Effect of clinically significant thresholds of eosinophil elevation on health care resource use in asthma.

BACKGROUND: Blood eosinophil counts correlate with exacerbations, but there is a lack of consensus on a clinically relevant definition of eosinophil count elevation. OBJECTIVE: To analyze health care resource use among patients with elevated blood eosinophil counts defined at 150 cells/µL or greater and 300 cells/µL or greater. METHODS: Data on patients who received a diagnosis of asthma between 2007 and 2016 were extracted from EMRClaims + database. Patients were defined as having elevated eosinophil counts if any test result during 3 months before follow-up found blood eosinophil count of 150 cells/µL or more or 300 cells/µL or more. Hospitalizations, emergency department visits, outpatient visits, and associated costs were compared. With logistic regression, likelihood of hospitalization was assessed in the presence of eosinophil elevation. RESULTS: Among 3687 patients who met the study criteria, 1152 received a test within 3 months before the follow-up period, of whom 644 (56%) had elevated eosinophil counts of 150 cells/µL or greater and 322 (29%) had eosinophil counts of 300 cells/µL or greater. Overall, the mean (SD) number of hospitalizations for patients with elevated eosinophil counts vs the comparator was significantly greater (0.29 [0.92] vs 0.17 [0.57], P < .001 at ≥150 cells/µL and 0.30 [0.95] vs 0.18 [0.61] at ≥300 cells/µL, P = .001). The total mean cost was significantly greater for patients with elevated eosinophil counts (at ≥150 cells/µL: $10,262 vs $7149, P < .001 and at ≥300 cells/µL: $9966 vs $7468, P = .003). CONCLUSION: Patients with asthma incurred greater health care resource use when their blood eosinophil counts were elevated at 150 cells/µL or greater and 300 cells/µL or greater as measured within 3 months of follow-up.

Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma.

BACKGROUND: Although systemic corticosteroid (SCS) treatment, irrespective of duration or dosage, is associated with adverse outcomes for patients with asthma, the longitudinal effects of this treatment on adverse outcomes, healthcare resource utilization (HCRU), and healthcare costs are unknown. METHODS: We identified patients initiating intermittent or long-term SCS who were diagnosed with active asthma from UK general practice with linked secondary care data. Control (non-SCS) patients were matched by sex and index date with those initiating SCS. Minimum baseline period was 1 year prior to index date; minimum follow-up duration was 2 years post-index date. Cumulative incidence of SCS-associated adverse outcomes and associated HCRU and costs were compared between SCS and non-SCS patient groups and among average SCS daily exposure categories. Associations between exposure and annualized HCRU and costs were assessed, adjusted for confounders. RESULTS: Analyses included 9413 matched pairs. Median (interquartile range) follow up was as follows: SCS group: 7.1 (4.1-11.8) years; control group: 6.4 (3.8-10.0) years. Greater SCS dosages were correlated with greater cumulative incidence. For example, patients with type 2 diabetes receiving an average daily dosage of ≥7.5 mg had a 15-year cumulative incidence (37.5%) that was 1.5-5 times greater than those receiving lower dosages. HCRU and costs increased annually for SCS patients but not for non-SCS patients. Increases in all-cause adverse outcome (excluding asthma)-associated HCRU and costs were dose-dependent. CONCLUSIONS: Over the long term, adverse outcomes associated with SCS initiation were relatively frequent and costly, with a positive dosage-response relationship with SCS exposure.

Burden of asthma among patients adherent to ICS/LABA: A real-world study.

OBJECTIVES: Asthma is a chronic respiratory condition with a U.S. prevalence of 7.4%. Despite numerous treatment options, asthma remains poorly controlled in some patients. Uncontrolled asthma is associated with high healthcare resource utilization (HCRU) and reduced productivity. This study assessed symptoms, productivity, and HCRU of patients adherent to medium/high-dosage inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) treatment, and the relationship of asthma control with these parameters. METHODS: Data were collected in the U.S. in 2013-2016 in the Adelphi Respiratory Disease Specific Programme, a cross-sectional survey. Participating physicians (n = 258) each completed a record form for eligible patients, who were receiving medium/high-dosage ICS/LABA treatment with self-reported moderate/high adherence, completed the Asthma Control Test (ACT) and the Work Productivity and Activity Impairment (WPAI) questionnaire, and were included in the analyses. RESULTS: Patients (n = 428) had a mean of 59% symptom-free days in the past month. Wheezing was the most troublesome symptom for 25% of patients. In the previous 12 months, the mean number of exacerbations was 1.3; 15% of exacerbations required emergency room treatment and/or hospitalization. Mean physician visits for asthma was 5.7. Asthma impacted leisure/personal time frequently/constantly for 11% of patients, with 20% overall work impairment. Asthma was poorly controlled (ACT score ≤15) in 18% of patients; poorer asthma control was associated with higher rates of exacerbations, work impairment, and HCRU. CONCLUSION: Given the substantial burden described, greater attention to asthma monitoring and management is necessary. Identification of novel treatments may be important for patients not responding to medium/high-dosage ICS/LABA treatment.

Characterizing patients with asthma who received Global Initiative for Asthma steps 4-5 therapy and managed in a specialty care setting.

BACKGROUND: Severe asthma is recognized in the European Respiratory Society/American Thoracic Society guidelines as a major unmet need in the management of asthma. OBJECTIVE: The study objective was to describe the clinical burden of Global Initiative for Asthma (GINA) steps 4-5 asthma for patients treated by specialists in the U.S. community setting. METHODS: Patients, ages ≥12 years, with asthma who received GINA step 4 or 5 treatment and were treated at a large U.S. allergy practice network between January 1, 2010, and April 30, 2016, were retrospectively identified by using electronic health records. Clinical outcomes included lung function (forced expiratory volume in one second of expiration [FEV1] and FEV1% predicted), symptom control (Asthma Control Test [ACT]), the fractional exhaled nitric oxide (FeNO) value (FeNO ≥25 ppb indicates airway inflammation), and asthma medication use. The change in outcomes from baseline to 12 and 24 months after the index date was calculated. RESULTS: Of 120,116 patients with asthma, 12,922 (10.8%) had severe asthma, 68% (n = 8751) while on step 4 therapy. The mean baseline prebronchodilation FEV1% predicted was 79.7%, and the mean baseline ACT score was 17.0. With uncontrolled asthma defined as an ACT score of ≤19 and/or an FEV1 value of <80% predicted and/or oral corticosteroid use of ≥2 bursts, 52.5% and 57.7% of patients on step 4 and step 5 therapy, respectively, had uncontrolled asthma at baseline. Of a subset of patients, 40.9% had an eosinophil count of ≥300 cells/mm3 and 44% had an FeNO concentration of ≥25 ppb. Small increases in the FEV1 value were observed from baseline to 12 months (n = 4022) and 24 months (n = 2326) postindex (0.07 and 0.04 L, respectively). CONCLUSION: A considerable proportion of patients had uncontrolled asthma while on current GINA steps 4-5 treatment, which indicated that additional therapies may be required to reduce the clinical burden of severe asthma.

Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

BACKGROUND: Mesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression. METHODS: A retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM-1 expression determined by immunohistochemistry of peritoneum or omentum specimens. A prospective cohort of EOC patients was identified and followed through primary treatment. Serum for sVCAM-1 evaluation, which was performed via enzyme-linked immunosorbent assay, was collected before surgery or neoadjuvant chemotherapy and at each treatment cycle. Peritoneal specimens were obtained during debulking to assess mesothelial VCAM-1 expression. RESULTS: A retrospective review identified 54 advanced-stage EOC patients. Patients expressing mesothelium VCAM-1 had shortened overall survival (44 vs 79 months, P = 0.035) and progression-free survival (18 vs 67 months, P = 0.010); the median time to platinum resistance was 36 months for VCAM-1-expressing patients and not yet determined for the VCAM-1-negative group. In our prospective observational cohort, 18 EOC patients completed primary treatment; 3 were negative for mesothelium VCAM-1 expression, and sVCAM-1 did not vary between groups. CONCLUSIONS: Mesothelium VCAM-1 expression is negatively associated with progression-free and overall survival in EOC. This is especially compelling in light of previous data suggesting that persistent VCAM-1 expression during treatment is an indicator of platinum resistance. Our pilot study had insufficient cases to determine whether sVCAM-1 would substitute for mesothelium expression. Cancer 2017;123:977-84. © 2016 American Cancer Society.

Lobular Breast Cancer and Abdominal Metastases: A Retrospective Review and Impact on Survival.

BACKGROUND: The predominant breast cancer subtypes, invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC), have similar recurrence and survival rates but differing patterns of metastatic recurrence. METHODS: A retrospective review of breast cancers treated at an academic medical center from 1999 to 2012 was performed. Demographic, pathologic, treatment, and follow-up data were collected for 179 ILC and 358 IDC patients (1:2 stage-matched). The median follow-up was 4.7 years. RESULTS: The baseline characteristics were similar in the two groups. ILC was more likely to be hormone-receptor-positive/HER2-negative and mammographically occult. The number of surgical resections, breast conservation rate, systemic treatment, and taxane use was similar between the groups. The overall recurrence rate was the same. ILC recurred more often in the abdominal cavity (24.3% in ILC vs. 4.1% in IDC, p = 0.001). The disease-free survival and overall survival were equal. On multivariate analysis, age, stage of disease, hormone receptor status, and systemic therapy were associated with survival, but histology was not. CONCLUSIONS: Compared to ductal breast cancers, lobular breast cancers recur more often in the abdominal cavity. Both ILC and IDC have comparable surgical and medical treatment outcomes and survival. Our data suggest that enhanced surveillance and imaging might be useful in ILC.

Comparative effectiveness of budesonide/formoterol combination and fluticasone/salmeterol combination among chronic obstructive pulmonary disease patients new to controller treatment: a US administrative claims database study.

BACKGROUND: Inhaled corticosteroid/long-acting ß2-agonist combinations (ICS/LABA) have emerged as first line therapies for chronic obstructive pulmonary disease (COPD) patients with exacerbation history. No randomized clinical trial has compared exacerbation rates among COPD patients receiving budesonide/formoterol combination (BFC) and fluticasone/salmeterol combination (FSC) to date, and only limited comparative data are available. This study compared the real-world effectiveness of approved BFC and FSC treatments among matched cohorts of COPD patients in a large US managed care setting. METHODS: COPD patients (≥40 years) naive to ICS/LABA who initiated BFC or FSC treatments between 03/01/2009-03/31/2012 were identified in a geographically diverse US managed care database and followed for 12 months; index date was defined as first prescription fill date. Patients with a cancer diagnosis or chronic (≥180 days) oral corticosteroid (OCS) use within 12 months prior to index were excluded. Patients were matched 1-to-1 on demographic and pre-initiation clinical characteristics using propensity scores from a random forest model. The primary efficacy outcome was COPD exacerbation rate, and secondary efficacy outcomes included exacerbation rates by event type and healthcare resource utilization. Pneumonia objectives included rates of any diagnosis of pneumonia and pneumonia-related healthcare resource utilization. RESULTS: Matching of the identified 3,788 BFC and 6,439 FSC patients resulted in 3,697 patients in each group. Matched patients were well balanced on age (mean=64 years), gender (BFC: 52% female; FSC: 54%), prior COPD-related medication use, healthcare utilization, and comorbid conditions. During follow-up, no significant difference was seen between BFC and FSC patients for number of COPD-related exacerbations overall (rate ratio [RR]=1.02, 95% CI=[0.96,1.09], p=0.56) or by event type: COPD-related hospitalizations (RR=0.96), COPD-related ED visits (RR=1.11), and COPD-related office/outpatient visits with OCS and/or antibiotic use (RR=1.01). The proportion of patients diagnosed with pneumonia during the post-index period was similar for patients in each group (BFC =17.3%, FSC =19.0%, odds ratio=0.92 [0.81,1.04], p=0.19), and no difference was detected for pneumonia-related healthcare utilization by place of service. CONCLUSION: This study demonstrated no difference in COPD-related exacerbations or pneumonia events between BFC and FSC treatment groups for patients new to ICS/LABA treatment in a real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01921127 .

Women at extreme risk for obesity-related carcinogenesis: Baseline endometrial pathology and impact of bariatric surgery on weight, metabolic profiles and quality of life.

OBJECTIVES: The study objectives were to determine baseline endometrial histology in morbidly obese women undergoing bariatric surgery and to assess the surgical intervention's impact on serum metabolic parameters, quality of life (QOL), and weight. METHODS: Women undergoing bariatric surgery were enrolled. Demographic and clinicopathologic data, serum, and endometrium (if no prior hysterectomy) were collected preoperatively and serum collected postoperatively. Serum global biochemical data were assessed pre/postoperatively. Welch's two sample t-tests and paired t-tests were used to identify significant differences. RESULTS: Mean age of the 71 women enrolled was 44.2 years, mean body mass index (BMI) was 50.9 kg/m(2), and mean weight loss was 45.7 kg. Endometrial biopsy results: proliferative (13/30; 43%), insufficient (8/30; 27%), secretory (6/30; 20%) and hyperplasia (3/30; 10%-1 complex atypical, 2 simple). QOL data showed significant improvement in physical component scores (PCS means 33.9 vs. 47.2 before/after surgery; p<0.001). Twenty women underwent metabolic analysis which demonstrated significantly improved glucose homeostasis, improved insulin responsiveness, and free fatty acid levels. Significant perturbations in tryptophan, phenylalanine and heme metabolism suggested decreased inflammation and alterations in the intestinal microbiome. Most steroid hormones were not significantly impacted with the exception of decreased DHEAS and 4-androsten metabolites. CONCLUSIONS: Bariatric surgery is accompanied by an improved physical quality of life as well as beneficial changes in glucose homeostasis, insulin responsiveness, and inflammation to a greater extent than the hormonal milieu. The potential cancer protective effects of bariatric surgery may be due to other mechanisms other than simply hormonal changes.

VCAM-1 on peritoneum and α4ß1 integrin in endometrium and their implications in endometriosis.

The objective of the study is to investigate vascular cellular adhesion molecule-1 (VCAM-1) expression on peritoneal mesothelial cells and α4ß1 integrin on eutopic endometrium as possible mechanisms in the pathogenesis of endometriosis. It is a case-control study carried out at an academic medical center. Participants are patients with (n=9) and without (n=15) endometriosis. The main outcome measures included VCAM-1 expression on peritoneal mesothelial cells and α4ß1 expression on eutopic endometrium using immunohistochemistry and flow cytometry, respectively. Patients with endometriosis were more likely to express VCAM-1 on peritoneal mesothelial cells, both in areas with and without macroscopic disease, compared with patients without endometriosis (9/9 vs. 3/15, P<0.001). No differences were found between cases and controls in regards to eutopic endometrial expression of α4ß1 integrin. The presence of VCAM-1 on peritoneal mesothelial cells is associated with endometriosis. This field effect, in addition to the similarity found with regards to the expression of α4ß1 integrin in eutopic endometrium between cases and controls, may implicate the expression of VCAM-1 in the peritoneum, and not changes in the eutopic endometrium, as a contributor to the pathogenesis of endometriosis.

Inhibition of α4ß1 integrin increases ovarian cancer response to carboplatin.

OBJECTIVE: The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves α4ß1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin α4ß1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of α4ß1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-α4ß1 integrin function-blocking antibody. METHODS: Integrin α4ß1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-α4ß1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines. RESULTS: Treatment of tumor-bearing mice with human-specific α4ß1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-α4ß1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-α4ß1 integrin antibodies resulted in increased cell death and doubling time. CONCLUSIONS: Our findings support a role for α4ß1 integrin in regulating treatment response to carboplatin, implicating α4ß1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.

Prevalence of anaemia in adults with chronic kidney disease in a representative sample of the United States population: analysis of the 1999-2018 National Health and Nutrition Examination Survey.

Background: Population-based estimates of anaemia prevalence in patients with chronic kidney disease (CKD) vary, and data on the prevalence of severe anaemia of CKD are limited. This study examined the prevalence of anaemia and anaemia eligible for erythropoiesis-stimulating agent (ESA) treatment in patients with CKD in the USA. Methods: National Health and Nutrition Examination Survey (NHANES) data from 1999-2000 to 2017-18 were used to determine the prevalence of diagnosed anaemia (haemoglobin <12 g/dL in women; <13 g/dL in men) and anaemia eligible for ESA treatment (haemoglobin <10 g/dL) in survey participants aged ≥18 years with stage 3-5 non-dialysis-dependent CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). The study objectives were to (i) obtain a more recent estimate of anaemia prevalence in patients with non-dialysis-dependent CKD and (ii) examine the characteristics of individuals with CKD and haemoglobin <10 g/dL. Results: Of 51 163 eligible NHANES participants, 2926 (5.7%) with stage 3-5 CKD were included. In all participants, the weighted prevalences of anaemia and haemoglobin <10 g/dL were 25.3% and 1.9%, respectively. Mean haemoglobin levels decreased numerically between 1999 and 2012 and remained stable thereafter. The prevalence of anaemia and haemoglobin <10 g/dL increased with advancing CKD stage. The odds of haemoglobin <10 g/dL were significantly higher in stage ≥3B versus 3A and in non-Hispanic Blacks versus other races. Conclusions: In our analysis, approximately 25% of individuals with stage 3-5 CKD in the USA had anaemia and approximately 2% had anaemia eligible for ESA treatment.

Dichotomous ovarian cancer-initiating potential of Pax8+ cells revealed by a mouse genetic mosaic model.

Different cellular compartments within a tissue present distinct cancer-initiating capacities. Current approaches to dissect such heterogeneity require cell-type-specific genetic tools based on a well-understood lineage hierarchy, which are lacking for many tissues. Here, we circumvented this hurdle and revealed the dichotomous capacity of fallopian tube Pax8+ cells in initiating ovarian cancer, utilizing a mouse genetic system that stochastically generates rare GFP-labeled mutant cells. Through clonal analysis and spatial profiling, we determined that only clones founded by rare, stem/progenitor-like Pax8+ cells can expand on acquiring oncogenic mutations whereas vast majority of clones stall immediately. Furthermore, expanded mutant clones undergo further attrition: many turn quiescent shortly after the initial expansion, whereas others sustain proliferation and manifest a bias toward Pax8+ fate, underlying early pathogenesis. Our study showcases the power of genetic mosaic system-based clonal analysis for revealing cellular heterogeneity of cancer-initiating capacity in tissues with limited prior knowledge of lineage hierarchy.

The prevalence of predialysis hyperkalemia and associated characteristics among hemodialysis patients: The RE-UTILIZE study.

INTRODUCTION: Hyperkalemia (HK), defined as serum potassium (K+ ) >5.0 mEq/L, is an independent predictor of mortality in patients on maintenance hemodialysis (HD). This study investigated the annual prevalence of HK and examined patient characteristics potentially associated with a higher annual HK prevalence. METHODS: This retrospective observational cohort study used Dialysis Outcomes and Practice Patterns Study (DOPPS) survey data from US patients undergoing in-center HD thrice weekly from 2018 to 2019. The primary endpoint was the proportion of patients with any predialysis HK (K+ >5.0 mEq/L) within 1 year from the index date (date of DOPPS enrollment), using the first hyperkalemic K+ value. Secondary endpoints were the proportion of patients with moderate-to-severe (K+ >5.5 mEq/L) or severe (K+ >6.0 mEq/L) HK. FINDINGS: Overall, 9347 patients on HD were included in this analysis (58% male and 49% aged >66 years). Any predialysis HK (K+ >5.0 mEq/L) occurred in 74% of patients within 1 year of the index date, 52% within 3 months, and 38% within 1 month. The annual prevalence of moderate-to-severe and severe HK was 43% and 17%, respectively. Recurrent HK (at least two K+ >5.0 mEq/L within 1 year) occurred in 60% of patients, and 2.8% of patients were prescribed an oral K+ binder. Multivariable logistic regression analysis showed younger age, female sex, Hispanic ethnicity, and renin-angiotensin-aldosterone system inhibitor use were significantly associated with a higher annual prevalence of any predialysis HK, while Black race, obesity, recent initiation of HD, and dialysate K+ bath concentration ≥3 mEq/L were associated with a lower prevalence of HK. DISCUSSION: The annual prevalence of predialysis HK and recurrence were high among US patients on HD, whereas oral K+ binder use was low. Further studies are needed to understand the impact of dialysate K+ bath concentrations on predialysis HK among patients on HD.

Real-World Management of Hyperkalemia in the Emergency Department: An Electronic Medical Record Analysis.

INTRODUCTION: Hyperkalemia is often managed in the emergency department (ED) and it is important to understand how ED management and post-discharge outcomes vary by hyperkalemia severity. This study was conducted to characterize ED management and post-discharge outcomes across hyperkalemia severities. METHODS: Adults with an ED visit with hyperkalemia (at least one serum potassium lab measure above 5.0 mEq/L) were selected from US electronic medical record data (2012-2018). Patient characteristics, potassium levels, treatments, and monitoring prior to and during the ED visit were compared by hyperkalemia severity (mild [> 5.0-5.5 mEq/L], moderate [> 5.5-6.0], severe [> 6.0]) using unadjusted analyses. Death, immediate inpatient admission, 30-day hyperkalemia recurrence, and 30-day inpatient admission were also assessed by severity. RESULTS: Of 6222 patients included, 4432 (71.2%) had mild hyperkalemia, 1085 (17.4%) had moderate, and 705 (11.3%) had severe hyperkalemia. Chronic kidney disease (39.9-50.1%) and heart failure (21.6-24.3%) were common. In the ED, electrocardiograms (mild, 56.5%; moderate, 69.6%; severe, 81.0%) and patients with at least two potassium laboratory values increased with severity (15.0%; 40.4%; 75.5%). Among patients with at least two potassium laboratory values, over half of patients (60.4%) had potassium levels ≤ 5.0 mEq/L prior to discharge. Use of potassium-binding treatments (sodium polystyrene sulfonate: mild = 4.1%; moderate = 17.1%; severe = 27.4%), temporizing agents (5.6%; 15.5%; 31.6%), or dialysis (0.4%; 0.8%; 3.0%) increased with severity; treatment at discharge was not common. Death (1.1%; 3.7%; 10.6%), immediate admission to inpatient care (5.8%; 8.7%; 12.7%), 30-day hyperkalemia recurrence (2.9%; 19.0%; 32.5%), 30-day inpatient admission with hyperkalemia (6.5%; 7.9%; 9.3%) also increased with severity. CONCLUSION: Patients with moderate and severe hyperkalemia experienced elevated risk of hyperkalemia recurrence and hyperkalemia-related inpatient readmission following discharge from the ED from a descriptive analysis. Future research to assess strategies to reduce hyperkalemia recurrence and inpatient admission in this patient population would be beneficial.

Qualitative Methodology for Planning and Executing In-Person and Virtual Neurosurgery Educational Opportunities for Medical Students: Lessons Learned from Five Years of Medical Student Neurosurgery Training Center Initiatives.

INTRODUCTION: There is a growing need for collaborative and broad-scale medical student neurosurgery educational initiatives. Here, we propose a comprehensive methodology and structure for hosting both in-person and virtual learning opportunities for early trainees interested in clinical neurosciences. METHODS: We conducted an internal review of educational courses hosted by Medical Student Neurosurgery Training Center from 2017 to 2022. Inspired by the lessons learned from these activities, we examine the elements vital to the planning, production, funding, and execution of future programs. RESULTS: Six domains were deemed important for carrying out medical student neurosurgery educational opportunities: directorship, curriculum, logistics, faculty and instructor outreach, funding, and marketing. Each of these elements is discussed in detail for both in-person and web-based programs, as well as an examination of the advantages and disadvantages of various implementation strategies. CONCLUSIONS: Based on the Medical Student Neurosurgery Training Center experience, successful production and hosting of both in-person and virtual educational endeavors seems to be contingent on a collaborative effort by medical students, resident physicians, and neurosurgery faculty. Including medical students throughout the planning phase adds to the overall educational value of each experience and promotes program longevity and consumer engagement. Curricula should be guided by clear learning objectives and a variety of teaching modalities available to the organization. Finally, methods for assessing course outcomes are important, including institutional review board-approved data curation and analysis. Further investigation of neurosurgical learning outcome measurement is needed and has the potential to shape the future of medical student education and neurosurgery career preparation.

Inpatient management and post-discharge outcomes of hyperkalemia.

OBJECTIVES: Patients with hyperkalemia are commonly treated in the inpatient setting; however, real-world evidence is limited. The purpose of this study was to describe the inpatient management and post-discharge outcomes among patients with hyperkalemia. METHODS: Electronic medical record data (2012-2018) were used to analyze US adult patients with an inpatient stay with hyperkalemia (≥1 potassium value >5.0mEq/L). Patient characteristics, treatments, and monitoring six months prior to and during the inpatient stay, and hyperkalemia recurrence and inpatient readmissions post-discharge were summarized and compared among patients with mild (>5.0-5.5mEq/L), moderate (>5.5-6.0), and severe (>6.0) hyperkalemia. RESULTS: Of the 21,793 patients, 69.2% had mild, 19.0% had moderate, and 11.8% had severe hyperkalemia during inpatient care. The most common inpatient treatments were temporizing agents (mild: 28.9%; moderate: 46.0%; severe: 73.0%), diuretics (32.7%; 37.1%; 34.6%), and sodium-polystyrene sulfonate (11.7%; 27.8%; 45.3%). Almost no patients (0.1%) received a potassium binder at discharge. Most patients (86.8%) had their potassium levels return to ≤5.0mEq/L during the inpatient stay. Death during the inpatient stay occurred in 12.3% of mild, 15.5% of moderate, and 19.5% of severe hyperkalemic patients. Within 30 days of discharge, hyperkalemia recurred in 13.3%, 15.4%, and 18.4% of patients with mild, moderate, and severe hyperkalemia, respectively. Additionally, 19.7%, 21.5%, and 19.6% of patients were readmitted to inpatient care within 30 days post-discharge. CONCLUSION: Among patients with hyperkalemia in the inpatient setting, treatment and normalization of serum potassium levels were common. However, death, readmission, and hyperkalemia recurrence were also fairly common across all cohorts. Future studies examining measures to reduce inpatient death, readmission, and hyperkalemia recurrence among patients with hyperkalemia in inpatient care are warranted.

Determinants of Hyperkalemia Progression Among Patients with Mild Hyperkalemia.

INTRODUCTION: The progression of mild hyperkalemia and the predictors of progression have not been well characterized. In this study we aimed to characterize the progression of hyperkalemia and identify the risk factors for hyperkalemia progression. METHODS: Adults with mild hyperkalemia (at least one serum potassium measure > 5.0 and ≤ 5.5 mEq/L) were identified using electronic medical records from the Research Action for Health Network (2012-2018). Progression to moderate-to-severe and progression to severe hyperkalemia were defined as the first occurrences of a serum potassium measure > 5.5 and > 6.0 mEq/L, respectively. Kaplan-Meier analyses were conducted to estimate progression rates for all patients and by pre-specified patient subgroups. Hazard ratios (HR) of moderate-to-severe and severe hyperkalemia progression were estimated using Cox models. RESULTS: Of 35,369 patients with mild hyperkalemia, 16.9% and 8.7% progressed to moderate-to-severe and severe hyperkalemia, respectively. Rates of hyperkalemia progression elevated with the severity of chronic kidney disease (CKD). The highest progression rates were seen in patients with CKD stage 5 (stage 5 vs. no CKD: moderate-to-severe, 50.2% vs. 12.0%; severe, 31.3% vs. 3.9%; p < 0.001). Higher progression rates were also observed in patients with heart failure, hypertension, and type II diabetes compared with patients without those conditions (all p < 0.001). The most prominent risk factors were CKD stage 5 (HR of progression to moderate-to-severe hyperkalemia, 3.32 [95% CI 3.03-3.64]; severe, 4.08 [3.55-4.69]), CKD stage 4 (2.19 [1.97-2.43], 2.28 [1.92-2.71]), CKD stage 3 (1.57 [1.46-1.68], 1.65 [1.46-1.87]), type I diabetes (1.37 [1.18-1.61], 1.54 [1.23-1.93]), and serum potassium (1.12 [1.10-1.15], 1.13 [1.10-1.17] per 0.1 mEq/L increase) (all p values < 0.05). CONCLUSION: Hyperkalemia progression rates increased significantly with CKD stage and were also higher among patients with higher baseline potassium level, heart failure, hypertension, and diabetes.

Prevalence of Metabolic Acidosis Among Patients with Chronic Kidney Disease and Hyperkalemia.

INTRODUCTION: Although hyperkalemia and metabolic acidosis often co-occur in patients with chronic kidney disease (CKD), the prevalence of metabolic acidosis among patients with CKD and hyperkalemia is understudied. Therefore, we used medical record data from the Research Action for Health Network to estimate this prevalence. METHODS: Adult patients with CKD stage 3-5, ≥ 1 outpatient potassium value > 5.0 mEq/l, and ≥ 1 outpatient bicarbonate value available were identified. Patients with end stage kidney disease (ESKD) in the prior year were excluded. The prevalence of metabolic acidosis in each calendar year from 2014 to 2017 among patients with CKD and hyperkalemia was estimated using two definitions of hyperkalemia (potassium > 5.0 mEq/l and > 5.5 mEq/l) and metabolic acidosis (bicarbonate < 18 mEq/l and < 22 mEq/l). RESULTS: In the 2017 patient cohort and among patients with CKD and hyperkalemia, patients with metabolic acidosis were younger (69 versus 74 years), more likely to have advanced CKD (35% versus 13%), and use oral sodium bicarbonate (21% versus 4%) than patients without metabolic acidosis. The prevalence of metabolic acidosis (< 22 mEq/l) ranged from 25 to 29% when hyperkalemia was defined by potassium > 5.0 mEq/l and ranged from 33 to 39% when hyperkalemia was defined by potassium > 5.5 mEq/l. CONCLUSION: Results demonstrated that prevalence estimates of metabolic acidosis varied based on the definition of hyperkalemia and metabolic acidosis utilized.

Budesonide/formoterol therapy: effective and appropriate use in asthma and chronic obstructive pulmonary disease.

Aim: Quality, real-world comparative effectiveness (CE) studies of asthma and chronic obstructive pulmonary disease therapy efficacy are scarce. We identified and evaluated peer-reviewed CE and appropriate-use evaluations of budesonide/formoterol combination (BFC) maintenance therapy. Materials & methods: Analyses were limited to retrospective, real-world utilization studies of BFC delivered by pressurized metered-dose inhalers. Results: In a CE study of BFC versus fluticasone/salmeterol combinations (FSC) in asthma, BFC users had fewer total exacerbations. In appropriate-use studies of asthma treatment, BFC patients were consistently more likely to meet treatment escalation recommendations. BFC comparisons with FSC or tiotropium for chronic obstructive pulmonary disease found differences in exacerbation rates and rescue inhaler use. Conclusion: We found available, good quality BFC CE and appropriate-use articles; however, all had limitations.

Notch3 signaling promotes tumor cell adhesion and progression in a murine epithelial ovarian cancer model.

High grade serous ovarian cancer (HGSC) is the most common and deadly type of ovarian cancer, largely due to difficulties in early diagnosis and rapid metastasis throughout the peritoneal cavity. Previous studies have shown that expression of Notch3 correlates with worse prognosis and increased tumorigenic cell behaviors in HGSC. We investigated the mechanistic role of Notch3 in a model of metastatic ovarian cancer using the murine ovarian surface epithelial cell line, ID8 IP2. Notch3 was activated in ID8 IP2 cells via expression of the Notch3 intracellular domain (Notch3IC). Notch3IC ID8 IP2 cells injected intraperitoneally caused accelerated ascites and reduced survival compared to control ID8 IP2, particularly in early stages of disease. We interrogated downstream targets of Notch3IC in ID8 IP2 cells by RNA sequencing and found significant induction of genes that encode adhesion and extracellular matrix proteins. Notch3IC ID8 IP2 showed increased expression of ITGA1 mRNA and cell-surface protein. Notch3IC-mediated increase of ITGA1 was also seen in two human ovarian cancer cells. Notch3IC ID8 IP2 cells showed increased adhesion to collagens I and IV in vitro. We propose that Notch3 activation in ovarian cancer cells causes increased adherence to collagen-rich peritoneal surfaces. Thus, the correlation between increased Notch3 signaling and poor prognosis may be influenced by increased metastasis of HGSC via increased adherence of disseminating cells to new metastatic sites in the peritoneum.