Clinical Questions Research Articles

254 Initiation of Low Molecular Weight Heparin Within 24 Hours Is Safe and Effective for VTE Prophylaxis in Spinal Cord Injury Patients

INTRODUCTION: Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a major clinical concern. Current guidelines recommend initiation of chemical prophylaxis within 72 hours of injury or surgery. Given the high reported incidence of VTE in this population, the safety and efficacy of earlier initiation is an important clinical question. METHODS: We analyzed prospectively collected data in a cohort of 162 SCI patients from a single quaternary center. Demographic and clinical data were recorded. Univariate and multivariate logistic regression analyses were performed to identify predictors of VTE in SCI patients treated with LMWH within 24 hours of injury or surgery. RESULTS: Mean age was 56.9 years (28% females). One hundred and thirty (87.8%) patients underwent SCI surgery. There was an extremity fracture in 18.2% and lumbar drain was placed in 22.3%. DVT occurred in 7.4%, PE in 6.1%, and any VTE in 12.2%. A multivariable regression model including age, sex, race, injury severity score, level of SCI, SCI surgery status, admission lower extremity motor score, and extremity fracture showed that only lower extremity motor score (OR 0.94, p=0.03) was significantly associated with VTE. There were 1.5% patients with post-SCI surgery-related bleeds requiring surgery takeback. There were 5.6% non-surgery related bleeds, and 1.2% wound dehiscence. CONCLUSIONS: Initiation of LMWH within 24 hours of injury or surgery maintained the incidence of any VTE event within the lower end of previously reported ranges with 1.5% of patients who underwent SCI surgery requiring surgery takeback due to bleeding complications. Admission lower extremity motor score was the sole predictor of VTE in this patient cohort.

420 Computable Phenotyping with “Big Data” as a Foundation for Artificial Intelligence Algorithm Construction: Puberty as a Transdisciplinary Case Example

OBJECTIVES/GOALS: Artificial intelligence (AI) depends on quality machine learning (ML) algorithms constructed with high-quality training data. This TL1 trainee project develops a disease-agnostic computable phenotype framework for ML algorithm construction, modeling male puberty as a case example. METHODS/STUDY POPULATION: A computable phenotype of male puberty was constructed to answer the question: “Does early pubertal timing increase the risk of developing type II diabetes (T2D) in males?” A computable phenotype of males < 18 years old was created in the TriNetX© Diamond Network utilizing Boolean operator data queries. TriNetX© contains patient electronic health record information (ICD-10 diagnoses, anthropometric measures). An exploratory analysis of patient counts reflecting various computable phenotypes allowed for outcome (T2D) comparison of males diagnosed with precocious puberty (E30.1, ICD code for early pubertal timing) to those without, controlling for body mass index (BMI). RESULTS/ANTICIPATED RESULTS: Subjects (n=12,996,132) displayed the following computable phenotype: Male, < 18 years old, without ever having a BMI documented >85th percentile. Males diagnosed with precocious puberty (E30.1) were 6.89 times more likely to develop T2D when aged 14-18 years old than those without (OR 6.89, 95% CI: 5.17-9.19, p<0.0001). Next steps involve training a ML model on each computable phenotype groupings’ health data, with anticipated results identifying underlying salient pathophysiologic variables. A generalized computable phenotype approach is further developed to: 1) explore clinical questions in large databases like TriNetX©, and 2) model disease development with AI/ML algorithm construction. DISCUSSION/SIGNIFICANCE: Computed phenotypes reveal males with precocious puberty may have increased T2D risk. Next steps utilize subject data to train an AI/ML algorithm, model development to identify salient pathophysiologic variables, and synthesize a generalized AI/ML developmental research framework for dissemination.

The 30,000 Foot View: Using Big Data to Address Complex Clinical Questions in the Most Vulnerable Older Adults

Older people of color, those who are socially isolated, veterans, and incarcerated older adults experience disparities in mental healthcare and high levels of psychiatric and physical comorbidity, including increased risk of suicide. The identification of risk factors and understanding the culture and context that impact risk are major public health challenges. Effective approaches to address these challenges are likely to involve using national databases and applying advanced methodologies to address complex clinical questions in older adults. By leveraging extensive epidemiological datasets, we can effectively pinpoint risk factors and consequences associated with mental health disorders in later stages of life. Moreover, these datasets allow us to disaggregate heterogeneous groups which are often treated as homogeneous (e.g. people of color, veterans, etc.). This disaggregation may reveal significant within group differences and provide important contextual information regarding these groups which can be used to deliver precision mental healthcare in an efficient manner and reduce the burden of mental illness in late life. In this session, we will explore innovative methodologies of utilizing national datasets to discern the cultural and contextual elements that impact the mental health and well-being of four high-risk, older adult populations. Emphasis will be placed on identifying patterns in mental healthcare disparities and comprehending how factors such as race, ethnicity, sex, gender, and incarceration contribute to feelings of loneliness, suicide rates, and dementia. Furthermore, we will also discuss the potential application of this data in developing precise risk assessment tools and targeted prevention and treatment strategies. interventions for late-life mental health issues.

Performance of Google's Artificial Intelligence Chatbot "Bard" (Now "Gemini") on Ophthalmology Board Exam Practice Questions.

To assess the performance of "Bard," one of ChatGPT's competitors, in answering practice questions for the ophthalmology board certification exam. In December 2023, 250 multiple-choice questions from the "BoardVitals" ophthalmology exam question bank were randomly selected and entered into Bard to assess the artificial intelligence chatbot's ability to comprehend, process, and answer complex scientific and clinical ophthalmic questions. A random mix of text-only and image-and-text questions were selected from 10 subsections. Each subsection included 25 questions. The percentage of correct responses was calculated per section, and an overall assessment score was determined. On average, Bard answered 62.4% (156/250) of questions correctly. The worst performance was 24% (6/25)on the topic of "Retina and Vitreous," and the best performance was on "Oculoplastics," with a score of 84% (21/25). While the majority of questions were entered with minimal difficulty, not all questions could be processed by Bard. This was particularly an issue for questions that included human images and multiple visual files. Some vignette-style questions were also not understood by Bard and were therefore omitted. Future investigations will focus on having more questions per subsection to increase available data points. While Bard answered the majority of questions correctly and is capable of analyzing vast amounts of medical data, it ultimately lacks the holistic understanding and experience-informed knowledge of an ophthalmologist. An ophthalmologist's ability to synthesize diverse pieces of information and draw from clinical experience to answer complex standardized board questions is at present irreplaceable, and artificial intelligence, in its current form, can be employed as a valuable tool for supplementing clinicians' study methods.

Chinese guideline for the diagnosis and treatment of Takayasu's arteritis (2023).

Takayasu's arteritis (TAK) is a chronic granulomatous inflammatory disease that involves aorta and its primary branches. It is characterized by wall thickening, stenosis/obliteration or aneurysm formation of the involved arteries. In order to standardize the diagnosis and treatment of TAK in China, a clinical practice guideline with an evidence-based approach is developed under the leadership of National Clinical Medical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID). Eleven recommendations for 11 clinical questions that are important to the diagnosis and treatment of TAK are developed based on the latest evidence and expert opinions combined with real clinical practice in China.

Performance of a Large Language Model in the Generation of Clinical Guidelines for Antibiotic Prophylaxis in Spine Surgery.

Large language models, such as chat generative pre-trained transformer (ChatGPT), have great potential for streamlining medical processes and assisting physicians in clinical decision-making. This study aimed to assess the potential of ChatGPT's 2 models (GPT-3.5 and GPT-4.0) to support clinical decision-making by comparing its responses for antibiotic prophylaxis in spine surgery to accepted clinical guidelines. ChatGPT models were prompted with questions from the North American Spine Society (NASS) Evidence-based Clinical Guidelines for Multidisciplinary Spine Care for Antibiotic Prophylaxis in Spine Surgery (2013). Its responses were then compared and assessed for accuracy. Of the 16 NASS guideline questions concerning antibiotic prophylaxis, 10 responses (62.5%) were accurate in ChatGPT's GPT-3.5 model and 13 (81%) were accurate in GPT-4.0. Twenty-five percent of GPT-3.5 answers were deemed as overly confident while 62.5% of GPT-4.0 answers directly used the NASS guideline as evidence for its response. ChatGPT demonstrated an impressive ability to accurately answer clinical questions. GPT-3.5 model's performance was limited by its tendency to give overly confident responses and its inability to identify the most significant elements in its responses. GPT-4.0 model's responses had higher accuracy and cited the NASS guideline as direct evidence many times. While GPT-4.0 is still far from perfect, it has shown an exceptional ability to extract the most relevant research available compared to GPT-3.5. Thus, while ChatGPT has shown far-reaching potential, scrutiny should still be exercised regarding its clinical use at this time.

Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Diagnostic imaging of the diabetic foot: an EANM evidence-based guidance.

Consensus on the choice of the most accurate imaging strategy in diabetic foot infective and non-infective complications is still lacking. This document provides evidence-based recommendations, aiming at defining which imaging modality should be preferred in different clinical settings. This working group includes 8 nuclear medicine physicians appointed by the European Association of Nuclear Medicine (EANM), 3 radiologists and 3 clinicians (one diabetologist, one podiatrist and one infectious diseases specialist) selected for their expertise in diabetic foot. The latter members formulated some clinical questions that are not completely covered by current guidelines. These questions were converted into statements and addressed through a systematic analysis of available literature by using the PICO (Population/Problem-Intervention/Indicator-Comparator-Outcome) strategy. Each consensus statement was scored for level of evidence and for recommendation grade, according to the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria. Nine clinical questions were formulated by clinicians and used to provide 7 evidence-based recommendations: (1) A patient with a positive probe-to-bone test, positive plain X-rays and elevated ESR should be treated for presumptive osteomyelitis (OM). (2) Advanced imaging with MRI and WBC scintigraphy, or [18F]FDG PET/CT, should be considered when it is needed to better evaluate the location, extent or severity of the infection, in order to plan more tailored treatment. (3) In a patient with suspected OM, positive PTB test but negative plain X-rays, advanced imaging with MRI or WBC scintigraphy + SPECT/CT, or with [18F]FDG PET/CT, is needed to accurately assess the extent of the infection. (4) There are no evidence-based data to definitively prefer one imaging modality over the others for detecting OM or STI in fore- mid- and hind-foot. MRI is generally the first advanced imaging modality to be performed. In case of equivocal results, radiolabelled WBC imaging or [18F]FDG PET/CT should be used to detect OM or STI. (5) MRI is the method of choice for diagnosing or excluding Charcot neuro-osteoarthropathy; [18F]FDG PET/CT can be used as an alternative. (6) If assessing whether a patient with a Charcot foot has a superimposed infection, however, WBC scintigraphy may be more accurate than [18F]FDG PET/CT in differentiating OM from Charcot arthropathy. (7) Whenever possible, microbiological or histological assessment should be performed to confirm the diagnosis. (8) Consider appealing to an additional imaging modality in a patient with persisting clinical suspicion of infection, but negative imaging. These practical recommendations highlight, and should assist clinicians in understanding, the role of imaging in the diagnostic workup of diabetic foot complications.

Immunogenicity of Hepatitis B Vaccination in Patients with Ulcerative Colitis on Infliximab Is Attenuated Compared to Those on 5-Aminosalicylic Acid Therapies: A Prospective Observational Study.

Hepatitis B virus (HBV) infection has been associated with chronic hepatitis and cirrhosis. Patients with inflammatory bowel disease (IBD) may be at a higher risk of HBV infection reactivation, especially those on biologic therapies. This study intends to compare the effectiveness of the HBV vaccine in patients with ulcerative colitis (UC) on infliximab (IFX) compared to those on 5-aminosalicylic acid (5-ASA). Patients with UC aged >18 years old were prospectively enrolled in the study. The patients were divided into two groups: patients treated with 5-ASA (control group) and patients treated with IFX (study group). HBV vaccination was administered (20 mcg) following the standard regimen, and Hepatitis B serum antibody (HbsAb) titers were assessed three months after the final dose. The response to HBV vaccines was categorized as an 'adequate' immune response (≥10 IU/L) and 'effective' immune response (≥100 IU/L). In our final analysis of 118 patients with UC, 54.2% were male and 52.5% had extensive colitis. HBsAb titer levels were significantly higher in the 5-ASA group (126.7 ± 37.5) compared to the IFX group (55.5 ± 29.4). Stratifying HBsAb levels into two categories (≥10-99 IU/L and ≥100 IU/L) revealed a significantly greater proportion of subjects in the 5-ASA group with levels ≥100 IU/L compared to the IFX group (76.7% vs. 12.1%, p < 0.001). Logistic regression analysis demonstrated that patients with UC receiving 5-ASA were 23.94 times more likely to exhibit HBsAb levels ≥ 100 compared to those treated with IFX (OR = 23.94, 95% CI 8.89-64.49). The immune response to hepatitis B vaccination in patients with ulcerative colitis treated with IFX is attenuated compared to those treated with 5-ASA. Therefore, emphasizing the importance of HBV vaccination for patients with IBD before starting anti-TNF therapy, especially IFX, and advocating for screening is imperative in high-risk countries. Determining what levels of HBsAb provide protection and what happens to the levels over time after a booster dose are important clinical questions to be answered by follow-up studies.

Clinical practice guidelines for prevention and treatment of postoperative gastrointestinal disorder with Integrated Traditional Chinese and Western Medicine (2023).

Postoperative gastrointestinal disorder (POGD) was a common complication after surgery under anesthesia. Strategies in combination with Traditional Chinese Medicine and Western medicine showed some distinct effects but standardized clinical practice guidelines were not available. Thus, a multidisciplinary expert team from various professional bodies including the Perioperative and Anesthesia Professional Committees of the Chinese Association of Integrative Medicine (CAIM), jointly with Gansu Province Clinical Research Center of Integrative Anesthesiology/Anesthesia and Pain Medical Center of Gansu Provincial Hospital of Traditional Chinese Medicine and WHO Collaborating Center for Guideline Implementation and Knowledge Translation/Chinese Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Center/Gansu Provincial Center for Medical Guideline Industry Technology/Evidence-based Medicine Center of Lanzhou University, was established to develop evidence-based guidelines. Clinical questions (7 background and 12 clinical questions) were identified through literature reviews and expert consensus meetings. Based on systematic reviews/meta-analyses, evidence quality was analyzed and the advantages and disadvantages of interventional measures were weighed with input from patients' preferences. Finally, 20 recommendations were developed through the Delphi-based consensus meetings. These recommendations included disease definitions, etiologies, pathogenesis, syndrome differentiation, diagnosis, and perioperative prevention and treatment.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update – XII – Recommendations on milk formula supplements with and without probiotics for infants and toddlers with CMA

BackgroundCow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit. ObjectiveThese evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA. MethodsWAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to review by stakeholders. ResultsAfter reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as “conditional” following the GRADE approach due to the very low certainty about the health effects based on the available evidence. ConclusionsIf breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers’ values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable.

In patients supported with peripheral veno-arterial extracorporeal membrane oxygenation, what factors are associated with the development of spinal cord ischaemia?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'in patients supported with peripheral veno-arterial extracorporeal membrane oxygenation, what factors are associated with the development of spinal cord ischaemia'? Altogether, more than 22 papers were found using the reported search, of which 10 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Of the 28 patients reported by included studies, the thoracic spinal cord was most commonly affected. Twenty patients (71%) survived to hospital discharge and 7 (25%) were reported to have neurological recovery. Potential confounders included coronary angiography, cardiac arrest requiring chest compressions and concomitant intra-aortic balloon pump. Consequently, all papers highlighted the likely multifactorial aetiology of spinal cord infarction in these patients. We propose that close neurological observation, particularly in patients who have received chest compressions, and management of potential aetiological factors is crucial to aid in timely diagnosis and potential prevention of this rare complication. Limiting sedation and neuromuscular blockade to enable neurologic assessment of the lower limbs may allow more timely diagnosis.

Interactive effects of hearing aid use and cognitive function in patients with hearing loss.

There has been a significant increase in scientific investigations of the hearing-dementia association among the research on potentially modifiable risk factors for cognitive impairment. We tested two clinical questions. Analysis 1: does persistent hearing aid (HA) use decrease the decline in cognitive function caused by ageing? Analysis 2: does cognitive function at the time of HA fitting predict future persistent HA use? This case-control study performed at two referral centres reported data obtained over a 4.5-year period. We recruited a group of patients with cognitive decline, aged 65 or older with or without hearing loss. The intervention consisted of the use of HAs. The primary outcome measures were adherence to continuous HA use and cognitive function measured using the Japanese version of the Mini-Mental State Examination Test and the Reading Cognitive Test Kyoto. Eighteen HA users and 18 controls were included in the first analysis. HA use was associated with a deceleration of cognitive decline 12 months later. In the second analysis, 11 participants with good adherence to HA use were compared with 12 participants who showed poor adherence to HA use. Among the variables employed in this study, cognitive function measured using the Reading Cognitive Test Kyoto was significantly lower in participants with poor adherence to HA. HA use in cognitively impaired individuals with hearing loss can slow age-related cognitive decline. Cognitively impaired people with hearing loss who fail to commit to HA use tend to have lower cognitive measurement scores before HA fitting. HA use is generally more challenging as people age and their cognitive abilities decline. Therefore, it is desirable that HAs be used when hearing loss and dementia are in their early stages.

Public Health Risks of PFAS-Related Immunotoxicity Are Real.

The discovery of per- and polyfluoroalkyl substances (PFAS) in the environment and humans worldwide has ignited scientific research, government inquiry, and public concern over numerous adverse health effects associated with PFAS exposure. In this review, we discuss the use of PFAS immunotoxicity data in regulatory and clinical decision-making contexts and question whether recent efforts adequately account for PFAS immunotoxicity in public health decision-making. Government and academic reviews confirm the strongest human evidence for PFAS immunotoxicity is reduced antibody production in response to vaccinations, particularly for tetanus and diphtheria. However, recent events, such as the economic analysis supporting the proposed national primary drinking water regulations and clinical monitoring recommendations, indicate a failure to adequately incorporate these data into regulatory and clinical decisions. To be more protective of public health, we recommend using all relevant immunotoxicity data to inform current and future PFAS-related chemical risk assessment and regulation. Biological measures of immune system effects, such as reduced antibody levels in response to vaccination, should be used as valid and informative markers of health outcomes and risks associated with PFAS exposure. Routine toxicity testing should be expanded to include immunotoxicity evaluations in adult and developing organisms. In addition, clinical recommendations for PFAS-exposed individuals and communities should be revisited and strengthened to provide guidance on incorporating immune system monitoring and other actions that can be taken to protect against adverse health outcomes.

Evaluating the validity of ChatGPT responses on common obstetric issues: Potential clinical applications and implications.

To evaluate the quality of ChatGPT responses to common issues in obstetrics and assess its ability to provide reliable responses to pregnant individuals. The study aimed to examine the responses based on expert opinions using predetermined criteria, including "accuracy," "completeness," and "safety." We curated 15 common and potentially clinically significant questions that pregnant women are asking. Two native English-speaking women were asked to reframe the questions in their own words, and we employed the ChatGPT language model to generate responses to the questions. To evaluate the accuracy, completeness, and safety of the ChatGPT's generated responses, we developed a questionnaire with a scale of 1 to 5 that obstetrics and gynecology experts from different countries were invited to rate accordingly. The ratings were analyzed to evaluate the average level of agreement and percentage of positive ratings (≥4) for each criterion. Of the 42 experts invited, 20 responded to the questionnaire. The combined score for all responses yielded a mean rating of 4, with 75% of responses receiving a positive rating (≥4). While examining specific criteria, the ChatGPT responses were better for the accuracy criterion, with a mean rating of 4.2 and 80% of the questions received a positive rating. The responses scored less for the completeness criterion, with a mean rating of 3.8 and 46.7% of questions received a positive rating. For safety, the mean rating was 3.9 and 53.3% of questions received a positive rating. There was no response with an average negative rating below three. This study demonstrates promising results regarding potential use of ChatGPT's in providing accurate responses to obstetric clinical questions posed by pregnant women. However, it is crucial to exercise caution when addressing inquiries concerning the safety of the fetus or the mother.

Expert consensus recommendations for improving and standardising the assessment of patients with generalised myasthenia gravis.

Regular and consistent disease assessment could provide a clearer picture of burden in generalised myasthenia gravis (gMG) and improve patient care; however, the use of assessment tools in practice lacks standardisation. This modified Delphi approach was taken to review current evidence on assessment tool use in gMG and develop expert-derived consensus recommendations for good practice. A European expert panel of 15 experienced gMG neurologists contributed to development of this consensus, four of whom formed a lead Sub-committee. The PICO (Population, Intervention, Control, Outcomes) framework was used to define six clinical questions on gMG assessment tools, a systematic literature review was conducted, and evidence-based statements were developed. According to a modified Delphi voting process, consensus was reached when ≥70% of the experts rated agreement with a statement as ≥8 on a scale of 1-10. Eighteen expert- and evidence-based consensus statements based on six themes were developed. Key recommendations include: consistent use of the Myasthenia Gravis Activities of Daily Living score (MG-ADL) across clinical settings, followed by a simple question (e.g., Patient Acceptable Symptom State [PASS]) or scale to determine patient satisfaction in clinical practice; use of a Quantitative Myasthenia Gravis [QMG] or quality of life [QoL] assessment when the MG-ADL indicates disease worsening; and consideration of symptom state to determine the timing and frequency of recommended assessments. Expert panel consensus was reached on all 18 statements after two voting rounds. This process provided evidence- and expert consensus-based recommendations for the use of objective and subjective assessment tools across gMG research and care to improve management and outcomes for patients.

Diabetic Disease of the Eye in Canada: Consensus Statements from a Retina Specialist Working Group.

Despite advances in systemic care, diabetic disease of the eye (DDE) remains the leading cause of blindness worldwide. There is a critical gap of up-to-date, evidence-based guidance for ophthalmologists in Canada that includes evidence from recent randomized controlled trials. Previous guidance has not always given special consideration to applying treatments and managing DDE in the context of the healthcare system. This consensus statement aims to assist practitioners in the field by providing a spectrum of acceptable opinions on DDE treatment and management from recognized experts in the field. In compiling evidence and generating consensus, a working group of retinal specialists in Canada addressed clinical questions surrounding the four themes of disease, patient, management, and collaboration. The working group reviewed literature representing the highest level of evidence on DDE and shared their opinions on topics surrounding the epidemiology and pathophysiology of diabetic retinopathy and diabetic macular edema; diagnosis and monitoring; considerations around diabetes medication use; strategic considerations for management given systemic comorbidities, ocular comorbidities, and pregnancy; treatment goals and modalities for diabetic macular edema, non-proliferative and proliferative diabetic retinopathy, and retinal detachment; and interdisciplinary collaboration. Ultimately, this work highlighted that the retinal examination in DDE not only informs the treating ophthalmologist but can serve as a global index for disease progression across many tissues of the body. It highlighted further that DDE can be treated regardless of diabetic control, that a systemic approach to patient care will result in the best health outcomes, and prevention of visual complications requires a multidisciplinary management approach. Ophthalmologists must tailor their clinical approach to the needs and circumstances of individual patients and work within the realities of their healthcare setting.

Abstract 5260: Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice

Abstract Eribulin (ERI) has been reported a microtubule dynamics inhibitor with unique tumor microenvironment modulations such as vascular remodeling activity. In the previous meeting (AACR2022, 2023), we reported that ERI and liposomal formulation of ERI (ERI-LF) also have immunomodulatory activity that induces CD8+ T cells via its vascular remodeling activity and ERI-LF showed more potent immune modulation and combination activities with anti-PD-1 antibody (PD-1 Ab) than ERI in syngeneic mice models and humanized mice models. Although immune-checkpoint inhibitors (ICI) are using as a key drug for various types of cancers in clinical setting, several clinical questions regarding suitable therapies after ICI therapy and efficacy of ICI rechallenge are remaining. In this study, we evaluated anti-tumor activities of combination of ERI-LF and PD-1 Ab in two syngeneic transplantation models using mouse non-small lung cancer cells, P-glycoprotein-knockout (Pgp-KO) KLN205 cells and Pgp-KO LL2 cells. As a result, combination of 1mg/kg ERI-LF (Q7D×2) with PD-1 Ab (200 ug/head, twice a week ×2 weeks) showed significant stronger antitumor activity compared with each monotherapy in only Pgp-KO KLN205 model, in which ERI-LF increased intratumoral microvascular density as a vascular remodeling activity, not in Pgp-KO LL2 model. We next conducted continuous treatment of PD-1 Ab in Pgp-KO KLN205 model to investigate tumor regrowth during treatment of PD-1 Ab. In this model, tumor growth was inhibited by PD-1 Ab until about two weeks after initiation of the treatment and then this inhibitory activity disappeared after two weeks even by continuous treatment of PD-1 Ab. We performed flow cytometry analysis (FCM) for tumor-infiltrating immune cells and RNAseq analysis using regrowing tumors compared with non-treatment tumors. Expressions of mRNA of several immune inhibitory receptors were upregulated in tumors with regrowth, although CD4+ cells and CD8+ cells were also increased in FCM using tumor samples. Furthermore, we investigated anti-tumor activity of combination of ERI-LF and PD-1 Ab against tumors which changed from inhibitory phase to regrowth phase during PD-1 Ab treatment in Pgp-KO KLN205 model. The combination of ERI-LF at 1mg/kg (Q7D×3) and PD-1 Ab (200 ug/head, twice a week ×3 weeks) also showed potent anti-tumor activity against tumors with regrowth by prior PD-1 Ab treatment as well as PD-1 Ab-naïve tumor, suggesting that this combination therapy might be effective after prior ICI therapy. Currently, Phase 1b/2 clinical trial of ERI-LF plus nivolumab in patients with selected solid cancers (NCT04078295) is underway. Patients with or without prior ICI therapy were enrolled in a small cell lung cancer cohort of this clinical study. Our preclinical results might provide a scientific rationale for a uniqueness of ERI-LF as a post ICI therapy. Citation Format: Moe Tamura, Yuki Niwa, Taro Semba. Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5260.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Does coping style mediate the relationship between knowledge and psychosocial outcomes in women with atrial fibrillation?

In patients affected by atrial fibrillation (AF) disease-specific knowledge and coping style may be associated with psychosocial well-being. This study aimed to determine if coping style (problem-focused, emotion-focused, avoidance-focused) mediated the relationship between patient knowledge and three psychosocial outcomes (anxiety, depression and life satisfaction). In 2021a total of 188 women with reported AF, and ages ranging from 18 to 83 years (mean 48.7, sd 15.5 years), completed an online questionnaire consisting of sociodemographic, clinical and AF knowledge questions and psychosocial instruments (Anxiety and depression, the Hospital Anxiety and Depression (HADS) scale; life satisfaction, Satisfaction With Life Scale (SWLS); and coping style (Brief COPE). Using Jamovi statistical software three individual mediational models (for anxiety, depression and life satisfaction) were constructed assessing the direct and indirect relationships between knowledge, coping style and each psychosocial outcome. Age was a covariate in each model. The mediation analyses demonstrated significant direct negative associations between AF knowledge and HADS anxiety and depression and positive associations with SWLS. There were also direct associations between each of the three coping styles and the three psychosocial outcomes. There were significant indirect effects of coping style between AF knowledge and each of the three outcomes confirming partial mediation effects. These findings highlight the crucial role of coping style in mediating the association between AF knowledge and psychosocial outcomes. As such, interventions aimed at increasing patient knowledge of AF may be more effective if adaptive problem-solving coping strategies are also demonstrated to these patients. Additionally, modification of maladaptive coping strategies as part of the psychological management of patients with AF is highly recommended.