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A 35-year-old woman with primary infertility underwent an ovarian cystectomy for a 5 x 4 cm left adnexal mass. There was no macroscopic evidence of metastatic disease. The final pathology report revealed a poorly differentiated serous cystadenocarcinoma. Because the patient desired to retain child-bearing capacity, she refused a surgical staging of her ovarian cancer. She elected to receive combination chemotherapy. This was then followed by a negative reassessment laparotomy. The patient was diagnosed with recurrent, metastatic ovarian carcinoma 10 years later.

Purpose: Gemcitabine, a pyrimidine nucleoside, is approved for the treatment of non-small cell lung cancer, pancreatic carcinoma, and breast cancer. Chemotherapy regimens are determined experimentally with static tissue culture systems, animal models, and in Phase I clinical trials. The aim of this study was to assess for gemcitabine-induced cell death following infusion of drug under clinically-relevant conditions of infusion rate and drug exposure in an in vitro bioreactor system.Methods: To estimate an appropriate harvest time for cells from the bioreactor after drug treatment, we estimated the temporal relationship between gemcitabine treatment for 1 h and cell death at a later time point with monolayer growth assays (i.e., static culture). Afterward, 5.3 mg gemcitabine was infused over 0.5 h in the bioreactor, followed by mono-exponential decay, simulating patient concentration-time profiles (n = 4). Controls were run with drug-free media (n = 4). Cells were harvested from the bioreactor at a later time point and assessed for cell death by flow cytometry.Results: According to monolayer growth assay results, cytotoxicity became more apparent with increasing time. The E Max for cells 48 h after treatment was 50% and after 144 h, 93% (P = 0.022; t test), while flow cytometry showed complete DNA degradation by 120 h. Gemcitabine was infused in the bioreactor. The gemcitabine area under the concentration-time curve (AUC) was 56.4 microM h and the maximum concentration was 87.5 +/- 2.65 microM. Flow cytometry results were as follows: the G1 fraction decreased from 65.1 +/- 4.91 to 28.6 +/- 12% (P = 0.005) and subG1 increased from 14.1 +/- 5.28 to 42.6 +/- 9.78% (P = 0.004) relative to control. An increase in apoptotic cells was observed by TUNEL assay.Conclusions: The in vitro bioreactor system will be expanded to test additional cell lines, and will serve as a useful model system for assessing the role of drug pharmacokinetics in delivery of optimized anticancer treatment. [ABSTRACT FROM AUTHOR]

Living in urban environments presents many challenges to wildlife, including exposure to potentially toxic pollutants. For example, the heavy metal lead (Pb) introduces numerous health problems to all animals, including humans. The little work that has been conducted on lead toxicity in reptiles suggests that lizards may be extraordinarily resilient to very high levels of lead pollution, by either avoiding or mitigating the toxicity. To assess the impact of lead exposure, we measured field blood levels and tested for the effects on ecologically-relevant performance measures in common wall lizards (Podarcis muralis) - a small reptile particularly capable of thriving in urban environments. We captured lizards from roadside and park habitats across Cincinnati, Ohio, USA and quantified the concentration of lead in blood samples (n = 71 adult lizards). Lizards from roadside populations had higher blood lead concentrations than lizards from park populations, and females had higher blood lead concentrations than males regardless of habitat type. We then tested two aspects of lizard performance important for survival: (1) balance, a cognitively-demanding task, to assess the effect of lead on cognition (n = 41), and (2) running endurance, an aerobic exercise dependent on oxygen (n = 43), to assess the impact of lead on blood oxygen-carrying capacity. We then used correlation analyses to quantify the relationship between lead levels and these ecologically-relevant performance measures. There was no effect of blood lead levels on running endurance, but contrary to our predictions there was a slight positive effect on balance performance, whereby lizards with higher blood lead concentrations slipped less often than lizards with lower blood lead concentrations. Understanding the effects of lead toxicity and resilience in a particularly resistant animal could help us better respond to public health and environmental pollution concerns., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Eric Gangloff reports financial support was provided by National Science Foundation. 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Greater screen time is associated with increased symptoms of autism spectrum disorder (autism), attention-deficit/hyperactivity disorder (ADHD), and lower scores on measures of development in preschool-aged community samples. In the current longitudinal study, we examined screen time differences at 18 months of age based on clinically-defined outcomes (i.e., Autism, ADHD Concerns, Comparison) determined at age 3-5 years in a genetically-enriched sample based on family history, along with prospective associations between toddler screen time and preschool autism/ADHD symptoms and developmental achievement. Participants (n = 82) included children at high and low familial likelihood for autism and ADHD. Children with Autism and ADHD Concerns outcomes experienced significantly more screen exposure at 18 months than children without autism or elevated symptoms of ADHD. Greater screen time at 18 months was also associated with preschool symptoms of autism and ADHD and lower developmental achievement across the sample. Preschoolers with neurodevelopmental challenges experienced more screen exposure earlier in development than same-age peers, increasing potential for negative developmental impacts., Competing Interests: Declarations. Competing Interests: Dr. Miller has received research grant funding from the National Institutes of Health and travel reimbursement and/or honoraria from the Society for Clinical Child and Adolescent Psychology. All other authors have no relevant financial or non-financial interests to disclose. Ethical Approval: The procedures used in the research were approved by the University of California, Davis Institutional Review Board and adhere to the tenets of the Declaration of Helsinki., (© 2024. The Author(s).)

Aspergillus fumigatus, a filamentous fungus, is an opportunistic pathogen and the major causative agent of the often-fatal disease, invasive aspergillosis (IA). Current treatments for IA are limited due to their high toxicity and/or the emergence of drug resistance; therefore, a need exists for the development of new therapeutics to treat IA. The Kdnase produced by A. fumigatus plays a vital role in maintaining cell wall integrity. As there are no known Kdnases in humans, developing inhibitors of Kdnase from this fungal pathogen is a promising therapeutic approach. The rapid testing of enzymatic activity in a high-throughput screen of large chemical libraries can be an efficient way to find new small molecule lead compounds. Herein we show that a Kdn glycoside with a self-immolative cleavable aglycon is a practical and efficient substrate for a high throughput assay to identify Kdnase inhibitors. We optimized the activity assay and screened over 27,000 compounds from two bioactive chemical libraries as potential inhibitors, and we compared the hit compounds' potency towards Aspergillus terreus and Trichophyton rubrum Kdnases, two other fungal Kdnases. We validated a number of hits and these small molecules are potential leads for the development of novel therapeutics to treat invasive aspergillosis., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: The Speech Accessibility Project (SAP) intends to facilitate research and development in automatic speech recognition (ASR) and other machine learning tasks for people with speech disabilities. The purpose of this article is to introduce this project as a resource for researchers, including baseline analysis of the first released data package., Method: The project aims to facilitate ASR research by collecting, curating, and distributing transcribed U.S. English speech from people with speech and/or language disabilities. Participants record speech from their place of residence by connecting their personal computer, cell phone, and assistive devices, if needed, to the SAP web portal. All samples are manually transcribed, and 30 per participant are annotated using differential diagnostic pattern dimensions. For purposes of ASR experiments, the participants have been randomly assigned to a training set, a development set for controlled testing of a trained ASR, and a test set to evaluate ASR error rate., Results: The SAP 2023-10-05 Data Package contains the speech of 211 people with dysarthria as a correlate of Parkinson's disease, and the associated test set contains 42 additional speakers. A baseline ASR, with a word error rate of 3.4% for typical speakers, transcribes test speech with a word error rate of 36.3%. Fine-tuning reduces the word error rate to 23.7%., Conclusions: Preliminary findings suggest that a large corpus of dysarthric and dysphonic speech has the potential to significantly improve speech technology for people with disabilities. By providing these data to researchers, the SAP intends to significantly accelerate research into accessible speech technology., Supplemental Material: https://doi.org/10.23641/asha.27078079.

Purpose: Therapeutic alliance (TA) is critical to rehabilitation outcomes for adults with acquired brain injuries (ABIs). The purpose of this viewpoint article is to review factors that contribute to TA and to suggest ways speech-language pathologists (SLPs) can integrate these factors into their ABI rehabilitation practice., Method: We evaluated literature describing client and clinician factors shown to affect-or not affect-TA in ABI rehabilitation and mapped findings onto suggested practices that SLPs may use to actively promote TA with their clients. Informed by our findings and TA frameworks, we integrated findings into a novel clinician self-reflection tool: the Therapeutic Alliance Reflection Checklist., Conclusions: TA is a key ingredient in ABI rehabilitation. We contend that SLPs can, and should, actively facilitate TA with clients; the self-reflection checklist can assist. We advocate for continued TA research and improved measurement across rehabilitation settings. We further contend that training in active TA-promoting skills is a critical component of speech-language pathology education.

Background: The Grading Recommendations, Assessment, Development, and Evaluations (GRADE) framework is widely applied in clinical guidelines to facilitate transparent evidence evaluation. While developing Infectious Diseases Society of America (IDSA) guidelines on the management of patients with coronavirus disease 2019 (COVID-19), panel members suggested developing and implementing a visual aid to enable quicker identification of key information by providers at bedside seeking guidance., Methods: We conducted a mixed-methods study evaluating the usability of a newly designed infographic/icon using a survey and focus groups. The survey incorporated a simulated COVID-19 IDSA guideline with and without the icon, followed by comprehension questions. Focus group discussions provided qualitative feedback on the GRADE methodology and icon usability., Results: The survey was returned by 289 health care providers. There was no statistical difference in the correct response rates between icon-aided and non-icon-aided guideline questions (McNemar's chi-square test, P > .1 for both questions). Interactions with the icon notably increased the time taken and number of clicks required to respond to the first question (Wilcoxon signed-rank test, P < .01). In contrast, response time did not differ between versions for the second question ( P = .38). Most subjects (85%) indicated that the icon improved the readability of the guidelines. A focus group follow-up suggested alternative designs for the icon., Conclusions: This study highlights the promise of iconography in clinical guidelines, although the specific icons tested did not measurably improve usability metrics. Future research should focus on icon design and testing within a formal usability framework, considering the impact of GRADE language on user experience., Competing Interests: Potential conflicts of interest. Y.F.Y., R.L.M., and R.A.M. disclose their affiliations as members of the GRADE working group and cofounders of the US GRADE network, with experience serving various societies as methodologists and GRADE experts. I.Y.C., J.C.O., J.E.G., M.M.M., and A.B. declare no disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Transgender and gender-diverse (TGD) individuals have a gender identity or expression that differs from the sex assigned to them at birth. They are an underserved population who experience health care inequities. Our primary objective was to identify if there are treatment differences between TGD and cisgender lesbian/gay/bisexual/queer (LGBQ) or heterosexual individuals presenting with abdominal pain to the emergency department (ED)., Methods: Retrospective observational cohort study of patients ≥12 years of age presenting to 21 EDs within a health care system with a chief complaint of abdominal pain between 2018 and 2022. TGD patients were matched 1:1:1:1 to cisgender LGBQ women and men and cisgender heterosexual women and men, respectively. Propensity score matching covariates included age, ED site, mental health history, and gastrointestinal history. The primary outcome was pain assessment within 60 min of arrival. The secondary outcome was analgesics administered in the ED., Results: We identified 300 TGD patients, of whom 300 TGD patients were successfully matched for a total cohort of 1300 patients. The median (IQR) age was 25 (20-32) years and most patients were treated in a community ED (58.2%). There was no difference between groups in pain assessment within 60 min of arrival (59.0% TGD vs. 63.2% non TGD, p = 0.19). There were no differences in the number of times pain was assessed (median [IQR] 2 [1-3] vs. 2 [1-4], p = 0.31) or the severity of pain between groups (5.5 [4-7] vs. 6 [4-7], p = 0.11). TGD patients were more likely to receive nonsteroidal anti-inflammatory drugs (32.0% vs. 24.9%, p = 0.015) and less likely to receive opioids than non-TGD patients (24.7% vs. 36.9%, p = <0.001). TGD and nonbinary patients, along with LGBQ cisgender women (24.7%) and heterosexual cisgender women (34%), were less likely to receive opioids than LGBQ cisgender men (54%) and heterosexual cisgender men (42.3%, p < 0.01)., Conclusion: There was no difference in frequency of pain assessment, regardless of gender identity or sexual orientation. More cisgender men, compared to TGD and cisgender women, received opioids for their pain., (© 2024 Society for Academic Emergency Medicine.)

Introduction: Real-world evidence is receiving considerable attention as a way to evaluate the efficacy and safety of medical products for substance use disorders (SUDs). However, the feasibility of using real-world data (RWD) to emulate clinical trials evaluating treatments for SUDs is uncertain. The aim of this study is to identify the number of clinical trials evaluating treatments for SUDs with reported results that could be feasibly emulated using observational data from contemporary insurance claims and/or electronic health record (EHR) data., Methods: In this cross-sectional study, all phase 2-4 trials evaluating treatments for SUDs registered on ClinicalTrials.gov with reported results were identified. Each trial was evaluated to determine if the indications, interventions, at least 80% of eligibility criteria, comparators, and primary end points could be ascertained using contemporarily available administrative claims and/or structured EHR data., Results: There were 272 SUD trials on ClinicalTrials.gov with reported results. Of these, when examining feasibility using contemporarily available administrative claims and/or structured EHR data, 262 (96.3%) had indications that were ascertainable; 194 (71.3%) had interventions that were ascertainable; 21 (7.7%) had at least 80% of eligibility criteria that were ascertainable; 17 (6.3%) had active comparators that were ascertainable; and 61 (22.4%) had primary end points that were ascertainable. In total, there were no trials for which all 5 characteristics were ascertainable using contemporarily available administrative claims and/or structured EHR data. When considering placebo comparators as ascertainable, there were 6 (2.2%) trials that had all 5 key characteristics classified as ascertainable from contemporarily available administrative claims and/or structured EHR data., Conclusions: No trials evaluating treatments for SUDs could be feasibly emulated using contemporarily available RWD, demonstrating a need for an increase in the resolution of data capture within a public health system to facilitate trial emulation., (© 2024. The Author(s).)

Therapy-related myeloid neoplasms (t-MN) are a growing concern due to the continued use of cytotoxic therapies to treat malignancies. Cytotoxic therapies have been shown to drive therapy-induced senescence in normal tissues, including in the bone marrow microenvironment (BMME), which plays a crucial role in supporting normal hematopoiesis. This review examines recent work that focuses on the contribution of BMME senescence to t-MN pathogenesis, as well as offers a perspective on potential opportunities for therapeutic intervention., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Angelo Jose Guilatco reports financial support was provided by National Cancer Institute. Angelo Jose Guilatco reports financial support was provided by the University of Michigan. Megan Moore Weivoda reports financial support was provided by National Institute on Aging. Megan Moore Weivoda reports a relationship with National Institute of Arthritis and Musculoskeletal and Skin Diseases that includes: funding grants. Mithun Vinod Shah reports a relationship with AbbVie Inc that includes: funding grants. Mithun Vinod Shah reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Mithun Vinod Shah reports a relationship with Astellas Pharma US Inc that includes: funding grants. Mithun Vinod Shah reports a relationship with MRKR Therapeutics that includes: funding grants. 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., (© 2024 Published by Elsevier GmbH.)

Urinary tract infection (UTI) is a frequent infection in childhood. The diagnosis is usually made by history and physical examination and confirmed by urine analysis. Cystitis is infection or inflammation confined to the bladder, whereas pyelonephritis is infection or inflammation of kidneys. Pyelonephritis can cause renal scarring, which is the most severe long-term sequela of UTI and can lead to accelerated nephrosclerosis, leading to hypertension and chronic renal failure. The role of imaging is to guide treatment by identifying patients who are at high risk to develop recurrent UTIs or renal scarring. This document provides initial imaging guidelines for children presenting with first febrile UTI with appropriate response to medical management, atypical or recurrent febrile UTI, and follow-up imaging for children with established vesicoureteral reflux. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: The use of potentially inappropriate medications (PIMs) is considered an important quality indicator for older adults seen in the ambulatory care setting., Study Objectives: To evaluate the pattern of potentially inappropriate medication (PIMs) use as specified in the Beers Criteria, for older adults during emergency department (ED) visits in the United States., Methods: Using data from the National Hospital Ambulatory Care Survey (NHAMCS) we identified older adults (age 65 or older) discharged home from an ED visit in 2019. We defined PIMs as those with an 'avoid' recommendation under the American Geriatrics Society (AGS) 2019 Beers Criteria in older adults. Logistic regression models were used to assess demographic, clinical, and hospital factors associated with the use of any PIMs upon ED discharge., Results: Overall, 5.9% of visits by older adults discharged from the ED included administration or prescriptions for PIMs. Among those who received any PIMs, 25.5% received benzodiazepines, 42.5 % received anticholinergics, 1.4% received nonbenzodiazepine hypnotics, and 0.5% received barbiturates. A multivariable model showed statistically significant associations for age 65 to 74 (OR 1.91, 95% CI 1.39-2.62 vs. age >=75), dementia (OR 0.45, 95% CI 0.21-0.95), lower immediacy (OR 2.45, 95% CI 1.56-3.84 vs. higher immediacy), and Northeastern rural region (OR 0.34, 95% CI 0.21-0.55 vs. Midwestern rural)., Conclusion: We found that younger age and lower immediacy were associated with increased prescriptions of PIMs for older adults seen, while dementia and Northeastern rural region was associated with reduced use of PIMs seen and discharged from EDs in United States., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: It was previously estimated that 1814 (1.6 % of incident cancers) were attributable to physical inactivity in Australia in 2010, when only three sites were considered. We estimated the burden of cancer due to physical inactivity in Australia for 13 sites., Design: The population attributable fraction estimated site-specific cancer cases attributable to physical inactivity for 13 cancers. The potential impact fraction was used to estimate cancers that could have been prevented in 2015 if Australian adults had increased their physical activity by a modest amount in 2004-05., Methods: We used 2004-05 national physical activity prevalence data, 2015 national cancer incidence data, and contemporary relative-risk estimates for physical inactivity and cancer. We assumed a 10-year latency period., Results: An estimated 6361 of the cancers observed in 2015 were attributable to physical inactivity, representing 4.8 % of all cancers diagnosed. If Australian adults had increased their physical activity by one category in 2004-05, 2564 cases (1.9 % of all cancers) could have been prevented in 2015., Conclusions: More than three times as many cancers are attributable to physical inactivity than previously reported. Physical activity promotion should be a central component of cancer prevention programmes in Australia., Competing Interests: Declaration of interest statement None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cognitive rehabilitation is a complex and specialized area of practice, as it aims to support individuals with diverse neuropsychological profiles, personal characteristics, and intersectionalities in achieving meaningful, functional change in personally relevant aspects of their everyday lives. In many ways, cognitive rehabilitation is the epitome of a 'black box': it has complicated internal processes that are mysterious to users. We argue that this complex practice has suffered from a lack of specificity of clinical processes and treatment components, resulting in negative consequences for both providers and clients., Aim: To unpack the black box of cognitive rehabilitation by describing a unifying set of frameworks that can effectively direct clinical practice across clinical disciplines: the International Classification of Functioning, Disability, and Health (ICF), the Rehabilitation Treatment Specification System (RTSS), and the Planning, Implementation, and Evaluation framework (PIE). We present a clinical case that illustrates the application of the three frameworks., Conclusion: Implementation of these three integrated frameworks supports clinical reasoning, replication of treatments, and communication across disciplines with the ultimate impact of improving rehabilitation outcomes. The frameworks provide a structure for clinicians to clearly define both the what and the how of treatment, with a level of specificity to maximize both effectiveness and efficiency of intervention., (© 2022 Royal College of Speech and Language Therapists.)

Purpose: Developmental assessment is part of a comprehensive autism evaluation. During in-person evaluations, developmental assessment is completed via direct testing by an examiner. In telehealth evaluations, developmental assessment relies on caregiver-report instruments. This study examined correspondence between caregiver report and direct testing of developmental skills., Methods: Participants were 93 children, aged 18-42 months, undergoing evaluation for possible autism spectrum disorder (ASD). Caregivers were interviewed with the Developmental Profile, 4th edition (DP-4) via telehealth platform and children were tested in person 2-4 weeks later using the Mullen Scales of Early Learning (MSEL)., Results: Correlations between the DP-4 and MSEL were high (ranging from 0.50 to 0.82) across standard scores, age equivalents, and functional categories, as well as across individual subtests and overall composite scores., Conclusion: The high convergent validity found in this study suggests that the DP-4 provides a suitable proxy for direct developmental testing using the MSEL in the context of telehealth evaluations for ASD in young children, delivering a good estimate of both developmental functioning and presence of delays., Trial Registration: Data were obtained from registered clinical trial NCT05047224, date of registration 2021-09-07., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Accurate, patient-centred evaluation of physical function in patients with cancer can provide important information on the functional impacts experienced by patients both from the disease and its treatment. Increasingly, digital health technology is facilitating and providing new ways to measure symptoms and function. There is a need to characterise the longitudinal measurement characteristics of physical function assessments, including clinician-reported outcome, patient-reported ported outcome (PRO), performance outcome tests and wearable data, to inform regulatory and clinical decision-making in cancer clinical trials and oncology practice., Methods and Analysis: In this prospective study, we are enrolling 200 English-speaking and/or Spanish-speaking patients with breast cancer or lymphoma seen at Mayo Clinic or Yale University who will receive intravenous cytotoxic chemotherapy. Physical function assessments will be obtained longitudinally using multiple assessment modalities. Participants will be followed for 9 months using a patient-centred health data aggregating platform that consolidates study questionnaires, electronic health record data, and activity and sleep data from a wearable sensor. Data analysis will focus on understanding variability, sensitivity and meaningful changes across the included physical function assessments and evaluating their relationship to key clinical outcomes. Additionally, the feasibility of multimodal physical function data collection in real-world patients with breast cancer or lymphoma will be assessed, as will patient impressions of the usability and acceptability of the wearable sensor, data aggregation platform and PROs., Ethics and Dissemination: This study has received approval from IRBs at Mayo Clinic, Yale University and the US Food and Drug Administration. Results will be made available to participants, funders, the research community and the public., Trial Registration Number: NCT05214144; Pre-results., Competing Interests: Competing interests: GT has received research funding from the from the Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938) that directly supports this work. She also receives grant funding from the US National Cancer Institute (NCI) U01 Tolerability Consortium (U01CA 2330463), and the Mayo Clinic Center for Clinical and Translational Research (CTSA) (KL2TR 023794). CG has received research funding from the NCCN Foundation (Astra-Zeneca) and Genentech, as well as funding from Johnson and Johnson to help devise and implement new approaches to sharing clinical trial data. Over the past three years, MMJ reports grant funding from the US Food and Drug Administration, National Institutes on Drug Abuse, Centers for Disease Control and Prevention, Agency for Healthcare Research and Quality, American Cancer Society, and the National Center for Advancing Translational Sciences. JSR currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938), from the Medical Devices Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from Arnold Ventures for the Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT); in addition, Ross is an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen. JDR currently receives research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing and from the US Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938). SH has received consulting fees outside of this work from Janssen, Genentech, AbbVie, Flatiron Health, BeiGene, AstraZeneca, ADC Therapeutics, Epizyme, Merck, Seattle Genetics, TG Therapeutics, Tyme, Pharmacyclics, SeaGen, and Arvinas. Over the past three years, KR reports grant funding from the US Food and Drug Administration, National Institutes of Health, United States Department of Defense, and American Cancer Society. SS has received consulting fees from Eisai, Celgene, SeaGen, and Cardinal Health. She has previously received research funding to her institution from Genetech and Pfizer. All other authors have no relevant conflicts of interest to disclose., (© Where applicable, author(s) (or their employer(s)) 2024. Re-use permitted under [CC BY]. Published by BMJ.)

Introduction: Computed tomography (CT) scans are often used when cross-sectional imaging is required for evaluation of postappendectomy abscess, exposing children to a source of ionizing radiation. Our aim was to decrease the use of CT scans in pediatric postappendectomy patients by 50% in 12 mo and to sustain those results for 1 y., Methods: A comprehensive magnetic resonance imaging protocol was introduced in 2018 at a tertiary children's hospital within a general health system to replace CT scans in suspected pediatric postappendectomy abscess. Diagnostic and clinical outcomes were compared preprotocol (2015-2017) and postprotocol (2018-2022) implementation using standard univariate statistics. P < 0.05 was considered significant. Quality improvement methodology was used to design and implement the protocol., Results: Sixty eight pediatric postappendectomy patients received cross-sectional imaging during the study period. Overall, CT scans were used exclusively (100%, n = 27) in the preimplementation period compared to 31.7% (n = 13) of cross-sectional imaging in the postimplementation period. However, in the first year of protocol implementation, CT scan use only decreased to 78% of cross-sectional studies performed. The majority of protocol deviations (54%) also occurred in this time period. With improved education and reinforcement, CT scan utilization decreased to approximately 24% of cross-sectional studies annually. Missed abscess rate, time to diagnosis, drainage procedure type, readmission, and reoperation were similar between preimplementation and postimplementation periods., Conclusions: Implementation of a postappendectomy abscess magnetic resonance imaging protocol was associated with decreased CT utilization in the pediatric population, while maintaining comparable diagnostic evaluation and clinical outcomes. Adherence to quality improvement principles facilitated achieving goals and sustaining gains., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/aims: There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials., Methods: This study compared participants' demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials' using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance)., Results: The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial., Conclusion: Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Wallach reported receiving research support through the Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT) at Yale University from Arnold Ventures and through the Yale–Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938) and being supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award K01A A028258. Dr McCoy reported receiving support from the National Institute of Health National Institute of Diabetes and Digestive and Kidney Diseases (K23DK114497, R03 DK127010), the National Institute on Aging (R01AG 079113), and the Patient-Centered Outcomes Research Institute (DB-2020C2-20306). She also serves as a consultant to Emmi® (Wolters Kluwer) on developing patient education materials related to diabetes. Dr Dhruva reported being funded by the Department of Veterans Affairs, the National Evaluation System for Health Technology (NEST), and Arnold Ventures. Dr Herrin reported working under contract to the Centers for Medicare & Medicaid Services on the development and evaluations of measures of health care quality. Dr Noseworthy reported receiving personal fees from Optum during the conduct of the study. Dr Shah reported receiving support through the Mayo Clinic from the Food and Drug Administration to establish the Yale–Mayo Clinic CERSI program (U01FD005938); the Centers for Medicare & Medicaid Innovation under the Transforming Clinical Practice Initiative; the Agency for Healthcare Research and Quality (R01HS025164, R01HS025402, R03HS025517, and K12HS026379); the National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health (R56HL130496, R01HL131535, and R01HL151662); the National Science Foundation; and the Patient-Centered Outcomes Research Institute to develop a clinical data research network (LHSNet). Dr. Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from Arnold Ventures; in addition, Dr. Ross was an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. that was settled September 2022.

The Institute for In Vitro Sciences (IIVS) is sponsoring a series of workshops to develop recommendations for optimal scientific and technical approaches for conducting in vitro assays to assess potential toxicity within and across tobacco and various next-generation products (NGPs) including heated tobacco products (HTPs) and electronic nicotine delivery systems (ENDSs). This publication was developed by a working group of the workshop members in conjunction with the sixth workshop in that series entitled "Dosimetry for conducting in vitro evaluations" and focuses on aerosol dosimetry for aerosol exposure to combustible cigarettes, HTP, and ENDS aerosolized tobacco products and summarizes the key challenges as well as documenting areas for future research., (© 2022 JT International SA and The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Although there are a number of guidance documents and frameworks for evaluation of carcinogenicity, none of the current methods fully reflects the state of the science. Common limitations include the absence of dose-response assessment and not considering the impact of differing exposure patterns (e.g., intermittent, high peaks vs. lower, continuous exposures). To address these issues, we have developed a framework for risk assessment of dietary carcinogens. This framework includes an enhanced approach for weight of evidence (WOE) evaluation for genetic toxicology data, with a focus on evaluating studies based on the most recent testing guidance to determine whether a chemical is a mutagen. Included alongside our framework is a discussion of resources for evaluating tissue dose and the temporal pattern of internal dose, taking into account the chemical's toxicokinetics. The framework then integrates the mode of action (MOA) and associated dose metric category with the exposure data to identify the appropriate approach(es) to low-dose extrapolation and level of concern associated with the exposure scenario. This framework provides risk managers with additional flexibility in risk management and risk communication options, beyond the binary choice of linear low-dose extrapolation vs. application of uncertainty factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Computed tomography scans have been used when cross-axial imaging is required to evaluate pediatric post-appendectomy abscesses. To reduce a source of radiation exposure, our institution converted to using contrast-enhanced magnetic resonance imaging to replace computed tomography scans in this clinical context. Our aim is to evaluate the performance of magnetic resonance imaging compared to computed tomography scans and associated clinical outcomes in this patient population., Methods: A contrast-enhanced comprehensive magnetic resonance imaging protocol was implemented to evaluate a post-appendectomy abscess in 2018. A retrospective chart review was performed from 2015 to 2022 for pediatric patients (<18 years old) with prior appendectomy and subsequent cross-sectional imaging to evaluate for an intraabdominal abscess. Patient characteristics and clinical parameters between the 2 modalities were abstracted and compared using standard univariate statistics., Results: There were a total of 72 post-appendectomy patients who received cross-axial imaging, which included 43 computed tomography scans and 29 magnetic resonance imaging during the study interval. Patient demographics were comparable between cohorts and rates of perforated appendicitis at the index operation (computed tomography: 79.1% vs magnetic resonance imaging: 86.2%). Missed abscess rate, abscess size, management technique, drainage culture results, readmission, and reoperation were similar between imaging modalities. Median request to scan time was longer for magnetic resonance imaging than computed tomography (191.5 vs 108 minutes, P = .04). The median duration of a comprehensive magnetic resonance imaging scan was 32 minutes (interquartile range 28-50.5 minutes)., Conclusion: Contrast-enhanced magnetic resonance imaging provides an alternative cross-sectional imaging modality to computed tomography scans to evaluate pediatric post-appendectomy abscesses., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To evaluate trends in emergency care sensitive conditions (ECSCs) from pre-COVID (March 2018-February 2020) through Omicron (December 2021-February 2022)., Methods: This cross-sectional analysis evaluated trends in ECSCs using claims (OptumLabs Data Warehouse) from commercial and Medicare Advantage enrollees. Emergency department (ED) visits for ECSCs (acute appendicitis, aortic aneurysm/dissection, cardiac arrest/severe arrhythmia, cerebral infarction, myocardial infarction, pulmonary embolism, opioid overdose, pre-eclampsia) were reported per 100,000 person months from March 2018 to February 2022 by pandemic wave. We calculated the percent change for each pandemic wave compared to the pre-pandemic period., Results: There were 10,268,554 ED visits (March 2018-February 2022). The greatest increases in ECSCs were seen for pulmonary embolism, cardiac arrest/severe arrhythmia, myocardial infarction, and pre-eclampsia. For commercial enrollees, pulmonary embolism visit rates increased 22.7% (95% confidence interval [CI], 18.6%-26.9%) during Waves 2-3, 37.2% (95% CI, 29.1%-45.8%] during Delta, and 27.9% (95% CI, 20.3%-36.1%) during Omicron, relative to pre-pandemic rates. Cardiac arrest/severe arrhythmia visit rates increased 4.0% (95% CI, 0.2%-8.0%) during Waves 2-3; myocardial infarction rates increased 4.9% (95% CI, 2.1%-7.8%) during Waves 2-3. Similar patterns were seen in Medicare Advantage enrollees. Pre-eclampsia visit rates among reproductive-age female enrollees increased 31.1% (95% CI, 20.9%-42.2%), 23.7% (95% CI, 7.5%,-42.3%), and 34.7% (95% CI, 16.8%-55.2%) during Waves 2-3, Delta, and Omicron, respectively. ED visits for other ECSCs declined or exhibited smaller increases., Conclusions: ED visit rates for acute cardiovascular conditions, pulmonary embolism and pre-eclampsia increased despite declines or stable rates for all-cause ED visits and ED visits for other conditions. Given the changing landscape of ECSCs, studies should identify drivers for these changes and interventions to mitigate them., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)