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Chase D Latour,1,2 Leah J McGrath,2 Mary Clouser,3 Carrie Nielson,3 Ying Yu,2 Akhila Balasubramanian,3 Alexander Breskin,1,2 M Alan Brookhart2,4 1Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Target RWE, Durham, NC, USA; 3Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA; 4Department of Population Health Sciences, Duke University, Durham, NC, USACorrespondence: Chase D Latour, Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Drive, 2101 McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC, USA, Tel +1 765 418 2743, Email chasedlatour@gmail.comPurpose: Regression-to-the-mean (RTM) is a statistical phenomenon that may occur in epidemiologic studies where inclusion in the study cohort is contingent upon experiencing a laboratory/clinical measurement beyond a defined threshold. When differential across treatment groups, RTM could bias the final study estimate. This poses substantial challenges in observational studies that index patients upon experiencing extreme laboratory or clinical values. Our objective was to investigate propensity score-based methods as a tool for mitigating this source of bias via simulation.Methods: We simulated a noninterventional comparative effectiveness study, comparing treatment with romiplostim to standard-of-care therapies for immune thrombocytopenia (ITP), a disease characterized by low platelet counts. Platelet counts were generated from normal distributions according to the underlying ITP severity, a strong confounder of treatment and outcome. Patients were assigned treatment probabilities based upon ITP severity, which created varied levels of differential and non-differential RTM. Treatments were compared via the difference in median platelet counts during 23 weeks of follow-up. We calculated four summary metrics of the platelet counts measured prior to cohort entry and built six propensity score models to adjust for those variables. We adjusted for these summary metrics using inverse probability of treatment weights.Results: Across all simulated scenarios, propensity score adjustment reduced bias and increased precision of the treatment effect estimator. Adjusting for combinations of the summary metrics was most effective at reducing bias. Adjusting for the mean of prior platelet counts or the difference between the cohort-qualifying platelet count and the largest prior count eliminated the most bias when assessed individually.Conclusion: These results suggest that differential RTM could be reasonably addressed by propensity score models with summaries of historical laboratory values. This approach can be easily applied to any comparative effectiveness or safety study, though investigators should carefully consider the best summary metric for their data.Keywords: bias correction, propensity scores, real-world evidence, immune thrombocytopenia

Sara N Levintow,1,2 Stephanie R Reading,3 Bradley C Saul,1 Ying Yu,1 Diane Reams,1 Leah J McGrath,1 Kiran Philip,3 Paul J Dluzniewski,3 M Alan Brookhart1,4 1NoviSci, Inc, Durham, NC, USA; 2Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA; 3Center for Observational Research, Amgen, Thousand Oaks, CA, USA; 4Department of Population Health Sciences, Duke University, Durham, NC, USACorrespondence: Sara N LevintowNoviSci, Inc, PMB 218, 201 W Main St, Ste 200, Durham, NC 27701 Email slevintow@novisci.comBackground: The 2013 ACC/AHA cholesterol treatment guidelines removed the recommendation to treat adults at risk of cardiovascular disease to goal levels of low-density lipoprotein cholesterol (LDL-C). We anticipated that the frequency of LDL-C testing in clinical practice would decline as a result. To test this hypothesis, we evaluated the frequency of LDL-C testing before and after the guideline release.Methods: We used the MarketScan® Commercial and Medicare Supplemental claims data (1/1/2007– 12/31/2016) to identify four cohorts: 1) statin initiators (any intensity), 2) high-intensity statin initiators, 3) ezetimibe initiators, and 4) patients at very high cardiovascular risk (≥ 2 hospitalizations for myocardial infarction or ischemic stroke, with prevalent statin use). Rates of LDL-C testing by calendar year quarter were estimated for each cohort. To estimate rates in the absence of a guideline change, we fit a time-series model to the pre-guideline rates and extrapolated to the post-guideline period, adjusting for covariates, seasonality, and time trend.Results: Pre- and post-guideline rates (LDL-C tests per 1,000 persons per quarter) were 248 and 235, respectively, for 3.9 million statin initiators; 263 and 246 for 1.3 million high-intensity statin initiators; 277 and 261 for 323,544 ezetimibe initiators; and 180 and 158 for 42,108 very high-risk patients. For all cohorts, observed post-guideline rates were similar to model-predicted rates. On average, the difference between observed and predicted rates was 8.5 for patients initiating any statin; 2.6 for patients initiating a high-intensity statin; 11.4 for patients initiating ezetimibe, and − 0.5 for high-risk patients.Conclusion: We observed no discernible impact of the release of the 2013 ACC/AHA guidelines on LDL-C testing rates. Rather, there was a gradual decline in testing rates starting prior to the guideline change and continuing throughout the study period. Our findings suggest that the guidelines had little to no impact on use of LDL-C testing.Keywords: low-density lipoprotein cholesterol, statin, ezetimibe, cardiovascular disease, guideline adherence, database, epidemiology

Leah J McGrath,1 Karynsa Kilpatrick,2 Robert A Overman,1 Diane Reams,1 Anjali Sharma,2 Ivy Altomare,3 Jeffrey Wasser,4 M Alan Brookhart1,5 1NoviSci, Inc., Durham, NC, USA; 2Amgen Inc, Thousand Oaks, CA, USA; 3Duke University Medical Center, Durham, NC, USA; 4University of Connecticut, Farmington, CT, USA; 5Department of Population Health Sciences, Duke University, Durham, NC, USACorrespondence: Leah J McGrathNoviSci, Inc, PMB 218, 201 W Main Street, Ste 200, Durham, NC 27701, USATel +1 919 390 1642Email lmcgrath@novisci.comPurpose: Patients with immune thrombocytopenia (ITP) have low platelet counts and an increased risk of bleeding. We described treatment patterns and clinical outcomes in routine practice in the United States (US).Patients and Methods: Using electronic health record data from hematology/oncology clinics linked to administrative claims in the US, we studied 447 adults newly diagnosed with primary ITP from 2011 to 2016. Patients with a secondary cause of thrombocytopenia were excluded. The incidence of ITP treatment initiation, bleeding events, and rescue therapy use were estimated using competing risk models.Results: At 1-year post-ITP diagnosis, 50% of patients were prescribed an oral corticosteroid, with the majority being prescribed immediately following diagnosis. Of the more common second-line options, rituximab use was the most frequent (1-year cumulative incidence: 16% [95% confidence interval: 12, 19]), followed by romiplostim (9% [7, 12] and eltrombopag (5% [3, 8]). Use of these drugs was similar at 2 years post-diagnosis. At 6 months post-ITP treatment initiation, the cumulative incidence of bleeding was similar among eltrombopag and romiplostim initiators (17% [6, 33] and 19% [9, 31], respectively) and was slightly lower in rituximab users (12% [6, 20]). However, during this same timeframe, rituximab users had a higher incidence of rescue therapy use (48% [36, 58] versus 29% [14, 46] in eltrombopag and 26% [14, 39] in romiplostim users). Although splenectomy was rare, at 6 months post-surgery nearly 20% had experienced a bleed and nearly 20% had required rescue.Conclusion: This study describes the health trajectory of adults with ITP who are managed in hematology clinics in the US and could inform the design of non-interventional studies of comparative effectiveness among treatments.Keywords: primary immune thrombocytopenia, thrombopoietin receptor agonists, rituximab, splenectomy, real-world evidence

Leah J McGrath,1 Robert A Overman,1 Diane Reams,1 Karynsa Cetin,2 Alexander Liede,3 Steven A Narod,4 M Alan Brookhart,1 Rohini K Hernandez2 1NoviSci, LLC, Durham, NC, USA; 2Amgen Inc, Thousand Oaks, CA, USA; 3Amgen Inc, South San Franscisco, CA, USA; 4Department of Medicine, University of Toronto, Toronto, Canada Purpose: Bone-modifying agents (BMAs) are recommended for women with bone metastasis from breast cancer to prevent skeletal-related events. We examined the usage patterns and identified the factors associated with the use of BMAs (denosumab and intravenous bisphosphonates) among women in the US. Patients and methods: Electronic health records from oncology clinics were used to identify women diagnosed with bone metastasis from breast cancer between 2013 and 2014. Patients were excluded if they had recently used a BMA or had concurrent cancer at an additional primary site. The incidence of BMA initiation, interruption, and reinitiation were estimated using competing risk regression models. A generalized linear model was used to estimate risk factors for treatment initiation and interruption. Results: There were 589 women diagnosed with bone metastasis from breast cancer. By 1 year, 68% of these patients (95% CI: 64%, 71%) had initiated treatment with a BMA. Denosumab and zoledronic acid were the most commonly used agents, whereas pamidronate was used infrequently. Young women were more likely to initiate a BMA than older women (adjusted risk difference: 6.4 [95% CI: 1.5, 10.9]). Of the 412 patients who initiated a BMA, 46% (95% CI: 41%, 51%) experienced an interruption within 1 year. Seventy-four percent (95% CI: 68%, 79%) of patients who interrupted their treatment had reinitiated therapy within 1 year of interruption. Conclusion: The majority of women diagnosed with bone metastasis from breast cancer initiate a BMA within 1 year of diagnosis, but a large proportion, particularly among the elderly, do not use these therapies. Keywords: bone-modifying agents, breast cancer, bone metastasis, treatment patterns, electronic health records, denosumab, zoledronic acid, pamidronate

Background: The Advisory Committee on Immunization Practices (ACIP) recommends early childhood vaccinations, but knowledge is limited about the magnitude and timing of vaccine delay for each recommended dose on a population level. We sought to characterize longitudinal patient-level patterns of early childhood vaccination schedule adherence., Methods: Using the Merative MarketScan Commercial Database (2009-2019), we identified commercially-insured infants who received at least one timely dose of a 2-month recommended vaccine. We categorized the number of recommended vaccines administered on the same date at 2, 4, 6, and 12-15 months of age (grace period: -7, +21 days). A Sankey diagram illustrated the number of vaccines received concomitantly during each age window and depicted transitions to different states over time (e.g., no vaccine delay to vaccine delay). For each vaccine dose, we estimated the cumulative incidence of receipt., Results: Among 1,239,364 eligible children, 28% of infants aged 4 months and 38% of infants aged 6 months did not receive timely, concomitant administration of all recommended vaccines. The number of timely vaccines received concomitantly and age at receipt varied most for doses recommended during the second year of life. Children with a previously delayed (versus timely) dose consistently experienced longer time to subsequent dose., Conclusions: National coverage improved over time for all recommended vaccine doses under study, most notably for measles, mumps, and rubella. However, many children do not receive vaccines on schedule. Interventions to maintain adherence to the recommended schedule are needed early in life., Competing Interests: Declaration of competing interest JGN and AMB have received investigator-initiated research contracts from Merck on topics unrelated to this article. At the time this research was conducted, LJM was an employee of and owned stock in NoviSci. She is now an employee and owns stock in Pfizer. No other authors have conflicts of interest to disclose. All authors attest they meet the ICMJE criteria for authorship. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anne Butler reports financial support and administrative support were provided by National Center for Advancing Translational Sciences. Anne Butler reports financial support was provided by National Center for Advancing Translational Sciences. Anne Butler reports a relationship with Merck & Co Inc. that includes: funding grants. Jason Newland reports a relationship with Merck & Co Inc. that includes: funding grants. Leah McGrath reports a relationship with Pfizer that includes: employment and equity or stocks. Leah McGrath reports a relationship with NoviSci that includes: employment and equity or stocks. JGN and AMB have received investigator-initiated research contracts from Merck on topics unrelated to this article. At the time this research was conducted, LJM was an employee of and owned stock in NoviSci. She is now an employee and owns stock in Pfizer. No other authors have conflicts of interest to disclose. If there are other authors, they 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 Elsevier Ltd. All rights reserved.)

Background: The COVID-19 pandemic has disproportionately affected marginalized groups in the United States. Although most children have mild or asymptomatic COVID-19, some experience severe disease and long-term complications. However, few studies have examined health disparities in severe COVID-19 outcomes among US children., Objective: To examine disparities in the clinical outcomes of infants and children aged <5 years hospitalized with COVID-19 by race/ethnicity and payer status., Methods: Children aged <5 years hospitalized with an admission diagnosis of COVID-19 (April 2021-February 2023) were selected from the PINC AI™ Healthcare Database. Hospital outcomes included length of stay (LOS), intensive care unit (ICU) admission, oxygen supplementation, invasive mechanical ventilation (IMV), and prolonged duration of each outcome. Multivariable logistic regression models compared hospitalization outcomes by race/ethnicity and payer status., Results: Among 10,190 children (mean age: 0.9 years, 56.5% male, 66.7% Medicaid-insured), race/ethnicity was distributed as follows: White non-Hispanic (35.1%), Hispanic (any or Unknown race; 28.3%), Black non-Hispanic (15.2%), Other race/ethnicity (8.9%) and Unknown (12.5%). Payer status varied by race/ethnicity. White non-Hispanic children had the highest proportion with commercial insurance (42.9%) while other racial/ethnic groups ranged between 13.8% to 26.1%. Black non-Hispanic children had the highest proportion with Medicaid (82.3%) followed by Hispanic children (76.9%). Black non-Hispanic children had higher odds of prolonged outcomes: LOS (adjusted odds ratio [aOR] = 1.20, 95% confidence interval [CI]:1.05-1.38), ICU days (aOR = 1.44, 95% CI: 1.07-1.93), and IMV days (aOR = 1.80, 95% CI: 1.09-2.97) compared to White non-Hispanic children. Similar patterns were observed for Hispanic and children of Other race/ethnicity. Medicaid-insured and children with other insurance had higher odds of prolonged LOS and oxygen days than commercially insured patients., Conclusion: There were disparities in clinical outcomes of COVID-19 by race/ethnicity and insurance type, particularly for prolonged-duration outcomes. Further research is required to fully comprehend the causes and consequences of these disparities and develop strategies to reduce them while ensuring equitable healthcare delivery., Competing Interests: This study was sponsored by Pfizer, which had a role in the collection, analysis, and interpretation of data, the writing of the article, and the decision to submit the manuscript for publication. All authors are employees and shareholders of Pfizer Inc. The author(s) declare that this study received funding from Pfizer. The funder had the following involvement with the study: a role in the collection, analysis, and interpretation of data, the writing of the article, and the decision to submit the manuscript for publication., (© 2024 Ochapa, McGrath, Alfred, Lopez and Nepal.)

Objective: To create a data-driven definition of post-COVID conditions (PCC) by directly measure changes in symptomatology before and after a first COVID episode., Materials and Methods: Retrospective cohort study using Optum® de-identified Electronic Health Record (EHR) dataset from the United States of persons of any age April 2020-September 2021. For each person with COVID (ICD-10-CM U07.1 "COVID-19" or positive test result), we selected up to 3 comparators. The final COVID symptom score was computed as the sum of new diagnoses weighted by each diagnosis' ratio of incidence in COVID group relative to comparator group. For the subset of COVID cases diagnosed in September 2021, we compared the incidence of PCC using our data-driven definition with ICD-10-CM code U09.9 "Post-COVID Conditions", first available in the US October 2021., Results: The final cohort contained 588,611 people with COVID, with mean age of 48 years and 38% male. Our definition identified 20% of persons developed PCC in follow-up. PCC incidence increased with age: (7.8% of persons aged 0-17, 17.3% aged 18-64, and 33.3% aged 65+) and did not change over time (20.0% among persons diagnosed with COVID in 2020 versus 20.3% in 2021). For cases diagnosed in September 2021, our definition identified 19.0% with PCC in follow-up as compared to 2.9% with U09.9 code in follow-up., Conclusion: Symptom and U09.9 code-based definitions alone captured different populations. Maximal capture may consider a combined approach, particularly before the availability and routine utilization of specific ICD-10 codes and with the lack consensus-based definitions on the syndrome., Competing Interests: Dr Andersen, Mr Khan, Dr Park, Dr Wiemken, Dr Emir, Ms Malhotra, and Dr McGrath are employees of Pfizer Inc and may hold stock or stock options. Dr Alhanai and Dr Ghassemi are co-founders of Ghamut Corporation which has received consulting fees from Pfizer Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Andersen 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.)

Background: Although COVID-19 morbidity is significantly lower in pediatrics than in adults, the risk of severe COVID-19 may still pose substantial health care resource burden. This study aimed to describe health care resource utilization (HCRU) and costs associated with COVID-19 in pediatrics 1-17 years old in England., Methods: A population-based retrospective cohort study of pediatrics with COVID-19 using Clinical Practice Research Datalink (CPRD Aurum) primary care data and, where available, linked Hospital Episode Statistics Admitted Patient Care secondary care data. HCRU and associated costs to the National Health Service were stratified by age, risk of severe COVID-19 and immunocompromised status, separately for those with and without hospitalization records (hospitalized cohort: COVID-19 diagnosis August 2020-March 2021; primary care cohort: COVID-19 diagnosis August 2020-January 2022)., Results: This study included 564,644 patients in the primary care cohort and 60 in the hospitalized cohort. Primary care consultations were more common in those 1-4 years of age (face-to-face: 4.3%; telephone: 6.0%) compared with those 5-11 (2.0%; 2.1%) and 12-17 years of age (2.2%; 2.5%). In the hospitalized cohort, mean (SD) length of stay was longer [5.0 (5.8) days] among those 12-17 years old (n = 24) than those 1-4 [n = 15; 1.8 (0.9) days] and 5-11 years old [n = 21; 2.8 (2.1) days]., Conclusions: Most pediatrics diagnosed with COVID-19 were managed in the community. However, hospitalizations were an important driver of HCRU and costs, particularly for those 12-17 years old. Our results may help optimize the management and resource allocation of COVID-19 in this population., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Post-COVID-19 conditions (PCC) is an umbrella term that encompasses a range of signs, symptoms and conditions present weeks after the acute phase of a SARS-CoV-2 infection. This systematic literature review summarises the heterogeneous methodology used to measure PCC across real-world studies and highlights trends by region, age group, PCC follow-up period and data source., Methods: Medline, EMBASE and the Cochrane Library were searched and supplemented with conference and grey literature searches. Eligible studies included individuals with (1) PCC or (2) a positive SARS-CoV-2 test or COVID-19 diagnosis who were followed over time. Included studies were published in English between 1 January 2020 and 14 November 2022., Findings: Of 291 publications included, 175 (60%) followed individuals with confirmed COVID-19 over time for PCC and 116 (40%) used a prespecified PCC definition. There was substantial heterogeneity in study design, geography, age group, PCC conditions/symptoms assessed and their classification and duration of follow-up. Among studies using a prespecified PCC definition, author-defined criteria (51%) were more common than criteria recommended by major public health organisations (19%). Measurement periods for PCC outcomes from date of acute COVID-19 test were primarily 3 to <6 months (39.2%), followed by 6 to <12 months (27.5%) and <3 months (22.9%). When classified by organ/system, constitutional-related PCC were the most frequently assessed in adult (86%) and paediatric (87%) populations. Within constitutional symptoms, fatigue was most frequently assessed in adult (91.6%) and paediatric (95.0%) populations, followed by fever/chills (37.9% and 55%, respectively)., Conclusions: PCC definitions are heterogenous across real-world studies, which limits reliable comparisons between studies. However, some similarities were observed in terms of the most frequently measured PCC-associated symptoms/conditions, which may aid clinical management of patients with PCC.CRD42022376111., Competing Interests: Competing interests: JY, KMA, LJMcG, JLN, MHK, AER and JRS are employees of Pfizer and may hold stock or stock options. LH, KM, IW and VB are employees of Adelphi Values PROVE., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To create case definitions for confirmed COVID-19 diagnoses, COVID-19 vaccination status and three separate definitions of high risk of severe COVID-19, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID-19 epidemiology in England., Design: Retrospective cohort study., Setting: Electronic healthcare records from primary care (Clinical Practice Research Datalink, CPRD) linked to secondary care data (Hospital Episode Statistics) data covering 24% of the population in England., Participants: 2 271 072 persons aged 1 year and older diagnosed with COVID-19 in CPRD Aurum between 1 August 2020 and 31 January 2022., Main Outcome Measures: Age, sex and regional distribution of COVID-19 cases and COVID-19 vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalised for COVID-19 (primary diagnosis code of ICD-10 U07.1 'COVID-19'). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the UK (National Health Service Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritisation for vaccination)., Results: Compared with national estimates, CPRD case estimates under-represented older adults in both the primary care (age 65-84: 6% in CPRD vs 9% nationally) and hospitalised (31% vs 40%) cohorts, and over-represented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East vs 15% nationally). The majority of non-hospitalised cases and all hospitalised cases had not completed primary series vaccination. In primary care, persons meeting high-risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score., Conclusions: CPRD primary care data are a robust real-world data source and can be used for some COVID-19 research questions, however, limitations of the data availability should be carefully considered. Included in this publication are supplemental files for a total of over 28 000 codes to define each of three definitions of high risk of severe disease., Competing Interests: Competing interests: KMA, LJM, MR, DM, JLN, CT, DM and JY are employees of Pfizer or Pfizer and may hold Pfizer stock or stock options. KKR and TT are employees of Adelphi Real World which has received consulting fees from Pfizer., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To quantify direct costs and healthcare resource utilisation (HCRU) associated with acute COVID-19 in adults in England., Design: Population-based retrospective cohort study using Clinical Practice Research Datalink Aurum primary care electronic medical records linked to Hospital Episode Statistics secondary care administrative data., Setting: Patients registered to primary care practices in England., Population: 1 706 368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13 105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1 693 263 within the primary care cohort indexed between August 2020 and January 2022. Patients with a COVID-19-related hospitalisation within 84 days of a positive test were included in the hospitalised cohort., Main Outcome Measures: Primary and secondary care HCRU and associated costs ≤4 weeks following positive COVID-19 test, stratified by age group, risk of severe COVID-19 and immunocompromised status., Results: Among the hospitalised cohort, average length of stay, including critical care stays, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75-84 (£8942) and ≥85 years (£8835) than in those aged <50 years (£7703). While few (6.0%) patients in critical care required mechanical ventilation, its use was higher in older adults (50-74 years: 8.3%; <50 years: 4.3%). HCRU and associated costs were often greater in those at higher risk of severe COVID-19 than in the overall cohort, although minimal differences in HCRU were found across the three different high-risk definitions. Among the primary care cohort, general practitioner or nurse consultations were more frequent among older adults and the immunocompromised., Conclusions: COVID-19-related hospitalisations in older adults, particularly critical care stays, were the primary drivers of high COVID-19 resource use in England. These findings may inform health policy decisions and resource allocation in the prevention and management of COVID-19., Competing Interests: Competing interests: JY, KMA, MR, LJM, CT, TM, KN, DM, Tamuno Alfred, MA and JLN are employees of Pfizer and may hold stock or stock options. KKR, TT, PP, BEB and RW are employees of Adelphi Real World, which received funds from Pfizer to conduct the study and develop the manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: No data comparing the estimated effectiveness of coadministering COVID-19 vaccines with seasonal influenza vaccine (SIV) in the community setting exist., Objective: To examine the comparative effectiveness associated with coadministering the BNT162b2 BA.4/5 bivalent mRNA COVID-19 vaccine (BNT162b2-biv [Pfizer BioNTech]) and SIV vs giving each vaccine alone., Design, Setting, and Participants: A retrospective comparative effectiveness study evaluated US adults aged 18 years or older enrolled in commercial health insurance or Medicare Advantage plans and vaccinated with BNT162b2-biv only, SIV only, or both on the same day between August 31, 2022, and January 30, 2023. Individuals with monovalent or another brand of mRNA bivalent COVID-19 vaccine were excluded., Exposure: Same-day coadministration of BNT162b2-biv and SIV; receipt of BNT162b2-biv only (for COVID-19-related outcomes) or SIV only (for influenza-related outcomes) were the comparator groups. For adults aged 65 years or older, only enhanced SIVs were included., Main Outcomes and Measures: COVID-19-related and influenza-related hospitalization, emergency department (ED) or urgent care (UC) encounters, and outpatient visits., Results: Overall, 3 442 996 individuals (57.0% female; mean [SD] age, 65 [16.7] years) were included. A total of 627 735 individuals had BNT162b2-biv and SIV vaccine coadministered, 369 423 had BNT162b2-biv alone, and 2 445 838 had SIV alone. Among those aged 65 years or older (n = 2 210 493; mean [SD] age, 75 [6.7] years; 57.9% female), the coadministration group had a similar incidence of COVID-19-related hospitalization (adjusted hazard ratio [AHR], 1.04; 95% CI, 0.87-1.24) and slightly higher incidence of emergency department or urgent care encounters (AHR, 1.12; 95% CI, 1.02-1.23) and outpatient visits (AHR, 1.06; 95% CI, 1.01-1.11) compared with the BNT162b2-biv-only group. Among individuals aged 18 to 64 years (n = 1 232 503; mean [SD] age, 47 [13.1] years; 55.4% female), the incidence of COVID-19-related outcomes was slightly higher among those who received both vaccines vs BNT162b2-biv alone (AHR point estimate range, 1.14-1.57); however, fewer events overall in this age group resulted in wider CIs. Overall, compared with those who received SIV alone, the coadministration group had a slightly lower incidence of most influenza-related end points (AHR point estimates 0.83-0.93 for those aged ≥65 years vs 0.76-1.08 for those aged 18-64 years). Negative control outcomes suggested residual bias and calibration of COVID-19-related and influenza-related outcomes with negative controls moved all estimates closer to the null, with most CIs crossing 1.00., Conclusions and Relevance: In this study, coadministration of BNT162b2-biv and SIV was associated with generally similar effectiveness in the community setting against COVID-19-related and SIV-related outcomes compared with giving each vaccine alone and may help improve uptake of both vaccines.

Introduction: We compared hospitalization outcomes of young children hospitalized with COVID-19 to those hospitalized with influenza in the United States., Methods: Patients aged 0-<5 years hospitalized with an admission diagnosis of acute COVID-19 (April 2021-March 2022) or influenza (April 2019-March 2020) were selected from the PINC AI Healthcare Database Special Release. Hospitalization outcomes included length of stay (LOS), intensive care unit (ICU) admission, oxygen supplementation, and mechanical ventilation (MV). Inverse probability of treatment weighting was used to adjust for confounders in logistic regression analyses., Results: Among children hospitalized with COVID-19 ( n  = 4,839; median age: 0 years), 21.3% had an ICU admission, 19.6% received oxygen supplementation, 7.9% received MV support, and 0.5% died. Among children hospitalized with influenza ( n  = 4,349; median age: 1 year), 17.4% were admitted to the ICU, 26.7% received oxygen supplementation, 7.6% received MV support, and 0.3% died. Compared to children hospitalized with influenza, those with COVID-19 were more likely to have an ICU admission (adjusted odds ratio [aOR]: 1.34; 95% confidence interval [CI]: 1.21-1.48). However, children with COVID-19 were less likely to receive oxygen supplementation (aOR: 0.71; 95% CI: 0.64-0.78), have a prolonged LOS (aOR: 0.81; 95% CI: 0.75-0.88), or a prolonged ICU stay (aOR: 0.56; 95% CI: 0.46-0.68). The likelihood of receiving MV was similar (aOR: 0.94; 95% CI: 0.81, 1.1)., Conclusions: Hospitalized children with either SARS-CoV-2 or influenza had severe complications including ICU admission and oxygen supplementation. Nearly 10% received MV support. Both SARS-CoV-2 and influenza have the potential to cause severe illness in young children., Competing Interests: All authors are employed by and hold stock in Pfizer., (© 2023 McGrath, Moran, Alfred, Reimbaeva, Di Fusco, Khan, Welch, Malhotra, Cane and Lopez.)

Background: Little is known about the relationship between coronavirus disease 2019 (COVID-19) severity and subsequent risk of experiencing a cardiovascular event (CVE) after COVID-19 recovery. We evaluated this relationship in a large cohort of United States adults., Methods: Using a claims database, we performed a retrospective cohort study of adults diagnosed with COVID-19 between 1 April 2020 and 31 May 2021. We evaluated the association between COVID-19 severity and risk of CVE >30 days after COVID-19 diagnosis using inverse probability of treatment-weighted competing risks regression. Severity was based on level of care required for COVID-19 treatment: intensive care unit (ICU) admission, non-ICU hospitalization, or outpatient care only., Results: A total of 1 357 518 COVID-19 patients were included (2% ICU, 3% non-ICU hospitalization, and 95% outpatient only). Compared to outpatients, there was an increased risk of any CVE for patients requiring ICU admission (adjusted hazard ratio [aHR], 1.80 [95% confidence interval {CI}, 1.71-1.89]) or non-ICU hospitalization (aHR, 1.28 [95% CI, 1.24-1.33]). Risk of subsequent hospitalization for CVE was even higher (aHRs, 3.47 [95% CI, 3.20-3.76] for ICU and 1.96 [95% CI, 1.85-2.09] for non-ICU hospitalized vs outpatient only)., Conclusions: COVID-19 patients hospitalized or requiring critical care had a significantly higher risk of experiencing and being hospitalized for post-COVID-19 CVE than patients with milder COVID-19 who were managed solely in the outpatient setting, even after adjusting for differences between these groups. These findings underscore the continued importance of preventing severe acute respiratory syndrome coronavirus 2 infection from progressing to severe illness to reduce potential long-term cardiovascular complications., Competing Interests: Potential conflicts of interest. All authors are employees and shareholders of Pfizer Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Purpose: Acute otitis media (AOM) is a common indication for antibiotics in children. We sought to characterize the frequency of nonguideline concordant antibiotic therapy for AOM in the United States, by agent and duration., Methods: Using national administrative claims data (2016-2019), we identified children aged 6 months to 17 years with an oral antibiotic dispensed within 3 days of a new diagnosis of suppurative AOM. Use of nonguideline concordant agents and durations, defined based on national treatment guidelines, were summarized by age, race, rurality, region, and insurance type. Subsequent oral antibiotic dispensing within the year after AOM diagnosis was also evaluated. We created sunburst diagrams to visualize longitudinal patterns of within-person antibiotic utilization for AOM, by agent and duration., Results: We identified 789 424 eligible commercially-insured and 502 239 medicaid-insured children. Among commercially insured children, 35% received nonguideline concordant agents for AOM, including cefdinir (16%), amoxicillin-clavulanate (12%), and azithromycin (7%). Fewer children age <2 years received a nonguideline concordant initial agent (27%) compared to age ≥6 years (41%). More children age <2 years received three or more antibiotics over the following year (34% vs. 3% for children age ≥6 years). The most common treatment duration was 10 days for all ages; treatment duration for the initial antibiotic was nonguideline concordant for 95% and 89% of children age 2-5 years and ≥6 years, respectively. Patterns were similar for medicaid-insured children., Conclusions: Nonguideline concordant antibiotic use is common when treating AOM in children, including use of broad-spectrum agents and longer-than-recommended antibiotic durations., (© 2022 John Wiley & Sons Ltd.)

Importance: A new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code (U09.9 Post COVID-19 condition, unspecified) was introduced by the Centers for Disease Control and Prevention on October 1, 2021., Objective: To examine the use of the U09.9 code and describe concurrently diagnosed conditions to understand physician use of this code in clinical practice., Design, Setting, and Participants: This cohort study of US patients with an ICD-10-CM code for post-COVID-19 condition used deidentified patient-level claims data aggregated by HealthVerity. Children and adolescents (aged 0-17 years) and adults (aged 18-64 and ≥65 years) with a post-COVID-19 condition code were identified between October 1, 2021, and January 31, 2022. To identify a prior COVID-19 diagnosis, 3 months of continuous enrollment (CE) before the post-COVID-19 diagnosis date was required., Main Outcomes and Measures: Presence of the ICD-10-CM U09.9 code., Results: There were 56 143 patients (7723 female patients [61.2%]; mean [SD] age, 47.6 [19.2] years) with a post-COVID-19 diagnosis code, with cases increasing in mid-December 2021 following the trajectory of the Omicron case wave by 3 to 4 weeks. The analysis cohort included 12 622 patients after the 3-month preindex CE criteria was applied. Among this cohort, the median (IQR) age was 49 (35-61) years; however, 1080 (8.6%) were pediatric patients. The U09.9 code was used most often in the outpatient setting, although 305 older adults (14.0%) were inpatients. Only 698 patients (5.5%) had at least 1 of the 5 codes listed as possible concurrent conditions in the coding guidance. Only 8879 patients (70.4%) had a documented acute COVID-19 diagnosis code (569 [52.7%] among children), and the median (IQR) time between acute COVID-19 and post-COVID-19 diagnosis codes was 56 (21-200) days. The most common concurrently coded conditions varied by age; children experienced COVID-19-like symptoms (eg, 207 [19.2%] had cough and 115 [10.6%] had breathing abnormalities), while 459 older adults aged 65 years or older (21.1%) experienced respiratory failure and 189 (8.7%) experienced viral pneumonia., Conclusions and Relevance: This retrospective cohort study found patients with a post-COVID-19 ICD-10-CM diagnosis code following the acute phase of COVID-19 disease among patients of all ages in clinical practice in the US. The use of the U09.9 code encompassed a wide range of conditions. It will be important to monitor how the use of this code changes as the pandemic continues to evolve.

Objectives: To describe the characteristics, healthcare resource use and costs associated with initial hospitalization and readmissions among pediatric patients with COVID-19 in the US., Methods: Hospitalized pediatric patients, 0-11 years of age, with a primary or secondary discharge diagnosis code for COVID-19 (ICD-10 code U07.1) were selected from 1 April 2020 to 30 September 2021 in the US Premier Healthcare Database Special Release (PHD SR). Patient characteristics, hospital length of stay (LOS), in-hospital mortality, hospital costs, hospital charges, and COVID-19-associated readmission outcomes were evaluated and stratified by age groups (0-4, 5-11), four COVID-19 disease progression states based on intensive care unit (ICU) and invasive mechanical ventilation (IMV) usage, and three sequential calendar periods. Sensitivity analyses were performed using the US HealthVerity claims database and restricting the analyses to the primary discharge code., Results: Among 4,573 hospitalized pediatric patients aged 0-11 years, 68.0% were 0-4 years and 32.0% were 5-11 years, with a mean (median) age of 3.2 (1) years; 56.0% were male, and 67.2% were covered by Medicaid. Among the overall study population, 25.7% had immunocompromised condition(s), 23.1% were admitted to the ICU and 7.3% received IMV. The mean (median) hospital LOS was 4.3 (2) days, hospital costs and charges were $14,760 ($6,164) and $58,418 ($21,622), respectively; in-hospital mortality was 0.5%. LOS, costs, charges, and in-hospital mortality increased with ICU admission and/or IMV usage. In total, 2.1% had a COVID-19-associated readmission. Study outcomes appeared relatively more frequent and/or higher among those 5-11 than those 0-4. Results using the HealthVerity data source were generally consistent with main analyses., Limitations: This retrospective administrative database analysis relied on coding accuracy and inpatient admissions with validated hospital costs., Conclusions: These findings underscore that children aged 0-11 years can experience severe COVID-19 illness requiring hospitalization and substantial hospital resource use, further supporting recommendations for COVID-19 vaccination.

Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard-of-care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 10 9 /L (95% CI: -59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Romiplostim has been approved in Europe since 2009 to treat patients with chronic primary immune thrombocytopenia (ITP). Using real-world data from seven European countries, we measured the effectiveness and safety outcomes within 24 weeks following romiplostim initiation by duration of ITP: less than 3 months ("newly diagnosed"), 3-12 months ("persistent"), and more than 12 months ("chronic")., Methods: Adults with ITP and ≥ 1 romiplostim administration between 2009 and 2012 were included. Endpoints included durable platelet response, median platelet count, rescue therapy, bleeding and adverse events. We used inverse probability of censoring weighted estimators to estimate cumulative risk of each outcome. There were 64 newly diagnosed, 50 persistent, and 226 chronic ITP patients at romiplostim initiation., Results: Durable platelet response at 24 weeks ranged from 32% [confidence interval (CI): 18-46%] in newly diagnosed patients to 53% (CI 37-68%) in persistent patients. Median platelet count during follow-up ranged from 88 (CI 80-96) × 10 9 /L in chronic patients to 131 (CI 102-160) × 10 9 /L in newly diagnosed patients., Conclusion: Regardless of ITP duration, over half of patients discontinued concomitant ITP medications. Few adverse events were observed. Although only approved for chronic patients, estimates of the romiplostim treatment effect were similar across patients being managed in European clinical practice, regardless of ITP duration at romiplostim initiation.

Purpose: Research using healthcare databases often includes patients frequently excluded from clinical trials; yet it is not known whether commonly used data represents the overall population or specific sub-populations of interest. We aimed to examine population representativeness from data sources in recent research studies in the United States (US)., Methods: We identified data sources from abstracts accepted to the 34th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. The final sample included research studies using ≥1 data source from the US. We classified data sources broadly as claims, linkage, electronic health records (EHR), survey, distributed data network, and other. Studies using claims and EHRs were further classified into more specific categories, including special populations of interest (eg, children)., Results: We identified 356 abstracts. The majority used claims data (n = 201, 56.5%), followed by data linkages (n = 46, 12.9%), and EHR data (n = 39, 11.0%). Among EHR studies, most (n = 16, 41.0%) came from network data sources (eg, Kaiser Permanente). Almost half (49.4%) of claims-based studies used commercial claims data sources, followed by Medicare (22.1%), Medicaid (11.3%), and Medicare Supplemental (6.1%). Only 15% of studies included children in the study population (n = 53), with 8% focused on a pediatric topic (n = 27)., Conclusions: We find that certain populations in the US are under-represented in pharmacoepidemiology, particularly Medicaid enrollees and children. Researchers should strive to utilize data sources that may be more representative of the US population, particularly vulnerable populations., (© 2020 John Wiley & Sons Ltd.)

Purpose: In contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications., Methods: Using MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12-month cumulative risk difference (RD) using inverse probability of treatment and censoring weights., Results: Among 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = -0.6%, 95% CI: -1.1, -0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations., Conclusions: Caution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies., (© 2020 John Wiley & Sons Ltd.)

Background: High-dose influenza vaccine (HDV) is an alternative vaccination strategy in patients with end-stage renal disease (ESRD), though the safety of HDV has not been evaluated in this population. The objective of this study was to estimate the relative occurrence of adverse vaccine reactions in patients with ESRD following vaccination with HDV compared with standard-dose influenza vaccine (SDV)., Methods: Using data from the United States Renal Data System, we identified patients with ESRD aged ≥ 65 years at influenza vaccination during yearly influenza seasons from 2010 through 2016. Patients were followed after vaccination to observe serious (anaphylaxis, angioedema, seizure, encephalopathy, Guillain-Barré syndrome [GBS], and short-term, all-cause mortality) and milder (urticaria/hives, rash, pain in limb, cellulitis, myalgia/myositis, fever, nausea and vomiting, diarrhea, and syncope) adverse events. Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for HDV versus SDV were estimated with Cox proportional hazards models., Results: Of 520,876 vaccinations observed (mean age = 74.7 years at vaccination; 63% white race), 7.4% were HDV. For serious events, the weighted HRs were null for seizure, encephalopathy, and mortality and inestimable due to too few cases for anaphylaxis, angioedema, and GBS. For milder vaccine reactions, the weighted HRs demonstrated generally increased risks in the HDV group, including rash (HR = 1.86; 95% CI, 1.34-2.57), diarrhea (HR = 1.26; 95% CI, 1.07-1.50), pain in limb (HR = 1.23; 95% CI, 1.12-1.34), and myalgia/myositis (HR = 1.16; 95% CI, 1.04-1.30)., Conclusions: The risks of serious adverse events were low and similar between treatment groups; however, HDV recipients had increased risks of several milder adverse events compared with SDV recipients, consistent with clinical trial findings in the general population of older adults. These results add important information to inform the risk-benefit tradeoff of the use of HDV versus SDV in patients with ESRD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JBL is an employee of RTI International, an independent, nonprofit research institute that provides research services for governmental and commercial clients, including pharmaceutical companies. LM is an employee of and owns stock in NoviSci, Inc. AMB is supported by a grant from the National Center for Advancing Translational Sciences (NCATS), NIH under award number KL2 TR002346. The other authors report no conflicts., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale & Objective: Studies of patients on maintenance dialysis therapy suggest that standard-dose influenza vaccine (SDV) may not prevent influenza-related outcomes. Little is known about the comparative effectiveness of SDV versus high-dose influenza vaccine (HDV) in this population., Study Design: Cohort study using data from the US Renal Data System., Setting & Participants: 507,552 adults undergoing in-center maintenance hemodialysis between the 2010 to 2011 and 2014 to 2015 influenza seasons., Exposures: SDV and HDV., Outcomes: All-cause mortality, hospitalization due to influenza or pneumonia, and influenza-like illness during the influenza season., Analytic Approach: Patients were eligible for inclusion in multiple yearly cohorts; thus, our unit of analysis was the influenza patient-season. To examine the relationship between vaccine dose and effectiveness outcomes, we estimated risk differences and risk ratios using propensity score weighting of Kaplan-Meier functions, accounting for a wide range of patient- and facility-level characteristics. For nonmortality outcomes, we used competing-risk methods to account for the high mortality rate in the dialysis population., Results: Within 225,215 influenza patient-seasons among adults 65 years and older, 97.4% received SDV and 2.6% received HDV. We observed similar risk estimates for HDV and SDV recipients for mortality (risk difference, -0.08%; 95% CI, -0.85% to 0.80%), hospitalization due to influenza or pneumonia (risk difference, 0.15%; 95% CI, -0.69% to 0.93%), and influenza-like illness (risk difference, 0.00%; 95% CI, -1.50% to 1.08%). Our findings were similar among adults younger than 65 years, as well as within other subgroups defined by influenza season, age group, dialysis vintage, month of influenza vaccination, and vaccine valence., Limitations: Residual confounding and outcome misclassification., Conclusions: The HDV does not appear to provide additional protection beyond the SDV against all-cause mortality or influenza-related outcomes for adults undergoing hemodialysis. The additional cost and side effects associated with HDV should be considered when offering this vaccine. Future studies of HDV and other influenza vaccine strategies are warranted., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Nonexperimental studies of the effectiveness of seasonal influenza vaccine in older adults have found 40%-60% reductions in all-cause mortality associated with vaccination, potentially due to confounding by frailty. We restricted our cohort to initiators of medications in preventive drug classes (statins, antiglaucoma drugs, and β blockers) as an approach to reducing confounding by frailty by excluding frail older adults who would not initiate use of these drugs. Using a random 20% sample of US Medicare beneficiaries, we framed our study as a series of nonrandomized "trials" comparing vaccinated beneficiaries with unvaccinated beneficiaries who had an outpatient health-care visit during the 5 influenza seasons occurring in 2010-2015. We pooled data across trials and used standardized-mortality-ratio-weighted Cox proportional hazards models to estimate the association between influenza vaccination and all-cause mortality before influenza season, expecting a null association. Weighted hazard ratios among preventive drug initiators were generally closer to the null than those in the nonrestricted cohort. Restriction of the study population to statin initiators with an uncensored approach resulted in a weighted hazard ratio of 1.00 (95% confidence interval: 0.84, 1.19), and several other hazard ratios were above 0.95. Restricting the cohort to initiators of medications in preventive drug classes can reduce confounding by frailty in this setting, but further work is required to determine the most appropriate criteria to use., (© The Author(s) 2019. 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: Estimating influenza vaccine effectiveness using an unvaccinated comparison group may result in biased effect estimates., Objectives: To explore the reduction of confounding bias in an active comparison of high-dose versus standard-dose influenza vaccines, as compared with vaccinated versus unvaccinated comparisons., Methods: Using Medicare data from the United States end-stage renal disease program (2009-2013), we compared the risk of all-cause mortality among recipients of high-dose vaccine (HDV) versus standard-dose vaccine (SDV), HDV versus no vaccine, and SDV versus no vaccine. To quantify confounding bias, analyses were restricted to the preinfluenza season, when the protective effect of vaccination should not yet be observed. We estimated the standardized mortality ratio-weighted cumulative incidence functions using Kaplan-Meier methods and calculated risk ratios (RRs) and risk differences between groups., Results: Among 350,921 eligible patients contributing 825,642 unique patient preinfluenza seasons, 0.8% received HDV, 70.5% received SDV, and 28.7% remained unvaccinated. Comparisons with unvaccinated patients yielded spurious decreases in mortality risk during the preinfluenza period, for HDV versus none [RR, 0.60; 95% confidence interval (CI), 0.51-0.70)] and SDV versus none (RR, 0.72; 95% CI, 0.70-0.75). The effect estimate was attenuated in the HDV versus SDV comparison (RR, 0.89; 95% CI, 0.77-1.03). Estimates on the absolute scale followed a similar pattern., Conclusions: The HDV versus SDV comparison yielded less-biased estimates of the all-cause mortality before influenza season compared to those with nonuser comparison groups. Vaccine effectiveness and safety researchers should consider the active comparator design to reduce bias due to differences in underlying health status between vaccinated and unvaccinated individuals.

Background: Prior to 2018, intravenous bisphosphonates (IV BPs) were the only therapies recommended to prevent skeletal-related events for patients diagnosed with multiple myeloma (MM). We examined patterns of IV BP initiation and interruption among patients with newly diagnosed MM (NDMM) in the United States., Methods: Electronic health records linked to administrative health insurance claims were used to identify adults with NDMM between 1 January 2011 and 30 April 2016. Patients were excluded for recent IV BP use or concurrent cancer. The incidences of IV BP initiation and interruption were estimated using competing risk regression. A generalized linear model was used to estimate risk factors for treatment initiation and interruption., Results: Among the 547 patients with NDMM, 64% initiated MM therapy within 30 days of diagnosis. By one year, 65% (95% CI: 59, 70) of patients with appropriately timed anti-MM therapy had initiated an IV BP. Zoledronic acid was the most commonly initiated IV BP. Patients with Stage III MM were more likely to initiate an IV BP (adjusted risk difference (RD): 6.3; 95% CI: 2.7, 10.1), while those with eGFR <30 mL/min were less likely to initiate (RD: -9.7; 95% CI: -13.8, -5.8). Of the 264 patients who initiated an IV BP, 77% (95% CI: 71, 82) experienced an interruption within one year. Patients on concurrent anti-MM therapy were less likely to experience an interruption in IV BP therapy., Conclusions: Many patients with NDMM do not initiate IV BPs, particularly those with renal complications. Interruptions of IV BPs were common., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Standard influenza vaccines may be of limited benefit to patients with end-stage renal disease (ESRD). These patients may benefit from high-dose influenza vaccine, currently indicated for patients aged ≥65 years. Studies in other populations have demonstrated that high-dose vaccine elicits a stronger immunological response. We compared vaccine uptake in the United States and predictors of receipt for high-dose and standard influenza vaccines., Methods: Using data from the United States Renal Data System (2010-2013), we conducted a cohort study of 421,482 adult patients on hemodialysis. We examined temporal trends in uptake of high-dose or standard trivalent influenza vaccine each influenza season, and used multivariate logistic regression to assess the association between individual-level variables (e.g., demographics, comorbidities) and facility-level variables (e.g., facility size and type) with vaccine receipt., Results: The proportion of patients with ESRD who were vaccinated with any influenza vaccine increased from 68.3% in 2010 to 72.4% in 2013. High-dose vaccines were administered to 0.9% of patients during the study period, and 16.7% of high-dose vaccines were administered to patients <65 years of age. Among patients aged ≥65 years, older patients (>79 vs. 65-69 years: OR, 1.29; 95% CI, 1.19-1.41) and patients at hospital-based versus free-standing dialysis facilities (OR, 2.31; 95% CI, 2.13-2.45) were more likely to receive high-dose vaccine, while blacks (vs. whites [OR, 0.66; 95% CI, 0.61-0.71]) and patients with longer duration of ESRD (>9 vs. 0 years: OR, 0.66; 95% CI, 0.55-0.78) were less likely to receive the high-dose vaccine., Conclusions: While the overall influenza vaccination rate has increased, use of high-dose vaccine among patients with ESRD was very low. Being an older patient, living in the Midwest, and receiving care at hospital-based facilities were the strongest predictors of receiving high-dose vaccine., (Copyright © 2018. Published by Elsevier Ltd.)

Introduction: It is recommended that all pregnant women in the U.S. receive tetanus, diphtheria, acellular pertussis (Tdap) immunization to prevent infant pertussis. This study's objective was to examine the clinical effectiveness of prenatal Tdap, and whether effectiveness varies by gestational age at immunization., Methods: A nationwide cohort study of pregnant women with deliveries in 2010-2014 and their infants was performed. Commercial insurance claims data were analyzed in 2016-2017 to identify Tdap receipt by the pregnant women, and hospitalizations and outpatient visits for pertussis in their infants until the infants reached 18 months of age. Pertussis occurrence was compared between infants of mothers who received prenatal Tdap (overall and stratified by gestational age at administration) and infants of unvaccinated mothers., Results: There were 675,167 mother-infant pairs in the cohort. Among infants whose mothers received prenatal Tdap, the rate of pertussis was 43% lower (hazard ratio=0.57, 95% CI=0.35, 0.92) than infants whose mothers did not receive prenatal or postpartum Tdap; this reduction was consistent across pertussis definitions (hazard ratio for inpatient-only pertussis=0.32, 95% CI=0.11, 0.91). Pertussis rates were also lower for infants whose mothers received Tdap during the third trimester. Infants whose mothers received Tdap at <27 weeks of gestation did not experience reductions in pertussis rates (hazard ratio for pertussis=1.10, 95% CI=0.54, 2.25)., Conclusions: Infants of mothers who received prenatal Tdap experienced half the rate of pertussis as compared with infants of unimmunized mothers. These results do not provide evidence to support changing the currently recommended timing of Tdap administration in pregnancy., (Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: To improve control of confounding by frailty when estimating the effect of influenza vaccination on all-cause mortality by controlling for a published set of claims-based predictors of dependency in activities of daily living (ADL)., Methods: Using Medicare claims data, a cohort of beneficiaries >65 years of age was followed from September 1, 2007, to April 12, 2008, with covariates assessed in the 6 months before follow-up. We estimated Cox proportional hazards models of all-cause mortality, with influenza vaccination as a time-varying exposure. We controlled for common demographics, comorbidities, and health care utilization variables and then added 20 ADL dependency predictors. To gauge residual confounding, we estimated pre-influenza season hazard ratios (HRs) between September 1, 2007 and January 5, 2008, which should be 1.0 in the absence of bias., Results: A cohort of 2 235 140 beneficiaries was created, with a median follow-up of 224 days. Overall, 52% were vaccinated and 4% died during follow-up. During the pre-influenza season period, controlling for demographics, comorbidities, and health care use resulted in a HR of 0.66 (0.64, 0.67). Adding the ADL dependency predictors moved the HR to 0.68 (0.67, 0.70). Controlling for demographics and ADL dependency predictors alone resulted in a HR of 0.68 (0.66, 0.70)., Conclusions: Results were consistent with those in the literature, with significant uncontrolled confounding after adjustment for demographics, comorbidities, and health care use. Adding ADL dependency predictors moved HRs slightly closer to the null. Of the comorbidities, health care use variables, and ADL dependency predictors, the last set reduced confounding most. However, substantial uncontrolled confounding remained., (Copyright © 2017 John Wiley & Sons, Ltd.)

Many countries recommend combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis immunization (Tdap) during pregnancy to stimulate transplacental transmission of pertussis antibodies to newborns. The immune system can be altered during pregnancy, potentially resulting in differing immunization risks in pregnant women. The safety of widespread Tdap immunization during pregnancy needs to be established. Our objective was to assess whether prenatal Tdap immunization was associated with adverse birth outcomes, and to evaluate the effect of timing of Tdap administration on these outcomes. We identified pregnancies at delivery in a large insurance claims database (2010-2014). Tdap immunization was categorized as optimal prenatal (27+weeks), early prenatal (<27weeks), postpartum (≤7days post-delivery), or none. Medical claims were searched to identify maternal adverse immunization reactions (e.g. anaphylaxis, fever, Guillian-Barre syndrome [GBS]), adverse birth outcomes (e.g. preeclampsia/eclampsia, premature rupture or membranes, chorioamnionitis) and newborn outcomes (e.g. respiratory distress, pulmonary hypertension, neonatal jaundice). Women with optimal or early prenatal Tdap were compared to those not immunized in pregnancy, using propensity score-weighted log-binomial regression and Cox proportional hazards models to estimate risk ratios (RR) and hazard ratios (HR). We identified 1,079,034 deliveries and 677,075 linked newborns; 11.5% were immunized optimally and 2.3% immunized early. There were 1 case of post-immunization anaphylaxis, and 12 cases of maternal encephalopathy (all post- delivery); there were no cases of GBS. Optimally-timed immunization was associated with small increased relative risks of: chorioamnionitis [RR=1.11, (95% CI: 1.07-1.15), overall risk=2.8%], and postpartum hemorrhage [RR=1.23 (95% DI: 1.18-1.28), overall risk=2.4%]; however, these relative increases corresponded to low absolute risk increases. Tdap was not associated with increased risk of any adverse newborn outcome. Overall, prenatal Tdap immunization was not associated with newborn adverse events, but potential associations with chorioamnionitis consistent with one previous study and postpartum hemorrhage require further investigation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To examine the uptake of prenatal tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) immunization among pregnant women in the United States., Methods: Using MarketScan data, we conducted a historical cohort study among pregnant women with employer-based commercial insurance in the United States who delivered between January 1, 2010, and December 31, 2014. We examined temporal trends of uptake, predictors of uptake, and timing of Tdap immunization., Results: Among 1,222,384 eligible pregnancies in 1,147,711 women, receipt of prenatal Tdap immunization increased from 0.0% of women who delivered in January 2010 to 9.8% who delivered in October 2012 (the date of the recommendation by the Advisory Committee on Immunization Practices for Tdap during every pregnancy) to 44.4% who delivered in December 2014. Among women who received Tdap during pregnancy, the majority were immunized between 27 weeks and 36 6/7 weeks of gestation per the Advisory Committee on Immunization Practices recommendation. In multivariable analyses among women who delivered between November 2012 and December 2014, rates of prenatal Tdap immunization were lower for women younger than 25 years of age (eg, 20-24 compared with 30-34 years rate ratio [RR] 0.83, 95% confidence interval [CI] 0.85-0.88), with other children (eg, three compared with zero children: RR 0.86, 95% CI 0.84-0.88), residing in the South compared with the Midwest (RR 0.81, 95% CI 0.80-0.82), or with emergency department visits in early pregnancy (RR 0.93, 95% CI 0.92-0.95). The proportion of pregnant women who received prenatal Tdap increased with increasing gestational age at birth., Conclusion: By the end of 2014, fewer than half of pregnant women in the United States were receiving prenatal Tdap immunization. Implementation and dissemination strategies are needed to increase Tdap coverage among pregnant women, especially those who are young, have other children, or reside in the South.

Background: Urban design may affect children's habitual physical activity by influencing active commuting and neighborhood play., Purpose: Our objective was to examine associations between neighborhood built-environment features near children's homes and objectively measured physical activity., Methods: We used geographical information system (GIS) protocols to select 2016 households from 48 low- and high-walkability neighborhoods within four New Zealand cities. Children (n = 227; mean age ± standard deviation [SD] 9.3 ± 2.1 years) from the selected households wore accelerometers that recorded physical activity in the period 2008-2010. We used multilevel linear models to examine the associations of GIS and street-audit measures, using the systematic pedestrian and cycling environmental scan (SPACES), of the residential environment (ranked into tertiles) on children's hourly step counts and proportions of time spent at moderate-to-vigorous intensity on school and non-school days., Results: During school-travel times (8:00-8:59 a.m. and 15:00-15:59 p.m.), children in the mid-tertile distance from school (~1 to 2 km) were more active than children with shorter or longer commute distances (1290 vs. 1130 and 1140 steps·h(-1); true between-child SD 440). After school (16:00-17:59 p.m.), children residing closest to school were more active (890 vs. 800 and 790 steps·h(-1); SD 310). Neighborhoods with more green space, attractive streets, or low-walkability streets showed a moderate positive association on non-school day moderate-to-vigorous steps, whereas neighborhoods with additional pedestrian infrastructure or more food outlets showed moderate negative associations. Other associations of residential neighborhoods were unclear but, at most, small., Conclusions: Designing the urban environment to promote safe child-pedestrian roaming may increase children's moderate-to-vigorous physical activity.

Nonexperimental studies of preventive interventions are often biased because of the healthy-user effect and, in frail populations, because of confounding by functional status. Bias is evident when estimating influenza vaccine effectiveness, even after adjustment for claims-based indicators of illness. We explored bias reduction methods while estimating vaccine effectiveness in a cohort of adult hemodialysis patients. Using the United States Renal Data System and linked data from a commercial dialysis provider, we estimated vaccine effectiveness using a Cox proportional hazards marginal structural model of all-cause mortality before and during 3 influenza seasons in 2005/2006 through 2007/2008. To improve confounding control, we added frailty indicators to the model, measured time-varying confounders at different time intervals, and restricted the sample in multiple ways. Crude and baseline-adjusted marginal structural models remained strongly biased. Restricting to a healthier population removed some unmeasured confounding; however, this reduced the sample size, resulting in wide confidence intervals. We estimated an influenza vaccine effectiveness of 9% (hazard ratio = 0.91, 95% confidence interval: 0.72, 1.15) when bias was minimized through cohort restriction. In this study, the healthy-user bias could not be controlled through statistical adjustment; however, sample restriction reduced much of the bias., (© The Author 2015. 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: Understanding attributes of the built environment that influence children's and adolescents' habitual physical activity can inform urban design., Objective: To conduct a systematic review and meta-analysis of studies linking aspects of the built environment with youth moderate-vigorous activity, including walking., Data Sources: The PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched using relevant key words for articles published between January 2000 and March 2013., Study Selection: The included articles reported associations between children's or adolescents' objectively measured physical activity and residential neighbourhoods or activity settings defined with geographical information systems (GIS), street audits or global positioning systems (GPS). Excluded articles did not delineate neighbourhoods by residential address or were not written in English. Of 320 potentially relevant articles, 31 met the inclusion criteria, but only 23 (with a total of 6,175 participants, aged 8-17 years) provided sufficient data to derive effects (associations) of built-environment features on child or adolescent habitual moderate-vigorous activity., Study Appraisal and Synthesis Methods: Ten criteria were used to appraise the inclusion of studies. The effects were analysed as the difference in mean minutes of daily moderate-vigorous activity either between two levels of a dichotomous variable (e.g., neighbourhood park available or not within 800 m) or between predicted means corresponding to a difference of two standard deviations of a simple linear numeric variable (e.g., housing density per square kilometre). The magnitude of the difference in means was evaluated via standardization. The meta-analysis was performed with the 14 studies using GIS or street audits to relate a total of 58 specific built-environment features to daily activity. Each feature was categorized with two dichotomous variables to indicate whether the feature promoted playing and/or walking, and these variables were included in the meta-analytic model as moderators interacting with age and proportion of males in the study as linear numeric covariates., Results: The meta-analysed effects of built-environment features that encourage play (including sports and fitness) and/or walking on youth moderate-vigorous activity ranged between trivial and small. There was a moderate effect of age (15 versus 9 years) whereby play facilities, parks, playgrounds and features that facilitate walking had negative effects on children's activity but positive effects on adolescents' activity. In studies that located youth physical activity with GPS, walking to school produced small increases in activity compared with transport by car or bus, greater proportions of activity took place in streets and urban venues (40-80%) than in green spaces (20-50%), and more than half of children's outdoor activity occurred with a parent nearby., Limitations: The meta-analysis cannot quantify the additive effect when several built-environment features are provided in a given neighbourhood., Conclusions: Children do not benefit to the same extent as adolescents from built-environment features that encourage walking and those designed or used for neighbourhood play.

Healthy worker survivor bias may occur in occupational studies due to the tendency for unhealthy individuals to leave work earlier, and consequently accrue less exposure, compared with their healthier counterparts. If occupational data are not analyzed using appropriate methods, this bias can result in attenuation or even reversal of the estimated effects of exposures on health outcomes. Recent advances in computing power, coupled with state-of-the-art statistical methods, have greatly increased the ability of analysts to control healthy worker survivor bias. However, these methods have not been widely adopted by occupational epidemiologists. We update the seminal review by Arrighi and Hertz-Picciotto (Epidemiology.1994; 5: 186-196) of the sources and methods to control healthy worker survivor bias. In our update, we discuss methodologic advances since the publication of that review, notably with a consideration of how directed acyclic graphs can inform the choice of appropriate analytic methods. We summarize and discuss methods for addressing this bias, including recent work applying g-methods to account for employment status as a time-varying covariate affected by prior exposure. In the presence of healthy worker survivor bias, g-methods have advantages for estimating less biased parameters that have direct policy implications and are clearly communicated to decision-makers.

High-dose inactivated, influenza vaccine was licensed by the FDA in December 2009 for adults aged 65 y and older. The ACIP did not issue or state a preference for a specific vaccine in the elderly population. The extent of its on-label and off-label use is unknown. Using the MarketScan Commercial Claims and Encounters and the Medicare Supplemental database, we identified individuals who received the high-dose influenza vaccine or the standard, seasonal trivalent influenza vaccine between January 1, 2010 and December 31, 2012. For people aged ≥65 y, we used multivariable regression to assess the association between patient and provider level variables and high-dose influenza vaccine versus standard influenza vaccine. We characterized all off-label high-dose vaccine administered to people younger than 65 y of age, and investigated whether sicker patients were targeted for off-label use by examining the association between various comorbid conditions and receipt of the high-dose vaccine among adults aged 18-64. Among patients aged ≥65 y who received an influenza vaccine, 18.4% received the high-dose vaccine. Uptake was minimal in 2010, but 25% and 32% of influenza shots were the high-dose formulation in 2011 and 2012, respectively. Almost 27,000 seniors received a second high-dose vaccine with a median of 368 d (IQR: 350-387 days) between doses. Older age, family practice physicians, and having PPO insurance were positively associated with receiving high-dose vaccine. There were 36,624 off-label high-dose vaccines administered. Half of the patients receiving off-label doses were aged 50-64. Adults aged 18-64 y receiving high-dose vaccine were more likely to have chronic comorbidities than people receiving standard influenza vaccine; however, there was not one specific illness that seemed to be targeted by physicians. In the first 3 y since licensure, use of the high-dose vaccine among seniors has been limited. The safety of this vaccine should be monitored closely among 2 groups of people - seniors receiving repeat doses and people <65.

Background: Traditional regression analysis techniques used to estimate associations between occupational radon exposure and lung cancer focus on estimating the effect of cumulative radon exposure on lung cancer. In contrast, public health interventions are typically based on regulating radon concentration rather than workers' cumulative exposure. Estimating the effect of cumulative occupational exposure on lung cancer may be difficult in situations vulnerable to the healthy worker survivor bias., Methods: Workers in the Colorado Plateau Uranium Miners cohort (n = 4,134) entered the study between 1950 and 1964 and were followed for lung cancer mortality through 2005. We use the parametric g-formula to compare the observed lung cancer mortality to the potential lung cancer mortality had each of 3 policies to limit monthly radon exposure been in place throughout follow-up., Results: There were 617 lung cancer deaths over 135,275 person-years of follow-up. With no intervention on radon exposure, estimated lung cancer mortality by age 90 was 16%. Lung cancer mortality was reduced for all interventions considered, and larger reductions in lung cancer mortality were seen for interventions with lower monthly radon exposure limits. The most stringent guideline, the Mine Safety and Health Administration standard of 0.33 working-level months, reduced lung cancer mortality from 16% to 10% (risk ratio = 0.67 [95% confidence interval = 0.61 to 0.73])., Conclusions: This work illustrates the utility of the parametric g-formula for estimating the effects of policies regarding occupational exposures, particularly in situations vulnerable to the healthy worker survivor bias.

Objectives: Guidelines to treat acute otitis media (AOM) were published in 2004. Initial declines in prescribing were shown, but it's unknown if they were sustained. We examine trends in antibiotic dispensing patterns to treat AOM among a large population of children. We also document trends in antibiotic failure., Study Design: Children aged 3 months to 12 years with an AOM diagnosis, enrolled in a commercial claims database between January 1, 2000-December 31, 2011 were included. Pharmacy claims within 7 days of diagnosis were searched for antibiotic prescriptions. Antibiotic failure was defined as a dispensing of a different antibiotic class within 2-18 days after the first prescription. We analyzed trends in antibiotic use and failure by class of antibiotic and year., Results: We identified over 4 million children under 13 years with AOM. The proportion of antibiotic dispensing decreased from 66.0% in 2005 to 51.9% in 2007, after which the instances of dispensing rebounded to pre-guideline levels. However, levels began decreasing again in 2010 and the antibiotic use rate in 2011 was 57.6%. Cephalosporin prescriptions increased by 41.5% over eleven years. Antibiotic failure decreased slightly, and macrolides had the lowest proportion of failures, while all other classes had failure rates around 10%., Conclusions: In recent years, antibiotic dispensing to treat AOM remains high. In addition, the use of broad-spectrum antibiotics is increasing despite having a high rate of treatment failure. Overprescribing of antibiotics and use of non-penicillin therapy for AOM treatment could lead to the development of antibiotic-resistant infections.

Background: Observational studies of preventive medications, such as vaccinations, can suffer from the healthy-user bias because vaccinated patients may be healthier than unvaccinated patients. Indicators of health status and frailty suitable for attenuating this bias could be identified in administrative data., Objective: To examine the association of baseline variables and time-dependent hospitalization and skilled nursing care with the receipt of influenza vaccination in patients with end-stage renal disease., Research Design: Observational cohort study using United States Renal Data System files each year from 1999 to 2005., Subjects: Population-based cohorts that included >115,000 adult, hemodialysis patients each year., Measures: We estimated hazard ratios for the association of baseline variables and time-dependent hospitalization days and skilled nursing days with influenza vaccination, controlling for demographic and baseline health status variables., Results: Vaccination coverage increased from 47% in 1999 to 60% in 2005. Patients with any length of hospitalization were less likely to be vaccinated, however, the association was stronger in patients with longer stays [15-25 d: hazard ratio=0.64 (95% confidence interval, 0.62-0.65); 26-30 d: 0.40 (0.38-0.42)]. Patients with any length of skilled nursing care of >1 day had similar estimates; these patients were also less likely to be vaccinated [26-30 d: 0.66 (0.64-0.69)]., Conclusions: Patients with long hospitalizations or skilled nursing stays were less likely to be vaccinated suggesting evidence of the healthy-user effect. These variables could be used to account for bias in studies of preventive services in patients on dialysis.

Abstract Health care utilization for HIV-1-infected patients appears to be declining in the United States as a result of highly active antiviral therapy (HAART); yet the opposite appears true in the HIV/hepatitis C virus (HCV) coinfected population. The reasons for this difference are not well understood. We examined the rates and reasons for emergency department visits and hospital admissions at an academic tertiary care medical center for HIV/HCV coinfected patients as compared to HIV-1 monoinfected patients, using a retrospective matched cohort study design. HIV/HCV coinfected patients had higher rates of health care utilization (emergency department visits 43.9 versus 7.1 per 100 person-years; hospital admissions 18.2 versus 6.7 per 100 person-years, for HIV coinfected and monoinfected, respectively). This increase was not solely due to liver related events. Instead, comorbidities such as diabetes, renal disease, and psychiatric/substance abuse played a larger role in the health-care utilization in the HIV/HCV coinfected population.

Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor beta1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2; however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (approximately 150 microg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum; however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.

1. Neotropical migrant birds show a clear preference for stopover habitats with ample food supplies; yet, the proximate cues underlying these decisions remain unclear. 2. For insectivorous migrants, cues associated with vegetative phenology (e.g. flowering, leaf flush, and leaf loss) may reliably predict the availability of herbivorous arthropods. Here we examined whether migrants use the phenology of five tree species to choose stopover locations, and whether phenology accurately predicts food availability. 3. Using a combination of experimental and observational evidence, we show migrant populations closely track tree phenology, particularly the flowering phenology of honey mesquite (Prosopis glandulosa), and preferentially forage in trees with more flowers. Furthermore, the flowering phenology of honey mesquite reliably predicts overall arthropod abundance as well as the arthropods preferred by migrants for food. 4. Together, these results suggest that honey mesquite flowering phenology is an important cue used by migrants to assess food availability quickly and reliably, while in transit during spring migration.