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Jennifer L Lund,1,2 Erzsébet Horváth-Puhó,2 Szimonetta Komjáthiné Szépligeti,2 Henrik Toft Sørensen,2 Lars Pedersen,2 Vera Ehrenstein,2 Til Stürmer1,2 1Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark Background: A principle of cohort studies is that cohort membership is defined by current rather than future exposure information. Pharmacoepidemiologic studies using existing databases are vulnerable to violation of this principle. We evaluated the impact of using data on future redemption of prescriptions to determine cohort membership, motivated by a published example seeking to emulate a “per-protocol” association between continuous versus never use of low-dose acetylsalicylic acid (ASA) and major bleeding (e.g., cerebral hemorrhage or gastrointestinal bleeding). Materials and methods: Danish medical registry data from 2004 to 2011 were used to construct two analytic cohorts. In Cohort 1, we used information about future redemption of low-dose ASA prescriptions to identify cohorts of continuous and never-ASA users. In Cohort 2, we identified ASA initiators and non-initiators using only contemporaneous data and censored follow-up for changes in use over time. We implemented propensity score-matched Poisson regression to evaluate associations between ASA use and major bleeding and estimated adjusted incidence rate differences (IRDs) per 1,000 person-years and ratios (IRRs) overall and stratified by time since initiation. Results: Among >6 million eligible Danish adults, we identified 403,693 low-dose ASA initiators (Cohort 2), of whom 189,150 were defined as continuous users (Cohort 1). Overall, IRDs and IRRs were similar across cohorts. However, the IRD for major bleeding in the first 90 days was substantially larger in Cohort 1 (IRD=25 per 1,000 person-years) compared with Cohort 2 (IRD=10 per 1,000 person-years). Conclusion: Using future medication redemption data to define baseline cohorts violates basic epidemiologic principles. Compared with an approach using only contemporaneous data to define cohorts, the approach based on future redemption data generated a substantially higher short-term association between low-dose ASA use and major bleeding on the absolute, but not the relative, scale possibly due to selection and immortal time biases. Keywords: pharmacoepidemiology, cohort studies, immortal time bias, selection bias

Jennifer L Lund,1 Suzanne F Cook,2 Jeffery K Allen,2 Charlotte F Carroll,2 Michael D Kappelman3 1Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; 2Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background and aims: Thiopurines, including 6-mercaptopurine (6-MP) and azathioprine (AZA), are the mainstay of maintenance therapy for Crohn's disease (CD). However, studies examining their effectiveness in routine practice among diverse patient populations are lacking. Among a cohort of new users of 6MP/AZA, we described treatment patterns and changes in subsequent therapy. Methods: Using the Truven Health Analytics databases, we identified all individuals diagnosed with CD and initiating 6-MP/AZA monotherapy from 2001–2008 (n=3,657). We estimated the proportion of CD patients remaining on 6-MP/AZA monotherapy, using Kaplan–Meier methods, and identified predictors of treatment noncontinuation, using multivariable Cox regression. Among the “noncontinuers,” we described subsequent patterns of maintenance therapy and summarized the diagnosis and procedure codes and prescription drug claims preceding treatment discontinuation. Results: The 1-year 6-MP/AZA treatment continuation rate was 42%. Children (age ≤18 years) and individuals with no prior anti-tumor necrosis factor (TNF) use were more likely to continue 6-MP/AZA, while those dispensed more (>4) outpatient prescriptions for any drug before initiation of 6-MP/AZA were less likely to continue maintenance treatment. Overall, 1,128 (39%) and 105 (4%) individuals experienced a clinical event potentially indicating active disease or 6-MP/AZA-intolerance prior to discontinuation, respectively. Most patients discontinued therapy; among the remaining patients who failed to continue 6-MP/AZA, most augmented with an anti-TNF. Conclusion: Most patients initiating 6-MP/AZA monotherapy did not continue beyond 1 year. In contrast to trial evidence showing 1-year remission rates of 40%–80%, this study observed a lower effectiveness of 6-MP/AZA treatment, possibly due to differences in disease severity, patient demographics, comorbidity, adherence, and health care utilization. Keywords: immunomodulators, outcomes research/measurement, inflammatory bowel disease, patterns of care

Jennifer L Lund,1 Trine Frøslev,1 Thomas Deleuran,1,2 Rune Erichsen,1 Tove Nilsson,1 Annette Nørkær Pedersen,3 Morten Høyer4 1Department of Clinical Epidemiology, 2Department of Medicine V (Hepatology and Gastroenterology), 3Hospital Pharmacy, 4Department of Oncology, Aarhus University Hospital, Aarhus, Denmark Background: The Danish National Registry of Patients (DNRP) is a potentially valuable resource for monitoring national trends in the use of chemotherapy and evaluating the benefits and harms of alternative treatments among colorectal cancer (CRC) patients in Denmark. However, the validity of chemotherapy reporting in the DNRP is unknown. In this study, we evaluated the validity of the DNRP for identifying the receipt of chemotherapy and specific treatments, and the timing and number of treatments among CRC patients, using medical records and pharmacy data as the reference standard. Methods: We selected a random sample of CRC patients with lymph node involvement who were diagnosed at Aarhus University Hospital (n = 25) or Aalborg University Hospital (n = 25) from 2009 to 2010. Administration dates, specific treatments, and number of treatment courses were abstracted for the 180 days post diagnosis from the DNRP, medical records, and pharmacy production databases. The prevalence of chemotherapy, timing of first administration, and number of courses were described. DNRP data were compared with the reference standard for each hospital, and the kappa, sensitivity, specificity, positive and negative predictive values, and 95% confidence intervals were calculated for the receipt of any chemotherapy and specific treatments. Results: The prevalence of chemotherapy was 72% and 68% among CRC patients treated in Aarhus and Aalborg, respectively, with >90% of patients without distant metastasis receiving treatment within 90 days from diagnosis. Patients received on average 4.6 and 4.7 treatment courses in Aarhus and Aalborg, respectively. Kappa, sensitivity, and specificity of chemotherapy reporting in the DNRP was high (≥0.88), but the sensitivity of individual chemotherapies varied by hospital. Conclusion: The validity of chemotherapy reporting in the DNRP was high, although some variation by hospital exists. The DNRP represents a population-based nationwide resource that can be used to provide timely and accurate evaluations of chemotherapy use among CRC patients in Denmark. Keywords: chemotherapy, colorectal cancer, administrative data

Over the past 10 years, the field of health services and management research has seen renewed interest in the use of qualitative research methods. This article examines the volume and characteristics of qualitative research articles published in nine major health services and management journals between 1998 and 2008. Qualitative research articles comprise 9% of research articles published in these journals. Although the publication rate of qualitative research articles has not kept pace with that of quantitative research articles, citation analysis suggests that qualitative research articles contribute comparably to the field's knowledge base. A wide range of policy and management topics has been examined using qualitative methods. Case study designs, interviews, and documentary sources were the most frequently used methods. Half of qualitative research articles provided little or no detail about key aspects the study's methods. Implications are discussed and recommendations are offered for promoting the publication of qualitative research. [ABSTRACT FROM AUTHOR]

Randomized trials estimate the average treatment effect within individuals who are eligible, invited, and agree to enroll. However, decision-makers often require evidence that extends beyond the trial's enrolled population to inform policy or actions for their specific target population. Each decision-maker has distinct target populations, the composition of which may not often align with that of the trial population. As researchers, we should identify a decision-maker for whom we aim to generate evidence early in the research process. We can then specify a target population of their interest and determine if a policy or action can be informed using results from a trial alone, or if additional complementary real-world data and analysis are required. In this commentary, we outline 5 key groupings of decision-makers: policymakers, payers, purchasers, providers, and patients. We then specify relevant target populations for decision-makers interested in the effectiveness of beta-blockers after a myocardial infarction with preserved ejection fraction. Finally, we summarize the scenarios in which results from a randomized trial may or may not apply to these target populations and suggest relevant analytic approaches that can generate evidence to better align with a decision-maker's needs. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Clinicians, researchers, regulators, and other decision-makers increasingly rely on evidence from real-world data (RWD), including data routinely accumulating in health and administrative databases. RWD studies often rely on algorithms to operationalize variable definitions. An algorithm is a combination of codes or concepts used to identify persons with a specific health condition or characteristic. Establishing the validity of algorithms is a prerequisite for generating valid study findings that can ultimately inform evidence-based health care. In this paper, we aim to systematize terminology, methods, and practical considerations relevant to the conduct of validation studies of RWD-based algorithms. We discuss measures of algorithm accuracy, gold/reference standards, study size, prioritization of accuracy measures, algorithm portability, and implications for interpretation. Information bias is common in epidemiologic studies, underscoring the importance of transparency in decisions regarding choice and prioritizing measures of algorithm validity. The validity of an algorithm should be judged in the context of a data source, and one size does not fit all. Prioritizing validity measures within a given data source depends on the role of a given variable in the analysis (eligibility criterion, exposure, outcome, or covariate). Validation work should be part of routine maintenance of RWD sources. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The oncology quality, characterization, and assessment of real-world data (Oncology QCARD) Initiative was formed to develop a set of minimum study design and data elements needed to evaluate the fitness of the real-world data (RWD) source(s) proposed in an initial study concept as part of early interaction with scientific reviewers., Methods: A multidisciplinary executive committee (EC) was established to guide the Oncology QCARD Initiative. The EC conducted a landscape review of published literature, guidances, and guidelines to evaluate relevant dimensions of data quality measurement. Guided by the review and informed by expert feedback, the Oncology QCARD Initial Protocol Characterization (IPC) provides a summary of minimum elements needed to adequately describe an initial clinical study concept that involves RWD and is intended to support decision-making., Results: Fit-for-use data and fit-for-purpose design emerged as themes from the landscape analysis. Data that are fit-for-use are both relevant (sufficiently capturing exposure, outcomes, and covariates) and reliable (understanding data accrual and quality control and whether the data represent the underlying concepts they are intended to represent) to answer a specific research question. A fit-for-purpose design takes appropriate steps to ensure internal and external validity and allows for transparency in reporting. The QCARD-IPC focuses on high-level characteristics of RWD sources and study design domains including data temporality, population, medical product exposure, comparators, and covariates, endpoints, statistical analysis, and data quality assurance plans., Conclusions: Evaluation of studies including RWD requires understanding the data source, study design, and potential biases to preliminarily evaluate whether selected RWD are fit-for-use for the research question. The Oncology QCARD-IPC provides a structured, transparent approach to facilitate early review and enhanced communication between study sponsors and scientific reviewers of initial study proposals including RWD., (© 2024 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Amplicon sequencing has long served as a robust method for characterising microbial communities, and despite inherent resolution limitations, it remains a preferred technique, offering cost- and time-effective insights into bacterial compositions. Here, we introduce ONT-AmpSeq, a user-friendly pipeline designed for processing amplicon sequencing data generated from Oxford Nanopore Technology (ONT) devices. Our pipeline enables efficient creation of taxonomically annotated operational taxonomic unit (OTU) tables from ONT sequencing data, with the flexibility to multiplex amplicons on the same barcode. The pipeline encompasses six main steps-statistics, quality filtering, alignment, clustering, polishing, and taxonomic classification-integrating various state-of-the-art software tools. We provide a detailed description of each step, along with performance tests and robustness evaluations using both test data and a ZymoBIOMICS ® Microbial Community Standard mock community dataset. Our results demonstrate the ability of ONT-AmpSeq to effectively process ONT amplicon data, offering valuable insights into microbial community composition. Additionally, we discuss the influence of polishing tools on taxonomic insight and the impact of taxonomic annotation methods on the derived microbial composition. Overall, ONT-AmpSeq represents a comprehensive solution for analysing ONT amplicon sequencing data, facilitating streamlined and reliable microbial community analysis. The pipeline, along with test data, is freely available for public use., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: Crohn's Disease (CD) is characterized by chronic intestinal inflammation and dysbiosis. This study aimed to investigate the effects of a plant-based diet (PBD) on gut microbiota composition and inflammation in CD patients and assess the utility of trn L gene sequencing for monitoring dietary adherence., Methods: Fourteen CD patients participated in a 12-week PBD intervention. Dietary adherence was monitored through self-reported food diaries and trnL sequencing, which detects plant residues in fecal samples. Gut microbiota was analyzed using 16S rRNA sequencing, and fecal calprotectin levels were measured as an indicator of intestinal inflammation., Results: Trn L sequencing identified 55 plant genera in fecal samples, compared to 41 reported in food diaries, highlighting its accuracy in assessing plant residue diversity. By week 4, participants demonstrated a 1.4-fold increase in plant intake, correlating with a significant increase in microbial diversity. Key genera associated with gut health, such as Faecalibacterium and Bacteroides , increased in abundance. Additionally, fecal calprotectin levels decreased from 472 mg/kg at baseline to 207 mg/kg at week 12, indicating reduced intestinal inflammation., Discussion: A PBD positively influenced gut microbiota composition and decreased intestinal inflammation in CD patients. The study also demonstrated that trn L sequencing is an effective tool for assessing dietary adherence in clinical settings, offering a more objective measure than self-reported food diaries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Østergaard, Cetin, Rasmussen, Lærke, Holst, Lauridsen and Nielsen.)

Background: Investigators often use claims data to estimate the diagnosis timing of chronic conditions. However, misclassification of chronic conditions is common due to variability in healthcare utilization and in claims history across patients., Objective: We aimed to quantify the effect of various Medicare fee-for-service continuous enrollment period and lookback period (LBP) on misclassification of COPD and sample size., Methods: A stepwise tutorial to classify COPD, based on its diagnosis timing relative to lung cancer diagnosis using the Surveillance Epidemiology and End Results cancer registry linked to Medicare insurance claims. We used 3 approaches varying the LBP and required continuous enrollment (i.e., observability) period between 1 to 5 years. Patients with lung cancer were classified based on their COPD related healthcare utilization into 3 groups: pre-existing COPD (diagnosis at least 3 months before lung cancer diagnosis), concurrent COPD (diagnosis during the -/+ 3months of lung cancer diagnosis), and non-COPD. Among those with 5 years of continuous enrollment, we estimated the sensitivity of the LBP to ascertain COPD diagnosis as the number of patients with pre-existing COPD using a shorter LBP divided by the number of patients with pre-existing COPD using a longer LBP., Results: Extending the LBP from 1 to 5 years increased prevalence of pre-existing COPD from ~ 36% to 51%, decreased both concurrent COPD from ~ 34% to 23% and non-COPD from ~ 29% to 25%. There was minimal effect of extending the required continuous enrollment period beyond one year across various LBPs. In those with 5 years of continuous enrollment, sensitivity of COPD classification (95% CI) increased with longer LBP from 70.1% (69.7% to 70.4%) for one-year LBP to 100% for 5-years LBP., Conclusion: The length of optimum LBP and continuous enrollment period depends on the context of the research question and the data generating mechanisms. Among Medicare beneficiaries, the best approach to identify diagnosis timing of COPD relative to lung cancer diagnosis is to use all available LBP with at least one year of required continuous enrollment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Metwally et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Patient reported outcome measures (PROMs) are increasingly used in oncology care, but pharmacists providing direct patient care have been overlooked. We engaged pharmacists and adults receiving oral oncolytics (chemotherapy medication taken by mouth) to develop a SmartForm© in the electronic health record (EHR) for PROM monitoring. Pharmacists verbally ask the patient side effect questions during routine telehealth encounters and enter responses in real time., Methods: Our development process was guided by the Knowledge to Action Framework. In phase 1 (Knowledge Inquiry), we prioritized side effects to assess in the EHR SmartForm© via interviews with patients and a Delphi panel with pharmacists. Adults receiving oral oncolytics for breast (n = 12), thoracic (n = 12), or hematological (n = 12) cancer were interviewed, with purposeful sampling for adults who were aged 65 + years or Black. Interviews were coded with content analysis. We conducted three Delphi rounds, with 11/19, 13/19, and 19/19 pharmacists, respectively. In phase 2 (Knowledge Synthesis), PROM items were selected and the EHR SmartForm© programmed. In phase 3 (Knowledge Tailoring), we conducted usability testing with pharmacists., Results: Pharmacists and patients were consistent in prioritizing side effects of oral oncolytics and 10 were retained. Patients advocated asking whether they can do their usual activities, while pharmacists added medication adherence. Usability testing yielded suggestions to simplify the SmartForm©., Conclusion: By presenting screenshots of our SmartForm©, our findings are useful to other healthcare systems looking for a PROM solution integrated in the EHR, with a reasonable pharmacist/clinician workload, and no requirement for patients to have internet access/comfort., (© 2024. The Author(s).)

Background: Frailty is a dynamic syndrome characterized by reduced physiological reserve to maintain homeostasis. Prospective studies have reported frailty worsening in women with breast cancer during chemotherapy, with improvements following treatment. We evaluated whether the Faurot frailty index, a validated claims-based frailty measure, could identify changes in frailty during chemotherapy treatment and identified predictors of trajectory patterns., Methods: We included women (65+ years) with stage I-III breast cancer undergoing adjuvant chemotherapy in the SEER-Medicare database (2003-2019). We estimated the Faurot frailty index (range: 0-1; higher scores indicate greater frailty) at chemotherapy initiation, 4 months postinitiation, and 10 months postinitiation. Changes in frailty were compared to a matched noncancer comparator cohort. We identified patterns of frailty trajectories during the year following chemotherapy initiation using K-means clustering., Results: Twenty-one thousand five hundred and ninety-nine women initiated adjuvant chemotherapy. Mean claims-based frailty increased from 0.037 at initiation to 0.055 4 months postchemotherapy initiation and fell to 0.049 10 months postinitiation. Noncancer comparators experienced a small increase in claims-based frailty over time (0.055-0.062). We identified 6 trajectory patterns: a robust group (78%), 2 resilient groups (16%), and 3 nonresilient groups (6%). Black women and women with claims for home hospital beds, wheelchairs, and Parkinson's disease were more likely to experience nonresilient trajectories., Conclusions: We observed changes in a claims-based frailty index during chemotherapy that are consistent with prior studies using clinical measures of frailty and identified predictors of nonresilient frailty trajectories. Our study demonstrates the feasibility of using claims-based frailty indices to assess changes in frailty during cancer treatment., (© The Author(s) 2024. Published by Oxford University Press.)

Background: To describe reasons for deviations from planned chemotherapy treatments in women with nonmetastatic breast cancer that contribute to less-than-planned receipt of chemotherapy., Methods: Electronic medical records for patients receiving chemotherapy were reviewed for adverse events and treatment modifications. Log-binomial regression models were used to estimate relative risks (RRs) with 95% CIs to examine associations between chemotherapy modifications, patient characteristics, and treatment modalities., Results: Delays in chemotherapy initiation (7%) were for surgical complications (58%), personal reasons (16%), and other (26%; port malfunction, infections, and obtaining extra imaging). Delays during chemotherapy (38%) were for infections (20%), neutropenia (13%), and personal reasons (13%). Dose reductions (38%) were for neuropathy (36%), unknown causes (9%), anemia (9%), and neutropenia (8%). Early treatment discontinuations (23%) were for neuropathy (29%). Patients receiving paclitaxel/nab-paclitaxel (RR 2.05; 95% CI, 1.47-2.87) and an anthracycline (RR 1.89; 95% CI, 1.39-2.57) reported more dose delays during chemotherapy. Black race (RR 1.46; 95% CI, 1.07-2.00), stage 3 (RR 1.79; 95% CI, 1.09-2.93), and paclitaxel/nab-paclitaxel receipt (RR 1.39; 95% CI, 1.02-1.90) increased the likelihood of dose reduction. Both Black race (RR 2.06; 95% CI, 1.35-3.15) and receipt of paclitaxel/nab-paclitaxel (RR 1.93; 95% CI, 1.19-3.13) increased the likelihood of early discontinuation. Patients receiving anthracyclines had higher rates of hospitalizations during chemotherapy (RR: 1.79; 95% CI, 1.11-2.89)., Conclusion: Toxicities are the most common reason for treatment modifications and need close monitoring in high-risk groups for timely intervention. Dose reductions and early treatment discontinuations occurred more for Black patients and need further study., (© The Author(s) 2024. Published by Oxford University Press.)

This study addresses the challenge of obtaining in situ information on substrate utilization rates for individual microbial species in complex microbial communities such as anaerobic digester sludge. To overcome this hurdle, a novel approach combining doubly-labelled deuterium, fluorescence in situ hybridization (FISH) and Raman microspectroscopy was developed. The method enables quantitative determination of anabolic heavy hydrogen incorporation into FISH-targeted, exemplified by methanogenic cells from the genera Methanosarcina and Methanothermobacter. The deuterium incorporation rates ascertained by Raman red-shifting of C-Hx vibrational region to C-Dx vibrations, quantified through Raman peak area ratios, were compared for different carbon sources. Methanosarcina exhibited highest kinetic rates with acetate and propionate, while Methanothermobacter demonstrated faster incorporation under acetate and methanol supplementation. This groundbreaking study demonstrates the feasibility of obtaining quantitative metabolic rate information at a single-cell level using deuterium, FISH probes, and Raman microspectroscopy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In the last decade, extensive fungal growth has developed in Danish museums parallel to climate change, challenging occupational health and heritage preservation. The growth was unexpected as the museums strived to control relative humidity below 60 %, and it should exceed 75 % to risk growth. A Danish case study found xerophilic Aspergillus species able to grow at low relative humidity in a museum repository. This cross-sectional study aimed to examine whether xerophilic growth from Aspergillus section Restricti has become a novel contaminant nationally distributed in Danish museum repositories striving to control relative humidity according to international environmental recommendations for heritage collections. The study examined The National Museum of Denmark and eight large State Recognized museums distributed throughout Denmark. It was based on 600 swab and tape-lift samples and 60 MAS100-Eco and filter air samples analyzed for fungi with cultivation and morphological identification, Big-Dye-Sanger sequencing, CaM-Nanopore and ITS-Illumina amplicon sequencing. The study showed growth from seven xerophilic Aspergillus species: A. conicus, A. domesticus, A. glabripes, A. halophilicus, A. magnivesiculatus, A. penicilloides, A. vitricola, of which three are new to Denmark, and 13 xerotolerant Aspergillus species. There was no growth from other fungal species. The multiple detection approach provided a broad characterization; however, there was variance in the detected species depending on the analysis approach. Cultivation and Big-Dye Sanger sequencing showed the highest Aspergillus diversity, detecting 17 species; CaM-Nanopore amplicon sequencing detected 12 species; and ITS-illumina amplicon sequencing detected two species but the highest overall diversity. Cultivation, followed by Big-Dye Sanger and CaM-amplicon sequencing, proved the highest compliance. The study concluded that xerophilic Aspergillus growth is nationally distributed and suggests species from Aspergillus section Restricti as a novel contaminant in climate-controlled museum repositories. To safeguard occupational health and heritage preservation research in sustainable solutions, avoiding xerophilic growth in museum collections is most important., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This study explores the genetic landscape of nitrous oxide (N 2 O) reduction in wastewater treatment plants (WWTPs) by profiling 1,083 high-quality metagenome-assembled genomes (HQ MAGs) from 23 Danish full-scale WWTPs. The focus is on the distribution and diversity of nitrous oxide reductase ( nosZ ) genes and their association with other nitrogen metabolism pathways. A custom pipeline for clade-specific nosZ gene identification with higher sensitivity revealed 503 nosZ sequences in 489 of these HQ MAGs, outperforming existing Kyoto Encyclopedia of Genes and Genomes (KEGG) module-based methods. Notably, 48.7% of the total 1,083 HQ MAGs harbored nosZ genes, with clade II being predominant, accounting for 93.7% of these genes. Taxonomic profiling highlighted the prevalence of nosZ -containing taxa within Bacteroidota and Pseudomonadota. Chloroflexota exhibited unexpected affiliations with both the sec and tat secretory pathways, and all were found to contain the accessory nosB gene, underscoring the importance of investigating the secretory pathway. The majority of non-denitrifying N 2 O reducers were found within Bacteroidota and Chloroflexota . Additionally, HQ MAGs with genes for dissimilatory nitrate reduction to ammonium and assimilatory nitrate reduction frequently co-occurred with the nosZ gene. Traditional primers targeting nosZ often focus on short-length amplicons. Therefore, we introduced custom-designed primer sets targeting near-full-length nosZ sequences. These new primers demonstrate efficacy in capturing diverse and well-characterized sequences, providing a valuable tool with higher resolution for future research. In conclusion, this comprehensive analysis enhances our understanding of N 2 O-reducing organisms in WWTPs, highlighting their potential as N 2 O sinks with the potential for optimizing wastewater treatment processes and mitigating greenhouse gas emissions., Importance: This study provides critical insights into the genetic diversity of nitrous oxide reductase (nosZ) genes and the microorganisms harboring them in wastewater treatment plants (WWTPs) by exploring 1,083 high-quality metagenome-assembled genomes (MAGs) from 23 Danish full-scale WWTPs. Despite the pivotal role of nosZ-containing organisms, their diversity remains largely unexplored in WWTPs. Our custom pipeline for detecting nosZ provides near-full-length genes with detailed information on secretory pathways and accessory nos genes. Using these genes as templates, we developed taxonomically diverse clade-specific primers that generate nosZ amplicons for phylogenetic annotation and gene-to-MAG linkage. This approach improves detection and expands the discovery of novel sequences, highlighting the prevalence of non-denitrifying N 2 O reducers and their potential as N 2 O sinks. These findings have the potential to optimize nitrogen removal processes and mitigate greenhouse gas emissions from WWTPs by fully harnessing the capabilities of the microbial communities., Competing Interests: The authors declare no conflict of interest.

The healthy user effect is a well-recognized bias in the field of pharmacoepidemiology and can be expected to overstate the effect of a preventive intervention when comparing long term users or "adherers" to non-users. Similar to the healthy worker effect observed in occupational epidemiology, the healthy user effect can be separated into a healthy initiator effect (baseline confounding) and a healthy adherer effect (selection bias). Restriction approaches and new user designs that implicitly condition on the indication and, similar healthy behaviors or health status can often mitigate the healthy initiator effect (confounding) or healthy adherer effect (selection bias) at the start of a study. Addressing the healthy adherer effect due to continued conditioning on adherence over the duration of a study is more challenging as methods to mitigate it require the ability to predict adherence, which is often difficult using databases common in pharmacoepidemiologic research. Here, we describe the healthy user effect, with supporting examples, and describe study design approaches available to pharmacoepidemiologists to mitigate the potential for bias., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center has developed a novel data resource, the Cancer Information and Population Health Resource (CIPHR), for conducting catchment area evaluation and cancer population health research that links the North Carolina Central Cancer Registry (NCCCR) to medical and pharmacy claims data from Medicare, Medicaid, and private plans operating within North Carolina. This study's aim was to describe the CIPHR data and provide examples of potential cohorts available in those data., Methods: We present the underlying populations included in the NCCCR and claims data before linkage and demonstrate estimated sample sizes when these data are linked and commonly used insurance enrollment criteria are applied., Results: Data for the years 2003-2020 are present in CIPHR and include 947 977 cancer cases from the NCCCR and 21.6 million enrollees in public and private health insurance (cancer and noncancer cases). When limited to first or only cancers (n = 672 377), 86% could be linked to insurance enrollment for at least 1 month during 2003-2020 (n = 582 638), with 62% of individuals linking to enrollment during the month of cancer diagnosis. Among all registry cancer cases, 47% (n = 317 898) had continuous insurance enrollment for at least 12 months before and after cancer diagnosis., Conclusion: CIPHR illustrates the utility of establishing and maintaining a statewide, comprehensive cancer population health database. This resource serves to characterize the cancer center catchment area and aids in tracking cancer outcomes and trends in care delivery as well as identifying disparities that require intervention and policy focus., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Although the limitations of hazard ratios (HRs) for quantifying treatment effects in right-censored data have been widely discussed, HRs are still preferentially reported over other, more interpretable effect measures. This may stem from the fact that there are few applied examples that directly contrast the HR and its interpretation with alternative effect measures., Methods: We analyzed data from two randomized clinical trials comparing panitumumab plus standard-of-care chemotherapy (SOCC) with SOCC alone as first- and second-line treatment for metastatic colorectal cancer. We report the effect of treatment with panitumumab on progression-free survival (PFS) using a Cox proportional hazards model to estimate the HR and the Kaplan-Meier estimator of cumulative incidence (risk). Further analyses included examining the cumulative incidence curves; kernel-smoothed, non-parametric hazards curves; fitting the Cox model with a continuous time variable; and estimating restricted mean survival as well as median survival., Results: The HR was 0.82 (95% confidence interval [CI]: 0.71, 0.93), while the risk ratio (or relative risk [i.e., ratio of the cumulative incidence among the treated versus comparator]) was 0.99 (95% CI: 0.96, 1.02). These two measures suggest apparently different conclusions: either a treatment benefit or no effect. Through subsequent analyses, we demonstrated that, while the cumulative incidence of the outcome was similar by the end of follow-up regardless of treatment, the panitumumab treated group experienced longer PFS than those randomized to SOCC. Substantial nonproportional hazards were evident with panitumumab treatment reducing the hazard of progression/mortality during the first ~1.75 years but associated with an increased hazard of progress/mortality thereafter., Discussion: This example underscores the difficulties in interpreting HRs, particularly in the setting of qualitative violations of proportional hazards, and the value of quantifying treatment effects via multiple effect measures., (© 2024 John Wiley & Sons Ltd.)

Background: Frailty is a dynamic aging-related syndrome, but measuring frailty transitions is challenging. The Faurot frailty index is a validated Medicare claims-based frailty proxy based on demographic and billing information. We evaluated whether 3-year changes in the Faurot frailty index were consistent with concurrent changes in the frailty phenotype in a cohort of older adults., Methods: We used longitudinal data from the National Health and Aging Trends Study (NHATS) with Medicare claims linkage (2010-2018). We identified older adults (66+ years) in the 2011 and 2015 NHATS cohorts with at least 1 year of Medicare fee-for-service continuous enrollment (N = 6 951). We described annual changes in mean claims-based frailty for up to 3 years, based on concurrent transitions in the frailty phenotype., Results: At baseline, 32% were robust, 48% prefrail, and 19% frail based on the frailty phenotype. Mean claims-based frailty for older adults who were robust at baseline and worsened to frail increased over 3 years (0.09-0.25). Similarly, those who worsened from prefrail to frail experienced an increase in mean claims-based frailty (0.14-0.26). Improvements in the frailty phenotype did not correspond to decreases in claims-based frailty. Older adults whose frailty phenotype improved over time had a lower baseline claims-based frailty score than those who experienced stable or worsening frailty., Conclusions: Older adults who experienced a frailty phenotype worsening over 3 years experienced concurrent increases in the Faurot frailty index. Our results suggest that claims data may be used to identify clinically meaningful worsening in frailty., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

European hedgehogs ( Erinaceus europaeus ) inhabit most of Denmark, except for a few smaller islands. Research from other European countries has shown that the hedgehog populations are in decline. The exposure to chemicals might contribute to this development, although their role is currently unknown. Our research studied the occurrence of 19 selected pesticides in the Danish hedgehog population as well as factors potentially explaining the levels of chemicals detected. We analysed 115 liver samples obtained from dead hedgehogs in 2016 for seven rodenticides, four insecticides and eight herbicides commonly used in Denmark at the time of sampling, applying a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Detection frequencies varied between 0.9% for fluroxypyr and trans-permethrin and 79% for bromadiolone. Rodenticides, insecticides and herbicides were detected in 84, 43, and 50% of the samples, respectively. The compounds most frequently detected included the insecticide imidacloprid (35%), the herbicide metamitron (29%) and the rodenticide bromadiolone (79%). Individual concentrations varied between non-detected to >2 μg/g. A total of 79% of the 115 hedgehogs contained more than one detectable pesticide, with up to nine of the 19 compounds detected in one individual. The detection frequencies were found to differ significantly between the Eastern and Western part of Denmark for difenacoum, difethialone and imidacloprid. However, no associations were found with sex, age, habitat type or the prevalence of mecC -MRSA and endoparasites in the hedgehogs tested. Whether or not the pesticide levels detected carry a health risk for the hedgehogs remains unknown as no adverse effect levels have yet been established for European hedgehogs for single compounds or pesticide mixtures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rasmussen, Roslev, Nielsen, Pertoldi and Vorkamp.)

Objective: To investigate the relationship between measures of radiographic joint space width (JSW) loss and magnetic resonance imaging (MRI)-based cartilage thickness loss in the medial weight-bearing region of the tibiofemoral joint over 12-24 months. To stratify this relationship by clinically meaningful subgroups (sex and pain status)., Design: We analyzed a subset of knees (n ​= ​256) from the Osteoarthritis Initiative (OAI) likely in early stage OA based on joint space narrowing (JSN) measurements. Natural logarithm transformation was used to approximate near normal distributions for JSW loss. Pearson Correlation coefficients described the relationship between ln-transformed JSW loss and several versions of deep learning-derived MRI-based cartilage thickness loss parameters (minimum, maximum, and mean) in subregions of the femoral condyle, tibial plateau, and combined femoral and tibial regions. Linear mixed-effects models evaluated the associations between the ln-transformed radiographic and MRI-derived measures including potential confounders., Results: We found weak correlations between ln-transformed JSW loss and MRI-based cartilage thickness ranging from R ​= ​-0.13 (p ​= ​0.20) to R ​= ​0.26 (p ​< ​0.01). Correlations were higher (still poor) among females compared to males and painful compared to non-painful knees. Model results showed weak associations for nearly all MRI-based measures, ranging from no association to β (95% CI) ​= ​0.25 (0.11, 0.39). Associations were higher among females compared to males and minimal differences between painful and non-painful knees., Conclusions: Despite its recommended use in disease-modifying OA drug clinical trials, results suggest that JSW loss is an ineffective proxy measure of cartilage thickness loss over 12-24 months and within a localized region of the tibiofemoral joint., (© 2024 The Authors.)

Understanding the potential for, direction, and magnitude of uncontrolled confounding is critical for generating informative real-world evidence. Many sensitivity analyses are available to assess robustness of study results to residual confounding, but it is unclear how researchers are using these methods. We conducted a systematic review of published active comparator cohort studies of drugs or biologics to summarize use of sensitivity analyses aimed at assessing uncontrolled confounding from an unmeasured variable. We reviewed articles in five medical and seven epidemiologic journals published between January 1, 2017, and June 30, 2022. We identified 158 active comparator cohort studies, 76 from medical and 82 from epidemiologic journals. Residual, unmeasured, or uncontrolled confounding was noted as a potential concern in 93% of studies, but only 84 (53%) implemented one or more sensitivity analysis to assess uncontrolled confounding from an unmeasured variable. The most common analyses were E-values among medical journal articles (21%) and restriction on measured variables among epidemiologic journal articles (22%). Researchers must rigorously consider the role of residual confounding in their analyses and the best sensitivity analyses for assessing this potential bias., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Randomized controlled trials (RCT) are the gold standard in determining efficacy of cancer screening tests. Yet, systematic differences between RCT and the general populations eligible for screening raise concerns about the generalizability and relevance of RCT findings to guide the development and dissemination of cancer screening programs. Observational studies from clinical practice settings have documented selective uptake in screening-i.e., variation across subgroups regarding who is screened and not screened-as well as suboptimal adherence to screening recommendations, including follow-up of positive findings with subsequent imaging studies and diagnostic invasive procedures. When the effectiveness of a screening intervention varies across subgroups, and there is selective uptake and suboptimal adherence to screening in clinical practice relative to that in the RCT, the effects of screening reported in RCTs are not expected to generalize to clinical practice settings. Understanding the impacts of selective uptake and suboptimal adherence on estimates of the effectiveness of cancer screening in clinical practice will generate evidence that can be used to inform future screening recommendations and enhance shared decision-making tools., (©2024 American Association for Cancer Research.)

Background: Recent cancer care advances have introduced new oral therapies, and yet population registries lack detailed treatment data, hampering investigations into therapy uptake, adherence, and outcomes., Objective: This study aimed to assess the representativeness and completeness of linking Surveillance, Epidemiology, and End Results (SEER) cancer registry data with data from two major retail pharmacy chains, collectively covering a large segment of the US market., Methods: A deterministic data linkage between 11 SEER cancer registries and retail pharmacy data (excluding mail order fills) was conducted for individuals diagnosed with selected cancers from 2013 to 2017, with follow-up through 2019. Descriptive characteristics of the linked and unlinked populations were examined. In a selected subcohort of older women (aged ≥65) with first and only primary breast cancer who had Medicare Part D claims for tamoxifen, we further validated the linkage using Medicare Part D event data as the reference standard., Results: Among 758 068 eligible individuals, only 6.4% were linked to CVS/Walgreens data; the linkage percentage varied by age, sex, race, ethnicity, registry, and cancer type. Within the subcohort of 5963 older women with breast cancer and a claim for tamoxifen in Part D data, 25% were identified as tamoxifen users in retail pharmacy data. Out of these 1490 women, 749 (50.3%) had complete longitudinal tamoxifen dispensing information from retail pharmacy data., Conclusion: Retail pharmacy data show promise in identifying oral anticancer treatments, enhancing SEER registry efforts, but they require further validation. We propose an evaluation framework, sharing insights and potential use cases for this resource., (Published by Oxford University Press 2024.)

Background: Gold standard dementia assessments are rarely available in large real-world datasets, leaving researchers to choose among methods with imperfect but acceptable accuracy to identify nursing home (NH) residents with dementia. In healthcare claims, options include claims-based diagnosis algorithms, diagnosis indicators, and cognitive function measures in the Minimum Data Set (MDS), but few studies have compared these. We evaluated the proportion of NH residents identified with possible dementia and concordance of these three., Methods: Using a 20% random sample of 2018-2019 Medicare beneficiaries, we identified MDS admission assessments for non-skilled NH stays among individuals with continuous enrollment in Medicare Parts A, B, and D. Dementia was identified using: (1) Chronic Conditions Warehouse (CCW) claims-based algorithm for Alzheimer's disease and non-Alzheimer's dementia; (2) MDS active diagnosis indicators for Alzheimer's disease and non-Alzheimer's dementias; and (3) the MDS Cognitive Function Scale (CFS) (at least mild cognitive impairment). We compared the proportion of admissions with evidence of possible dementia using each criterion and calculated the sensitivity, specificity, and agreement of the CCW claims definition and MDS indicators for identifying any impairment on the CFS., Results: Among 346,013 non-SNF NH admissions between 2018 and 2019, 57.2% met criteria for at least one definition (44.7% CFS, 40.7% CCW algorithm, 26.0% MDS indicators). The MDS CFS uniquely identified the greatest proportion with evidence of dementia. The CCW claims algorithm had 63.7% sensitivity and 78.1% specificity for identifying any cognitive impairment on the CFS. Active diagnosis indicators from the MDS had lower sensitivity (47.0%), but higher specificity (91.0%)., Conclusions: Claims- and MDS-based methods for identifying NH residents with possible dementia have only partial overlap in the cohorts they identify, and neither is an obvious gold standard. Future studies should seek to determine whether additional functional assessments from the MDS or prescriptions can improve identification of possible dementia in this population., (© 2024 The American Geriatrics Society.)

Importance: Patients with acute myeloid leukemia (AML) recognize days spent at home (home time) vs in a hospital or nursing facility as an important factor in treatment decision making. No study has adequately described home time among older adults with AML., Objective: To describe home time among older adults with AML (aged ≥66 years) and compare home time between 2 common treatments: anthracycline-based chemotherapy and hypomethylating agents (HMAs)., Design, Setting, and Participants: A cohort of adults aged 66 years or older with a new diagnosis of AML from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database in 2004 to 2016 was identified. Individuals were stratified into anthracycline-based therapy, HMAs, or chemotherapy, not otherwise specified (NOS) using claims., Main Outcomes and Measures: The primary outcome was home time, quantified by subtracting the total number of person-days spent in hospitals and nursing facilities from the number of person-days survived and dividing by total person-days. A weighted multinomial regression model with stabilized inverse probability of treatment weighting to estimate adjusted home time was used., Results: The cohort included 7946 patients with AML: 2824 (35.5%) received anthracyclines, 2542 (32.0%) HMAs, and 2580 (32.5%) were classified as chemotherapy, NOS. Median (IQR) survival was 11.0 (5.0-27.0) months for those receiving anthracyclines and 8.0 (3.0-17.0) months for those receiving HMAs. Adjusted home time for all patients in the first year was 52.4%. Home time was highest among patients receiving HMAs (60.8%) followed by those receiving anthracyclines (51.9%). Despite having a shorter median survival, patients receiving HMAs had more total days at home and 33 more days at home in the first year on average than patients receiving anthracyclines (222 vs 189)., Conclusions and Relevance: This retrospective study of older adults with AML using SEER-Medicare data and propensity score weighting suggests that the additional survival afforded by receiving anthracycline-based therapy was entirely offset by admission to the hospital or to nursing facilities.

Rationale: Chronic obstructive pulmonary disease (COPD) is a common comorbidity among patients with lung cancer, and an important determinant of their outcomes, however, it is commonly underdiagnosed., Objective: Our objective was to estimate the prevalence of COPD among a cohort of U.S. lung cancer patients, the timing of a COPD diagnosis relative to their lung cancer diagnosis, and the association between an earlier diagnosis of COPD and stage of lung cancer, with consideration of patient sociodemographic modifying factors., Methods: We conducted an analysis of the Medicare-linked Surveillance, Epidemiology, and End Results database including patients aged 68+ years who were diagnosed with lung cancer between 2008 to 2017. Exposure: Prevalence of COPD was identified using claims and subclassified based on the timing of its diagnosis relative to the lung cancer diagnostic episode-"preexisting" if diagnosed > 3 months before lung cancer, and "concurrent" if diagnosed around the same time as the lung cancer (+/-3 months). Outcome: The stage of cancer at diagnosis (early versus late) was the outcome., Results: Among 159,542 patients with lung cancer, 73.5% had COPD. Among those with COPD, 34.4% were diagnosed within 3 months of their lung cancer diagnosis and considered to have "concurrent COPD." We observed a positive association between preexisting COPD diagnosis and early-stage lung cancer (prevalence ratio= 1.27; 95% confidence interval= 1.23-1.30), in adjusted models which were stronger for male, non-Hispanic Black, and Hispanic patients., Conclusions: Seven out of 10 patients with lung cancer have COPD, however, many do not receive their COPD diagnosis until around the time of their lung cancer diagnosis. Among these patients, an early COPD diagnosis may improve early detection of lung cancer., (JCOPDF © 2024.)

Introduction: Skeletal muscle density (SMD) measurements from imaging scans identify myosteatosis and could screen patients for geriatric assessment. We assessed SMD performance as a screening tool to identify older adults with cancer likely to be frail and who could benefit from in-depth assessment; we compared performance by sex and diabetes status., Materials and Methods: We analyzed patients in the Cancer & Aging Resilience Evaluation (CARE) Registry. Frailty and diabetes were captured using a patient-reported geriatric assessment (CARE tool). Frailty was defined using CARE frailty index (CARE-FI) based on principles of deficit accumulation. SMD was calculated from computed tomography scans (L3 vertebrae). Analyses were conducted by sex and diabetes status. Scatterplots and linear regression described crude associations between SMD and frailty score. Classification performance (frail vs. non-frail) was analyzed with (1) area under the receiver operating characteristic curves (AUC) and confidence intervals (CIs); and (2) sensitivity/specificity for sex-specific SMD quartile cut-offs (Q1, median, Q3). Performance was compared between patients with and without diabetes using differences and estimated CIs (2000 bootstrap replicates). We additionally calculated positive and negative likelihood ratios (LR+, LR-)., Results: The analytic cohort included 872 patients (39% female, median age 68 years, 27% with diabetes) with predominately stage III/IV gastrointestinal cancer; >60% planning to initiate first-line chemotherapy. SMD was negatively associated with frailty score; models were best fit in male patients with diabetes. AUC estimates for female (range: 0.58-0.62) and male (0.58-0.68) patients were low. Q3 cut-offs had high sensitivity (range: 0.76-0.89), but poor specificity (0.25-0.34). Diabetes did not impact estimates for female patients. Male patients with diabetes had greater sensitivity estimates compared to those without (sensitivity differences: 0.23 [0.07, 0.38], 0.08 [-0.07, 0.24], and 0.11 [0.00, 0.22] for Q1, median, Q3, respectively). LR estimates were most notable for male patients with diabetes (LR+ = 2.92, Q1 cut-off; LR- = 0.46, Q3 cut-off)., Discussion: Using SMD alone to screen older patients for geriatric assessment requires improvement. High-sensitivity cut-off points could miss 11-24% of patients with frailty, and many non-frail patients may be flagged. Screening with SMD is practical but work is needed to understand clinical andresource impacts of different cut-off points. Future research should evaluate performance with additional clinical data and in subgroups., Competing Interests: Declaration of Competing Interest ST received dissertation support through the Bristol Meyers Squibb Pre-Doctoral Fellowship in Worldwide Health Economics & Outcomes Research. TS receives investigator-initiated research funding and support as Principal Investigator [R01AG056479] from the National Institute on Aging; and as Co-Investigator [R01CA174453, R01HL118255, R01MD011680], National Institutes of Health. He also receives salary support as Director of Comparative Effectiveness Research (CER), NC TraCS Institute, UNC Clinical and Translational Science Award [UL1TR002489], the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Takeda, AbbVie, Boehringer Ingelheim), from pharmaceutical companies (Novo Nordisk), and from a generous contribution from Dr. Nancy A. Dreyer to the Department of Epidemiology, UNC-CH. Dr. Stürmer does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, and Novo Nordisk. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: To estimate the causal effect of surgery vs chemotherapy on survival in patients with T1-3NxM0 pancreatic cancer in a rigorous framework addressing selection bias and immortal time bias., Methods: We used population-based Danish health-care registries to conduct a cohort study emulating a hypothetical randomized trial to estimate the absolute difference in survival, comparing surgery with chemotherapy. We included pancreatic cancer patients diagnosed during 2008-2021. Exposure was surgery or chemotherapy initiated within a 16-week grace period after diagnosis. At the time of diagnosis, data of each patient were duplicated; one copy was assigned to the surgery protocol, and one copy to the chemotherapy protocol of the hypothetical trial. Copies were censored when the assigned treatment deviated from the observed treatment. To account for informative censoring, uncensored patients were weighted according to confounders. For comparison, we also applied a more conventional analysis using propensity score-based inverse probability weighting., Results: We included 1744 patients with a median age of 68 years: 73.6% underwent surgery, and 18.6% had chemotherapy without surgery; 7.8% received no treatment. The 3-year survival was 39.7% (95% confidence interval [CI] = 36.7% to 42.6%) after surgery and 22.7% (95% CI = 17.7% to 28.4%) after chemotherapy, corresponding to an absolute difference of 17.0% (95% CI = 10.8% to 23.1%). In the conventional survival analysis, this difference was 23.0% (95% CI = 17.0% to 29.0%)., Conclusion: Surgery was superior to chemotherapy in achieving long-term survival for pancreatic cancer. The difference comparing surgery and chemotherapy was substantially smaller when using the clone-censor-weight approach than conventional survival analysis., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Because the markups on cancer drugs vary by payor, providers' financial incentive to use high-price drugs is differential according to each patient's insurance type. We evaluated the association between patient insurer (commercial vs Medicaid) and the use of high-priced cancer treatments., Materials and Methods: We linked cancer registry, administrative claims, and demographic data for individuals diagnosed with cancer in North Carolina from 2004 to 2011, with either commercial or Medicaid insurance. We selected cancers with multiple FDA-approved, guideline-recommended chemotherapy options and large price differences between treatment options: advanced colorectal, lung, and head and neck cancer. The outcome was a receipt of a higher-priced option, and the exposure was insurer: commercial versus Medicaid. We estimated risk ratios (RRs) for the association between insurer and higher-priced treatment using log-binomial models with inverse probability of exposure weights., Results: Of 812 patients, 209 (26%) had Medicaid. The unadjusted risk of receiving higher-priced treatment was 36% (215/603) for commercially insured and 27% (57/209) for Medicaid insured (RR: 1.31, 95% CI: 1.02-1.67). After adjustment for confounders the association was attenuated (RR: 1.15, 95% CI: 0.81-1.65). Exploratory subgroup analysis suggested that commercial insurance was associated with increased receipt of higher-priced treatment among patients treated by non-NCI-designated providers (RR: 1.53, 95% CI: 1.14-2.04)., Conclusions: Individuals with Medicaid and commercial insurance received high-priced treatments in similar proportion, after accounting for differences in case mix. However, modification by provider characteristics suggests that insurance type may influence treatment selection for some patient groups. Further work is needed to determine the relationship between insurance status and newer, high-price drugs such as immune-oncology agents., (© The Author(s) 2024. Published by Oxford University Press.)

Antifungal resistance has emerged as a significant health concern with increasing reports of resistant variants in previously susceptible species. At present, little is known about occupational exposure to antifungal-resistant fungi. This study aimed to investigate Danish workers' occupational exposure to airborne fungi resistant to first-line treatment drugs. A retrospective study was performed on a unique collection of personal exposure samples gathered over a twenty-year period from Danish working environments, in sectors including agriculture, animal handling, waste management, and healthcare. A total of 669 samples were cultivated at 37 °C and fungal colonies were identified using MALDI-TOF MS. Subsequently, identification was confirmed by amplicon sequencing the genes of calmodulin and beta-tubulin to unveil potential cryptic species. Infectious fungi (495 isolates from 23 species) were tested for resistance against Itraconazole, Voriconazole, Posaconazole, and Amphotericin B. Working environments were highly variable in the overall fungal exposure, and showed vastly different species compositions. Resistance was found in 30 isolates of the species Aspergillus fumigatus (4 of 251 isolates), A. nidulans (2 of 13), A. niger complex (19 of 131), A. versicolor (3 of 18), and A. lentulus (2 of 2). Sequence analysis revealed several cryptic species within the A. niger complex including A. tubingensis, A. luchuensis, and A. phoenicis. Among the resistant A. fumigatus isolates, two contained the well-described TR 34 /L98H mutation in the cyp51A gene and promoter region, while the remainder harbored silent mutations. The results indicate that the working environment significantly contributes to exposure to resistant fungi, with particularly biofuel plant workers experiencing high exposure. Differences in the prevalence of resistance across working environments may be linked to the underlying species composition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hydrothermal liquefaction (HTL) shows promise for converting wet biomass waste into biofuel, but the resulting high-strength process water (PW) requires treatment. This study explored enhancing energy recovery by anaerobic digestion using semi-batch reactors. Co-digesting manure with HTL-PW from wheat straw-manure co-HTL yielded methane (43-49% of the chemical oxygen demand, COD) at concentrations up to 17.8 gCOD·L -1 , whereas HTL-PW from sewage sludge yielded methane (43% of the COD) up to only 12.8 gCOD·L -1 and complete inhibition occurred at 17 gCOD·L -1 . Microbial community shifts confirmed inhibition of methanogenic archaea, while hydrolytic-fermentative bacteria were resilient. Differences in chemical composition, particularly higher levels of N-containing heterocyclic compounds in PW of sewage sludge, likely caused the microbial inhibition. The considerable potential of combining HTL with anaerobic digestion for enhanced energy recovery from straw-manure in an agricultural context is demonstrated, yet sewage sludge HTL-PW requires more advanced approaches to deal with methanogenesis inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Many older adults with cancer have ≥2 impairments on geriatric assessment, which affects present and future frailty status, treatment tolerability, and outcomes. Our objective was to identify and describe distinct geriatric assessment impairment classes using latent class analysis (LCA) in older patients with gastrointestinal malignancies and assess 1-year mortality., Methods: We used the Cancer & Aging Resilience Evaluation (CARE) Study, a registry of older adults (≥60 years) at University of Alabama at Birmingham. The analytic cohort included patients with gastrointestinal malignancies who completed a self-administered geriatric assessment (CARE tool) before chemotherapy and had ≥1 geriatric assessment impairment. Thirteen geriatric assessment impairments were used as indicators in LCA. Resultant classes were described, mortality was estimated, and risk contrasts (differences and hazard ratios) were calculated with 95% confidence intervals. For comparison, estimates were provided for frailty categories (robust, prefrail, and frail) determined from 44 items in the CARE tool. Stratified analyses included high-risk (pancreatic, hepatobiliary, and esophageal) versus low-risk gastrointestinal cancers, and stage (IV vs I-III)., Results: Six geriatric assessment impairment classes were identified: Mild impairment (LC1); Social support impairment (LC2); Weight loss alone (LC3); Impaired, low anxiety/depression (LC4); Impaired with anxiety/depression (LC5); and Global impairment (LC6). One-year mortality was 14%, 22%, 29%, 34%, 50%, and 50% for LC1-LC6, respectively. For frailty categories, estimates ranged from 18% (robust) to 40% (frail). In stratified analyses, LC4-LC6 consistently had higher mortality estimates compared to LC1., Conclusions: The 6 geriatric assessment impairment classes showed a wider spread of mortality estimates compared to frailty categories and could be used to identify vulnerable patients and to plan interventions., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Frailty is an aging-related syndrome of reduced physiological reserve to maintain homeostasis. The Faurot frailty index has been validated as a Medicare claims-based proxy for predicting frailty using billing information from a user-specified ascertainment window., Objectives: We assessed the validity of the Faurot frailty index as a predictor of the frailty phenotype and 1-year mortality using varying frailty ascertainment windows., Research Design: We identified older adults (66+ y) in Round 5 (2015) of the National Health and Aging Trends Study with Medicare claims linkage. Gold standard frailty was assessed using the frailty phenotype. We calculated the Faurot frailty index using 3, 6, 8, and 12 months of claims prior to the survey or all-available lookback. Model performance for each window in predicting the frailty phenotype was assessed by quantifying calibration and discrimination. Predictive performance for 1-year mortality was assessed by estimating risk differences across claims-based frailty strata., Results: Among 4253 older adults, the 6 and 8-month windows had the best frailty phenotype calibration (calibration slopes: 0.88 and 0.87). All-available lookback had the best discrimination (C-statistic=0.780), but poor calibration. Mortality associations were strongest using a 3-month window and monotonically decreased with longer windows. Subgroup analyses revealed worse performance in Black and Hispanic individuals than counterparts., Conclusions: The optimal ascertainment window for the Faurot frailty index may depend on the clinical context, and researchers should consider tradeoffs between discrimination, calibration, and mortality. Sensitivity analyses using different durations can enhance the robustness of inferences. Research is needed to improve prediction across racial and ethnic groups., Competing Interests: T.S. receives salary support from the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Takeda, AbbVie, Boehringer Ingelheim, As tellas, and Sarepta) and from a generous contribution from Dr. Nancy A. Dreyer to the Department of Epidemiology, University of North Carolina at Chapel Hill. T.S. does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, and Novo Nordisk. J.L.L. receives research support from Roche to the University of North Carolina; her spouse was formerly employed by GlaxoSmithKline and previously owned stock in the company. K.R-H. receives research support unrelated to this work from Pfizer Global Medical Foundation to the University of North Carolina. D.H.K. received personal fees from Alosa Health and VillageMD for unrelated work. The remaining authors, J.K.E., K.R.F., and E.D.D., declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Feast-famine (FF) regimes improved the removal of recalcitrant pharmaceuticals in moving bed biofilm reactors (MBBRs), but the optimal FF cycle remained unresolved. The effects of FF cycle time on the removal of bulk substrates (organic carbon and nitrogen) and trace pharmaceuticals by MBBR are systematically evaluated in this study. The feast to famine ratio was fixed to 1:2 to keep the same loading rate, but the time for the FF cycles varied from 18 h to 288 h. The MBBR adapted to the longest FF cycle time (288 h equaling 48 × HRT) resulted in significantly higher degradation rates (up to +183%) for 12 out of 28 pharmaceuticals than a continuously fed (non-FF) reactor. However, other FF cycle times (18, 36, 72 and 144 h) only showed a significant up-regulation for 2-3 pharmaceuticals compared to the non-FF reactor. Enantioselective degradation of metoprolol and propranolol occurred in the second phase of a two phase degradation, which was different for the longer FF cycle time. N-oxidation and N-demethylation pathways of tramadol and venlafaxine differed across the FF cycle time suggestin the FF cycle time varied the predominant transformation pathways of pharmaceuticals. The abundance of bacteria in the biofilms varied considerably between different FF cycle times, which possibly caused the biofilm to remove more recalcitrant bulk organic C and pharmaceuticals under long cycle times., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Delivery of cancer treatments, such as chemotherapy, requires a complex set of decisions that can change over time. Traditional measures of chemotherapy delivery, such as relative dose intensity, measure the amount of chemotherapy received by the end of treatment but mask the timing of dose reductions, delays, and discontinuation. These events may be important for delivering timely interventions to support adherence and lower the risk of recurrence., Materials and Methods: We used an institutional database to identify women diagnosed with stage I-III breast cancer receiving adjuvant chemotherapy with a standard 4-cycle regimen of docetaxel + cyclophosphamide (TC, every 21 days) from April 2014 to December 2019. LCD was calculated as the amount of a given chemotherapy agent delivered at a specified time, t, divided by the total planned standard chemotherapy dose at time t. We visualized LCD curves for each chemotherapy agent and reported the median LCD and interquartile range (IQR) at the end of the regimen, overall and by age group (<65 years vs. 65+ years)., Results: The study population included 80 women. At the end of treatment, overall median LCDs for both cyclophosphamide and docetaxel were 100% (IQR: 99.6%, 100%), suggesting that TC was well tolerated. However, the lower quartile LCD for cyclophosphamide was 98.7% in older women treated with TC compared with 99.7% in younger women., Conclusion: Within our cohort, adjuvant TC was well tolerated with LCD curves showing largely on-time and full-dose administration. Subgroup analyses showed only slight decreases in adjuvant TC LCD for patients aged 65+ versus <65 years., (© The Author(s) 2024. Published by Oxford University Press.)

Little is known about caregivers' perspectives on deprescribing bisphosphonates for older adults with dementia. Caregivers agreed that fracture prevention was important for maintaining functional independence but acknowledged that changing goals of care may justify deprescribing. Conversations grounded in "what matters most" can align fracture prevention treatment with goals of care., Purpose: The long-term fracture prevention benefits of bisphosphonates may begin to be overshadowed by the potential burden of adverse effects and polypharmacy for older adults living with dementia as the disease progresses. We characterized factors that influence caregiver decision-making for continuing versus deprescribing bisphosphonates for persons living with dementia., Methods: We conducted 11 interviews with family or informal caregivers of older adults living with dementia in the community or in long-term care who had been treated with bisphosphonates. Interviews focused on experiences caring for someone who has experienced a fracture, perceived benefits and harms of bisphosphonates, and experiences with deprescribing. Analyses were conducted using a qualitative framework methodology guided by the Health Belief Model., Results: Most caregivers were male (n = 8), younger than 65 (n = 8) and were an adult child caregiver (n = 8). Three caregivers were Black and five were Latino/a. Attempts to maintain functional independence despite high likelihood of falls was frequently discussed as contributing to fracture risk, in this population. Many caregivers perceived fracture prevention treatment as important, while several noted that it may become less important near the end of life. Perceived benefits of fracture prevention treatment for persons with dementia included improved quality of life and maintaining independence. Although most indicated that bisphosphonates were well tolerated, gastrointestinal adverse effects, preference for fewer treatments, and dementia-related behaviors that interfere with medication administration may be reasons for deprescribing., Conclusion: Conversations grounded in caregiver experiences and "what matters most" may help optimize fracture prevention treatment for older adults with dementia., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Purpose: Mortality data can complement primary end points from cancer clinical trials. Yet, identifying deaths after trial completion is challenging, as timely and comprehensive vital status data are unavailable in the United States. We developed and evaluated a multisource approach to capture death data after clinical trial completion., Methods: Individuals age 70 years and older with incurable solid tumors or lymphoma and ≥1 aging-related condition were enrolled from October 2014 to March 2019 (ClinicalTrials.gov identifier: NCT02107443 and NCT02054741). Participants provided consent to link trial information to external sources. We developed a stepped approach for extended death capture using (1) active trial follow-up up to 1 year, (2) linkage to the National Death Index (NDI), and (3) obituary searches, thus generating a 5-year survival curve. In a random sample of 50 participants who died during trial follow-up, we estimated sensitivity of death data using NDI and obituary sources and computed survival times by data source., Results: The two trials enrolled 1,169 participants; mean age was 76 years; 46% were female; and gastrointestinal cancer (30%) and lung cancer (26%) were the most common cancer types. Across data sources, maximum follow-up was >7 years; 5-year survival was 18%. In total, there were 841 deaths: 603 identified during trial follow-up; 199 from the NDI; and 39 from obituary searches. The sensitivity for death capture was 92% for the NDI and 94% for the obituary searches compared with the trial data, and computed survival times were similar across data sources., Conclusion: Extending clinical trial mortality follow-up through linkage with external data sources was feasible and accurate. Future cancer clinical trials should collect necessary consent and patient identifiers for vital status linkages that can enhance understanding of longer-term outcomes.

Background: Limited research has evaluated the validity of claims-based definitions for deprescribing., Objectives: Evaluate the validity of claims-based definitions of deprescribing against electronic health records (EHRs) for deprescribing of benzodiazepines (BZDs) after a fall-related hospitalization., Methods: We used a novel data linkage between Medicare fee-for-service (FFS) and Part D with our health system's EHR. We identified patients aged ≥66 years with a fall-related hospitalization, continuous enrollment in Medicare FFS and Part D for 6 months pre- and post-hospitalization, and ≥2 BZD fills in the 6 months pre-hospitalization. Using a standardized EHR abstraction tool, we adjudicated deprescribing for a sub-sample with a fall-related hospitalization at UNC. We evaluated the validity of claims-based deprescribing definitions (e.g., gaps in supply, dosage reductions) versus chart review using sensitivity and specificity., Results: Among 257 patients in the overall sample, 44% were aged 66-74 years, 35% had Medicare low-income subsidy, 79% were female. Among claims-based definitions using gaps in supply, the prevalence of BZD deprescribing ranged from 8.2% (no refills) to 36.6% (30-day gap). When incorporating dosage, the prevalence ranged from 55.3% to 65.8%. Among the validation sub-sample (n = 47), approximately one-third had BZDs deprescribed in the EHR. Compared to EHR, gaps in supply from claims had good sensitivity, but poor specificity. Incorporating dosage increased sensitivity, but worsened specificity., Conclusions: The sensitivity of claims-based definitions for deprescribing of BZDs was low; however, the specificity of a 90-day gap was >90%. Replication in other EHRs and for other low-value medications is needed to guide future deprescribing research., (© 2024 John Wiley & Sons Ltd.)

Objective. Closed-loop myoelectric prostheses, which combine supplementary sensory feedback and electromyography (EMG) based control, hold the potential to narrow the divide between natural and bionic hands. The use of these devices, however, requires dedicated training. Therefore, it is crucial to develop methods that quantify how users acquire skilled control over their prostheses to effectively monitor skill progression and inform the development of interfaces that optimize this process. Approach. Building on theories of skill learning in human motor control, we measured speed-accuracy tradeoff functions (SAFs) to comprehensively characterize learning-induced changes in skill-as opposed to merely tracking changes in task success across training-facilitated by a closed-loop interface that combined proportional control and EMG feedback. Sixteen healthy participants and one individual with a transradial limb loss participated in a three-day experiment where they were instructed to perform the box-and-blocks task using a timed force-matching paradigm at four specified speeds to reach two target force levels, such that the SAF could be determined. Main results. We found that the participants' accuracy increased in a similar way across all speeds we tested. Consequently, the shape of the SAF remained similar across days, at both force levels. Further, we observed that EMG feedback enabled participants to improve their motor execution in terms of reduced trial-by-trial variability, a hallmark of skilled behavior. We then fit a power law model of the SAF, and demonstrated how the model parameters could be used to identify and monitor changes in skill. Significance. We comprehensively characterized how an EMG feedback interface enabled skill acquisition, both at the level of task performance and movement execution. More generally, we believe that the proposed methods are effective for measuring and monitoring user skill progression in closed-loop prosthesis control., (Creative Commons Attribution license.)

Background: In the presence of effect measure modification, estimates of treatment effects from randomized controlled trials may not be valid in clinical practice settings. The development and application of quantitative approaches for extending treatment effects from trials to clinical practice settings is an active area of research., Methods: In this article, we provide researchers with a practical roadmap and four visualizations to assist in variable selection for models to extend treatment effects observed in trials to clinical practice settings and to assess model specification and performance. We apply this roadmap and visualizations to an example extending the effects of adjuvant chemotherapy (5-fluorouracil vs. plus oxaliplatin) for colon cancer from a trial population to a population of individuals treated in community oncology practices in the United States., Results: The first visualization screens for potential effect measure modifiers to include in models extending trial treatment effects to clinical practice populations. The second visualization displays a measure of covariate overlap between the clinical practice populations and the trial population. The third and fourth visualizations highlight considerations for model specification and influential observations. The conceptual roadmap describes how the output from the visualizations helps interrogate the assumptions required to extend treatment effects from trials to target populations., Conclusions: The roadmap and visualizations can inform practical decisions required for quantitatively extending treatment effects from trials to clinical practice settings., Competing Interests: T.S. receives salary support from the Center for Pharmacoepidemiology (current members are GlaxoSmithKline, UCB BioSciences, Takeda Pharmaceutical Company, AbbVie, and Boehringer Ingelheim), and owns stock in Novartis, Roche and Novo Nordisk. J.L.L. spouse was formerly employed by GlaxoSmithKline and previously owned stock in the company. She has also received research support to UNC from AbbVie and Roche. D.W. has engaged in consulting for PRI Health Solutions on behalf of Sanofi-Pasteur on unrelated work. S.S. was a consultant for CERobs Consulting, LLC on projects unrelated to the submitted work. She is currently a full-time employee at Pfizer Inc. The initial manuscript draft was completed before her employment at Pfizer Inc. The other authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: Older adults with advanced cancer are less likely to tolerate treatment with cytotoxic chemotherapy compared with younger patients due to their aging-related conditions. Hence, oncologists sometimes opt to employ primary treatment modifications (deviation from standard of care) during the first cycle of chemotherapy., Objective: To examine the association between primary treatment modification and treatment tolerability in older adults with advanced cancer who were starting new palliative chemotherapy regimens., Design, Setting, and Participants: This cohort study was a secondary analysis of the GAP70+ (Geriatric Assessment Intervention for Reducing Toxicity in Older Patients with Advanced Cancer) trial, which was conducted between July 2014 and March 2019. The GAP70+ trial included patients aged 70 years or older who had advanced (ie, incurable) cancer, had 1 or more geriatric assessment domain impairments, and planned to start a new palliative chemotherapy regimen. Data analysis was conducted in November 2022., Exposures: Receipt of standard-of-care chemotherapy regimens vs primary treatment modification defined as any change from National Comprehensive Cancer Network guidelines or published clinical trials (eg, primary dose reduction, schedule change)., Main Outcomes and Measures: Tolerability outcomes were assessed within 3 months of treatment. These outcomes included the following: (1) any grade 3 to 5 toxic effect, according to the National Cancer Institute Common Terminology Criteria for Adverse Events; (2) patient-reported functional decline, defined as the development of worse dependency in activities of daily living using scale scores; and (3) a composite adverse outcome (an end point that combined toxic effects, functional decline, and 6-month overall survival). Multivariable cluster-weighted generalized estimating equation models examined the association between primary treatment modification and outcomes adjusting for covariates., Results: This study included 609 patients with a mean (SD) age of 77.2 (5.2) years; more than half (333 [54.7%]) were men. Race and ethnicity was available for 607 patients: 39 (6.4%) were Black, 539 (88.5%) were non-Hispanic White, and 29 (4.8%) were of other race or ethnicity. Nearly half (281 [46.1%]) received a primary modified treatment regimen. The most common cancer types were gastrointestinal cancer (228 [37.4%]) and lung cancer (174 [28.6%]). In multivariable analysis, primary treatment modification was associated with a reduced risk of grade 3 to 5 toxic effects (relative risk [RR], 0.85 [95% CI, 0.77-0.94]) and functional decline (RR, 0.80 [95% CI, 0.67-0.95]). Patients who received primary treatment modification had 32.0% lower odds of having a worse composite adverse outcome (odds ratio, 0.68 [95% CI, 0.48-0.97])., Conclusions and Relevance: In this cohort study, primary treatment modification was associated with improved tolerability of chemotherapeutic regimens among older adults with advanced cancer and aging-related conditions. These findings may help optimize cancer treatment dosing in older adults with advanced cancer and aging-related conditions.

Purpose: Multiple myeloma (MM) is a prevalent hematologic malignancy in older adults, who often experience physical disability, increased health care usage, and reduced treatment tolerance. Home health (HH) services are frequently used by this group, but the relationship between disability, HH use, and MM treatment receipt is unclear. This study examines the connections between disability, treatment receipt, and survival outcomes in older adults with newly diagnosed MM using a nationwide data set., Methods: The SEER-Medicare data set was used to identify adults aged 66 years and older diagnosed with MM from 2010 to 2017, who used HH services the year before diagnosis. Disability was assessed with the Outcome and Assessment Information Set, using a composite score derived from items related to ability to complete activities of daily living. Mortality, therapy receipt, and health care utilization patterns were evaluated., Results: Of 37,280 older adults with MM, 6,850 (18.2%) used HH services before diagnosis. Moderate disability at HH assessment resulted in similar MM-directed therapy receipt as mild disability, with comparable health care usage after diagnosis to severe disability. HH users had a higher comorbidity burden and higher mortality (adjusted risk ratio for 3-year mortality: 1.59 [95% CI, 1.55 to 1.64]). Severe functional disability before diagnosis was strongly related to postdiagnosis mortality., Conclusion: Among older adults with MM receiving HH services, disability is a predictor of early mortality. Moderately disabled individuals undergo similar therapy intensity as the mildly disabled but experience increased acute care utilization. Previous HH use could identify patients with MM requiring intensive support during therapy initiation.