An Unusual Case of Bicuspid Aortic Valve With Prolapse Masquerading as Cusp Perforation.

We present a unique clinical scenario of a 58-year-old male with a past medical history of hypertension who initially presented with chest pain and was ruled in for non-ST elevation myocardial infarction (NSTEMI) but rapidly developed respiratory failure secondary to aortic insufficiency complicated by cardiogenic shock (CS), attributed to aortic valve prolapse. Intriguingly, the patient had a normal ECG on presentation, underscoring the dynamic nature of valvular pathology. The development of CS highlights the importance of early recognition, prompt diagnosis, and interdisciplinary management in such complex cases.

Amiodarone-Associated Optic Neuropathy in a Patient With Associated Arrhythmia.

Amiodarone is a commonly used antiarrhythmic used to treat atrial fibrillation and ventricular tachycardias. While this agent can present with pulmonary, thyroid, and hepatic side effects, it can also, less commonly cause neurologic toxicity, particularly optic neuropathy. Optic neuropathy can manifest as acute vision loss. The management of amiodarone-associated optic neuropathy (AAON) includes early recognition of symptom manifestation so that the medication can be discontinued promptly. Here, we describe a case of a 64-year-old male who developed acute onset complete left-sided vision loss after initiation of amiodarone.

Heart in Disguise: Unmasking a Novel Gene Deletion in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is an underrecognized condition with a myriad of etiologies, but it is often labeled idiopathic. However, genetic mutations are emerging as a more common cause of idiopathic DCM than previously believed. Herein, we present a case of a previously healthy 45-year-old woman who presented with three weeks of exertional dyspnea and orthopnea. An echocardiogram showed DCM with severely reduced systolic function and diastolic dysfunction. She was extensively worked up for potential etiologies of her heart failure which included HIV testing, parasite smear, viral serologies, autoimmune testing, cardiac MRI for infiltrative diseases, and coronary catheterization. She was ultimately tested for genetic mutations which revealed a 49-51 exon deletion of the dystrophin (Duchenne muscular dystrophy (DMD)) gene. This case highlights the guideline-based evaluation and management of new-onset heart failure in a healthy 45-year-old female without known predisposing risk factors or family history. It also sheds light on the expansive genetic etiologies that have only recently been identified in those with idiopathic cardiomyopathy. Further research is crucial to improve our understanding of genetic associations of cardiomyopathy.

Social Determinants of Digital Health Adoption: Pilot Cross-sectional Survey.

BACKGROUND: Interest in and funding for digital health interventions have rapidly grown in recent years. Despite the increasing familiarity with mobile health from regulatory bodies, providers, and patients, overarching research on digital health adoption has been primarily limited to morbidity-specific and non-US samples. Consequently, there is a limited understanding of what personal factors hold statistically significant relationships with digital health uptake. Moreover, this limits digital health communities' knowledge of equity along digital health use patterns. OBJECTIVE: This study aims to identify the social determinants of digital health tool adoption in Georgia. METHODS: Web-based survey respondents in Georgia 18 years or older were recruited from mTurk to answer primarily closed-ended questions within the following domains: participant demographics and health consumption background, telehealth, digital health education, prescription management tools, digital mental health services, and doctor finder tools. Participants spent around 15 to 20 minutes on a survey to provide demographic and personal health care consumption data. This data was analyzed with multivariate linear and logistic regressions to identify which of these determinants, if any, held statistically significant relationships with the total number of digital health tool categories adopted and which of these determinants had absolute relationships with specific categories. RESULTS: A total of 362 respondents completed the survey. Private insurance, residence in an urban area, having a primary care provider, fewer urgent emergency room (ER) visits, more ER visits leading to inpatient stays, and chronic condition presence were significantly associated with the number of digital health tool categories adopted. The separate logistic regressions exhibited substantial variability, with 3.5 statistically significant predictors per model, on average. Age, federal poverty level, number of primary care provider visits in the past 12 months, number of nonurgent ER visits in the past 12 months, number of urgent ER visits in the past 12 months, number of ER visits leading to inpatient stays in the past 12 months, race, gender, ethnicity, insurance, education, residential area, access to the internet, difficulty accessing health care, usual source of care, status of primary care provider, and status of chronic condition all had at least one statistically significant relationship with the use of a specific digital health category. CONCLUSIONS: The results demonstrate that persons who are socioeconomically disadvantaged may not adopt digital health tools at disproportionately higher rates. Instead, digital health tools may be adopted along social determinants of health, providing strong evidence for the digital health divide. The variability of digital health adoption necessitates investing in and building a common framework to increase mobile health access. With a common framework and a paradigm shift in the design, evaluation, and implementation strategies around digital health, disparities can be further mitigated and addressed. This likely will begin with a coordinated effort to determine barriers to adopting digital health solutions.

A Late Diagnosis of Transthyretin Amyloidosis.

Cardiac amyloidosis is a rare disease caused by the accumulation of protein-based fibrils that deposit into the myocardium, causing disease. The accumulation of amyloid in the heart tissue causes the heart to become increasingly stiff, reducing compliance, with the eventual decline of the heart's systolic function over time as the disease progresses. The restrictive physiology of the disease usually prompts investigation; however, if allowed to progress, the systolic function becomes affected in the later stages of the disease. We present a case of late-stage transthyretin-related amyloidosis (ATTR).

Improving eligibility criteria for first-line trials for patients with DLBCL using a US-based Delphi-method survey.

Recent first-line randomized controlled trials (RCTs) for patients with diffuse large B-cell lymphoma (DLBCL) have shown negative results, which may be due in part to onerous eligibility criteria limiting enrollment of poor-risk patients who require immediate treatment. We conducted a Delphi-method survey with lymphoma experts in the United States to define recommendations for essential and potentially unnecessary enrollment criteria for modern first-line DLBCL RCTs aimed at increasing clinical diversity of ensuing study groups. We first tabulated enrollment criteria from 19 DLBCL RCTs spanning the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) era to identify common eligibility criteria from prior DLBCL RCTs for inclusion in the Delphi-method survey. We tabulated 451 total eligibility criteria comprising 51 criterion categories across 19 first-line DLBCL RCTs in the R-CHOP era. We then surveyed lymphoma clinical trial experts representing 8 academic medical centers in the United States regarding essential and unnecessary eligibility criteria for modern DLBCL RCTs. Seventeen of 29 invited clinical investigators completed the round-1 questionnaire (response rate, of 58.6%), 15 of 17 round-1 participants (88.2%) completed the round-2 survey, and all round-1 participants reviewed finalized recommendations for eligibility criteria for modern first-line DLBCL RCTs. We defined consensus recommendations for 31 modernized eligibility criteria including threshold values for 10 quantitative eligibility criteria aimed at facilitating enrollment of a clinically diverse study population in first-line DLBCL RCTs designed to improve standard-of-care therapy.

Retrospective analysis of trends in surgery volumes between 2016 and 2019 and impact of the insurance deductible: Cross-sectional study.

BACKGROUND: Understanding trends in surgical volumes can help Ambulatory Surgery Centers (ASCs) prevent clinician burnout and provide adequate staffing while maintaining the quality of patient care throughout the year. Health insurance deductibles reset in January each year and may contribute to an annual rhythm where the levee of year-end deductibles is breached in the last few months of every year, resulting in a flood of cases and several accompanying challenges. This study aims to identify and analyze monthly and yearly surgical volume patterns in ASCs and explore a relationship with the deductible reset. METHODS: De-identified, aggregate visit data for 2016-2019 were obtained retrospectively from 14 ambulatory surgery centers within the same benchmarking consortium in the Southeast. The ASCs subspecialty types consisted of orthopedics, urology, otolaryngology, and multispecialty. Kaiser Family Foundation survey data from 2016 to 2019 was used to inform deductible trends. Augmented Dickey-Fuller tests, linear regressions, and two-sample T-tests were conducted to explore and establish patterns in surgical volume between 2016 and 2019. RESULTS: Overall, average orthopedic surgical volume increased 38.04% from January to December in 2016-2019 with an average difference of 64 cases (95% CI: 47-80), while that of all ASCs combined increased 19.24% within the same timeframe with an average difference of 37 cases (95% CI: 21-52). Average health insurance deductibles rose 12% from $1476 to $1655 within the same timeframe. Regression analysis showed a stronger association between year and volume for orthopedic ASCs (R (Claxton et al., 2019) [2] = 0.796) than for all ASCs combined (R (Claxton et al., 2019) [2] = 0.645). Regression analysis also showed a stronger association between month and volume for orthopedic ASCs (R (Claxton et al., 2019) [2] = 0.488-0.805) than for all ASCs combined (R (Claxton et al., 2019) [2] = 0.115-0.493). CONCLUSION: This study is first to identify regular and predictable yearly and monthly increases in orthopedic ASCs surgical volume. The study also identifies yearly increases in surgical volume for all ASCs. The combination of increasing yearly demand for orthopedic surgery and growing association between month and volume leads to an unnecessary year-end rush. The study aims to inform future policy decisions as well as help ASCs better manage resources throughout the year.

Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.

BACKGROUND: Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities. METHODS: To understand the influences of genetic ancestry on tumor genomic alterations, the authors estimated the genetic ancestry of 1001 previously described patients with DLBCL using unsupervised model-based Admixture global ancestry analysis applied to exome sequencing data and examined the mutational profile of 150 DLBCL driver genes in tumors obtained from this cohort. RESULTS: Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared with patients with DLBCL with European ancestry, patients with African ancestry were aged >10 years younger at the time of diagnosis and were more likely to present with B symptoms, elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. Patients with African ancestry demonstrated worse overall survival compared with patients with European ancestry (median, 4.9 years vs 8.8 years; P = .04). Recurrent mutations of MLL2 (KMT2D), HIST1H1E, MYD88, BCL2, and PIM1 were found across all ancestry groups, suggesting shared mechanisms underlying tumor biology. The authors also identified 6 DLBCL driver genes that were more commonly mutated in patients with African ancestry compared with patients with European ancestry: ATM (21.0% vs 7.75%; P < .001), MGA (19.7% vs 5.33%; P < .001), SETD2 (17.3% vs 5.17%; P < .001), TET2 (12.3% vs 5.82%; P = .029), MLL3 (KMT2C) (11.1% vs 4.36%; P = .013), and DNMT3A (11.1% vs 4.52%; P = .016). CONCLUSIONS: Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. To the authors' knowledge, the results of the current study provide the first-ever characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL.

Using Informatics Tools to Identify Opportunities for Precision Medicine in Diffuse Large B-cell Lymphoma.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is genetically and clinically heterogeneous. Despite advances in genomic subtyping, standard frontline chemoimmunotherapy has remained unchanged for years. As high-throughput analysis becomes more accessible, characterizing drug-gene interactions in DLBCL could support patient-specific treatment strategies. MATERIALS AND METHODS: From our systematic literature review, we compiled a comprehensive list of somatic mutations implicated in DLBCL. We extracted reported and primary sequencing data for these mutations and assessed their association with signaling pathways, cell-of-origin subtypes, and clinical outcomes. RESULTS: Twenty-two targetable mutations present in ≥ 5% of patients with DLBCL were associated with unfavorable outcomes, yielding a predicted population of 31.7% of DLBCL cases with poor-risk disease and candidacy for targeted therapy. A second review identified 256 studies that had characterized the drug-gene interactions for these mutations via in vitro studies, mouse models, and/or clinical trials. CONCLUSIONS: Our novel approach linking the data from our systematic reviews with informatics tools identified high-risk DLBCL subgroups, DLBCL-specific drug-gene interactions, and potential populations for precision medicine trials.

Cost-effectiveness of New Targeted Agents in the Treatment of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is clinically heterogeneous. Integration of oral targeted therapies (OTTs) in the management of CLL has fundamentally altered CLL treatment pathways and improved outcomes for patients with CLL.We review the cost-effectiveness of OTTs in the treatment of CLL. We used MeSH (Medical Subject Heading) terms and keywords to search the National Library of Medicine online MEDLINE database (PubMed) for articles related to cost-effectiveness of OTTs in CLL care.Oral targeted therapies add considerable expense to the treatment of CLL for patients and the health care system. Cost-effectiveness analyses of OTTs are not uniform in their conclusions and depend on patient groups selected for analysis. Given the substantial increase in expense associated with integration of OTTs in CLL treatment, cost reduction methods are needed to ensure equitable access to novel therapies for all patients with CLL.

Cost burden of diffuse large B-cell lymphoma.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is a clinically heterogeneous disease. Treatment pathways for DLBCL are diverse and integrate established and novel therapies.Areas covered: We review the cost burden of DLBCL and the cost-effectiveness of DLBCL management including precision and cellular medicine. We utilized Medical Subject Heading (MeSH) terms and keywords to search the National Library of Medicine online MEDLINE database (PubMed) for articles related to cost, cost burden, and cost-of-illness of DLBCL and cost-effectiveness of DLBCL management strategies published in English as of June 2019.Expert commentary: Available and developing DLBCL therapies offer improved outcomes and often curative treatment at considerable financial expense, and the total cost burden for DLBCL management is substantial for patients and the healthcare system. In the era of personalized medicine, CAR T cells and targeted therapies provide exciting avenues for current and future DLBCL care and can further increase treatment cost. Determinations of cost and cost-effectiveness in DLBCL treatment pathways should continue to guide care providers and systems in identifying cost reduction strategies to provide appropriate therapies to the greatest number of patients in treating DLBCL.

Remaining challenges in predicting patient outcomes for diffuse large B-cell lymphoma.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is an aggressive malignancy with heterogeneous outcomes. Diverse methods for DLBCL outcomes assessment ranging from clinical to genomic have been developed with variable predictive and prognostic success.Areas covered: The authors provide an overview of the various methods currently used to estimate prognosis in DLBCL patients. Models incorporating cell of origin, genomic features, sociodemographic factors, treatment effectiveness measures, and machine learning are described.Expert opinion: The clinical and genetic heterogeneity of DLBCL presents distinct challenges in predicting response to therapy and overall prognosis. Successful integration of predictive and prognostic tools in clinical trials and in a standard clinical workflow for DLBCL will likely require a combination of methods incorporating clinical, sociodemographic, and molecular factors with the aid of machine learning and high-dimensional data analysis.

Exploring enantiospecific ligand-protein interactions using cellular membrane affinity chromatography: chiral recognition as a dynamic process.

The chiral recognition mechanisms responsible for the enantioselective binding on the alpha3beta4 nicotinic acetylcholine receptor (alpha3 beta4 nAChR) and human organic cation transporter 1 (hOCT1) have been reviewed. The results indicate that chiral recognition on the alpha3beta4 nAChR is a process involving initial tethering of dextromethorphan and levomethorphan at hydrophobic pockets within the central lumen followed by hydrogen bonding interactions favoring dextromethorphan. The second step is the defining enantioselective step. Studies with the hOCT1 indentified four binding sites within the transporter that participated in chiral recognition. Each of the enantiomers of the compounds used in the study interacted with three of these sites, while (R)-verapamil interacted with all four. Chiral recognition arose from the conformational adjustments required to produce optimum interactions. With respect to the prevailing interaction-based models, the data suggest that chiral recognition is a dynamic process and that the static point-based models should be amended to reflect this.

Identification of P-glycoprotein substrates using open tubular chromatography on an immobilized P-glycoprotein column: Comparison of chromatographic results with Caco-2 permeability.

The Caco-2 cell monolayer model was used to classify 13 compounds as P-glycoprotein (Pgp) substrates or non-substrates. The apparent permeability coefficients (Papp) in the basal-to-apical direction (Papp(B-A)) and in the apical-to-basal direction (Papp(A-B)) were determined for each compound and a compound was designated as a Pgp substrate if Papp(B-A)/Papp(A-B), the permeability ratio, exceeded 2.0. The same compounds were chromatographed on open tubular glass columns containing membranes from cell lines that either expressed Pgp (Pgp+-OT column) or did not express Pgp (Pgp(-)-OT column). The differential retentions in min, Deltat values, of the compounds were determined using the following relationship Deltat=t((Pgp(+)-OT))-t((Pgp(-)-OT)). A statistically significant correlation was observed between the Deltat values and the permeability ratios, r2=0.7749 (p=0.0063), indicating that the differential chromatography approach could be used to quantitatively assess permeability ratios. The results also indicated that a Deltat value > or =0.5 min was a reliable measure of a permeability ratios >2 and could be used as a rapid qualitative determination of whether a test compound was a Pgp substrate. The chromatographic study took 1h to complete and a single pair of columns could be used to screen at least 150 compounds a week and 600 compounds during the 4-week lifetime of the columns.

Determination of the enantiomers of ketamine and norketamine in human plasma by enantioselective liquid chromatography-mass spectrometry.

A sensitive enantioselective liquid chromatographic assay with mass spectrometric detection has been developed and validated for the simultaneous determination of plasma concentrations of (R)- and (S)-ketamine, and (R)- and (S)-norketamine. The compounds were extracted from human plasma using solid-phase extraction and then directly injected into the LC-MS system for detection and quantification. Enantioselective separations were achieved on a liquid chromatographic chiral stationary phase based upon immobilized alpha(1)-acid glycoprotein (the Chiral AGP column). The separations were achieved using a mobile phase composed of 2-propanol-ammonium acetate buffer (10 mM, pH 7.6) (6:94, v/v), a flow-rate of 0.5 ml/min and a temperature of 25 degrees C. Under these conditions, the analysis time was 20 min. Detection of the ketamine, norketamine and bromoketamine (internal standard) enantiomers was achieved using selected ion monitoring at m/z 238.1, 224.1 and 284.0, respectively. Extracted calibration curves were linear from 1 to 125 ng/ml per enantiomer for each analyte with correlation coefficients better than 0.9993 and intra- and inter-day RSDs of less than 8.0%. The method was applied to samples from a clinical study of ketamine in pain management.

Multidimensional on-line screening for ligands to the alpha3beta4 neuronal nicotinic acetylcholine receptor using an immobilized nicotinic receptor liquid chromatographic stationary phase.

The alpha3beta4 subtype of the neuronal nicotinic acetylcholine receptor (nAChR) subtype was immobilized on a liquid chromatographic support and the resulting column used for the rapid and direct on-line screening for nAChR ligands. A multidimensional chromatographic system was developed consisting of the immobilized receptor column (NR column) connected via a switching valve to a C(18) column that was, in turn, connected to a single quadrupole mass spectrometer. A mixture of 18 compounds, containing alpha3beta4 nAChR (7) and compounds that are not alpha3beta4 nAChR ligands (11), was injected onto the NR column. The mobile phase consisted of ammonium acetate (10 mM, pH 7.4)-methanol (95:5, v/v) and the flow-rate was 0.2 ml/min. For the first 8 min the eluent was directed to waste. At t=8 min, the switching valve was rotated and the NR column connected to the C(18) column. The eluent from the NR column was directed to the C(18) column for 12 min. At t=20 min, the switching valve was rotated and the NR column was disconnected from the C(18) column. The compounds trapped on the C(18) column were separated and eluted onto the mass spectrometer using a mobile phase of ammonium acetate (10 mM, pH 7.4)-methanol (40:60, v/v) at a flow-rate of 1.0 ml/min. Detection was accomplished using total ion monitoring. The multidimensional system correctly isolated six of the seven alpha3beta4 nAChR ligands and only one of the 11 non-ligands was found with the alpha3beta4 nAChR ligands. The results indicate that the multidimensional liquid chromatographic system can be used for the on-line screening of chemical mixtures for alpha3beta4 nAChR ligands.