Citations

AbstractIron overload is a severe general complication of hereditary anemias. Treatment with iron chelators is hampered by important side‐effects, high costs, and the lack of availability in many countries with a high prevalence of hereditary anemias. In this phase III randomized placebo‐controlled trial, we assigned adults with non‐transfusion‐dependent hereditary anemias with mild‐to‐moderate iron overload to receive esomeprazole (at a dose of 40 mg twice daily) or placebo for 12 months in a cross‐over design. The primary end point was change of liver iron content measured by MRI. A total of 30 participants were enrolled in the trial. Treatment with esomeprazole resulted in a statistically significant reduction in liver iron content that was 0.55 mg Fe/g dw larger than after treatment with placebo (95%CI [0.05 to 1.06]; p = 0.03). Median baseline liver iron content at the start of esomeprazole was 4.99 versus 4.49 mg Fe/g dw at start of placebo. Mean delta liver iron content after esomeprazole treatment was −0.57 (SD 1.20) versus −0.11 mg Fe/g dw (SD 0.75) after placebo treatment. Esomeprazole was well tolerated, reported adverse events were mild and none of the patients withdrew from the study due to side effects. In summary, esomeprazole resulted in a significant reduction in liver iron content when compared to placebo in a heterogeneous group of patients with non‐transfusion‐dependent hereditary anemias. From an international perspective this result can have major implications given the fact that proton pump inhibitors may frequently be the only realistic therapy for many patients without access to or not tolerating iron chelators.

Abstract Objective To assess the utility of the novel patient‐identified (PI) most bothersome symptom (MBS) measure from PROMISE‐2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. Background Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI‐MBS could improve clinical decision‐making. Methods In PROMISE‐2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses ( n = 1072). PI‐MBS was an exploratory outcome requiring each patient to self‐report their MBS in response to an open‐ended question. At baseline and week 12, patients rated overall improvement in PI‐MBS. The relationships among PI‐MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9–12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6‐item Headache Impact Test total, EuroQol 5‐dimensions 5‐levels visual analog scale, and 36‐item Short‐Form Health Survey component scores were assessed. Results Treatment groups had similar baseline characteristics and reported a total of 23 unique PI‐MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI‐MBS at week 12 correlated with changes in MMDs ( ρ = −0.49; p < 0.0001) and other patient‐reported outcomes. Controlling for changes in MMDs, PI‐MBS improvement predicted other patient‐reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI‐MBS were 0.31 ( p < 0.0001 vs. placebo) and 0.54 ( p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. Conclusions Improvement in PI‐MBS at week 12 was associated with improvement in other patient‐reported outcome measures, and PI‐MBS may be an important patient‐centered measure of treatment benefits in patients with chronic migraine.

Objective The objective of this study was to determine whether a triple therapy regimen incorporating twice-daily saquinavir is as effective as a three-times daily regimen. Methods This was an open-label, Phase III, multicentre, 48-week study involving 837 HIV-1-infected patients randomised to one of the following: saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1600 mg twice-daily, plus two NRTIs (arm B); saquinavir SGC 1200 mg twice-daily and nelfinavir 1250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was the virological response in arm A versus B and in arm A versus C with respect to the percentage of patients whose plasma HIV-1 RNA levels fell below the level of quantification for the Amplicor assay (<400 copies/ml) at weeks 24 and 48. Results At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels <400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the intention-to-treat analysis. The treatment difference between arm B–arm A was -1.8% (95% confidence intervals -10.1, 6.5) and for arm C–arm A was -4.5% (95% confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These differences fell within the maximum allowable difference (±12%) for arm B compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels <400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C). Conclusions A twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs was of equivalent efficacy to the three-times daily regimen studied. All regimens were generally well tolerated.

Background Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. Methods In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. Results Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. Conclusions Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. Trial registration number NCT02475213.

Cardiovascular disease surveillance involves quantifying the evolving population‐level burden of cardiovascular outcomes and risk factors as a data‐driven initial step followed by the implementation of interventional strategies designed to alleviate this burden in the target population. Despite widespread acknowledgement of its potential value, a national surveillance system dedicated specifically to cardiovascular disease does not currently exist in the United States. Routinely collected health care data such as from electronic health records (EHRs) are a possible means of achieving national surveillance. Accordingly, this article elaborates on some key strengths and limitations of using EHR data for establishing a national cardiovascular disease surveillance system. Key strengths discussed include the: (1) ubiquity of EHRs and consequent ability to create a more “national” surveillance system, (2) existence of a common data infrastructure underlying the health care enterprise with respect to data domains and the nomenclature by which these data are expressed, (3) longitudinal length and detail that define EHR data when individuals repeatedly patronize a health care organization, and (4) breadth of outcomes capable of being surveilled with EHRs. Key limitations discussed include the: (1) incomplete ascertainment of health information related to health care–seeking behavior and the disconnect of health care data generated at separate health care organizations, (2) suspect data quality resulting from the default information‐gathering processes within the clinical enterprise, (3) questionable ability to surveil patients through EHRs in the absence of documented interactions, and (4) the challenge in interpreting temporal trends in health metrics, which can be obscured by changing clinical and administrative processes.

Introduction: The Framingham Heart Study Dementia Risk Score (FDRS) was developed in a general population of elderly individuals. It is unknown how the FDRS variables predict dementia in heart failure (HF) and atrial fibrillation (AF) populations. Thus, we aimed to evaluate the predictive ability of the FDRS variables in population-based cohorts of individuals with HF and AF and to determine whether the addition of other comorbidities and risk factors improves risk prediction for dementia. Methods: Residents aged ≥50 from 7 southeast MN counties with a first diagnosis of HF (ICD-9 428/ICD-10 I50) or AF (ICD-9 427.3/ICD-10 I48 with AF on electrocardiogram/Holter monitor) between 1/1/2013 and 12/31/2017 were identified. Patients with dementia (defined by ICD codes) prior to or within 6 months after their index event and patients who died within 6 months after index were excluded. For both cohorts, models were constructed to predict dementia ≥ 6 months post index including the variables in the FDRS (age, marital status, BMI, stroke/TIA, diabetes and cancer). Additional comorbidities and risk factors were added to the models. For all models c-statistics were calculated. Results: Among 3,291 patients with HF (mean age 76 years, 53% male), 626 cases of dementia occurred and among 4,107 patients with AF (mean age 74 years, 57% male), 736 cases of dementia occurred. Among patients with HF, the FDRS variables predicted dementia with a c-statistic of 0.68 (Table). Adding additonal comorbidities and risk factors impoved the c-statistic slightly to 0.69 (p=0.01). Among patients with AF, the FDRS variables also performed well (c-stastic: 0.73; Table) and adding other comorbidities and risk factors improved the performance (c-statistic: 0.75; p<0.01). Conclusions: The variables from the FDRS predict dementia well in both HF and AF populations. The addition of comorbidities and other CVD risk factors only modestly improved prediction, thus indicating that the FDRS variables are appropriate to predict dementia in patients with HF and AF.

Background Electronic medical records are increasingly used to identify disease cohorts; however, computable phenotypes using electronic medical record data are often unable to distinguish between prevalent and incident cases. Methods and Results We identified all Olmsted County, Minnesota residents aged ≥18 with a first‐ever International Classification of Diseases, Ninth Revision (ICD‐9) diagnostic code for atrial fibrillation or atrial flutter from 2000 to 2014 (N=6177), and a random sample with an International Classification of Diseases, Tenth Revision (ICD‐10) code from 2016 to 2018 (N=200). Trained nurse abstractors reviewed all medical records to validate the events and ascertain the date of onset (incidence date). Various algorithms based on number and types of codes (inpatient/outpatient), medications, and procedures were evaluated. Positive predictive value (PPV) and sensitivity of the algorithms were calculated. The lowest PPV was observed for 1 code (64.4%), and the highest PPV was observed for 2 codes (any type) >7 days apart but within 1 year (71.6%). Requiring either 1 inpatient or 2 outpatient codes separated by >7 days but within 1 year had the best balance between PPV (69.9%) and sensitivity (95.5%). PPVs were slightly higher using ICD‐10 codes. Requiring an anticoagulant or antiarrhythmic prescription or electrical cardioversion in addition to diagnostic code(s) modestly improved the PPVs at the expense of large reductions in sensitivity. Conclusions We developed simple, exportable, computable phenotypes for atrial fibrillation using structured electronic medical record data. However, use of diagnostic codes to identify incident atrial fibrillation is prone to some misclassification. Further study is warranted to determine whether more complex phenotypes, including unstructured data sources or using machine learning techniques, may improve the accuracy of identifying incident atrial fibrillation.

Background: Some patients with heart failure (HF) will go on to develop advanced HF, characterized by severe HF symptoms despite attempts to optimize medical therapy. The goals of this study were to examine the risk of developing advanced HF in patients with newly diagnosed HF, identify risk factors for developing advanced HF, and evaluate the impact of advanced HF on outcomes. Methods: This was a population-based, retrospective cohort study of Olmsted County, Minnesota, residents with a new clinical diagnosis of HF between 2007 and 2017. Risk factors for the development of advanced HF (2018 European Society of Cardiology criteria) were examined using cause-specific Cox proportional hazard regression models. The associations of development of advanced HF with risks of hospitalization and mortality were examined using the Andersen-Gill and Cox models, respectively. Results: There were 4597 residents with incident HF from 2007 to 2017. The cumulative incidence of advanced HF was 11.5% (95% CI, 10.5%–12.5%) at 6 years after incident HF diagnosis overall and was 14.4% (95% CI, 12.3%–16.9%), 11.4% (95% CI, 8.9%–14.6%), and 11.7% (95% CI, 10.3%–13.2%) in patients with incident HF with reduced, mildly reduced, and preserved ejection fraction, respectively. Key demographics, comorbidities, and echocardiographic characteristics were independently associated with the development of advanced HF. Development of advanced HF was associated with increased risks of all-cause hospitalization (adjusted hazard ratio, 3.0 [95% CI, 2.7–3.4]; P <0.001), HF hospitalization (hazard ratio, 10.2 [95% CI, 8.7–12.1]), all-cause mortality (hazard ratio, 5.0 [95% CI, 4.5–5.6]; P <0.001), and cardiovascular mortality (hazard ratio, 7.8 [95% CI, 6.7–9.1]). Conclusions: In this population-based study, development of advanced HF was common and was associated with markedly increased morbidity and mortality.

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P &lt; 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6). In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Our study suggests a limited role of gene–environment interactions in breast cancer risk.

BACKGROUND: “Moral distress” describes the psychological strain a provider faces when unable to uphold professional values because of external constraints. Recurrent or intense moral distress risks moral injury, burnout, and physician attrition but has not been systematically studied among neurosurgeons. OBJECTIVE: To develop a unique instrument to test moral distress among neurosurgeons, evaluate the frequency and intensity of scenarios that may elicit moral distress and injury, and determine their impact on neurosurgical burnout and turnover. METHODS: An online survey investigating moral distress, burnout, and practice patterns was emailed to attending neurosurgeon members of the Congress of Neurological Surgeons. Moral distress was evaluated through a novel survey designed for neurosurgical practice. RESULTS: A total of 173 neurosurgeons completed the survey. Half of neurosurgeons (47.7%) reported significant moral distress within the past year. The most common cause was managing critical patients lacking a clear treatment plan; the most intense distress was pressure from patient families to perform futile surgery. Multivariable analysis identified burnout and performing ≥2 futile surgeries per year as predictors of distress ( P < .001). Moral distress led 9.8% of neurosurgeons to leave a position and 26.6% to contemplate leaving. The novel moral distress survey demonstrated excellent internal consistency (Cronbach alpha = 0.89). CONCLUSION: We developed a reliable survey assessing neurosurgical moral distress. Nearly, half of neurosurgeons suffered moral distress within the past year, most intensely from external pressure to perform futile surgery. Moral distress correlated with burnout risk caused 10% of neurosurgeons to leave a position and a quarter to consider leaving.