Negative Clinical Outcomes Research Articles

Original Research: Nurse-Reported Missed Care and Its Association with Staff Demographics and the Work Environment.

Nurses have primary responsibility for many of the care processes and interventions intended to improve patients' health during hospital stays. Accordingly, missed nursing care can negatively impact patient safety and lead to negative clinical outcomes. Missed nursing care is standard care that is not completed, incomplete, or seriously delayed. There is scant literature on nurse-reported missed care (NRMC) in Singapore. Identifying the prevalence of, types of, and reasons for missed care, including staff-related factors, is imperative to understanding the implications of missed care and identifying opportunities for improvement. Ours is a correlation study of NRMC using convenience sampling. Nurses working on all inpatient units in an acute care hospital in Singapore were recruited to complete the MISSCARE survey, a quantitative tool measuring missed nursing care and the reasons for it. Descriptive statistics was applied to analyze demographics, types of NRMC, and reasons for NRMC. The Pearson χ2 test was used to analyze the correlation between demographics and satisfaction variables and NRMC. A total of 314 participants out of 1,944 eligible nurses (response rate, 16%) were recruited. The most commonly reported missed care activities were setting up meals for patients who can feed themselves (87.3%), ambulation (70.1%), attending interdisciplinary conferences (64.3%), providing emotional support to patients and/or family (58%), and turning patients every two hours (56.7%). The most cited reasons for missed care were inadequate number of staff (84.4%), caregiver not in unit or unavailable (76.1%), heavy admission and discharge activity (75.5%), urgent patient situations (74.2%), and unexpected rise in patient volume and/or acuity (73.2%). Younger age, greater experience in role and current unit, inadequate staffing and teamwork, low satisfaction with current role and with being a nurse, and planning to leave the current position were factors significantly associated with greater levels of missed care. This study demonstrated evidence of NRMC and its associated factors within the local setting. In addition to expanding nursing resources, analyzing nursing work processes, providing support for younger nurses, and improving nursing satisfaction are possible mitigating factors in preventing missed care. Strategies targeting workforce and resource management, greater support for new and younger nurses, and job satisfaction should be considered to address missed care.

Efficacy and Safety of Beta-Tricalcium Phosphate/Polylactic-Co-Glycolic Acid for Implantation of Bone Defects.

Bone defects are often observed after surgery for fractures and bone tumors. Their treatment is technically difficult and sometimes results in negative clinical and economic outcomes. To repair bone defects, a bone graft is implanted by selecting a transplant material from an autologous or artificial bone. Each method has its advantages and disadvantages. Compared to the gold standard of autologous bone graft, bone graft substitutes are not limited by the amount of harvested graft and avoid complications at the donor site. ORB-03 is a new cotton-like bone graft substitute composed of beta-tricalcium phosphate (β-TCP) and a bioabsorbable polymer, polylactic-co-glycolic acid (PLGA). ORB-03 is easy to mold and can fill various bone defect shapes, and its three-dimensional microfiber scaffold can enhance the differentiation of osteoblasts and promote osteogenesis. We investigated the efficacy, ease of handling, and safety of ORB-03 as a bone graft substitute. A multicenter, open-label, single-group study was conducted at six institutions. Between July 2018 and August 2019, 60 patients with bone defects caused by fracture, benign tumors, or an iliac donor site from bone harvesting were enrolled in this study; 54 patients were finally included for the safety analysis and 48 patients for the image analysis. During surgery, ORB-03 was mixed with the patient's blood and molded into a bone defect. To evaluate the efficacy of ORB-03, radiography and computed tomography (CT) were performed at intervals until 24 weeks after surgery. The effective rate and its accurate bilateral 95% confidence interval (CI) were calculated based on the efficacy criteria at 24 weeks postoperatively. The ease with which ORB-03 could be handled in surgery was evaluated. Adverse events that occurred after surgery were evaluated, and those associated with ORB-03 were examined. Bone fusion was good in all cases, and the radiography and CT effective rates were 100.0% and 91.5%, respectively. Handling was easy in all cases. There were four adverse events, none of which were clinically problematic. ORB-03 was found to be easy to handle, safe, and effective as a bone graft substitute for bone defects.

Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response.

The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.

Prescription opioid utilization patterns, and associated outcomes, among privately insured patients prescribed opioids to manage pain associated with osteoarthritis

Objective To describe utilization patterns, negative clinical outcomes and economic burden of patients diagnosed with osteoarthritis (OA) of the hip and/or knee who received a prescription for tramadol or non-tramadol opioids vs. non-opioid drugs. Methods Optum Healthcare Solutions, Inc. commercial claims data were used (1/2012--3/2017). Adults with ≥2 diagnoses of OA of the hip and/or knee, and ≥30 days supply of pain medications were identified during the three-year period from the date of first prescription (index date) after the first OA diagnosis. Drug utilization statistics in the follow-up period were summarized by initial treatment (i.e. tramadol, non-tramadol opioids, non-opioid drugs). Opioid initiators were matched to those initiated on non-opioid treatments using a propensity score model accounting for baseline characteristics. Matched pairs analysis compared outcomes for these cohorts. Results Of 62,715 total patients, 15,270 (24.3%) initiated treatment with opioids, including 3,513 (5.6%) on tramadol and 11,757 (18.7%) on non-tramadol opioids. Opioid initiators had more comorbidities, higher baseline healthcare costs, and were more likely to have OA of the hip. Among non-opioid initiators, 27.5% switched to tramadol and 63% switched to non-tramadol opioids. Among tramadol initiators, 71% switched to non-tramadol opioids. Patients initiated on opioids had 20.4% (p < .01) higher all-cause healthcare costs and higher percentages experiencing multiple negative clinical outcomes (all p < .01) compared to matched controls. Conclusions Most patients with OA of the hip and/or knee either initiate on or switch to opioids for long-term management of OA-related pain despite known risks. This highlights the need for new treatments that delay or prevent use of opioids.

The efficacy of fat-free mass index and appendicular skeletal muscle mass index in cancer malnutrition: a propensity score match analysis.

Reduced muscle mass (RMM) is a phenotypic criterion for malnutrition; the appendicular skeletal muscle mass index (ASMI) and fat-free mass index (FFMI) are both applicable indicators in the global leadership initiative on malnutrition (GLIM) guideline. However, their sensitivity and prognostic effect remain unclear. Clinical data of 2,477 patients with malignant tumors were collected. Multi-frequency bioelectrical impedance analysis was used to obtain ASMI and FFMI. RMM was confirmed by ASMI (< 7.0 kg/m2 for men and < 5.7 kg/m2 for women) or FFMI (< 17 kg/m2 for men and < 15 kg/m2 for women). Propensity score match analysis and logistic regression analysis were used to evaluate the efficacy of FFMI and ASMI in diagnosing severe malnutrition and multivariate Cox regression analysis to determine the efficacy of RMM in predicting survival. In total, 546 (22.0%) and 659 (26.6%) participants were diagnosed with RMM by ASMI (RMM.ASMI group) and FFMI (RMM.FFMI group); 375 cases overlapped. Body mass index (BMI), midarm circumference, triceps skinfold thickness, and maximum calf circumference were all significantly larger in the RMM.FFMI group for both sexes (P < 0.05). A 1:1 matched dataset constructed by propensity score match contained 810 cases. RMM.FFMI was an influential factor of severe malnutrition with HR = 3.033 (95% CI 2.068-4.449, P < 0.001), and RMM.ASMI was a predictive factor of overall survival (HR = 1.318, 95% CI 1.060-1.639, P = 0.013 in the RMM.ASMI subgroup, HR = 1.315, 95% CI 1.077-1.607, P = 0.007 in the RMM.FFMI subgroup). In general, RMM indicates negative clinical outcomes; when defined by FFMI, it predicts nutritional status, and when defined by ASMI, it is related to poor survival in cancer patients.

The Development and Effect of Systemic Hypertension on Clinical and Radiological Outcome in Adult Moyamoya Angiopathy Following Revascularization Surgery: Experience of a Single European Institution.

Patients with Moyamoya Angiopathy (MMA) display structurally altered vessels with decreased cerebral autoregulatory capacity, so aggressive lowering of systemic hypertension may aggravate ischemic symptoms, whereas uncontrolled hypertension may promote hemorrhage. This study provides an in-depth analysis of the role of hypertension in adult MMA patients including long-term analysis of clinical and radiological development. In this single-center retrospective analysis of 137 adult MMA patients with 206 surgically treated hemispheres angiographic images, clinical/operative data were reviewed and scored. Univariate Cox-regression analysis was performed to evaluate hypertension as a predictor for negative angiographic and clinical outcomes following revascularization surgery. A total of 50% of patients were being treated for hypertension prior to the first surgery. Patients with and without hypertension did not differ in terms of age, gender, diagnosis, symptom onset or disease severity (Berlin and Suzuki Grades). Although hypertension did not statistically significantly affect postoperative collaterals, moyamoya vessels or STA-MCA bypass patency, patients with hypertension showed higher rates of bypass patency and better bypass filling compared to those without hypertension. No significant differences in adverse events were found in patients with and without systemic hypertension and the presence of systemic hypertension was not found to predict negative clinical or radiological outcomes. In conclusion, the rate of systemic hypertension in MMA patients appears to be higher than the general population; however, this is not associated with an increased risk of postoperative complications or negative angiographic development following revascularization procedures. Systemic hypertension may also positively influence the rate of bypass patency and filling following revascularization procedures.

CO132 Predictive Validity of Pt-Global Web-Tool/PG-SGA, and Impact of Malnutrition on Renal Outcomes in Chronic Kidney Disease Patients: A Hospital-Based Prospective Cohort

Dialysis dependence, end-stage renal disease, cardiovascular events, and all-cause mortality are a couple of negative clinical outcomes that have been demonstrated to be significantly associated with CKD progression. This study aimed to investigate the impact of malnutrition on renal outcomes in a prospective CKD cohort and also sought to determine the predictive validity of the Pt-Global web tool/PG-SGA.

Comprehensive analysis of the diagnostic and therapeutic value of the hypoxia-related gene PLAUR in the progression of atherosclerosis

Atherosclerosis (AS) is a major contributor to a variety of negative clinical outcomes, including stroke and myocardial infarction. However, the role and therapeutic value of hypoxia-related genes in AS development has been less discussed. In this study, Plasminogen activator, urokinase receptor (PLAUR) was identified as an effective diagnostic marker for AS lesion progression by combining WGCNA and random forest algorithm. We validated the stability of the diagnostic value on multiple external datasets including humans and mice. We identified a significant correlation between PLAUR expression and lesion progression. We mined multiple single cell-RNA sequencing (sc-RNA seq) data to nominate macrophage as the key cell cluster for PLAUR mediated lesion progression. We combined cross-validation results from multiple databases to predict that HCG17-hsa-miR-424-5p-HIF1A, a competitive endogenous RNA (ceRNA) network, may regulate hypoxia inducible factor 1 subunit alpha (HIF1A) expression. The DrugMatrix database was used to predict alprazolam, valsartan, biotin A, lignocaine, and curcumin as potential drugs to delay lesion progression by antagonizing PLAUR, and AutoDock was used to verify the binding ability of drugs and PLAUR. Overall, this study provides the first systematic identification of the diagnostic and therapeutic value of PLAUR in AS and offers multiple treatment options with potential applications.

Association of CD47 Expression with Clinicopathologic Characteristics and Survival Outcomes in Muscle Invasive Bladder Cancer.

CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan-Meier method, respectively. A total of 87 MIBC patients were included. The median age was 66 (39-84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 (p = 0.006), non-responders (p = 0.002), and at stage ≥ 3 (p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance. CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

(075) Partnered Sexual Desire Influences Sex-related Alcohol and Drug Expectancies and Subsequent Sex-linked Substance Use

Abstract Introduction The use of recreational substances in a sexual context (sex-linked substance use) is common among young adults, with up to a third indicating that that they used alcohol, cannabis, or both during their recent partnered sexual activity (Willis et al., 2021; Herbenick et al., 2018). Sex-linked substance use (SLSU) is associated with a variety of positive and negative clinical outcomes including increased sexual pleasure, but also greater risk for condomless sex. Expectations of how one will behave and feel during sex while under the influence have been shown to predict SLSU habits. Contextual factors like relationship status may contribute to these expectancies, with studies finding that young women who are casually dating have more positive sexual expectancies of alcohol compared to women who are not dating or are in a long-term relationship (e.g., Patrick et al., 2014; Pedersen et al., 2009). Given the relationship between SLSU, relationship status, and sexual expectancies, it is likely that other contextual factors of a relationship, like partnered sexual desire, may play a role in sexual outcomes of women’s substance use. However, little is known about how partnered sexual desire is related to either substance sex-related expectancies in college-aged women. Objective To investigate how relationship status and partnered sexual desire is related to differences in alcohol and drug sexual expectancies and SLSU. Methods We surveyed 512 women (mean age 20.09, SD = 1.56) in the Midwestern US. Participants completed the Brief Comprehensive Expectancies of Alcohol and Drug scales, assessing their alcohol and drug expectancies, including sex-related expectancies (e.g., “to be a better lover” and to “enjoy sex more”); the Sexual Desire Inventory, assessing partnered and solitary sexual desire; and reported their relationship status, frequency of SLSU, and demographics. Using independent sample t-tests and multivariate general linear models, we examined how relationship status and partnered &amp; solitary sexual desire interacted to predict differences in alcohol and drug sex-related expectancies and SLSU. Results Contrary to previous research findings, relationship status alone was not related to either alcohol or drug sex-related expectancies or SLSU. However, there was a marginally significant interaction between relationship status and sexual expectancies in predicting women’s SLSU. Specifically, the association between more positive sexual expectancies and higher frequency of SLSU was relatively stronger in partnered women. Moreover, regardless of relationship status, women who reported higher levels of partner desire reported more positive sexual alcohol and drug expectancies. Additionally, women who reported more positive sexual alcohol and drug expectancies reported more frequent SLSU. In contrast, solitary sexual desire was not a significant predictor of either substance-related sexual expectancies. Conclusions Our results indicate that partnership and partnered desire may interact with alcohol and drug sexual expectancies to predict women’s SLSU. These findings question the predominant assumption that women’s use of substances in sexual settings is primarily in casual sexual contexts and points to the need for targeted interventions to address the functions of SLSU in the context of women’s long-term relationships. Clinically, these findings reinforce the value of including our patient’s partner when addressing sexual dysfunction secondary to substance use. Disclosure No

Facing financial barriers to healthcare: patient-informed adaptation of a conceptual framework for adults with a history of cancer.

Cancer-related financial hardship is associated with negative clinical outcomes, which may be partially explained by cost-related delayed or forgone care in response to financial barriers. We sought to understand patient experiences facing financial barriers to medical care following a cancer diagnosis. We conducted virtual, semi-structured interviews in Fall 2022 with 20 adults with a history of cancer who had experienced cancer-related financial hardship in the prior year. We used template analysis within a pragmatic paradigm, combining constructivist and critical realist theoretical perspectives, to analyze interview transcripts and adapt an existing conceptual framework of financial barriers to care. The majority of interviewees identified as women (70%), non-Hispanic white (60%), and reported an annual household income of <$48,000 (60%). As interviewees sought to overcome financial barriers, they described substantial frustration at the limitations and complexities of United States health and social care systems, resulting in a reliance on a fragmented, uncertain resource landscape. The administrative burden resulting from bureaucratic systems and the advocacy responsibilities required to navigate them ultimately fell on interviewees and their caregivers. Thus, participants described their ability to overcome financial barriers as being influenced by individual and interpersonal factors, such as social support, comfort asking for help, time, prior experience navigating resources, and physical and mental health. However, participants noted health system organizational factors, such as whether all new patients proactively met with a social worker or financial navigator, as having the potential to lessen the administrative and financial burden experienced. We present an adapted conceptual framework outlining multi-level factors influencing patient experiences coping with financial barriers to medical care. In addition to influencing whether a patient ultimately delays or forgoes care due to cost, financial barriers also have the potential to independently affect patient mental, physical, and financial health.

Vipareeta Avipareeta Swapna Nidarshaneeyam chapter of Sushruta Sutra Sthana - an explorative study

Vipareeta Avipareeta Swapna Nidarshaneeyam (VASN) is the 29th chapter of Sutra Sthana of Sushruta Samhita. This chapter has 81 verses that deal with various Shakunas (omens), Doota (caregiver) and Swapna (dreams). The aim of the present work is to provide a comprehensive and critical analysis of the contents of VASN chapter with the help of contemporary prognostic and dream literature. Characteristic features of a caregiver and their influence on patient’s clinical outcome, various omens (both good and bad) and dreams (both auspicious and inauspicious) and their positive or negative prognostic consequences are documented in the VASN chapter. Shakunas of the VASN chapter denote the belief systems that were prevalent in ancient India and the prognostic significance needs to be evaluated further. Interpretation of dreams that are documented in VASN chapter seems to be congruent with the findings of contemporary dream research. Interdisciplinary studies among Ayurveda, Jyotishya Shastra (medical astrology) and modern prognostic science are required to authenticate the good and bad omens and their association with the positive or negative clinical outcomes.

Prevalence and clinical impact of frailty in COPD: a systematic review and meta-analysis

BackgroundFrailty has been increasingly identified as a risk factor of adverse outcomes in chronic obstructive pulmonary disease (COPD). The prevalence and impact of frailty on health outcomes in people with COPD require clarification.MethodsPubMed, Embase, The Cochrane Library and Web of Science (January 1, 2002, to July 1, 2022) were comprehensively searched to identify studies related to frailty and COPD. Comparisons were made between people who did and did not have frailty for pulmonary function, dyspnea severity, 6-minute walking distance, activities of daily life, and mortality.ResultsTwenty studies (9 cross-sectional, 10 cohort studies,1 clinical trial) from Europe (9), Asia (6), and North and South America (4), Oceania (1) involving 11, 620 participants were included. The prevalence of frailty was 32.07% (95% confidence interval (CI) 26.64–37.49) with a range of 6.43–71.70% based on the frailty tool used. People with frailty had lower predicted forced expiratory volume in the first second (mean difference − 5.06%; 95%CI -6.70 to -3.42%), shorter 6-minute walking distance (mean difference − 90.23 m; 95%CI -124.70 to -55.76), poorer activities of daily life (standardized mean difference − 0.99; 95%CI -1.35 to -0.62), higher CAT(COPD Assessment Test) score(mean difference 6.2; 95%CI 4.43 to 7.96) and mMRC (modified Medical Research Council) grade (mean difference 0.93; 95%CI 0.85 to 1.02) compared with those who did not (P < 0.001 for all). Meta-analysis showed that frailty was associated with an increased risk of long-term all-cause mortality (HR 1.68; 95% CI 1.37–2.05; I2 = 0%, P < 0.001).ConclusionFrailty is prevalent in people with COPD and linked with negative clinical outcomes including pulmonary function, dyspnea severity, exercise capacity, quality of life and mortality.

Protocol for development of an assessment tool for competency of ECG interpretation: expert consensus by the RAND/UCLA appropriateness method and cross-sectional testing using multidimensional item response theory

IntroductionAlthough the ECG is an important diagnostic tool in medical practice, the competency of ECG interpretation is considered to be poor. Diagnostic inaccuracy involving the misinterpretation of ECG can lead...

Cortical thinning in relation to impaired insight into illness in patients with treatment resistant schizophrenia

Impaired insight into illness is a common element of schizophrenia that contributes to treatment nonadherence and negative clinical outcomes. Previous studies suggest that impaired insight may arise from brain abnormalities. However, interpretations of these findings are limited due to small sample sizes and inclusion of patients with a narrow range of illness severity and insight deficits. In a large sample of patients with schizophrenia, the majority of which were designated as treatment-resistant, we investigated the associations between impaired insight and cortical thickness and subcortical volumes. A total of 94 adult participants with a schizophrenia spectrum disorder were included. Fifty-six patients (60%) had treatment-resistant schizophrenia. The core domains of insight were assessed with the VAGUS insight into psychosis scale. We obtained 3T MRI T1-weighted images, which were analysed using CIVET and MAGeT-Brain. Whole-brain vertex-wise analyses revealed impaired insight, as measured by VAGUS average scores, was related to cortical thinning in left frontotemporoparietal regions. The same analysis in treatment-resistant patients showed thinning in the same regions, even after controlling for age, sex, illness severity, and chlorpromazine antipsychotic dose equivalents. No association was found in non-treatment-resistant patients. Region-of-interest analyses revealed impaired general illness awareness was associated with cortical thinning in the left supramarginal gyrus when controlling for covariates. Reduced right and left thalamic volumes were associated with VAGUS symptom attribution and awareness of negative consequences subscale scores, respectively, but not after correction for multiple testing. Our results suggest impaired insight into illness is related to cortical thinning in left frontotemporoparietal regions in patients with schizophrenia, particularly those with treatment resistance where insight deficits may be more chronic.

Early Adverse Event Derived Biomarkers in Predicting Clinical Outcomes in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immunotherapy.

Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics. Comprehensive analysis of the AE-derived biomarkers enhances the chance of discovering new predictive AE biomarkers of clinical outcomes. We utilized a set of AE-associated parameters (grade, treatment relatedness, occurrence, frequency, and duration) to derive 24 AE biomarkers. We further innovatively defined early AE biomarkers by landmark analysis at an early time point to assess the predictive value. Statistical methods included the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), two-sample t-test for mean difference of AE frequency and duration between disease control (DC: complete response (CR) + partial response (PR) + stable disease (SD)) versus progressive disease (PD), and Pearson correlation analysis for relationship of AE frequency and duration versus treatment duration. Two study cohorts (Cohort A: vorinostat + pembrolizumab, and B: Taminadenant) from two immunotherapy trials in late-stage non-small cell lung cancer were used to test the potential predictiveness of AE-derived biomarkers. Data from over 800 AEs were collected per standard operating procedure in a clinical trial using the Common Terminology Criteria for Adverse Events v5 (CTCAE). Clinical outcomes for statistical analysis included PFS, OS, and DC. An early AE was defined as event occurrence at or prior to day 30 from initial treatment date. The early AEs were then used to calculate the 24 early AE biomarkers to assess overall AE, each toxicity category, and each individual AE. These early AE-derived biomarkers were evaluated for global discovery of clinical association. Both cohorts showed that early AE biomarkers were associated with clinical outcomes. Patients previously experienced with low-grade AEs (including treatment related AEs (TrAE)) had improved PFS, OS, and were associated with DC. The significant early AEs included low-grade TrAE in overall AE, endocrine disorders, hypothyroidism (pembrolizumab's immune-related adverse event (irAE)), and platelet count decreased (vorinostat related TrAE) for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of high-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included high-grade TrAE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, three toxicity categories, and five related individual AEs for Cohort B. One low-grade TrAE, alanine aminotransferase increased (vorinostat + pembrolizumab related), was an irAE and correlated with worse OS in Cohort A. The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine.

Predictors of clinical outcomes in space-occupying cerebellar infarction undergoing suboccipital decompressive craniectomy.

Despite current clinical guidelines recommending suboccipital decompressive craniectomy (SDC) in cerebellar infarction when patients present with neurological deterioration, the precise definition of neurological deterioration remains unclear and accurate timing of SDC can be challenging. The current study aimed at characterizing whether clinical outcomes can be predicted by the GCS score immediately prior to SDC and whether higher GCS scores are associated with better clinical outcomes. In a single-center, retrospective analysis of 51 patients treated with SDC for space-occupying cerebellar infarction, clinical and imaging data were evaluated at the time points of symptom onset, hospital admission, and preoperatively. Clinical outcomes were measured by the mRS. Preoperative GCS scores were stratified into three groups (GCS, 3-8, 9-11, and 12-15). Univariate and multivariate Cox regression analyses were performed using clinical and radiological parameters as predictors of clinical outcomes. In cox regression analysis GCS scores of 12-15 at surgery were significant predictors of positive clinical outcomes (mRS, 1-2). For GCS scores of 3-8 and 9-11, no significant increase in proportional hazard ratios was observed. Negative clinical outcomes (mRS, 3-6) were associated with infarct volume above 6.0 cm3, tonsillar herniation, brainstem compression, and a preoperative GCS score of 3-8 [HR, 2.386 (CI, 1.160-4.906); p = 0.018]. Our preliminary findings suggest that SDC should be considered in patients with infarct volumes above 6.0 cm3 and with GCS between 12 and 15, as these patients may show better long-term outcomes than those in whom surgery is delayed until a GCS score below 11.

Polypharmacy Among Patients With Major Depressive Disorder and Co-occurring Substance Use Disorders in a Psychiatric Hospital Setting: Prevalence and Risk Factors.

Major depressive disorder (MDD) is common among patients admitted to a psychiatric hospital who frequently present with comorbid conditions such as substance use disorders (up to 50%). Polypharmacy (ie, being prescribed 3 or more medications) may be relatively common in dual-diagnosis patients. This study sought to examine prevalence and risk factors associated with psychotropic polypharmacy in hospitalized patients with MDD and co-occurring SUDs. An electronic chart review was conducted with 1315 individuals admitted to a psychiatric hospital; 505 (38.4%) were identified as having co-occurring MDD + SUD. We examined psychotropic polypharmacy and clinical severity to explore risk for concerning drug interactions. Potentially problematic polypharmacy patterns were identified among those with MDD + SUD and were related to negative clinical outcomes, particularly in terms of increased sedation potential for individuals with an opioid use disorder (OUD). Groups at the highest risk for polypharmacy included patients who were female, older in age, lower in functioning, and presenting with a co-occurring OUD. Having an OUD was associated with particularly risky polypharmacy combinations, while having a cannabis use disorder was associated with the least polypharmacy. Results highlight a high prevalence of polypharmacy among a group that has an elevated risk for negative outcomes. There is a continued need to improve identification of complex patient presentations and adjust medications in a hospital setting to improve treatment outcomes and reduce future mortality.

Adherence to hydroxyurea and clinical outcomes among children with sickle cell anemia.

Hydroxyurea lowers the incidence of vaso-occlusive pain crises (VOC) and acute chest syndrome (ACS) among children with sickle cell anemia (SCA). Our objective was to assess the relationship between levels of adherence to hydroxyurea and clinical outcomes among children and adolescents with SCA. This retrospective cohort study included Medicaid data (2005-2012) from Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. The study population consisted of children 1-17 years old with SCA enrolled in Medicaid for 3 years. Among children that initiated hydroxyurea, the medication possession ratio (MPR) was calculated as the proportion of days covered by hydroxyurea. Six months after initiation of hydroxyurea, clinical outcomes were assessed through the end of the study period: numbers of VOC-related inpatient admissions and emergency department visits, and encounters for ACS. Multivariable Poisson models were used to predict outcomes by MPR quartile adjusting for previous healthcare utilization, state, and age. Hydroxyurea was initiated by 515 children. The median MPR was 0.53 (interquartile range=0.3-0.8). The annual median number of visits was 0.0 for ACS, 1.3 for VOC-related emergency department, and 1.4 for VOC-related inpatient admissions. For each outcome, the highest quartile of MPR had the lowest predicted count; this difference was significant for ACS visits when compared with the lowest quartile of MPR. This study demonstrated a high level of adherence (>75%) was essential to achieve a lower incidence of common negative clinical outcomes. Further, moderate and severe hydroxyurea nonadherence may be more common than previously appreciated among children, emphasizing the importance of developing and testing innovative strategies to increase adherence.

Abstract 987: Seamless statistical analysis of adverse event data for clinical association

Abstract Purpose: Adverse event (AE) is a critical element in clinical trial to evaluate patient safety profile of the drug for benefit-risk assessment. AE is also shown to have clinical association. However, due to its complexity, utilization of AE data has been suboptimal. This study takes a unique approach to utilize AE parameters and to derive a set of innovative AE metrics which could have the potential as a predictive biomarker of treatment response and survival outcomes. Methods: The AE-derived biomarkers integrated toxicity severity level (grade) and treatment relatedness, with further tune-up by AE occurrence, frequency, and duration. Implementation of AE-derived biomarkers was performed in a comprehensive strategy starting from overall AE, toxicity category, down to individual AE. Landmark analysis at day 30 from initial treatment date was used to define early AE biomarkers. Two study cohorts (Cohort A and B) from two immunotherapy trials in late-stage non-small cell lung cancer were used to evaluate the potential of AE-derived biomarkers. Clinical outcomes for statistical analysis included progression-free survival, overall survival, disease control, and duration of treatment. Results: Both cohorts showed that early AEs were associated with clinical outcomes. Patients experienced with low-grade AEs (including treatment related AEs) at early time point had improved PFS, OS, and were associated with disease control. The significant early AEs included treatment related low-grade AE in overall AE, endocrine disorders, hypothyroidism (immune-related adverse event (irAE)), and platelet count decreased for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of higher-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included treatment related high-grade AE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, 3 toxicity categories, and 5 related individual AEs for Cohort B. One treatment related low-grade AE, alanine aminotransferase increased, was irAE and correlated with worse OS in Cohort A. Conclusions: The study demonstrated evidence of AE utility in predicting positive and negative clinical outcomes. It could be treatment related AEs or combination of treatment related and not related AEs. Grade level played a key role in determining direction of clinical outcomes with low-grade leaning to positive effect and high-grade to negative impact. Significant AEs covering overall AEs, toxicity category AEs, to individual AEs provided relatively comprehensive view of AE results for clinical relevance. Citation Format: Dung-Tsa Chen, Jhanelle Gray, Andreas Saltos, Trevor A Rose, Alberto Chiappori, Zachary Thompson, Ram Thapa. Seamless statistical analysis of adverse event data for clinical association [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 987.