Algorithm-agnostic significance testing in supervised learning with multimodal data.

MOTIVATION: Valid statistical inference is crucial for decision-making but difficult to obtain in supervised learning with multimodal data, e.g. combinations of clinical features, genomic data, and medical images. Multimodal data often warrants the use of black-box algorithms, for instance, random forests or neural networks, which impede the use of traditional variable significance tests. RESULTS: We address this problem by proposing the use of COvariance MEasure Tests (COMETs), which are calibrated and powerful tests that can be combined with any sufficiently predictive supervised learning algorithm. We apply COMETs to several high-dimensional, multimodal data sets to illustrate (i) variable significance testing for finding relevant mutations modulating drug-activity, (ii) modality selection for predicting survival in liver cancer patients with multiomics data, and (iii) modality selection with clinical features and medical imaging data. In all applications, COMETs yield results consistent with domain knowledge without requiring data-driven pre-processing, which may invalidate type I error control. These novel applications with high-dimensional multimodal data corroborate prior results on the power and robustness of COMETs for significance testing. AVAILABILITY AND IMPLEMENTATION: COMETs are implemented in the cometsR package available on CRAN and pycometsPython library available on GitHub. Source code for reproducing all results is available at https://github.com/LucasKook/comets. All data sets used in this work are openly available.

NnSnRK1-NnATG1-mediated autophagic cell death governs flower bud abortion in shaded lotus.

Many plants can terminate their flowering process in response to unfavourable environments, but the mechanisms underlying this response are poorly understood. In this study, we observed that the lotus flower buds were susceptible to abortion under shaded conditions. The primary cause of abortion was excessive autophagic cell death (ACD) in flower buds. Blockade of autophagic flux in lotus flower buds consistently resulted in low levels of ACD and improved flowering ability under shaded conditions. Further evidence highlights the importance of the NnSnRK1-NnATG1 signalling axis in inducing ACD in lotus flower buds and culminating in their timely abortion. Under shaded conditions, elevated levels of NnSnRK1 activated NnATG1, which subsequently led to the formation of numerous autophagosome structures in lotus flower bud cells. Excessive autophagy levels led to the bulk degradation of cellular material, which triggered ACD and the abortion of flower buds. NnSnRK1 does not act directly on NnATG1. Other components, including TOR (target of rapamycin), PI3K (phosphatidylinositol 3-kinase) and three previously unidentified genes, appeared to be pivotal for the interaction between NnSnRK1 and NnATG1. This study reveals the role of autophagy in regulating the abortion of lotus flower buds, which could improve reproductive success and act as an energy-efficient measure in plants.

Chromatographic purification of the plasmin-like enzyme from clamworm (Perinereis aibuhitensis Grub) and its fibrinolytic activity by metal ions.

In this study, fibrinolytic protease was isolated and purified from Perinereis aibuhitensis Grub, and the extraction process was optimized. The properties of the enzyme, such as the amino acid composition, thermal stability, optimal temperature, and pH, were investigated. After detoxification, proteins collected from fresh Clamworm (Perinereis aibuhitensis Grub) were concentrated via ammonium sulfate precipitation. The crude protease was purified using gel filtration resin (Sephadex G-100), anion exchange resin (DEAE-Sepharose FF), and hydrophobic resin (Phenyl Sepharose 6FF). The molecular weight of the protease was determined by polyacrylamide gel electrophoresis (SDS-PAGE). The optimum temperature and optimum pH of the protease were determined. The activity of crude protease in the 40-60% salt-out section was the highest, reaching 467.53 U/mg. The optimal process for purifying crude protein involved the application of DEAE-Sepharose FF and Phenyl Sepharose 6FF, which resulted in the isolation of a single protease known as Asp60-D1-P1 with the highest fibrinolytic activity; additionally, the enzyme activity was measured at 3367.76 U/mg. Analysis by Native-PAGE and SDS-PAGE revealed that the molecular weight of Asp60-D1-P1 was 44.5 kDa, which consisted of two subunits with molecular weights of 6.5 and 37.8 kDa, respectively. The optimum temperature for Asp60-D1-P1 was 40°C, and the optimal pH was 8.0.

Development of a new health-related quality of life measure for people with diabetes who experience hypoglycaemia: the Hypo-RESOLVE QoL.

AIMS/HYPOTHESIS: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL. METHODS: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement. RESULTS: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ2=472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46-0.59), internal consistency (α=0.91) and test-retest reliability (intraclass correlation coefficient =0.87). CONCLUSIONS/INTERPRETATION: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint. DATA AVAILABILITY: All data generated or analysed during this study are included in the published article and its online supplementary files ( https://doi.org/10.15131/shef. DATA: 23295284.v2 ).

Restorabite™: Phase II trial of jaw stretching exercises using a novel device for patients with trismus following head and neck cancer.

Patients treated for oral cancer, may experience restricted mouth opening (trismus). Barriers such as cost have limited the utilization of traditional jaw stretching devices, and consequently, patients experience problems with swallowing, oral care, communication, and cancer surveillance. The safety and efficacy of Restorabite™, a new device designed to overcome these barriers, is evaluated prospectively over 12 months. This phase II investigator-led trial included patients with chronic trismus underwent 10-weeks of trismus therapy using Restorabite™. Safety, adherence, changes in mouth opening, and patient-reported outcomes are presented. 114/120 participants with trismus completed the intervention, and 104 had their progress monitored for 12 months. Thirteen participants withdrew due to tumour recurrence. At the completion of the intervention, mouth opening improved by 10.4 mm (p < .001). This increased to 13.7 mm at 12 months (p < .001). Patient reported outcome all significantly improved and 47 participants were no longer classified as having trismus. There were no serious treatment related adverse events. In patients with trismus following head and neck cancer treatment, a 10-week programme of jaw stretching exercises using Restorbite™ safely improves mouth opening and associated quality of life outcomes with high adherence and the benefits are maintained for 12-months.

Heterogeneity in the effect of type 2 diabetes on dementia incidence in a diverse cohort of Asian American and non-Latino White older adults.

Dementia incidence is lower among Asian Americans than among Whites, despite higher prevalence of type 2 diabetes, a well-known dementia risk factor. Determinants of dementia, including type 2 diabetes, have rarely been studied in Asian Americans. We followed 4846 Chinese, 4129 Filipino, 2784 Japanese, 820 South Asian, and 123 360 non-Latino White members of a California-based integrated health-care delivery system from 2002 to 2020. We estimated dementia incidence rates by race/ethnicity and type 2 diabetes status, and we fitted Cox proportional hazards and Aalen additive hazards models for the effect of type 2 diabetes (assessed 5 years before baseline) on age of dementia diagnosis, controlling for sex/gender, educational attainment, nativity, height, race/ethnicity, and a race/ethnicity × diabetes interaction. Type 2 diabetes was associated with higher dementia incidence in Whites (hazard ratio [HR] = 1.46; 95% CI, 1.40-1.52). Compared with Whites, the estimated effect of diabetes was larger in South Asians (HR = 2.26; 95% CI, 1.48-3.44), slightly smaller in Chinese (HR = 1.32; 95% CI, 1.08-1.62) and Filipino (HR = 1.31; 95% CI, 1.08-1.60) individuals, and similar in Japanese individuals (HR = 1.44; 95% CI, 1.15-1.81). Heterogeneity in this association across Asian subgroups may be related to type 2 diabetes severity. Understanding this heterogeneity may inform prevention strategies to prevent dementia for all racial and ethnic groups.

Simple graphical rules for assessing selection bias in general-population and selected-sample treatment effects.

When analyzing a selected sample from a general population, selection bias can arise relative to the causal average treatment effect (ATE) for the general population, and also relative to the ATE for the selected sample itself. We provide simple graphical rules that indicate: (1) if a selected-sample analysis will be unbiased for each ATE; (2) whether adjusting for certain covariates could eliminate selection bias. The rules can easily be checked in a standard single-world intervention graph. When the treatment could affect selection, a third estimand of potential scientific interest is the "net treatment difference", namely the net change in outcomes that would occur for the selected sample if all members of the general population were treated versus not treated, including any effects of the treatment on which individuals are in the selected sample . We provide graphical rules for this estimand as well. We decompose bias in a selected-sample analysis relative to the general-population ATE into: (1) "internal bias" relative to the net treatment difference; (2) "net-external bias", a discrepancy between the net treatment difference and the general-population ATE. Each bias can be assessed unambiguously via a distinct graphical rule, providing new conceptual insight into the mechanisms by which certain causal structures produce selection bias.

Replicability in cancer omics data analysis: measures and empirical explorations.

In biomedical research, the replicability of findings across studies is highly desired. In this study, we focus on cancer omics data, for which the examination of replicability has been mostly focused on important omics variables identified in different studies. In published literature, although there have been extensive attention and ad hoc discussions, there is insufficient quantitative research looking into replicability measures and their properties. The goal of this study is to fill this important knowledge gap. In particular, we consider three sensible replicability measures, for which we examine distributional properties and develop a way of making inference. Applying them to three The Cancer Genome Atlas (TCGA) datasets reveals in general low replicability and significant across-data variations. To further comprehend such findings, we resort to simulation, which confirms the validity of the findings with the TCGA data and further informs the dependence of replicability on signal level (or equivalently sample size). Overall, this study can advance our understanding of replicability for cancer omics and other studies that have identification as a key goal.

Heterogeneous cryo-EM projection image classification using a two-stage spectral clustering based on novel distance measures.

Single-particle cryo-electron microscopy (cryo-EM) has become one of the mainstream technologies in the field of structural biology to determine the three-dimensional (3D) structures of biological macromolecules. Heterogeneous cryo-EM projection image classification is an effective way to discover conformational heterogeneity of biological macromolecules in different functional states. However, due to the low signal-to-noise ratio of the projection images, the classification of heterogeneous cryo-EM projection images is a very challenging task. In this paper, two novel distance measures between projection images integrating the reliability of common lines, pixel intensity and class averages are designed, and then a two-stage spectral clustering algorithm based on the two distance measures is proposed for heterogeneous cryo-EM projection image classification. In the first stage, the novel distance measure integrating common lines and pixel intensities of projection images is used to obtain preliminary classification results through spectral clustering. In the second stage, another novel distance measure integrating the first novel distance measure and class averages generated from each group of projection images is used to obtain the final classification results through spectral clustering. The proposed two-stage spectral clustering algorithm is applied on a simulated and a real cryo-EM dataset for heterogeneous reconstruction. Results show that the two novel distance measures can be used to improve the classification performance of spectral clustering, and using the proposed two-stage spectral clustering algorithm can achieve higher classification and reconstruction accuracy than using RELION and XMIPP.

The Parent PrU: A measure to assess personal utility of pediatric genomic results.

PURPOSE: We aimed to adapt and validate an existing patient-reported outcome measure, the personal-utility (PrU) scale, for use in the pediatric genomic context. METHODS: We adapted the adult version of the PrU and obtained feedback from 6 parents whose child had undergone sequencing. The resulting measure, the Parent PrU, was administered to parents of children in 4 pediatric cohorts of the Clinical Sequencing Evidence-Generating Research consortium after they received their children's genomic results. We investigated the measure's structural validity and internal consistency. RESULTS: We conducted a principal-axis factor analysis with oblimin rotation on data from 755 participants to determine structural validity. These analyses yielded a 3-factor solution, accounting for 76% of the variance in the 16 items. We used Cronbach's α to assess the internal consistency of each factor: (1) child benefits (α = .95), (2) affective parent benefits (α = .90), and (3) parent control (α = .94). CONCLUSION: Our evidence suggests that the Parent PrU scale has potential as a measure for assessing parent-reported personal utility of their children's genomic results. Additional research is needed to further validate the Parent PrU scale, including by comparing its findings with utility assessments reported by clinicians and children themselves.

Patient-Reported Outcome Measures for Patients With CKD: The Case for Patient-Reported Outcomes Measurement Information System (PROMIS) Tools.

Chronic kidney disease (CKD), kidney failure, and kidney replacement therapies are associated with high symptom burden and impaired health-related quality of life (HRQOL). Symptoms change with disease progression or transition between treatment modalities and frequently go unreported and unmanaged. Tools that reliably monitor symptoms may improve the management of patients with CKD. Patient-reported outcome measures (PROMs) assess symptom severity; physical, psychological, social, and cognitive functioning; treatment-related side effects; and HRQOL. Systematic use of PROMs can improve patient-provider communication, patient satisfaction, clinical outcomes, and HRQOL. Potential barriers to their use include a lack of engagement, response burden, and limited guidance about PROM collection, score interpretation, and workflow integration. Well-defined, acceptable, and effective clinical response pathways are essential for implementing PROMs. PROMs developed by the Patient-Reported Outcomes Measurement Information System (PROMIS) address some challenges and may be suitable for clinical use among patients with CKD. PROMIS tools assess multiple patient-valued, clinically actionable symptoms and functions. They can be administered as fixed-length, customized short forms or computer adaptive tests, offering precise measurement across a range of symptom severities or function levels, tailored questions to individuals, and reduced question burden. Here we provide an overview of the potential use of PROMs in CKD care, with a focus on PROMIS.

Minimal important change and difference in health outcome: An overview of approaches, concepts, and methods.

OBJECTIVE: To provide an overview of approaches, concepts, and methods used to define and assess minimal important change and difference in health outcome. METHOD: A narrative review of the literature, guided by a conceptual framework. RESULTS: We distinguish between (i) interpretation of health outcome in individuals versus groups, (ii) change within individuals or groups versus difference between change within individuals or groups; and (iii) the responder approach (based on the proportion of patients that obtain a defined response) versus the group average approach (based on the average amount of change in a group). We review approaches, concepts, and methods. CONCLUSION: By bringing together and juxtaposing various approaches, concepts, and methods, we set a precursory step in the direction of consensus building in the field concerned with defining and assessing minimal important change and difference in health outcome. We emphasize the need for conceptual clarification and terminological standardization. We argue that assessing minimal importance of change and difference in health outcome is essentially a value judgment involving a range of considerations and perspectives.

Evidence-based hierarchy of pain outcome measures for osteoarthritis clinical trials and meta-analyses.

OBJECTIVE: To rank commonly used patient-reported outcome measures (PROMs) for assessing pain in osteoarthritis trials according to their assay sensitivity, defined as the ability of a PROM to distinguish an effective from a less effective intervention or placebo, proposing a hierarchy for PROM selection in trials and data-extraction in meta-analyses. DESIGN: Analysis of trials with placebo, sham, or non-intervention control that included ≥100 patients per arm with knee/hip osteoarthritis, reporting treatment effects on ≥2 pain PROMs. Treatment effects from all PROMs were standardized on a 0-100 scale. Negative mean differences indicated a larger effect of the experimental treatment compared to control. We ranked PROMs by assay sensitivity using a Bayesian multi-outcome synthesis random-effects model. RESULTS: 135 trials comprising 57,141 participants were included. The ranking of PROMs from highest to lowest assay sensitivity was as follows: pain overall, pain on stairs, pain at night, pain on walking, pain at rest, WOMAC pain, WOMAC global, Lequesne index. Pain overall, the highest-ranked PROM, had a pooled mean difference of -6.96 (95%CrI -7.94, -6.02), while WOMAC pain, the most reported PROM in our study, had a pooled mean difference of -4.90 (95%CrI -5.55, -4.26). The pooled ratio of mean differences between pain overall and WOMAC pain was 1.42 (95%CrI 1.30, 1.55), representing a 42% larger effect size with pain overall. CONCLUSIONS: Pain overall has better assay sensitivity than other pain PROMs. Investigators should consider the hierarchy proposed in this study to guide PROM selection in osteoarthritis clinical trials and data extraction in osteoarthritis meta-analyses.

Development of a core domain set for ankle osteoarthritis: An international consensus study of patients and health professionals.

OBJECTIVES: To develop an internationally agreed-upon core domain set for ankle osteoarthritis (OA). METHODS: In a three-part Delphi process, a group of multidisciplinary health professionals with expertise in ankle OA and people with ankle OA responded to online questionnaires. The questionnaires proposed a list of 29 candidate domains derived from a systematic review of ankle OA research, and interviews with people with ankle OA and health professionals. Consensus was defined a priori as ≥70% agreement in people with ankle OA and health professionals whether a domain should or should not be included in a core domain set. An online consensus meeting was held to discuss and resolve undecided candidate domains. RESULTS: A total of 100 people (75 health professionals and 25 people with ankle OA) from 18 countries (4 continents) participated in this study. Five domains reached consensus for inclusion in a core domain set for ankle OA - pain severity, health-related quality of life, function, disability and ankle range of motion. Twenty-one candidate domains reached agreement not to be included in the core domain set, and three domains remained undecided (ankle instability, physical capacity, and mental health). CONCLUSION: This international consensus study, which included people with ankle OA and health professionals, has established a core domain set for ankle OA with five domains that should be measured and reported in all ankle OA trials - pain severity, health-related quality of life, function, disability and ankle range of motion. This core domain set will guide the reporting of outcomes in clinical trials on ankle OA. Future research should determine which outcome measurement instruments should be used to measure each of the core domains.

30 years with the Knee injury and Osteoarthritis Outcome Score (KOOS).

This narrative review describes the development and use of patient-reported outcomes over 30 years, focusing on the Knee injury and Osteoarthritis Outcome Score (KOOS). KOOS is a five-subscale patient-reported instrument intended for use from the time of knee injury to the development of osteoarthritis. Numerous studies have confirmed that the psychometric properties of the KOOS and its short-form KOOS-12 are acceptable. More recent research has focused on the use and interpretation of KOOS scores in clinical trials using thresholds, such as minimal important differences, patient-acceptable symptom states, and treatment failure. As an indication of KOOS's popularity, the total 3854 PubMed results for KOOS have increased exponentially since the first KOOS paper was published 25 years ago and now seem to have plateaued at around 650 annually. The selected articles are not based on a systematic search, but on the author's own publications, reading, and literature search that grew organically from that.

Development of a measuring app for systemic sclerosis-related digital ulceration (SALVE: Scleroderma App for Lesion VErification).

OBJECTIVES: To test the hypothesis that photographs (in addition to self-reported data) can be collected daily by patients with systemic sclerosis (SSc) using a smartphone app designed specifically for digital lesions, and could provide an objective outcome measure for use in clinical trials. METHODS: An app was developed to collect images and patient reported outcome measures (PROMS) including Pain score and the Hand Disability in Systemic Sclerosis-Digital Ulcers (HDISS-DU) questionnaire. Participants photographed their lesion(s) each day for 30 days and uploaded images to a secure repository. Lesions were analysed both manually and automatically, using a machine learning approach. RESULTS: 25 patients with SSc-related digital lesions consented of whom 19 completed the 30-day study, with evaluable data from 27 lesions. Mean (standard deviation [SD]) baseline Pain score was 5.7 (2.4) and HDISS-DU 2.2 (0.9), indicating high lesion and disease-related morbidity. 506 images were used in the analysis (mean number of used images per lesion 18.7, SD 8.3). Mean (SD) manual and automated lesion areas at day 1 were 11.6 (16.0) and 13.9 (16.7) mm2 respectively. Manual area decreased by 0.08mm2 per day (2.4mm2 over 30 days) and automated area by 0.1mm2 (3.0mm2 over 30 days). Average gradients of manual and automated measurements over 30 days correlated strongly (r = 0.81). Manual measurements were on average 40% lower than automated, with wide limits of agreement. CONCLUSION: Even patients with significant hand disability were able to use the app. Automated measurement of finger lesions could be valuable as an outcome measure in clinical trials.

Timing of Breast Cancer Related Lymphedema Development Over 3 Years: Observations from a Large, Prospective Randomized Screening Trial Comparing Bioimpedance Spectroscopy (BIS) Versus Tape Measure.

BACKGROUND: The PREVENT randomized control trial monitored progression to chronic breast cancer-related lymphedema (cBCRL) following intervention for subclinical breast cancer-related lymphedema (sBCRL) assessed by bioimpedance spectroscopy (BIS) versus tape-measure (TM). This multi-institutional trial demonstrated a 92% risk reduction of developing cBCRL. This secondary analysis reviews the timing of sBCRL and cBCRL following breast cancer (BC) treatment. PATIENTS AND METHODS: Women at risk of cBCRL (n = 919) were screened regularly up to 36 months after BC treatment using either BIS or TM. Following diagnosis of sBCRL, patients underwent a 4-week compression sleeve intervention. The time in months from BC treatment to detection was reviewed at 3-month intervals. RESULTS: In total 209 patients developed sBCRL (BIS: n = 89, TM: n = 120) and were eligible for intervention. 30 progressed to cBCRL postintervention (BIS: 7, TM: 23). More than half of patients had measurements consistent with sBCRL within 9 months of BC treatment. Patients continued to have initial detections of sBCRL, regardless of screening method, with rates remaining consistent in years two and three (p > 0.242) post surgery. Additionally, 39 patients progressed to cBCRL without developing sBCRL or receiving intervention across the 3-year period. CONCLUSIONS: The timing of sBCRL detection demonstrates that patients continue to be at risk years after treatment and may continue to progress to cBCRL years after surgery. Early detection of sBCRL allows for early intervention decreasing the likelihood of progression to cBCRL. Patients should continue to be monitored for a minimum of 3 years following completion of cancer treatment. Specifically, careful targeted monitoring over the initial 9-month period is important.

Association between triglyceride-glucose related indices and all-cause and cause-specific mortality in the general population: a cohort study.

BACKGROUND: Although triglyceride-glucose (TyG) index is a reliable indicator of insulin resistance and cardiometabolic disease, its effectiveness in predicting mortality risk has not been adequately validated. We aimed to investigate the association between the TyG-related indices and all-cause and cause-specific mortality in the general population. METHODS: A total of 27,642 individuals were included from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. Three indicators were constructed, including the TyG index, TyG combined with waist-to-height ratio (TyG-WHtR), and TyG combined with waist circumference (TyG-WC). Mortality data was acquired through the linkage of NHANES data with National Death Index records. Weighted Cox proportional hazards models were used to estimate the independent association between the TyG-related indices and mortality. Nonlinear associations were explored using restricted cubic splines. RESULTS: Multivariable adjusted models showed a progressive increase in all-cause and cause-specific mortality across quartiles of the TyG-related indices. Compared with the lowest quartile of the TyG index, the highest quartile had adjusted hazard ratios of 1.26 (95% CI 1.04-1.52) for all-cause mortality, 1.38 (1.04-1.74) for cardiovascular mortality, and 1.23 (1.01-1.50) for non-cardiovascular mortality, respectively. For the TyG-WHtR index, the corresponding hazard ratios were 1.60 (1.25-2.05), 1.86 (1.26-2.50), and 1.48 (1.10-1.99), respectively. For the TyG-WC index, the corresponding hazard ratios were 1.42 (1.11-1.75), 1.48 (1.04-1.96), and 1.38 (1.05-1.72), respectively. The associations between the three TyG-related indices and all-cause, cardiovascular and non-cardiovascular mortality were J-shaped. Interaction tests revealed significant effect modification by age, low-density lipoprotein cholesterol (LDL-C) level, and statin use (all P values < 0.05). CONCLUSIONS: The TyG-related indices were independent predictors of all-cause and cause-specific mortality in the general population. Young individuals should be particularly vigilant, whereas low LDL-C levels and statin use are potentially protective.

Long-term patient-reported outcomes among patients undergoing revascularization vs medical therapy for intermittent claudication.

OBJECTIVE: Society for Vascular Surgery guidelines recommend revascularization for patients with intermittent claudication (IC) if it can improve patient function and quality of life. However, it is still unclear if patients with IC achieve a significant functional benefit from surgery compared with medical management alone. This study examines the relationship between IC treatment modality (operative vs nonoperative optimal medical management) and patient-reported outcomes for physical function (PROMIS-PF) and satisfaction in social roles and activities (PROMIS-SA). METHODS: We identified patients with IC who presented for index evaluation in a vascular surgery clinic at an academic medical center between 2016 and 2021. Patients were stratified based on whether they underwent a revascularization procedure during follow-up vs continued nonoperative management with medication and recommended exercise therapy. We used linear mixed-effect models to assess the relationship between treatment modality and PROMIS-PF, PROMIS-SA, and ankle-brachial index (ABI) over time, clustering among repeat patient observations. Models were adjusted for age, sex, diabetes, Charlson Comorbidity Index, Clinical Frailty Score, tobacco use, and index ABI. RESULTS: A total of 225 patients with IC were identified, of which 40% (n = 89) underwent revascularization procedures (42% bypass; 58% peripheral vascular intervention) and 60% (n = 136) continued nonoperative management. Patients were followed up to 6.9 years, with an average follow-up of 5.2 ± 1.6 years. Patients who underwent revascularization were more likely to be clinically frail (P = .03), have a lower index ABI (0.55 ± 0.24 vs 0.72 ± 0.28; P < .001), and lower baseline PROMIS-PF score (36.72 ± 8.2 vs 40.40 ± 6.73; P = .01). There were no differences in patient demographics or medications between treatment groups. Examining patient-reported outcome trends over time; there were no significant differences in PROMIS-PF between groups, trends over time, or group differences over time after adjusting for covariates (P = .07, P = .13, and P =.08, respectively). However, all patients with IC significantly increased their PROMIS-SA over time (adjusted P = .019), with patients managed nonoperatively more likely to have an improvement in PROMIS-SA over time than those who underwent revascularization (adjusted P = .045). CONCLUSIONS: Patient-reported outcomes associated with functional status and satisfaction in activities are similar for patients with IC for up to 7 years, irrespective of whether they undergo treatment with revascularization or continue nonoperative management. These findings support conservative long-term management for patients with IC.

Trimester-Specific Urinary Strontium Concentrations during Pregnancy and Longitudinally Assessed Fetal Growth: Findings from a Prospective Cohort.

BACKGROUND: Studies have claimed that strontium (Sr) is associated with fetal growth, but the research evidence is insufficient. OBJECTIVES: Our study aimed to evaluate associations of trimester-specific urinary Sr concentrations with fetal growth parameters and birth size indicators. METHODS: In this prospective cohort, 9015 urine samples (first trimester: 3561, 2nd trimester: 2756, 3rd trimester: 2698) from 3810 mothers were measured for urinary Sr levels using inductively coupled plasma mass spectrometry (ICP-MS) and adjusted to urine specific gravity. We calculated standard deviation scores (SD-scores) for ultrasound-measured fetal growth parameters (head circumference, abdominal circumference, femur length, and estimated fetal weight) at 16, 24, 31, and 37 wk of gestation and birth size indicators (birth weight, birth length, and Ponderal index). Generalized linear models and generalized estimating equations models were used. Models were adjusted for potential covariates (gestational age, maternal age, body mass index, parity, passive smoking during pregnancy, education, folic acid supplements use, physical activity, maternal and paternal height, and infant sex). RESULTS: Positive associations of naturally logarithm-transformed Sr concentrations with fetal growth parameters and birth size indicators were observed. With each doubling increase in the urinary ln-Sr level in all 3 trimesters resulting in a percent change in SD-scores fetal growth parameters at 24, 31, and 37 wk of gestation and birth size indicators, 5.09%-8.23% in femur length, 7.57%-11.53% in estimated fetal weight, 6.56%-10.42% in abdominal circumference, 6.25% in head circumference, 5.15%-7.85% in birth weight, and 5.71%-9.39% in birth length, respectively. Most of the above statistical results could only be observed in male fetuses. CONCLUSIONS: Our findings suggest a potential association between Sr concentration and increased fetal growth, but these results and underlying mechanisms need further confirmation and clarification.