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Clustering functional data aims to identify unique functional patterns in the entire domain, but this can be challenging due to phase variability that distorts the observed patterns. Curve registration can be used to remove this variability, but determining the appropriate level of warping flexibility can be complicated. Curve registration also requires a target to which a functional object is aligned, typically the cross-sectional mean of functional objects within the same cluster. However, this mean is unknown prior to clustering. Furthermore, there is a trade-off between flexible warping and the number of resulting clusters. Removing more phase variability through curve registration can lead to fewer remaining variations in the functional data, resulting in a smaller number of clusters. Thus, the optimal number of clusters and warping flexibility cannot be uniquely identified. We propose to use external information to solve the identification issue. We define a cross validated Kullback-Leibler information criterion to select the number of clusters and the warping penalty. The criterion is derived from the predictive classification likelihood considering the joint distribution of both the functional data and external variable and penalizes the uncertainty in the cluster membership. We evaluate our method through simulation and apply it to electrocardiographic data collected in the Chronic Renal Insufficiency Cohort study. We identify two distinct clusters of electrocardiogram (ECG) profiles, with the second cluster exhibiting ST segment depression, an indication of cardiac ischemia, compared to the normal ECG profiles in the first cluster., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd.)

Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group and the Children's Oncology Group have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, the authors outline the proposed strategic approach of the Children's Oncology Group Soft Tissue Sarcoma Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement., (© 2024 American Cancer Society.)

Sparse data bias, where there is a lack of sufficient cases, is a common problem in data analysis, particularly when studying rare binary outcomes. Although a two-step meta-analysis approach may be used to lessen the bias by combining the summary statistics to increase the number of cases from multiple studies, this method does not completely eliminate bias in effect estimation. In this paper, we propose a one-shot distributed algorithm for estimating relative risk using a modified Poisson regression for binary data, named ODAP-B. We evaluate the performance of our method through both simulation studies and real-world case analyses of postacute sequelae of SARS-CoV-2 infection in children using data from 184 501 children across eight national academic medical centers. Compared with the meta-analysis method, our method provides closer estimates of the relative risk for all outcomes considered including syndromic and systemic outcomes. Our method is communication-efficient and privacy-preserving, requiring only aggregated data to obtain relatively unbiased effect estimates compared with two-step meta-analysis methods. Overall, ODAP-B is an effective distributed learning algorithm for Poisson regression to study rare binary outcomes. The method provides inference on adjusted relative risk with a robust variance estimator., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd.)

During the illustrious career of Martin C. Mihm Jr., MD, the diagnosis of melanoma underwent significant changes, to which he made many contributions. In early descriptions, melanomas were fungating tumor masses that were obviously malignant, and highly lethal. In seminal work by Dr. Mihm and his mentor, Wallace H. Clark, Jr., MD, the early phases of development of these neoplasms were recognized and distinguished from the more advanced disease. It was generally believed that the early stage of melanoma, termed radial growth phase (RGP) and characterized by absence of vertical growth phase (VGP) and by favorable microstaging attributes could be recognized, excised, and cured, thus preventing the development of advanced disease. However, strenuous efforts in this direction over several decades have resulted in little or no change in mortality, leading to the recognition that many of these neoplasms, at least, may not be true biological malignancies, and to the conclusion that overdiagnosis commonly occurs in this disease, which is defined as representing diagnosis as melanoma of a neoplasm that would not have had the capacity to cause death or symptoms in the lifetime of the host. Although there may be other subsets of neoplasms in this category, an important category of overdiagnosis in melanomas is concentrated in T1a melanomas that lack VGP. If these neoplasms can be recognized with sensitive and specific criteria, which may already be available, changes in terminology may be appropriate, recognizing that some of them may have low malignant potential, whereas others may have no capacity at all for metastasis and may not warrant the use of the term "melanoma.", (© 2024 The Author(s). Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM., Methods: Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM-derived cell lines. Validation was performed using multiplex immunofluorescence., Results: In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF-α levels. In vitro, MLiM cell lines released TNF-α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour-infiltrating lymphocytes., Conclusions: MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses., Highlights: Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen-type I levels. Melanoma liver metastases tumour cells secrete enhanced levels of TNF-α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes. Activation of CXCR4 promotes AKT and NF-κB signalling pathways to promote collagen-type I secretion in adjacent normal hepatocytes. Elevated collagen levels were associated with reduced tumour-infiltrating lymphocytes., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

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

Continuous pulse oximetry (cSpO 2 ) monitoring use outside established guidelines is common in children hospitalized with bronchiolitis. We analyzed clinicians' real-time rationale for continuous monitoring in stable children with bronchiolitis not requiring supplemental oxygen. Data for this study were collected as part a multicenter deimplementation trial for cSpO 2  in children hospitalized with bronchiolitis. We analyzed 371 clinician responses across 36 hospitals; 258 (70%) responses did not include a clinical reason for monitoring ("nonclinical"; e.g., respondent forgot to discontinue monitoring, did not know why the patient was monitored, or was following an order). The remaining 113 (30%) responses contained a clinical reason for monitoring ("clinical"; e.g., recently requiring oxygen, physical exam concerns, or concerns relating to patient condition or history). Strategies to reduce unnecessary monitoring should include changes in workflow to facilitate shared understanding of monitoring goals and timely discontinuation of monitoring., (© 2024 The Author(s). Journal of Hospital Medicine published by Wiley Periodicals LLC on behalf of Society of Hospital Medicine.)

Background: Large colon volvulus is a cause of colic in horses with high morbidity and mortality when not promptly treated. More treatment options are needed to improve the outcome of these cases by protecting against the damage caused by ischaemia and reperfusion injury., Objectives: To determine the effect of preconditioning with dexmedetomidine prior to induction of ischaemia-reperfusion (IR) injury in a large colon volvulus model in the horse., Study Design: Randomised blinded in vivo experiments., Methods: Horses received either a dexmedetomidine (DEX) or saline (CON) constant rate infusion (CRI) immediately following induction of anaesthesia. Venous, arterial, and transmural occlusion of a section of the large colon was performed for 3 h, after which the ligatures and clamps were removed to allow for reperfusion for 3 h. Biopsies of the large colon were taken at baseline, 1 and 3 h of ischaemia, and at 1 and 3 h of reperfusion., Results: The severity of crypt epithelial loss (DEX = 2.1 [0.8-2.8], CON = 3.1 [2.5-4], p = 0.03) and mucosal haemorrhage was decreased (DEX = 2.1 [1.3-3], CON = 3.5 [2.5-4], p = 0.03) in group DEX compared to group CON when graded on a scale of 0-4. Crypt length remained longer (DEX = 369.5 ± 91.7 μm, CON = 238.5 ± 72.6 μm, p = 0.02) and interstitium to crypt (I:C) ratio remained lower (DEX = 1.4 (1-1.7), CON = 2.6 [1.8-5.9], p = 0.03) in group DEX compared to group CON during reperfusion., Main Limitations: Clinical applicability of pharmacologic preconditioning is limited., Conclusion: Preconditioning with a dexmedetomidine CRI prior to IR injury demonstrated a protective effect histologically on the large colon in the horse. Further investigation into postconditioning with dexmedetomidine is warranted as a possible intervention in colic cases suspected of being large colon volvulus., (© 2024 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Small leucine-rich proteoglycans, such as decorin and biglycan, play pivotal roles in collagen fibrillogenesis during development, healing, and aging in tendon. Previous work has shown that the absence of decorin and biglycan affects fibril shape and mechanical properties during tendon healing. However, the roles of decorin and biglycan in the healing process of aged tendons are unclear. Therefore the objective of this study was to evaluate the differential roles of decorin and biglycan during healing of patellar tendon injury in aged mice. Aged (300 days old) female Dcn +/+ /Bgn +/+ control (WT, n = 52), Dcn flox/flox (I-Dcn -/- , n = 36), Bgn flox/flox (I-Bgn -/- , n = 36), and compound Dcn flox/flox /Bgn flox/flox (I-Dcn -/- /Bgn -/- , n = 36) mice with a tamoxifen-inducible Cre were utilized. Targeted gene expression, collagen fibril diameter distributions, mechanical properties, and histological assays were employed to assess the effects of knockdown of decorin and/or biglycan at the time of injury. Knockdown resulted in alterations in fibril diameter distribution and scar area, but surprisingly did not lead to many differences in mechanical properties. Biglycan played a larger role in early healing stages, while decorin is more significant in later stages, particularly in scar remodeling. This study highlights some of the differential roles of biglycan and decorin in the regulation of fibril structure and scar area, as well as influencing gene expression during healing in aged mice., (© 2024 The Author(s). Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Objective: To compare, using state-of-the-art psychophysical tests, the olfactory function of patients complaining and not complaining of olfactory hypersensitivity., Study Design: Retrospective cross-sectional., Setting: The Smell and Taste Center at the University of Pennsylvania., Methods: University of Pennsylvania Smell Identification Test (UPSIT) scores were obtained from 148 patients complaining of hyperosmia and 494 patients with no such complaints; detection threshold test scores were obtained from 77 and 483 patients of these respective groups. The effects of subject group, age, and sex on the test scores were assessed using analyses of variance. Categorical variables were evaluated by χ 2 . Responses to items within a detailed intake questionnaire, for example, the Beck Depression Inventory (BDI-II), were also evaluated., Results: Unexpectedly, those complaining of hyperosmia had lower olfactory test scores than those with no such complaints (respective UPSIT means [95% confidence interval [CIs]] = 27.86 (26.85, 28.87) and 32.19 (31.67, 32.71); P < .001; respective threshold means (log vol/vol) = -4.49 (-4.89, -4.09) and -5.22 (-5.36, -5.06); P < .001). Remarkably, 70.95% of the self-identified hyperosmics exhibited mild to severe microsmia. The hyposmia complainers also exhibited elevated BDI scores (11.02 [9.53, 12.51] vs 7.58 [6.80, 8.34])., Conclusion: When objectively tested, many patients who complain of hypersensitivity to odors are actually less sensitive to them. The basis of this phenomenon is unclear. It could reflect the presence of emotionally disturbing altered smell sensations, or one or more comorbidities, such as hypochondria or osmophobia. These findings point to the importance of objective testing of persons with complaints of chemosensory dysfunction and reiterate the inaccuracy of self-reports., (© 2024 The Author(s). Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objective: Many guidelines recommend limiting glucocorticoids in patients with rheumatoid arthritis (RA), but 40% of patients remain on glucocorticoids long term. We evaluated the cardiovascular risk of long-term glucocorticoid prescription by studying patients on stable disease-modifying antirheumatic drugs (DMARDs)., Methods: Using two claims databases, we identified patients with RA on stable DMARD therapy for >180 days. Proportional hazards models with inverse-probability weights and clustering to account for multiple observations were used to estimate the effect of glucocorticoid dose on composite cardiovascular outcomes (stroke or myocardial infarction [MI])., Results: There were 135,583 patients in Medicare and 39,272 in Optum's de-identified Clinformatics Data Mart (CDM) database. Medicare and CDM patients had an incidence of 1.3 and 0.8 composite cardiovascular outcomes per 100 person-years, respectively. In the older, comorbid Medicare cohort, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes in adjusted models with predicted one-year incidence of 1.4% (95% confidence interval [CI] 1.2%-1.6%) for ≤5 mg, 1.6% (95% CI 1.4%-1.9%) for >5 to 10 mg, and 1.8% (95% CI 1.2%-2.5%) for >10 mg versus 1.1% (95% CI 1.1%-1.2%) among patients not receiving glucocorticoids. There was no significant association among the CDM cohort. However, in the subgroup of younger patients with RA and higher cardiovascular risk, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes., Conclusion: Among older patients with more comorbidities and younger patients with higher cardiovascular risk with RA on stable DMARD therapy, glucocorticoids were associated with a dose-dependent increased risk of MI and stroke, even at doses ≤5 mg/day. By contrast, no association was noted among younger, healthier patients with RA., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To evaluate whether postoperative radiotherapy (PORT) improves survival among patients who received maxillectomy for pT4aN0 maxillary gingival or hard palate squamous cell carcinoma (SCC) with respect to tumor size., Study Design: Retrospective analysis., Setting: National Cancer Database from 2004 to 2019., Methods: Included adult patients who received maxillectomy (partial, subtotal, or total) and neck dissection for treatment-naive margin negative pT4aN0 SCC of the maxillary gingiva or hard palate. Adjusted for age, gender, race, insurance status, income, education, urban/rural, facility type, region, comorbidity index, tumor grade, and tumor extension. Inverse probability weights were incorporated into a multivariable Cox proportional hazards model. A priori post hoc subgroup analysis was performed according to tumor size., Results: We included 416 patients who underwent maxillectomy for pT4aN0 SCC of the maxillary gingiva or hard palate (mean [standard deviation] age, 71.5 [11.3] years; male, 190 [45.7%]; tumor size 2 cm, 362 [87%]). Overall, 49.3% of patients received PORT (205 patients). PORT was associated with a 50% improvement in survival compared to surgery alone (adjusted hazard ratio [aHR], 0.50; 95% confidence interval [95% CI], 0.32-0.81). On subgroup analysis, PORT was associated with improved survival for tumors 2 cm (aHR, 0.47; 95% CI, 0.29-0.77), but not for tumors < 2 cm (aHR, 1.15; 95% CI, 0.33-4.08)., Conclusion: The vast majority of patients with pT4aN0 bone-invading SCC of the maxillary gingiva and hard palate benefit from PORT. Patients with tumors < 2 cm did not demonstrate a survival benefit from adjuvant treatment, suggesting that bony invasion alone may not be sufficient criteria for treatment escalation., (© 2024 The Author(s). Otolaryngology‐Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology‐Head and Neck Surgery Foundation.)

Background: Emergency physicians care for most children presenting to U.S. emergency departments (EDs). Pediatric exposure during emergency medicine (EM) residency can be variable and critically ill children are rarely encountered. A recent needs assessment revealed that emergency physicians feel less prepared to manage various conditions in children and that infants, regardless of presenting complaint, pose particular challenges. Emergency physician perceptions of the experience of caring for pediatric patients have not been widely examined through a qualitative lens., Methods: We designed an interview-based qualitative study to explore emergency physician perspectives on pediatric patient care. We recruited emergency physicians who graduated from residency in 2015-2019 and all rotated through the same large tertiary children's hospital. Four trained interviewers conducted in-depth, one-on-one virtual interviews. An interdisciplinary team transcribed and then coded the interviews. The team performed a conventional content analysis for themes. Recruitment continued until thematic saturation was achieved., Results: Twelve participants completed interviews. These participants trained in five diverse residency programs. Likewise, the participants now practice in a variety of settings. Three major themes emerged from the data: (1) experience and exposure are key to establishing comfort caring for children; (2) simulation, pathways, and the pediatric anesthesia rotation are educationally useful; and (3) caring for children poses unique emotional challenges. Participants shared many recommendations for future pediatric education for EM trainees, including increasing autonomy and exposure to neonates and considering how care might differ in a community setting., Conclusions: This interview-based qualitative study elucidates key themes in recently graduated emergency physicians' perceived experience of caring for children. Our findings have important educational implications for this group of emergency physicians and those who share similar experiences in training and practice., Competing Interests: The authors declare no conflicts of interest., (© 2024 Society for Academic Emergency Medicine.)

Airway clearance therapies (ACT) are often used to optimize respiratory function for children with neurologic impairment (CNI) hospitalized with acute respiratory infections (ARI). In a five-center retrospective cohort study of CNI aged 1-18 years hospitalized between 2013 and 2015 with ARI, we assessed the association of admission ACT with hospital outcomes (days to return to baseline respiratory support and length of stay [LOS]). Generalized estimated equation (GEE) models examined the association between ACT and outcomes, while accounting for clustering. Propensity scores estimating the likelihood of receiving ACT were included in the GEE models as inverse probability of treatment weights to account for confounding. In adjusted analyses, children receiving admission ACT required similar time to return to respiratory baseline (adjusted risk ratio [aRR] 1.24, 95%CI: 0.95,1.62) and had similar LOS (aRR 1.08, 95%CI: 0.88,1.32) compared with children not receiving ACT. Future studies should seek to identify subpopulations of CNI who benefit most from ACT., (© 2024 Society of Hospital Medicine.)

Some genetic counselors (GCs) may find theories, models, and frameworks (TMFs) useful in clinical skills selection and when reflecting on or evaluating genetic counseling practice. This paper aims to demonstrate how TMFs can be used to postulate how different skills may impact patients'/clients' decisions, behaviors, and outcomes and consider how multiple TMFs can inform the use of various skills or strategies to achieve different goals. Additionally, we provide examples of TMFs that may help GCs in nonclinical aspects of their work, such as implementing and evaluating new interventions or service delivery models. To guide the selection of appropriate TMFs, we provide a set of questions to consider and include examples of skills and approaches that align with different TMFs. While TMFs provide a structured approach and valuable guidance that may help advance genetic counseling practice, they have certain limitations. Additional research is necessary to determine the effectiveness of using TMFs to guide clinical practice and improve patient/client outcomes., (© 2024 National Society of Genetic Counselors.)

Objectives: We used Cluster Analysis of Migraine-associated Symptoms (CAMS) to critically evaluate current International Classification of Headache Disorders-Third Edition (ICHD-3) migraine-associated symptoms criteria., Background: Diagnostic criteria play a central role in guiding clinical trial inclusion, and therefore available treatments. Migraine and tension-type headaches (TTH) are differentiated in ICHD-3 by many headache characteristics, including associated symptoms. A diagnosis of probable migraine indicates some but not all features of migraine are met. Photophobia and phonophobia, or nausea and/or vomiting, are required to meet a diagnosis of migraine; however, CAMS-a model that describes associated symptoms across youth with headache-indicates that a broader range of symptoms contain information about migraine burden., Methods: In this multisite retrospective cross-sectional study, we evaluated ICHD-3 migraine criteria. Youth aged 6-17 years with migraine (including probable migraine) or TTH were included in the analysis. We used CAMS to evaluate the migraine-associated symptom criterion. With CAMS as a guide, we evaluated how changes to the migraine-associated symptom criterion altered who met the diagnosis of migraine., Results: Of the 9017 participants included in this study, 66.7% were female and had a median (interquartile range) age of 13 (10-15) years. Most participants had migraine or probable migraine (99.0%), and the remainder had TTH (1.0%). A sizable percentage (10.1%) of youth under the umbrella diagnosis of migraine were diagnosed with probable migraine because they did not meet migraine-associated symptom criterion D; however, many in this group reported several non-ICHD migraine-associated symptoms. We explored alterations to criterion D based on CAMS. Allowing for photophobia or phonophobia re-categorized 55.6% of youth as having migraine, though some only had one symptom. Including lightheadedness or lightheadedness and spinning re-categorized 19.7% and 25.8% of youth with migraine, respectively, but all of those who were re-categorized had at least two migraine-associated symptoms., Conclusion: The ICHD-3 captures the most prevalent migraine-associated symptoms; however, many youths with probable migraine who do not meet full criteria due to insufficient associated symptoms nonetheless experience multiple non-ICHD migraine-associated symptoms. Changes to criterion D should be considered for the ICHD-4., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: To conduct a retrospective cross-sectional multicenter study to validate the relationships between migraine-associated symptoms., Background: Symptoms associated with headache-photophobia and phonophobia, nausea, and/or vomiting-are required criteria for migraine diagnosis based on the International Classification of Headache Disorders-Third Edition (ICHD-3). However, individuals with migraine report high rates of other symptoms (e.g., lightheadedness, difficulty thinking). We recently completed a single-center study assessing the relationships between an expanded set of migraine-associated symptoms., Methods: A pre-registered cross-sectional multicenter retrospective analysis was conducted on standardized questionnaire data of youth ages 6-17 years from two headache registries at pediatric tertiary care centers. Cluster Analysis of Migraine-associated Symptoms (CAMS) was implemented to assess associations between 11 migraine-associated symptoms. We explored differences between the two centers, and how CAMS was associated with demographics, including sex and age, and headache burden., Results: There were 10,721 participants who were 66.5% female and had a median (interquartile range) age of 13 (10-15) years. The first three CAMS dimensions accounted for 46.5% of the variance and were consistent across sites. The first dimension indicated those reporting any migraine-associated symptoms were likely to report multiple. The second dimension separated symptoms into those included in ICHD-3 migraine diagnostic criteria and non-ICHD symptoms (e.g., lightheadedness, difficulty thinking). The third dimension separated sensory hypersensitivity and vestibular symptoms. An abundance of migraine-associated symptoms correlated with greater headache severity (Spearman's ρ = 0.18, 95% confidence interval [CI] 0.17-0.20; small effect size) and disability (ρ = 0.26, 95% CI 0.25-0.28; small effect size). We also observed differences in associated symptoms across age and sex., Discussion: Associations between an expanded set of migraine-associated symptoms are informative for headache burden and reveal intriguing changes across child development and sex. We were able to replicate findings across two centers, indicating that these symptom clusters are inherent to migraine., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Introduction: Precision Health (PH) holds the promise of revolutionizing healthcare by enabling personalized disease prevention and management through the integration of genomic data, lifestyle factors, environmental influences, and other social determinants of health (SDoH). However, the absence of a baseline assessment of knowledge, skills, and attitudes (KSAs) of practicing nurses' capacity for PH hinders its integration. The purpose of this study is to determine the capacity of practicing Registered Nurses (RNs) for PH across the United States and to assess the validity and reliability of a tool designed for this use-the Precision Health Nurse Capacity Scale (PHNCS)., Design/method: A descriptive exploratory study was conducted to evaluate the capacity of practicing RNs for this evolving phenomenon, PH, using a convenience sample. The survey was sent via email and made available to all members of the American Nurses Association (ANA) who work in a variety of practice environments. The ANA represents the over 4 million nurses practicing in the United States., Results: The majority of nurse respondents felt it is important for nurses to become more educated about all aspects of PH including SDoH but they lack confidence in the integration of PH. The PHNCS was found to be a valid and reliable tool in measuring the capacity of nurses to practice PH., Conclusion: The incorporation of PH into nursing practice suffers an immediate impediment: the lack of know-how of the US nursing workforce. This inaugural data on KSAs for PH establishes a logical baseline from which the requisite education and training should commence., Clinical Relevance: Precision Health is an emerging healthcare approach in the United States and globally. Enabling it will require a nursing workforce prepared with the requisite KSAs. Determining the capacity of the nursing workforce is a foundational step to begin this process., (© 2024 Sigma Theta Tau International.)

Fanconi anemia (FA) is generally classified as a DNA repair disorder, conferring a genetic predisposition to cancer and prominent bone marrow failure (BMF) in early childhood. Corroborative human and murine studies point to a fetal origin of hematopoietic stem cell (HSC) attrition under replicative stress. Along with intriguing recent insights into non-canonical roles and domain-specific functions of FA proteins, these studies have raised the possibility of a DNA repair-independent BMF etiology. However, deeper mechanistic insight is critical as current curative options of allogeneic stem cell transplantation and emerging gene therapy have limited eligibility, carry significant side effects, and involve complex procedures restricted to resource-rich environments. To develop rational and broadly accessible therapies for FA patients, the field will need more faithful disease models that overcome the scarcity of patient samples, leverage technological advances, and adopt investigational clinical trial designs tailored for rare diseases., (© 2024 Wiley Periodicals LLC.)

Objective: Surgical resection is associated with higher overall survival (OS) than definitive radiotherapy (RT) or chemoradiotherapy (CRT) in cT4b sinonasal squamous cell carcinoma (SCC). Our study investigates the survival benefit of surgical resection in cT4b sinonasal non-SCC., Methods: The 2004 to 2019 National Cancer Database was queried for patients with cT4b sinonasal non-SCC undergoing definitive treatment with (1) surgical resection + additional therapy (RT, chemotherapy, or both), (2) RT alone, or (3) CRT. Surgical resection + additional therapy and definitive RT/CRT were compared with Kaplan-Meier and multivariable Cox regression models., Results: Of 629 patients satisfying inclusion criteria, 513 (81.6%) underwent surgical resection + additional therapy and 116 (18.4%) underwent definitive RT/CRT. The most frequent histologic types were undifferentiated carcinoma (23.7%), adenoid cystic carcinoma (22.6%), and adenocarcinoma (20.7%). Few patients presented with clinical nodal metastasis (15.7%). There were 4 (0.8%) mortalities within 90 days of surgical resection. Patients undergoing surgical resection with positive surgical margins had higher 5-year OS than those undergoing definitive RT/CRT (56.3% vs. 39.4%, p  = .039) and similar 5-year OS as those with negative margins (56.3% vs. 63.9%, p  = .059). Patients undergoing neoadjuvant chemotherapy had similar 5-year OS as those undergoing definitive RT/CRT (60.9% vs. 39.5%, p  = .053). Age at diagnosis, tumor diameter, and surgical resection + additional therapy (aHR 0.64, 95% CI 0.45-0.91) were associated with OS ( p  < .05)., Conclusion: Surgical resection + additional therapy was associated with higher OS than definitive RT/CRT in cT4b sinonasal non-SCC. Surgical resection may benefit select patient with cT4b sinonasal non-SCC., Level of Evidence: 4., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

LGBTQ+ individuals face discrimination in healthcare settings. Magnet hospitals have been associated with positive patient outcomes, yet it remains uncertain whether Magnet designation is associated with hospitals' LGBTQ+ inclusivity in policies and practices. This study examined 801 American hospitals across 47 states that participated in the Healthcare Equality Index (HEI) in 2021. Multilevel modeling was utilized to investigate the association between Magnet status and HEI scores, adjusting for hospital type and state-level covariates, including LGBTQ+ inclusiveness in laws, political climate, racial/ethnic minority population, and Medicaid expansion status. Among the 801 hospitals, 32.1% (257 hospitals) held Magnet status. Magnet hospitals demonstrated higher HEI scores compared to non-Magnet hospitals (γ = 2.13, p = 0.022), despite significant variations across states (intraclass correlation = 0.22). No significant cross-level interactions were found. Overall, Magnet designation is independently associated with improved LGBTQ+ inclusivity in hospitals regardless of the state in which the hospital is located. Policymakers and healthcare leaders should consider leveraging the Magnet Recognition Program as a benchmark for promoting LGBTQ+ inclusivity within hospitals. Additionally, all healthcare institutions should prioritize comprehensive evaluations and improvements to their policies and practices to ensure inclusivity for LGBTQ+ patients., (© 2024 The Author(s). Research in Nursing & Health published by Wiley Periodicals LLC.)

Caregivers who interact with children at home can provide a critical, complementary perspective on a child's behaviour functioning. This research used a parent-administered measure of problem behaviours to study perceptions of child behaviours across home situations. We applied latent profile analysis to identify subgroups of children with common behavioural tendencies in a nationally representative sample (N = 709) of 4- to 13-year-old children in Trinidad and Tobago. This study (a) identified latent profiles of children's over- and underactive behaviour problems in varied home settings and (b) examined how profile membership predicted academic skills and teacher-observed problem behaviours. The best-fitting four-profile model included one profile of adjusted behaviours (56%), one of the elevated attention-seeking behaviours (21%), a profile featuring withdrawn and disengaged behaviours (15%) and a relatively rare profile emphasising aggressive behaviours (8%). Children classified in the last profile displayed the poorest academic outcomes and the highest levels of teacher-observed behaviour problems., (© 2024 The Author(s). International Journal of Psychology published by John Wiley & Sons Ltd on behalf of International Union of Psychological Science.)

We report five cases of spider angiomas in children treated topically with timolol 0.5% (ophthalmic solution or gel-forming solution), for 6 months. Parents and patients were advised to apply one drop twice daily. Four of them showed either partial (2) or complete response (2) and only one patient had no clinical change. No adverse effects were reported. This pilot case series shows that topical timolol may prove useful as a noninvasive, available and well-tolerated treatment option for spider angiomas in children who seek a treatment alternative to pulsed dye laser., (© 2024 Wiley Periodicals LLC.)

Methadone has a high potential for risky drug-drug interactions that can lead to opioid overdose, yet evidence on the magnitude of this risk remains limited. Since methadone is transported via P-glycoprotein (P-gp), the use of statins that inhibit P-gp may elevate methadone plasma concentrations, potentially leading to opioid overdose. We explored this hypothesis by examining whether concomitant use of methadone and P-gp-inhibiting statins was associated with opioid overdose. Using Medicaid claims data from 2003 to 2020, we conducted a cohort study among new concomitant users of methadone and statins. We compared overdose rates among individuals exposed to P-gp-inhibiting statins (simvastatin, atorvastatin, or lovastatin) vs. those exposed to rosuvastatin (negative control), adjusting for baseline covariates. We identified 69,263 individuals newly exposed to methadone and a statin of interest; the overall incidence rate of opioid overdose was 26.0 per 1,000 person-years. Adjusted hazard ratios (HRs) for methadone + P-gp-inhibiting statins consistently showed no association, ranging from 0.76 (95% CI = 0.48-1.22) for atorvastatin to 0.78 (95% CI = 0.50-1.22) for simvastatin, compared with methadone + rosuvastatin. Similar results were observed in sensitivity analysis that treated all P-gp-inhibiting statins as a single exposure group, as well as analyses stratified by baseline diagnosis of opioid use disorder or overdose, the duration of baseline methadone use, and calendar year intervals. Our findings suggest that concomitant use of methadone with simvastatin, atorvastatin, or lovastatin is not associated with the risk of opioid overdose compared to concomitant use of methadone and rosuvastatin., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Patients with systemic lupus erythematosus (SLE) were excluded from sodium-glucose co-transporter 2 inhibitors (SGLT2i) clinical trials. It is unknown whether the cardiorenal benefits of SGLT2i extend to patients with SLE and comorbid type 2 diabetes (T2D)., Methods: We performed an emulated clinical trial in an insurance-based cohort in the U.S., evaluating SGLT2i versus dipeptidyl peptidase 4 inhibitors (DPP4i) for primary prevention of cardiovascular, renal, and other clinical outcomes among patients with both SLE patients and comorbid T2D. SGLT2i initiators were matched to DPP4i initiators using propensity scores (PS) based on clinical and demographic factors. Hazard ratios (HR with 95% confidence intervals) were calculated using Cox models., Results: Outcomes among 2,165 patients starting SGLT2i and 2,165 PS-matched patients starting DPP4i were compared. Over 753.1 (±479.2) mean days, SGLT2i recipients had significantly lower risks of incident acute kidney injury (HR 0.49, 95% CI 0.39-0.63), chronic kidney disease (HR 0.61, 0.50-0.76), end-stage renal disease (HR 0.40, 0.20-0.80), heart failure (HR 0.72, 0.56-0.92), and emergency department visits (HR 0.90, 0.82-0.99). Risks of all-cause mortality (HR 0.89, 0.65-1.21), lupus nephritis (HR 0.67, 0.38-1.15), myocardial infarction (HR 0.81, 0.54-1.23), stroke (HR 1.03, 0.74-1.44), and hospitalizations (HR 0.76, 0.51-1.12) did not differ. Genital infection risk (HR 1.31, 1.07-1.61) was increased, but urinary tract infection risk (HR 0.90, 0.79-1.03) did not differ. No significant difference was observed for diabetic ketoacidosis risk (HR 1.065, 0.53-2.14) and fractures (HR 0.95, 0.66-1.36)., Conclusions: In this emulated clinical trial, SGLT2i vs. DPP4i use was associated with significantly reduced risks of several cardiorenal complications among patients with both SLE and T2D., (This article is protected by copyright. All rights reserved.)

Purpose: We determined if metabolic syndrome, its components, and adipokines (adiponectin, leptin, Fibroblast Growth Factor-21) were associated with response to advanced therapies among patients with rheumatoid arthritis (RA)., Methods: This study included participants with RA initiating either TNFi or non-TNFi biologic therapies from the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) cohort within the CorEvitas registry. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III definition. Adipokines were assessed on stored samples from a sub-sample of responders and non-responders (N=200). The primary outcome was the achievement of a change as large as the minimal clinically important difference (MCID) for the Clinical Disease Activity Index (CDAI) at 6 months., Results: Among 2,368 participants, 687 (29%) had metabolic syndrome. Metabolic syndrome was associated with lower odds of achieving CDAI MCID [OR (95% CI): 0.69 (0.56,0.86) p=0.001] with a dose-dependent decrease in response rate according to the number of components present. Model fit was superior for metabolic syndrome compared to BMI. Associations between metabolic syndrome and MCID achievement were similar between patients receiving TNFi [OR (95% CI): 0.65 (0.49,0.87) p=0.003] v. non-TNF therapies [OR (95% CI): 0.76 (0.55,1.04) p=0.08)] (p-for-interaction=0.49). Adipokines were not associated with MCID achievement., Conclusions: Metabolic syndrome is associated with lower response rates with the initiation of an advanced therapy in RA, with similar effects for both TNFi and non-TNFi agents. Adipokines were strongly associated with metabolic syndrome but were not associated with clinical response., (This article is protected by copyright. All rights reserved.)

Background: Age-related macular degeneration (AMD) is a retinal disorder characterized by central retinal (macular) damage. Approximately 10% to 20% of non-exudative AMD cases progress to the exudative form, which may result in rapid deterioration of central vision. Individuals with exudative AMD (eAMD) need prompt consultation with retinal specialists to minimize the risk and extent of vision loss. Traditional methods of diagnosing ophthalmic disease rely on clinical evaluation and multiple imaging techniques, which can be resource-consuming. Tests leveraging artificial intelligence (AI) hold the promise of automatically identifying and categorizing pathological features, enabling the timely diagnosis and treatment of eAMD., Objectives: To determine the diagnostic accuracy of artificial intelligence (AI) as a triaging tool for exudative age-related macular degeneration (eAMD)., Search Methods: We searched CENTRAL, MEDLINE, Embase, three clinical trials registries, and Data Archiving and Networked Services (DANS) for gray literature. We did not restrict searches by language or publication date. The date of the last search was April 2024., Selection Criteria: Included studies compared the test performance of algorithms with that of human readers to detect eAMD on retinal images collected from people with AMD who were evaluated at eye clinics in community or academic medical centers, and who were not receiving treatment for eAMD when the images were taken. We included algorithms that were either internally or externally validated or both., Data Collection and Analysis: Pairs of review authors independently extracted data and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool with revised signaling questions. For studies that reported more than one set of performance results, we extracted only one set of diagnostic accuracy data per study based on the last development stage or the optimal algorithm as indicated by the study authors. For two-class algorithms, we collected data from the 2x2 table whenever feasible. For multi-class algorithms, we first consolidated data from all classes other than eAMD before constructing the corresponding 2x2 tables. Assuming a common positivity threshold applied by the included studies, we chose random-effects, bivariate logistic models to estimate summary sensitivity and specificity as the primary performance metrics., Main Results: We identified 36 eligible studies that reported 40 sets of algorithm performance data, encompassing over 16,000 participants and 62,000 images. We included 28 studies (78%) that reported 31 algorithms with performance data in the meta-analysis. The remaining nine studies (25%) reported eight algorithms that lacked usable performance data; we reported them in the qualitative synthesis. Study characteristics and risk of bias Most studies were conducted in Asia, followed by Europe, the USA, and collaborative efforts spanning multiple countries. Most studies identified study participants from the hospital setting, while others used retinal images from public repositories; a few studies did not specify image sources. Based on four of the 36 studies reporting demographic information, the age of the study participants ranged from 62 to 82 years. The included algorithms used various retinal image types as model input, such as optical coherence tomography (OCT) images (N = 15), fundus images (N = 6), and multi-modal imaging (N = 7). The predominant core method used was deep neural networks. All studies that reported externally validated algorithms were at high risk of bias mainly due to potential selection bias from either a two-gate design or the inappropriate exclusion of potentially eligible retinal images (or participants). Findings Only three of the 40 included algorithms were externally validated (7.5%, 3/40). The summary sensitivity and specificity were 0.94 (95% confidence interval (CI) 0.90 to 0.97) and 0.99 (95% CI 0.76 to 1.00), respectively, when compared to human graders (3 studies; 27,872 images; low-certainty evidence). The prevalence of images with eAMD ranged from 0.3% to 49%. Twenty-eight algorithms were reportedly either internally validated (20%, 8/40) or tested on a development set (50%, 20/40); the pooled sensitivity and specificity were 0.93 (95% CI 0.89 to 0.96) and 0.96 (95% CI 0.94 to 0.98), respectively, when compared to human graders (28 studies; 33,409 images; low-certainty evidence). We did not identify significant sources of heterogeneity among these 28 algorithms. Although algorithms using OCT images appeared more homogeneous and had the highest summary specificity (0.97, 95% CI 0.93 to 0.98), they were not superior to algorithms using fundus images alone (0.94, 95% CI 0.89 to 0.97) or multimodal imaging (0.96, 95% CI 0.88 to 0.99; P for meta-regression = 0.239). The median prevalence of images with eAMD was 30% (interquartile range [IQR] 22% to 39%). We did not include eight studies that described nine algorithms (one study reported two sets of algorithm results) to distinguish eAMD from normal images, images of other AMD, or other non-AMD retinal lesions in the meta-analysis. Five of these algorithms were generally based on smaller datasets (range 21 to 218 participants per study) yet with a higher prevalence of eAMD images (range 33% to 66%). Relative to human graders, the reported sensitivity in these studies ranged from 0.95 and 0.97, while the specificity ranged from 0.94 to 0.99. Similarly, using small datasets (range 46 to 106), an additional four algorithms for detecting eAMD from other retinal lesions showed high sensitivity (range 0.96 to 1.00) and specificity (range 0.77 to 1.00)., Authors' Conclusions: Low- to very low-certainty evidence suggests that an algorithm-based test may correctly identify most individuals with eAMD without increasing unnecessary referrals (false positives) in either the primary or the specialty care settings. There were significant concerns for applying the review findings due to variations in the eAMD prevalence in the included studies. In addition, among the included algorithm-based tests, diagnostic accuracy estimates were at risk of bias due to study participants not reflecting real-world characteristics, inadequate model validation, and the likelihood of selective results reporting. Limited quality and quantity of externally validated algorithms highlighted the need for high-certainty evidence. This evidence will require a standardized definition for eAMD on different imaging modalities and external validation of the algorithm to assess generalizability., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Therapeutic exercise has not been widely adopted in pediatric pulmonary hypertension (PH), despite adult data supporting its safety and efficacy. While physical limitations may prevent children with PH from participating in physical activity, other barriers to and facilitators of physical activity are unknown. Youth ages 8-18 years with World Symposium of PH diagnostic Groups 1-4, functional class I or II, and ambulatory status were prospectively enrolled in a cross-sectional study including separate 30-min participant and caregiver interviews regarding attitudes toward physical activity and a proposed exercise intervention in pediatric PH. Interview questions were guided by Social Cognitive Theory and explored autonomy, self-confidence, and self-efficacy. Interviews were transcribed, coded, and analyzed using an iterative process to determine themes and patterns. Demographics and relevant PH condition-specific data were abstracted from the medical record. Thirty PH participant/caregiver dyads were interviewed. Facilitators of physical activity included enjoyment/interest in the activity, socialization, incentivization, and feelings of safety and normalcy. Barriers to physical activity included lack of interest, fear/anxiety, and self-consciousness. Findings were similar in children and adults. Participants rarely reported restriction of activity by caregivers or medical providers. Attitudes toward engagement in a proposed exercise program were generally positive and reflected personal experiences with physical activity. Monitored exercise interventions that focus on patients' interests, cultivate confidence, respect limitations, and acknowledge the need for extrinsic incentivization may have benefits in pediatric PH. Future trials should test the impact of these characteristics on patient wellbeing and clinical outcomes., Competing Interests: The Authors declare that there is no conflict of interest., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Objective: Toxic shock syndrome (TSS) is a rare but serious complication after sinonasal surgery and a commonly cited consideration for prescribing antibiotics when nasal packing or stents are placed. Most reports are limited to case reports or small series. The aim of this systematic review was to describe the incidence, risk factors, and clinical course of patients who developed TSS as a complication of endoscopic sinus surgery (ESS) and/or septoplasty., Data Sources: A systematic review was conducted using MEDLINE, EMBASE, CINAHL, Web of Science, and Cochrane Library databases., Review Methods: Eligibility criteria were patients of any age who developed TSS as a complication of ESS and/or septoplasty., Results: Twenty-five studies were included in the final review. Seventy cases were identified over 38 years (1982-2020). The pooled incidence of TSS after sinonasal surgery was 0.0003 (0.0002-0.0004, 95% confidence interval, CI) or 30 per 100,000 persons. Among 33 patients with single-subject data, mean age was 33.8 years (29.73-37.87, 95% CI). Seventeen (51.5%) patients had nasal packing, 3 (9.1%) had stents, 5 (15.2%) had both, 7 (21.2%) had none. Fourteen (42.4%) patients had nonabsorbable packing and 5 (15.2%) had absorbable packing. Sixteen (48%) patients received peri-operative antibiotics. Thirty-two (97%) patients had full recovery., Conclusion: The incidence of TSS after sinonasal surgery is very rare. TSS can occur with and without nasal packing and prophylactic antibiotics were not protective. Outcomes were favorable with appropriate recognition and management. Further study is needed to determine which patients are most at risk for TSS., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)