPM including alpha-1 antitrypsin deficiency. METHODS: We conducted a retrospective analysis of anonymized patient-level claims data from a German health insurance provider (AOK PLUS). The APPM cohort comprised patients with APPM (identified using the German Modification of the International Classification of Diseases-10th Revision [ICD-10-GM] code E88.0 between 01/01/2010-30/09/2020) and incident liver disease (ICD-10-GM codes K74, K70.2-3 and K71.7 between 01/01/2012-30/09/2020). The control cohort comprised patients without APPM but with incident liver disease. Outcomes were incidence/prevalence of liver disease in patients with APPM, demographics/baseline characteristics, diagnostic procedures, progression-free survival (PFS), disease progression and mortality. RESULTS: Overall, 2680 and 26299 patients were included in the APPM (fibrosis, 96; cirrhosis, 2584) and control (fibrosis, 1444; cirrhosis, 24855) cohorts, respectively. Per 100000 individuals, annual incidence and prevalence of APPM and liver disease was 10-15 and 36-51, respectively. In the APPM cohort, median survival was 4.7 years [95% confidence interval (CI): 3.5-7.0] and 2.5 years (95%CI: 2.3-2.8) in patients with fibrosis and cirrhosis, respectively. A higher proportion of patients in the APPM cohort experienced disease progression (92.0%) compared with the control cohort (67.2%). Median PFS was shorter in the APPM cohort (0.9 years, 95%CI: 0.7-1.1) compared with the control cohort (3.7 years, 95%CI: 3.6-3.8; P < 0.001). Patients with cirrhosis in the control cohort had longer event-free survival for ascites, hepatic encephalopathy, hepatic failure and esophageal/gastric varices than patients with cirrhosis in the APPM cohort (P < 0.001). Patients with fibrosis in the control cohort had longer event-free survival for ascites, cirrhosis, hepatic failure and esophageal/gastric varices than patients with fibrosis in the APPM cohort (P < 0.001). In the APPM cohort, the most common diagnostic procedures within 12 mo after the first diagnosis of liver disease were imaging procedures (66.3%) and laboratory tests (51.0%). CONCLUSION: Among patients with liver disease, those with APPM experience substantial burden and earlier liver disease progression than patients without APPM.

Undertreatment in patients with advanced urothelial cancer: systematic literature review and meta-analysis.

Aim: To assess rates of no systemic treatment (NST), attrition across lines of therapy, and factors influencing treatment selection in patients with locally advanced or metastatic urothelial cancer (la/mUC). Methods: Systematic literature review to identify real-world studies reporting NST or attrition rates in la/mUC from 2017-2022 (including data reported since 2015). Results: Of 2439 publications screened, 29 reported NST rates, ranging from 40-74% in eight European-based studies, 14-60% in 12 US-based studies, and 9-63% in nine studies in other locations (meta-analysis estimate, 39%). Factors associated with NST or no second-line therapy included older age, female sex, poor performance status, poor renal function and distant metastases. Conclusion: A substantial proportion of patients with la/mUC do not receive guideline-recommended treatment.

People with advanced bladder cancer have a short survival. Bladder cancer is called advanced when it has spread outside of the urinary tract. Several drug treatments are available for people with advanced bladder cancer. However, sometimes people do not receive any drug treatment. We looked at published studies to see how many people with advanced bladder cancer did not receive any drug treatment and the reasons why. We also looked at how long people lived with or without drug treatment. We found that many people with advanced bladder cancer did not receive drug treatment. The number of people who received no drug treatment varied in studies from different countries. People who were older, were female, had poor health or kidney problems, or had cancer that had spread to other parts of the body were less likely to receive drug treatment. People who did not receive drug treatment lived for an average of 2 to 7 months, compared with 9 to 35 months for people who received drug treatment. More studies are needed to investigate the reasons why drug treatment is sometimes not used in people with advanced bladder cancer who could receive treatment, so that more people can benefit from available treatments.

Epidemiology, real-world treatment and mortality of patients with status epilepticus in Germany: insights from a large healthcare database.

Status epilepticus is a life-threatening emergency, and to date, few studies have reported on its long-term treatment and outcomes. This study aimed to estimate the incidence, the treatment and outcomes, the healthcare resource utilization and the costs of status epilepticus in Germany. Data from 2015 to 2019 were obtained from German claims (AOK PLUS). Patients with ≥1 status epilepticus event and no event in the preceding 12 months (baseline) were included. A subgroup of patients with an epilepsy diagnosis during baseline was also analysed. Of the 2782 status epilepticus patients (mean age = 64.3 years; 52.3% female), 1585 (57.0%) were previously diagnosed with epilepsy. The age- and sex-standardized incidence was 25.5 cases/100 000 persons in 2019. The mortality rate after 12 months was 39.8% overall (19.4% and 28.2% after 30 and 90 days, respectively) and 30.4% in the epilepsy patient subgroup. Factors associated with higher mortality were age, comorbidity status, presence of brain tumours and an acute stroke. An epilepsy-related hospitalization at onset of or 7 days prior to the status epilepticus event as well as prescription of antiseizure medication during baseline was associated with a better survival rate. Overall, 71.6% of patients (85.6% in the epilepsy subgroup) were prescribed with out-patient antiseizure medication and/or rescue medication within 12 months. All patients sustained on average 1.3 status epilepticus-related hospitalizations (20.5% had more than one) during a mean follow-up period of 545.2 days (median 514 days); total direct costs including in-patient and out-patient status epilepticus treatments were 10 826€ and 7701€ per patient-year overall and for the epilepsy patient subgroup, respectively. The majority of status epilepticus patients received an out-patient treatment in line with epilepsy guidelines, and patients previously diagnosed with epilepsy have a higher likelihood to receive it. The mortality in the affected patient population is high; risk factors were older age, higher comorbidity burden, the presence of brain tumours or an acute stroke.

Historical DNA solves century-old mystery on sessility in freshwater gastropods.

Extinction rates are increasing unabatedly but resources available for conservation action are limited. Therefore, some conservationists are pushing for ecology- and evolution-based conservation choices, prioritizing taxa with phylogenetic and trait-based originality. Extinction of original taxa may result in a disproportionate loss of evolutionary innovations and potentially prevent transformative changes in living systems. Here, we generated historical DNA data from an almost 120-year-old syntype of the enigmatic sessile snail Helicostoa sinensis from the Three Gorges region of the Yangtze River (PR China), using a next-generation sequencing protocol developed for ancient DNA. In a broader phylogenetic context, we assessed the phylogenetic and trait-based originality of this enigmatic taxon to solve the century-old puzzle of sessility in freshwater gastropods. Our multi-locus data confirm the phylogenetic and trait-based originality of H. sinensis. It is an ultra-rare, subfamily-level taxon (Helicostoinae stat. nov.) within the family Bithyniidae, which exhibits the evolutionary innovation of sessility. While we conservatively classify H. sinensis as "Critically Endangered", there is mounting evidence of the biological annihilation of this endemic species. Although rapidly rising extinction rates in invertebrates are increasingly recognized, the potential loss of originality in these "little things that run the world" has received little attention. We therefore call for comprehensive surveys of originality in invertebrates, particularly from extreme environments such as rapids of large rivers, as a basis for urgently needed ecology- and evolution-based conservation decisions.

Real-world systemic treatment of patients with psoriasis: A retrospective study based on German claims data.

BACKGROUND AND OBJECTIVES: Psoriasis is a common skin disorder with a high physical and psychological burden for patients. Up to 30% of the patients are candidates for a systemic treatment. The aim of this study was to describe the characteristics and the real-world systemic treatment of psoriasis patients. PATIENTS AND METHODS: This study was based on German medical claims data. A cross-sectional analysis observed all psoriasis patients in 2020. A longitudinal analysis was conducted, addressing psoriasis patients who newly started a systemic treatment. RESULTS: In total, 116,507 prevalent psoriasis patients and 13,449 newly treated patients were followed. Of all prevalent patients, 15.2% received systemic treatment in 2020 (8.7% systemic corticosteroids). Of the newly treated patients, 95.2% started with conventional treatment (79.2% systemic corticosteroids), 4.0% with biologics and 0.9% with apremilast. The rate of treatment discontinuation/switch after one year was highest for corticosteroids (91.3%) and lowest for biologics (23.1%). CONCLUSIONS: Around 15% of psoriasis patients in Germany received a systemic treatment, with > 50% of these prescribed systemic corticosteroids. Therefore, we conclude that systemic treatment is not in line with guideline recommendations in a substantial number of observed patients. The lowest discontinuation/switch rates for biologics support their wider use.

Improved Persistence to Medication, Decreased Cardiovascular Events and Reduced All-Cause Mortality in Hypertensive Patients With Use of Single-Pill Combinations: Results From the START-Study.

BACKGROUND: Single-pill combination improves adherence and persistence to medication in hypertension. It remains unclear whether this also reduces cardiovascular outcomes and all-cause mortality. We analyzed whether single-pill combinations are superior to identical multiple pills on persistence to medication, cardiovascular outcomes, and all-cause mortality. METHODS: This was a retrospective claims data (German AOK PLUS) analysis. Data from hypertensive patients ≥18 years treated with renin-angiotensin system combinations given as single pill or identical multipills covering the years 2012 to 2018 were analyzed and followed up to at least 1 year. After 1:1 propensity score matching, persistence to medication, cardiovascular events, and all-cause mortality were compared using non-parametric tests. Results were reported as incidence rate ratios and hazard ratios. RESULTS: After propensity score matching data from 57 998 patients were analyzed: 10 801 patients received valsartan/amlodipine, 1026 candesartan/amlodipine, 15 349 ramipril/amlodipine, and 1823 amlodipine/valsartan/hydrochlorothiazide as single pill or identical multipill. No relevant differences in patient characteristics were observed within the 4 groups. In all groups, a significant lower all-cause mortality, a significant a higher persistence to medication, a significant lower event rate in 15 out of 20 comparisons, and a tendency in the remaining 5 comparisons was observed under single pills compared with multipill combinations. CONCLUSIONS: Antihypertensive combination therapy reduces all-cause mortality and cardiovascular events when provided as single pill compared to identical drugs as multipills. This strongly supports the European Society of Cardiology/European Society of Hypertension and International Society of Hypertension guidelines recommending the use of a single-pill combination and thus should be more rigorously implemented into daily clinical practice.