Association Between Cardiovascular Health Status and Healthcare Utilization in a Large Integrated Healthcare System.

Introduction: The American Heart Association Life's Simple 7 schema can be used to categorize patients' cardiovascular health status as poor, intermediate, or ideal on the basis of smoking, BMI, physical activity, dietary patterns, blood pressure, cholesterol, and fasting blood sugar. This study examined the association between cardiovascular health status and subsequent healthcare utilization. Methods: This was an observational cohort study of adults from an integrated healthcare delivery system-Kaiser Permanente Northern California-that had outpatient care between 2013 and 2014. Patients were categorized by American Heart Association cardiovascular health status: poor, intermediate, or ideal. Individual-level healthcare utilization and costs in 2015 were accumulated for each patient and compared across the 3 cardiovascular health categories and stratified by age groups. Results: A total of 991,698 patients were included in the study. A total of 194,003 (19.6%) were aged 18-39 years; 554,129 (55.9%) were aged 40-64 years; and 243,566 (24.6%) were aged ≥65 years. A total of 259,931 (26.2%) had ideal cardiovascular health; 521,580 (52.6%) had intermediate cardiovascular health; and 210,187 (21.2%) had poor cardiovascular health. Healthcare utilization measured by average relative cost per patient increased monotonically across age categories (p<0.001). In addition, cardiovascular health category was inversely associated with lower cost in each age group (p<0.001). Conclusions: Adults who were younger and had more ideal cardiovascular health had relatively lower healthcare costs across age groups. Interventions to promote better cardiovascular health may improve patient outcomes and reduce overall healthcare expenditures.

Chronic phase advances reduces recognition memory and increases vascular cognitive dementia-like impairments in aged mice.

Disrupted or atypical light-dark cycles disrupts synchronization of endogenous circadian clocks to the external environment; extensive circadian rhythm desynchrony promotes adverse health outcomes. Previous studies suggest that disrupted circadian rhythms promote neuroinflammation and neuronal damage post-ischemia in otherwise healthy mice, however, few studies to date have evaluated these health risks with aging. Because most strokes occur in aged individuals, we sought to identify whether, in addition to being a risk factor for poor ischemic outcome, circadian rhythm disruption can increase risk for vascular cognitive impairment and dementia (VCID). We hypothesized that repeated 6 h phase advances (chronic jet lag; CJL) for 8 weeks alters cerebrovascular architecture leading to increased cognitive impairments in aged mice. Female CJL mice displayed impaired spatial processing during a spontaneous alternation task and reduced acquisition during auditory-cued associative learning. Male CJL mice displayed impaired retention of the auditory-cued associative learning task 24 h following acquisition. CJL increased vascular tortuosity in the isocortex, associated with increased risk for vascular disease. These results demonstrate that CJL increased sex-specific cognitive impairments coinciding with structural changes to vasculature in the brain. We highlight that CJL may accelerate aged-related functional decline and could be a crucial target against disease progression.

Dim light at night shifts microglia to a pro-inflammatory state after cerebral ischemia, altering stroke outcome in mice.

Circadian rhythms are endogenous biological cycles that regulate physiology and behavior and are set to precisely 24-h by light exposure. Light at night (LAN) dysregulates physiology and function including immune response; a critical component that contributes to stroke pathophysiological progression of neuronal injury and may impair recovery from injury. The goal of this study is to explore the effects of dim LAN (dLAN) in a murine model of ischemic stroke to assess how nighttime lighting from hospital settings can affect stroke outcome. Further, this study sought to identify mechanisms underlying pathophysiological changes to immune response after circadian disruption. Male and female adult Swiss Webster (CFW) mice were subjected to transient or permanent focal cerebral ischemia, then were subsequently placed into either dark night conditions (LD) or one night of dLAN (5 lx). 24 h post-stroke, sensorimotor impairments and infarct sizes were quantified. A single night of dLAN following MCAO increased infarct size and sensorimotor deficits across both sexes and reduced survival in males after 24 h. Flow cytometry was performed to assess microglial phenotypes after MCAO, and revealed that dLAN altered the percentage of microglia that express pro-inflammatory markers (MHC II+ and IL-6) and microglia that express CD206 and IL-10 that likely contributed to poor ischemic outcomes. Following these results, microglia were eliminated in the brain using Plexikkon 5622 (PLX 5622) a CSFR1 inhibitor, then received an MCAO were exposed to LD or dLAN conditions then collected 24 h. Microglial depletion by PLX 5622 resulted in infarct sizes that were comparable between lighting conditions. This study provides supporting evidence that environmental lighting exacerbates ischemic injury and post-stroke mortality by a biological mechanism, that exposure to dLAN causes a fundamental shift of activated microglial phenotypes from beneficial to detrimental at an early time point after stroke, resulting in irreversible neuronal death.

Alignment in Total Knee Arthroplasty: Avoid Crossing Over from Varus to Valgus.

BACKGROUND: Ideal target limb alignment remains a debated topic in total knee arthroplasty (TKA). We aimed to determine the effect of limb alignment correction on patient-reported outcomes and knee range-of-motion (ROM) following TKA. METHODS: In this retrospective analysis, patients (N = 409) undergoing primary TKA at a single institution were studied. Using full leg-length radiographs, limb alignment was measured pre-and postoperatively. Patients were categorized by pre-operative (Pre-op) alignment (varus > 0°; valgus < 0°). Pre-op varus patients were then divided as follows based on post-operative alignment: neutral (VAR-NEUT, 0°±2); remaining in varus (VAR-rVAR, ≥3°); cross-over to valgus (VAR-CO, ≤-3°). Similarly, Pre-op valgus patients were divided as follows for post-operative alignment: neutral (VAL-NEUT, 0°±2); remaining in valgus (VAL-rVAL, ≤-3°); cross-over to varus (VAL-CO, ≥3°). The Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS Jr.) survey scores were collected at pre-op as well as at 6-weeks, 3-, 6-, and 12-months post-op. Knee ROM was collected at 2 weeks, 6 to 12 weeks, and > 6-months post-op. An analysis of variance (ANOVA) repeated on time followed by a Bonferroni post-hoc test was used to compare outcomes for the postoperative alignment subgroups. RESULTS: Pre-op Varus patients: Those in the VAR-CO group (overcorrected to -4.03° ± 1.95valgus) were observed to have lower KOOS Jr. scores at 3-, 6-, and 12-months post-op compared to those in the NEUT group (P < 0.05). This finding was paired with reduced ROM at 6 to 12 weeks post-op in the VAR-CO group compared to VAR-NEUT and VAR-rVAR (P < 0.05). Pre-op Valgus patients: Those in the VAL-rVal group (left in -4.39° ± 1.39valgus) were observed to have reduced knee flexion at 6 to 12 weeks post-op compared to VAL-NEUT and VAL-CO. CONCLUSION: These findings indicate that post-operative valgus alignment via either crossing over to valgus (VAR-CO) or remaining in valgus (VAL-rVAL) alignment may result in less preferable outcomes than correction to neutral or slightly varus alignment.

Willingness to take less medication for type 2 diabetes among older patients: The Diabetes & Aging Study.

BACKGROUND: To examine the willingness of older patients to take less diabetes medication (de-intensify) and to identify characteristics associated with willingness to de-intensify treatment. METHODS: Survey conducted in 2019 in an age-stratified, random sample of older (65-100 years) adults with diabetes on glucose-lowering medications in the Kaiser Permanente Northern California Diabetes Registry. We classified survey responses to the question: "I would be willing to take less medication for my diabetes" as willing, neutral, or unwilling to de-intensify. Willingness to de-intensify treatment was examined by several clinical characteristics, including American Diabetes Association (ADA) health status categories used for individualizing glycemic targets. Analyses were weighted to account for over-sampling of older individuals. RESULTS: A total of 1337 older adults on glucose-lowering medication(s) were included (age 74.2 ± 6.0 years, 44% female, 54.4% non-Hispanic white). The proportions of participants willing, neutral, or unwilling to take less medication were 51.2%, 27.3%, and 21.5%, respectively. Proportions of willing to take less medication varied by age (65-74 years: 54.2% vs. 85+ years: 38.5%) and duration of diabetes (0-4 years: 61.0% vs. 15+ years: 44.2%), both p < 0.001. Patients on 1-2 medications were more willing to take less medication(s) compared with patients on 10+ medications (62.1% vs. 46.6%, p = 0.03). Similar proportions of willingness to take less medications were seen across ADA health status, and HbA1c. Willingness to take less medication(s) was similar across survey responses to questions about patient-clinician relationships. CONCLUSIONS: Clinical guidelines suggest considering treatment de-intensification in older patients with longer duration of diabetes, yet patients with these characteristics are less likely to be willing to take less medication(s).

Analytical and Functional Similarity of Aflibercept Biosimilar ABP 938 with Aflibercept Reference Product.

INTRODUCTION: ABP 938 is being developed as a biosimilar candidate to aflibercept reference product (RP), a biologic used for certain angiogenic eye disorders. This study was designed to provide a comparative analytical assessment of the structural and functional attributes of ABP 938 and aflibercept RP sourced from the United States (US) and the European Union (EU). METHODS: Structural and functional characterization studies were performed using state-of-the-art analytical techniques that were appropriate to assess relevant quality attributes and capable of detecting qualitative and quantitative differences in primary structure, higher-order structure and biophysical properties, product-related substances and impurities, general properties, and biological activities. RESULTS: ABP 938 had the same amino acid sequence and exhibited similar secondary and tertiary structures, and biological activity as aflibercept RP. There were minor differences in a small number of biochemical attributes which are not expected to impact clinical performance. In addition, aflibercept RP sourced from the US and EU were analytically similar. CONCLUSIONS: ABP 938 was structurally and functionally similar to aflibercept RP. Since aflibercept RP sourced from the US and EU were analytically similar, this allows for the development of a scientific bridge such that a single-source RP can be used in nonclinical and clinical studies.

Eylea^® (aflibercept) is a biologic medication approved for the treatment of patients with certain eye diseases that can result in low vision or blindness. Biosimilars are biologic medications that are highly similar to an existing approved biologic medication, often called a reference product. Biosimilars have the potential to reduce medication costs despite having no clinically significant differences in quality, efficacy, and safety from their reference products. ABP 938 is currently being developed as a biosimilar to aflibercept reference product. We have conducted similarity studies to compare multiple batches of ABP 938 and aflibercept reference product sourced from both the United States and the European Union, using state-of-the-art analytical methods. The results demonstrated that ABP 938 had the same amino acid sequence and similar structural and biological activities as aflibercept reference product. Before biosimilars can be used as medicines, studies such as this one are required by the Food and Drug Administration and other regulatory authorities to ensure that biosimilars are as safe and effective as their reference products.

Care Partner Engagement in Secure Messaging Between Patients With Diabetes and Their Clinicians: Cohort Study.

BACKGROUND: Patient engagement with secure messaging (SM) via digital patient portals has been associated with improved diabetes outcomes, including increased patient satisfaction and better glycemic control. Yet, disparities in SM uptake exist among older patients and racial and ethnic underserved groups. Care partners (family members or friends) may provide a means for mitigating these disparities; however, it remains unclear whether and to what extent care partners might enhance SM use. OBJECTIVE: We aim to examine whether SM use differs among older patients with diabetes based on the involvement of care partner proxies. METHODS: This is a substudy of the ECLIPPSE (Employing Computational Linguistics to Improve Patient-Provider Secure Emails) project, a cohort study taking place in a large, fully integrated health care delivery system with an established digital patient portal serving over 4 million patients. Participants included patients with type 2 diabetes aged ≥50 years, newly registered on the patient portal, who sent ≥1 English-language message to their clinician between July 1, 2006, and December 31, 2015. Proxy SM was identified by having a registered proxy. To identify nonregistered proxies, a computational linguistics algorithm was applied to detect words and phrases more likely to appear in proxy messages compared to patient-authored messages. The primary outcome was the annual volume of secure messages (sent or received); secondary outcomes were the length of time to the first SM sent by patient or proxy and the number of annual SM exchanges (unique message topics generating ≥1 reply). RESULTS: The mean age of the cohort (N=7659) at this study's start was 61 (SD 7.16) years; 75% (n=5573) were married, 15% (n=1089) identified as Black, 10% (n=747) Chinese, 12% (n=905) Filipino, 13% (n=999) Latino, and 30% (n=2225) White. Further, 49% (n=3782) of patients used a proxy to some extent. Compared to nonproxy users, proxy users were older (P<.001), had lower educational attainment (P<.001), and had more comorbidities (P<.001). Adjusting for patient sociodemographic and clinical characteristics, proxy users had greater annual SM volume (20.7, 95% CI 20.2-21.2 vs 10.9, 95% CI 10.7-11.2; P<.001), shorter time to SM initiation (hazard ratio vs nonusers: 1.30, 95% CI 1.24-1.37; P<.001), and more annual SM exchanges (6.0, 95% CI 5.8-6.1 vs 2.9, 95% CI 2.9-3.0, P<.001). Differences in SM engagement by proxy status were similar across patient levels of education, and racial and ethnic groups. CONCLUSIONS: Among a cohort of older patients with diabetes, proxy SM involvement was independently associated with earlier initiation and increased intensity of messaging, although it did not appear to mitigate existing disparities in SM. These findings suggest care partners can enhance patient-clinician telecommunication in diabetes care. Future studies should examine the effect of care partners' SM involvement on diabetes-related quality of care and clinical outcomes.

Moving towards establishing centres of excellence in cardiac amyloidosis: an International Cardio-Oncology Society statement.

The prevalence of amyloidosis has been increasing, driven by a combination of improved awareness, evolution of diagnostic pathways, and effective treatment options for both transthyretin and light chain amyloidosis. Due to the complexity of amyloidosis, centralised expert providers with experience in delineating the nuances of confirmatory diagnosis and management may be beneficial. There are many potential benefits of a centre of excellence designation for the treatment of amyloidosis including recognition of institutions that have been leading the way for the optimal treatment of this condition, establishing the expectations for any centre who is engaging in the treatment of amyloidosis and developing cooperative groups to allow more effective research in this disease space. Standardising the expectations and criteria for these centres is essential for ensuring the highest quality of clinical care and community education. In order to define what components are necessary for an effective centre of excellence for the treatment of amyloidosis, we prepared a survey in cooperation with a multidisciplinary panel of amyloidosis experts representing an international consortium. The purpose of this position statement is to identify the essential elements necessary for highly effective clinical care and to develop a general standard with which practices or institutions could be recognised as a centre of excellence.

Novel computerized measure of apathy associates with care partner burden and instrumental activities of daily living in Parkinson's disease.

BACKGROUND: Impairment in goal-directed behavior (GDB) contributes to apathy, a prevalent syndrome in Parkinson's disease (PD). The Philadelphia Apathy Computerized Task (PACT) is a performance-based measure of GDB that may be less confounded by reduced patient insight, cognitive impairment, and care partner burnout. OBJECTIVE: To examine how the PACT is related to patient function and care partner burden. METHODS: PD patients with normal cognition (n = 19) or mild cognitive impairment (n = 14) and their care partners were recruited. Participants completed the PACT, a computerized paradigm consisting of subtasks specific to each component of GDB: initiation, motivation, and planning. Care partners completed the Zarit Burden Interview (ZBI) and the Penn Parkinson's Daily Activities Questionnaire (PDAQ-15). The associations between mean latency on each PACT subtask and ZBI and PDAQ-15 scores, respectively, were tested using Spearman's rank correlation coefficients. Significant associations were further delineated using multivariate regression with the following covariates: age, years of education, MoCA score, daily levodopa equivalency dose, UPDRS Part III score, and GDS-15 score. RESULTS: Worse performance on the planning subtask of the PACT related to higher ZBI scores and lower PDAQ-15 scores when adjusting for covariates. Decreased initiation was associated with higher ZBI and decreased motivation with lower PDAQ-15. CONCLUSIONS: Specific components of the PACT are related to patient and care partner outcomes in PD. The main advantage of this measure is to minimize the confounds of poor insight and care partner distress. We propose future research directions to refine the PACT for potential use in research and clinical practice.

Incremental Utility of First-Pass Perfusion CMR for Prognostic Risk Stratification of Cancer-Associated Cardiac Masses.

BACKGROUND: Cardiac magnetic resonance (CMR) differentiates cardiac metastasis (CMET) and cardiac thrombus (CTHR) based on tissue characteristics stemming from vascularity on late gadolinium enhancement (LGE). Perfusion CMR can assess magnitude of vascularity; utility for cardiac masses (CMASS) is unknown. OBJECTIVES: This study sought to determine if perfusion CMR provides diagnostic and prognostic utility for CMASS beyond binary differentiation of CMET and CTHR. METHODS: The population comprised adult cancer patients with CMASS on CMR; CMET and CTHR were defined using LGE-CMR: CMASS+ patients were matched to CMASS- control subjects for cancer type/stage. First-pass perfusion CMR was interpreted visually and semiquantitatively for CMASS vascularity, including contrast enhancement ratio (CER) (plateau vs baseline) and contrast uptake rate (CUR) (slope). Follow-up was performed for all-cause mortality. RESULTS: A total of 462 cancer patients were studied, including patients with (CMET = 173, CTHR = 69) and without CMASS on LGE-CMR. On perfusion CMR, CER and CUR were higher within CMET vs CTHR (P < 0.001); CUR yielded better performance (AUC: 0.89-0.93) than CER (AUC: 0.66-0.72) (both P < 0.001) to differentiate LGE-CMR-evidenced CMET and CTHR, although both CUR (P = 0.10) and CER (P = 0.01) typically misclassified CMET with minimal enhancement. During follow-up, mortality among CMET patients was high but variable; 47% of patients were alive 1 year post-CMR. Patients with semiquantitative perfusion CMR-evidenced CMET had higher mortality than control subjects (HR: 1.42 [95% CI: 1.06-1.90]; P = 0.02), paralleling visual perfusion CMR (HR: 1.47 [95% CI: 1.12-1.94]; P = 0.006) and LGE-CMR (HR: 1.52 [95% CI: 1.16-2.00]; P = 0.003). Among patients with CMET on LGE-CMR, mortality was highest among patients (P = 0.002) with lesions in the bottom perfusion (CER) tertile, corresponding to low vascularity. Among CMET and cancer-matched control subjects, mortality was equivalent (P = NS) among patients with lesions in the upper CER tertile (corresponding to higher lesion vascularity). Conversely, patients with CMET in the middle (P = 0.03) and lowest (lowest vascularity) (P = 0.001) CER tertiles had increased mortality. CONCLUSIONS: Perfusion CMR yields prognostic utility that complements LGE-CMR: Among cancer patients with LGE-CMR defined CMET, mortality increases in proportion to magnitude of lesion hypoperfusion.

SGLT2 Inhibitor Use and Risk of Clinical Events in Patients With Cancer Therapy-Related Cardiac Dysfunction.

BACKGROUND: Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart failure (HF). Sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF. OBJECTIVES: This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy-related cardiac dysfunction (CTRCD) or HF. METHODS: The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the TriNetX research network. Patients aged ≥18 years with a history of type 2 diabetes mellitus, cancer, and exposure to potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1, 2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period. RESULTS: The study cohort included 1,280 patients with CTRCD/HF (n = 640 per group; mean age: 67.6 years; 41.6% female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296 [95% CI: 0.22-0.40]; P = 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P = 0.003), acute kidney injury (OR: 0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839]; P = 0.012) were also less frequent in patients on SGLT2 inhibitors. CONCLUSIONS: SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF.

Management of Pericardial Effusion in Patients With Solid Tumor: An Algorithmic, Multidisciplinary Approach Results in Reduced Mortality After Paradoxical Hemodynamic Instability.

OBJECTIVE: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage versus interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts. BACKGROUND: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage. METHODS: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent s urgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020. RESULTS: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage ( P =0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs 4%; 90-day: 4% vs 6%, P =0.7) and mortality (30-day: 21% vs 17%, P =0.3; 90-day: 39% vs 37%, P =0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33-2.1] vs 6.5 mo [5.0-8.9], P <0.001; IR percutaneous drainage, 3.7 mo [0.23-6.8] vs 5.0 mo [4.0-8.1], P =0.044). CONCLUSIONS: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and postintervention intensive care resulted in lower incidence of PHI and improved outcomes.

Social enrichment alters the response of brain leukocytes to chemotherapy and tumor development in aged mice.

Aging is a risk factor for the development of breast cancer. Foundational science studies have supported associations among neuroinflammation, breast cancer, and chemotherapy, but to date, these associations are based on studies using young adult rodents. The current study examined the neuroinflammatory effects of chemotherapy in aged, tumor-naïve and tumor-bearing mice with or without social enrichment. Mice received two intravenous injections of doxorubicin (A) and cyclophosphamide (C) at a two-week interval. Brain immune cells were enriched/assessed via flow cytometry, seven days following the second chemotherapy injection. Social enrichment enhanced peripheral immune cell trafficking in aged tumor-naive mice treated with AC. Group housed aged tumor bearing mice receiving AC had reduced percentage of IL-6+ monocytes and granulocytes relative to their singly housed counterparts. Notably, group housing aged experimental mice with young cage partners significantly reduced TNF + monocytes, tumor volume, and tumor mass. These data illustrate the importance of social enrichment in attenuating neuroinflammation and are the first to demonstrate that social support with young housing partners reduces tumor growth in aged mice.

Clinical Outcomes in Hospitalized Patients with Cancer and New versus Preexistent Atrial Fibrillation.

BACKGROUND: There is limited information on the prognostic impact of new onset versus preexistent atrial fibrillation (AF) in hospitalized patients with cancer. OBJECTIVES: We sought to determine the clinical impact of new onset AF (NOAF) compared with preexistent AF in hospitalized patients with cancer. METHODS: All patients with cancer hospitalized over the course of one year with clinically manifest new or preexistent AF were enrolled in the Memorial Sloan Kettering Cancer Center (MSKCC) AF registry. The relationship of NOAF to the primary composite outcome of all cause death, cardiovascular (CV) rehospitalization or cerebrovascular event (CVE), as well as secondary CV endpoints, were analyzed using proportional hazards regression. Where applicable, the competing risk of death was accounted for using methodology described by Fine and Gray. RESULTS: Among 606 patients included in the analysis, 313 (51.7%) had NOAF and 293 (48.3%) had preexistent AF. Patients with NOAF were younger and had less frequent prior history of CV disease compared with patients with preexistent AF. At follow up, patients with NOAF had a higher adjusted hazard for the primary composite outcome versus patients with prior AF (HR 1.64, 95% CI 1.27, 2.13, p=0.002), as well as the secondary CV composite outcome of clinical AF recurrence, CV death, CV rehospitalization or CVE (HR 2.17, 95% CI 1.57, 2.99, P<0.0001). CONCLUSIONS: In hospitalized patients with cancer and electrocardiographically manifest new versus preexistent AF, NOAF was associated with a higher risk for the primary composite outcome of all-cause death, CV rehospitalization or CVE.

Sex hormone signaling and regulation of immune function.

Immune responses to antigens, including innocuous, self, tumor, microbial, and vaccine antigens, differ between males and females. The quest to uncover the mechanisms for biological sex differences in the immune system has intensified, with considerable literature pointing toward sex hormonal influences on immune cell function. Sex steroids, including estrogens, androgens, and progestins, have profound effects on immune function. As such, drastic changes in sex steroid concentrations that occur with aging (e.g., after puberty or during the menopause transition) or pregnancy impact immune responses and the pathogenesis of immune-related diseases. The effect of sex steroids on immunity involves both the concentration of the ligand and the density and distribution of genomic and nongenomic receptors that serve as transcriptional regulators of immune cellular responses to affect autoimmunity, allergy, infectious diseases, cancers, and responses to vaccines. The next frontier will be harnessing these effects of sex steroids to improve therapeutic outcomes.

Overdose and mortality risk following a non-fatal opioid overdose treated by Emergency Medical Services in King County, Washington.

BACKGROUND: Emergency Medical Services (EMS) agencies respond to hundreds of thousands of acute overdose events each year. We conducted a retrospective cohort study of EMS patients who survived a prior opioid overdose in 2019-2021 in King County, Washington. METHODS: A novel record linkage algorithm was applied to EMS electronic health records and the state vital statistics registry to identify repeat overdoses and deaths that occurred up to 3 years following the index opioid overdose. We measured overdose incidence rates and applied survival analysis techniques to assess all-cause and overdose-specific mortality risks. RESULTS: In the year following the index opioid overdose, the overdose (fatal or non-fatal) incidence rate was 23.3 per 100 person-year, overdose mortality rate was 2.7 per 100 person-year, and all-cause mortality rate was 5.2 per 100 person-year in this cohort of overdose survivors (n=4234). Overdose incidence was highest in the first 30 days following the index overdose (43 opioid overdoses and 4 fatal overdoses per 1000 person-months), declined precipitously, and then plateaued from the third month onwards (10-15 opioid overdoses and 1-2 fatal overdoses per 1000 person-months). Overdose incidence rates, measured at 30 days, were highest among overdose survivors who were young, male, and experienced a low severity index opioid overdose, but these differences diminished when measured at 12 months. CONCLUSIONS: Among EMS patients who survived an opioid overdose, the risk of subsequent overdose is high, especially in the weeks following the index opioid overdose. Non-fatal overdose may represent a pivotal time to connect patients with harm-reduction, treatment, and other support services.

Severe hypoglycemia and falls in older adults with diabetes: The Diabetes & Aging Study.

Objective: To estimate rates of severe hypoglycemia and falls among older adults with diabetes and evaluate their association. Research Design and Methods: Survey in an age-stratified, random sample adults with diabetes age 65-100 years; respondents were asked about severe hypoglycemia (requiring assistance) and falls in the past 12 months. Prevalence ratios (adjusted for age, sex, race/ethnicity) estimated the increased risk of falls associated with severe hypoglycemia. Results: Among 2,158 survey respondents, 79 (3.7%) reported severe hypoglycemia, of whom 68 (86.1%) had no ED visit or hospitalization for hypoglycemia. Falls were reported by 847 (39.2%), of whom 745 (88.0%) had no fall documented in outpatient or inpatient records. Severe hypoglycemia was associated with a 70% greater prevalence of falls (adjusted prevalence ratio = 1.7 (95% CI, 1.3-2.2)). Conclusion: While clinical documentation of events likely reflects severity or care-seeking behavior, severe hypoglycemia and falls are common, under-reported life-threatening events.

Functional similarity of ABP 959 and eculizumab in simulated serum models of aHUS and NMOSD.

ABP 959 is being developed as a biosimilar to Soliris® (eculizumab) reference product (RP), which was approved under orphan designation for a group of rare diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD). Development of biosimilars for therapeutics approved for rare disease indications must provide scientific rationale based on the totality of evidence (TOE). To support the TOE and the scientific justification for extrapolation to all approved indications for eculizumab RP, including but not limited to aHUS and NMOSD, we utilized simulated ex-vivo pharmacodynamic (PD) assessments to compare the complement component 5 (C5) inhibitory activity of ABP 959 and the RP. Hemolysis activity of CH50 and AH50, and Wieslab CP, AP, and LP endpoints represent the three complement activation pathways (classical, alternative, and lectin), all of which share the terminal pathway and require C5 for activity. These endpoints were evaluated in normal serum, simulated aHUS serum, and simulated NMOSD serum to provide a robust comparison. The results support the conclusion that ABP 959 and eculizumab RP exhibit highly similar inhibition of C5 function regardless of the type of serum used. This work presents a full comparison of the effect of C5 inhibition across five complement functional assays. Using this approach to confirm functional similarity of ABP 959 with eculizumab RP contributes to the TOE for biosimilarity and provides support for extrapolation based on inhibition of C5 function to other rare disease indications approved for eculizumab RP.