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Animals must balance various costs and benefits when deciding when to breed. The costs and benefits of breeding at different times have received much attention, but most studies have been limited to investigating short-term season-to-season fitness effects. However, breeding early, versus late, in a season may influence lifetime fitness over many years, trading off in complex ways across the breeder?s lifepan. In this study, we examined the complete life histories of 867 female tree swallows (Tachycineta bicolor) breeding in Ithaca, New York, between 2002 and 2016. Earlier breeders outperformed later breeders in short-term measures of reproductive output and offspring quality. Though there were weak indications that females paid long-term future survival costs for breeding early, lifetime fledgling output was markedly higher overall in early-breeding birds. Importantly, older females breeding later in the season did not experience compensating life-history advantages that suggested an alternative equal-fitness breeding strategy. Rather, most or all of the swallows appear to be breeding as early as they can, and differences in lay dates appear to be determined primarily by differences in individual quality or condition. Lay date had a significant repeatability across breeding attempts by the same female, and the first lay date of females fledged in our population was strongly influenced by the first lay date of their mothers, indicating the potential for ongoing selection on lay date. By examining performance over the entire lifespan of a large number of individuals, we were able to clarify the relationship between timing of breeding and fitness and gain new insight into the sources of variability in this important life history trait.

Liquid chromatography–high-resolution mass spectrometry (LC-HRMS), as applied to untargeted metabolomics, enables the simultaneous detection of thousands of small molecules, generating complex datasets. Alignment is a crucial step in data processing pipelines, whereby LC-MS features derived from common ions are assembled into a unified matrix amenable to further analysis. Variability in the analytical factors that influence liquid chromatography separations complicates data alignment. This is prominent when aligning data acquired in different laboratories, generated using non-identical instruments, or between batches from large-scale studies. Previously, we developed metabCombiner for aligning disparately acquired LC-MS metabolomics datasets. Here, we report significant upgrades to metabCombiner that enable the stepwise alignment of multiple untargeted LC-MS metabolomics datasets, facilitating inter-laboratory reproducibility studies. To accomplish this, a “primary” feature list is used as a template for matching compounds in “target” feature lists. We demonstrate this workflow by aligning four lipidomics datasets from core laboratories generated using each institution’s in-house LC-MS instrumentation and methods. We also introduce batchCombine, an application of the metabCombiner framework for aligning experiments composed of multiple batches. metabCombiner is available as an R package on Github and Bioconductor, along with a new online version implemented as an R Shiny App.

In a phase 3 study, galcanezumab significantly reduced the frequency of episodic cluster headache attacks across weeks 1-3 (primary endpoint) compared with placebo. However, multiple pain dimensions may contribute to the total burden of episodic cluster headache pain. This post hoc analysis assessed the impact of galcanezumab on the total pain burden of episodic cluster headache using a composite measure. Patients with episodic cluster headache were randomized 1:1 to galcanezumab 300 mg or placebo once monthly for 8 weeks. Mean weekly total pain burden was calculated (daily cluster headache attack frequency × average duration × average pain severity summed over 7 days) using data collected in an electronic patient-reported outcomes diary. Change from baseline in weekly total pain burden across weeks 1-3 was compared between galcanezumab and placebo. To explore construct validity, mean weekly total pain burden scores were stratified by Patient Global Impression of Improvement (PGI-I) responses at the week 4 clinic visit. The reduction from baseline in mean weekly total pain burden was significantly greater with galcanezumab (N=49) than with placebo (N=57): the least squares mean difference was -11.18 severity-weighted hours (p=0.035). Median weekly total pain burden decreased as PGI-I ratings improved, from 33.6 to 5.0 severity-weighted hours for patients who felt \"very much worse\" and \"very much better,\" respectively. Galcanezumab significantly reduced mean weekly total pain burden compared with placebo in patients with episodic cluster headache. The composite pain measure demonstrated construct validity. Total pain burden may provide a holistic measure of the pain of episodic cluster headache. ClinicalTrials.gov, NCT02397473.

Distal radius fractures (DRFs) are common injuries among older adults and can result in substantial disability. Current evidence regarding long-term outcomes in older adults is scarce. To compare outcomes across treatment groups at 24 months among adults with DRFs who participated in the WRIST trial. The Wrist and Radius Injury Surgical Trial (WRIST) randomized, international, multicenter trial was conducted from April 1, 2012, through December 31, 2016. Participants were adults aged 60 years or older with isolated, unstable DRFs at 24 health systems in the US, Canada, and Singapore. Data analysis was performed from March 2019 to March 2021. Participants were randomized to open reduction and volar locking plate system (VLPS), external fixation with or without supplementary pinning (EFP), and percutaneous pinning (CRPP). The remaining participants chose closed reduction and casting. The primary outcome was the 24-month Michigan Hand Outcomes Questionnaire (MHQ) summary score. Secondary outcomes were scores on the MHQ subdomains hand strength and wrist motion. A total of 304 adults were recruited for the study, and 187 were randomized to undergo surgery, 65 to VLPS, 64 to EFP, and 58 to CRPP; 117 participants opted for closed reduction and casting. Assessments were completed at 24 months for 182 participants (160 women [87.9%]; mean [SD] age, 70.1 [8.5] years). Mean MHQ summary scores at 24 months were 88 (95% CI, 83-92) for VLPS, 83 (95% CI, 78-88) for EFP, 85 (95% CI, 79-90) for CRPP, and 85 (95% CI, 79-90) for casting, with no clinically meaningful difference across groups after adjusting for covariates (χ23 = 1.44; P = .70). Pain scores also did not differ across groups at 24 months (χ23 = 2.64; P = .45). MHQ summary scores changed from 82 (95% CI, 80-85) to 85 (95% CI, 83-88) (P = .12) between 12 and 24 months across groups. The rate of malunion was higher in the casting group (26 participants [59.1%]) than in the other groups (4 participants [8.0%] for VLPS, 8 participants [17.0%] for EFP, and 4 participants [9.8%] for CRPP; χ23 = 43.6; P < .001), but malunion was not associated with the 24-month outcome difference across groups. The study did not find clinically meaningful patient-reported outcome differences 24 months after injury across treatment groups, with little change between 12 and 24 months. These findings suggest that long-term outcomes need not necessarily be considered in deciding between treatment options. Patient needs and recovery goals that fit to relative risks and benefits of each treatment type will be more valuable in treatment decision-making. ClinicalTrials.gov Identifier: NCT01589692.

Untargeted lipidomics allows analysis of a broader range of lipids than targeted methods and permits discovery of unknown compounds. Previous ring trials have evaluated the reproducibility of targeted methods, but inter-laboratory comparison of compound identification and unknown feature detection in untargeted lipidomics has not been attempted. To address this gap, five laboratories analyzed a set of mammalian tissue and biofluid reference samples using both their own untargeted lipidomics procedures and a common chromatographic and data analysis method. While both methods yielded informative data, the common method improved chromatographic reproducibility and enabled identification of over 2,000 unique lipids using the LipidBlast spectral library. LC-MS/MS and ion mobility data, aided by hybrid search and spectral networking analysis, revealed spectral and chromatographic patterns useful for classification of unknown features, a subset of which were highly reproducible between labs. Overall, our method offers enhanced compound identification performance compared to targeted lipidomics, demonstrates the potential of harmonized methods to improve inter-site reproducibility for quantitation and feature alignment, and may serve as a reference to aid future annotation of untargeted lipidomics data.Competing Interest StatementThe authors have declared no competing interest.