Accurate Modeling of Ejection Fraction and Stroke Volume With Mobile Phone Auscultation: Prospective Case-Control Study.

BACKGROUND: Heart failure (HF) contributes greatly to morbidity, mortality, and health care costs worldwide. Hospital readmission rates are tracked closely and determine federal reimbursement dollars. No current modality or technology allows for accurate measurement of relevant HF parameters in ambulatory, rural, or underserved settings. This limits the use of telehealth to diagnose or monitor HF in ambulatory patients. OBJECTIVE: This study describes a novel HF diagnostic technology using audio recordings from a standard mobile phone. METHODS: This prospective study of acoustic microphone recordings enrolled convenience samples of patients from 2 different clinical sites in 2 separate areas of the United States. Recordings were obtained at the aortic (second intercostal) site with the patient sitting upright. The team used recordings to create predictive algorithms using physics-based (not neural networks) models. The analysis matched mobile phone acoustic data to ejection fraction (EF) and stroke volume (SV) as evaluated by echocardiograms. Using the physics-based approach to determine features eliminates the need for neural networks and overfitting strategies entirely, potentially offering advantages in data efficiency, model stability, regulatory visibility, and physical insightfulness. RESULTS: Recordings were obtained from 113 participants. No recordings were excluded due to background noise or for any other reason. Participants had diverse racial backgrounds and body surface areas. Reliable echocardiogram data were available for EF from 113 patients and for SV from 65 patients. The mean age of the EF cohort was 66.3 (SD 13.3) years, with female patients comprising 38.3% (43/113) of the group. Using an EF cutoff of ≤40% versus >40%, the model (using 4 features) had an area under the receiver operating curve (AUROC) of 0.955, sensitivity of 0.952, specificity of 0.958, and accuracy of 0.956. The mean age of the SV cohort was 65.5 (SD 12.7) years, with female patients comprising 34% (38/65) of the group. Using a clinically relevant SV cutoff of <50 mL versus >50 mL, the model (using 3 features) had an AUROC of 0.922, sensitivity of 1.000, specificity of 0.844, and accuracy of 0.923. Acoustics frequencies associated with SV were observed to be higher than those associated with EF and, therefore, were less likely to pass through the tissue without distortion. CONCLUSIONS: This work describes the use of mobile phone auscultation recordings obtained with unaltered cellular microphones. The analysis reproduced the estimates of EF and SV with impressive accuracy. This technology will be further developed into a mobile app that could bring screening and monitoring of HF to several clinical settings, such as home or telehealth, rural, remote, and underserved areas across the globe. This would bring high-quality diagnostic methods to patients with HF using equipment they already own and in situations where no other diagnostic and monitoring options exist.

Impact of cost on prescribing diabetes medications for older adults with type 2 diabetes in the outpatient setting.

BACKGROUND: Newer diabetes medications have cardiorenal benefits beyond blood sugar lowering that make them a preferred treatment option in many patients. Despite this, studies have shown that prescribing of these medications remains suboptimal with medication costs being hypothesized as a reason for underutilization. OBJECTIVE: To understand clinicians' decision-making processes for prescribing diabetes medications in older adults, focusing on higher cost medications. METHODS: Observations of patient encounters and semi-structured interviews were conducted with clinicians from primary care, endocrinology, and geriatrics to elucidate themes into diabetes medication prescribing. A qualitative descriptive approach was used to analyze the data from interviews using an inductive coding scheme with themes derived from the data. RESULTS: Twenty-one interviews were conducted. Five themes were identified: 1) out-of-pocket costs drive prescribing decisions 2) out-of-pocket costs can be variable due to changing insurance plans or changing coverage 3) clinicians have difficulty with determining patient-specific out-of-pocket costs 4) clinicians manage the tradeoffs existing between cost, efficacy, and safety and 5) clinicians can use cost-modifying strategies such as patient assistance. CONCLUSION: Addressing the challenges that medication costs pose to prescribing evidence-based medications for type 2 diabetes is necessary to optimize diabetes care for older adults.

Sonographic Assessment of Hand Injuries: Diagnostic Accuracy and Review of Pathology.

Background: The high soft-tissue contrast of magnetic resonance imaging (MRI) makes it useful for evaluation of hand injuries, but its limitations include cost, imaging artifacts, and patient claustrophobia. Ultrasound is readily available, fast, noninvasive, and radiation free, but its utility for the evaluation of hand soft-tissue injury and pathology is less well known. Purpose: We sought to examine the accuracy of ultrasound for the evaluation of hand injury at a single institution. Methods: We queried a radiology information system for ultrasound cases between 2014 and 2020 at a tertiary care institution using the keyword "hand" and injury terms. We performed a retrospective chart review of cases found according to the type of injury detected on ultrasound. To evaluate the diagnostic accuracy of ultrasound in hand injury and pathology, we recorded postimaging clinical diagnoses and surgical findings. Results: We found 154 patients who underwent ultrasound for hand injuries and had confirmed surgical diagnosis and/or robust clinical follow-up. Tendon injury was the most commonly diagnosed condition on ultrasound (70/154); others detected were retained foreign body (31), mass (21), ligamentous injury (9), pulley injury (8), nerve injury (11), and traumatic arthropathy (4). Ultrasound correctly characterized hand injury in 150/154 cases (97.4%) based on surgical and/or clinical follow-up. Ultrasound failed to diagnose 3 cases of partial tendon tear and 1 case of digital nerve injury. Conclusion: In this retrospective, single-institution review, ultrasound was found to be highly accurate in the detection of soft tissue hand injury and pathology, demonstrating a high concordance rate with surgical and clinical findings. Further study is warranted.

Kidney Damage and Stress Biomarkers for Early Identification of Drug-Induced Kidney Injury: A Systematic Review.

INTRODUCTION: Acute kidney injury (AKI) resulting from nephrotoxic medication use is prominent in hospitalized patients and is attributable to overall increases in mortality and costs of care. Serum creatinine (SCr), the current standard for identifying drug-induced AKI (DIAKI) is often delayed in its response to kidney insult by 26-36 h. OBJECTIVE: This systematic review seeks to evaluate the clinical utility of several novel kidney damage and stress biomarkers for the prediction/timely detection of DIAKI, in comparison with traditional methods. METHODS: A systematic review of the CINAHL, Cochrane Library, Embase, and PubMed databases was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, for articles analyzing the use of ß2-microglobulin (B2M), interleukin (IL)-18, kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), and tissue inhibitor of metalloproteinase-2 * insulin-like growth factor-binding protein 7 [TIMP-1]*[IGFBP-7], for identifying DIAKI. Primary outcomes included time to DIAKI diagnosis using traditional methods and the time to significant difference in biomarker concentrations between DIAKI and non-AKI study subjects. Secondary outcomes included biomarker concentrations at the time of significant difference between the AKI status groups. RESULTS: Fifteen unique articles were identified from the literature search. Twelve studies consisted of strictly hospitalized patient populations and three studies included hospitalized patients and patients discharged to home treatment. No studies reported values for urine volume output. Seventy-three percent of studies reported earlier times to significant difference of novel biomarker concentrations between the AKI and non-AKI groups than diagnosis of DIAKI by SCr alone. Significant variation was observed for individual urine biomarker concentrations at time of significant difference between the AKI status groups. CONCLUSIONS: All analyzed biomarkers showed potential for use as early clinical markers of DIAKI, however further consensus on threshold urine concentrations for DIAKI is needed for meaningful implementation of these biomarkers in clinical practice.

Biophysical Regulations of Epigenetic State and Notch Signaling in Neural Development Using Microgroove Substrates.

A number of studies have recently shown how surface topography can alter the behavior and differentiation patterns of different types of stem cells. Although the exact mechanisms and molecular pathways involved remain unclear, a consistent portion of the literature points to epigenetic changes induced by nuclear remodeling. In this study, we investigate the behavior of clinically relevant neural populations derived from human pluripotent stem cells when cultured on polydimethylsiloxane microgrooves (3 and 10 µm depth grooves) to investigate what mechanisms are responsible for their differentiation capacity and functional behavior. Our results show that microgrooves enhance cell alignment, modify nuclear geometry, and significantly increase cellular stiffness, which we were able to measure at high resolution with a combination of light and electron microscopy, scanning ion conductance microscopy (SICM), and atomic force microscopy (AFM) coupled with quantitative image analysis. The microgrooves promoted significant changes in the epigenetic landscape, as revealed by the expression of key histone modification markers. The main behavioral change of neural stem cells on microgrooves was an increase of neuronal differentiation under basal conditions on the microgrooves. Through measurements of cleaved Notch1 levels, we found that microgrooves downregulate Notch signaling. We in fact propose that microgroove topography affects the differentiation potential of neural stem cells by indirectly altering Notch signaling through geometric segregation and that this mechanism in parallel with topography-dependent epigenetic modulations acts in concert to enhance stem cell neuronal differentiation.

Brahma safeguards canalization of cardiac mesoderm differentiation.

Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm-/- cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm-/- cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle-node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.

A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions.

Stochastic fluctuations in gene expression ("noise") are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as "discordant transcription through repair" ("DiThR," which is pronounced "dither"), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.

Dual-view light-sheet imaging through a tilted glass interface using a deformable mirror.

Light-sheet microscopy has become indispensable for imaging developing organisms, and imaging from multiple directions (views) is essential to improve its spatial resolution. We combine multi-view light-sheet microscopy with microfluidics using adaptive optics (deformable mirror) which corrects aberrations introduced by the 45o-tilted glass coverslip. The optimal shape of the deformable mirror is computed by an iterative algorithm that optimizes the point-spread function in two orthogonal views. Simultaneous correction in two optical arms is achieved via a knife-edge mirror that splits the excitation path and combines the detection paths. Our design allows multi-view light-sheet microscopy with microfluidic devices for precisely controlled experiments and high-content screening.

Loperamide-Induced Cardiac Events: Case Reports and Review.

Reports of cardiac arrhythmia secondary to loperamide toxicity have become increasingly common in the literature. We present two patients in their mid-20s, each having overdosed on loperamide and subsequently manifesting life-threatening cardiac arrhythmias not otherwise explained by known pathology. An analysis of the limited research available indicates that loperamide's capacity to block ion channels may be responsible for these events. A better mechanistic understanding of loperamide's effects can help inform clinical management of patients with these life-threatening symptoms as at this time no set guidelines for management have yet been established.

Noise-driven cellular heterogeneity in circadian periodicity.

Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.

Varenicline and Nicotine Replacement Use Associated With US Food and Drug Administration Drug Safety Communications.

Importance: Drug safety communications released by the US Food and Drug Administration (FDA) are often based on limited evidence on safety signals after approval. Varenicline may serve as a relevant case study because it was the target of several FDA communications in 2008 and 2009; ultimately, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) dismissed safety concerns on increased suicidal thoughts and aggressive and erratic behavior on December 16, 2016. Objective: To examine the association between FDA drug safety communications and the use of varenicline. Design, Setting, and Participants: Retrospective, longitudinal, cross-sectional study of Veterans Health Administration (VHA) outpatient data from October 1, 2001, through December 31, 2018, and Medicaid drug state use data from July 1, 2006, through September 30, 2018, on varenicline prescribing. Main Outcomes and Measures: Prescribing records for varenicline and nicotine replacement therapy (NRT) in the VHA were extracted, and the number of unique varenicline and NRT users in the VHA per quarter was measured. An interrupted time series analysis was performed to describe the association between FDA safety warnings and the use of varenicline and NRT. To test the generalizability of the findings, similar analyses were conducted using the number of prescriptions reimbursed for varenicline by Medicaid every quarter in 2006-2018. Results: After its addition to the VHA national drug formulary in January 2007, varenicline use presented a steady increase, reaching a peak of 32 581 quarterly unique users in the first quarter of 2008. Within 12 months of the February 1, 2008, public health advisory, quarterly varenicline use in VHA patients decreased by 68.7% (from 32 581 to 10 182 patients; P < .001 for slope change), and NRT use increased by 32.1% (from 55 728 to 73 629 patients; P < .001 for slope change). In Medicaid prescriptions, varenicline use decreased by 38.0% (from 109 308 to 67 761 prescriptions; P < .001 for slope change) within 12 months of the 2008 public health advisory. Twelve months after the publication of the EAGLES trial, which showed no significant increase in psychiatric/behavioral effects with varenicline relative to NRT, use of varenicline increased by 42.7% in VHA patients (from 9251 to 13 199 patients; P = .01 for slope change) and by 26.0% in Medicaid prescriptions (112 063 to 141 122; P = .26 for slope change ). Conclusions and Relevance: With use of varenicline as a case study, early communications from the FDA and VHA followed by a labeling change appeared to be associated with a considerable decrease in drug use, which may have been associated with negative public health consequences.

Quantification of pulmonary/systemic shunt ratio by single-acquisition phase-contrast cardiovascular magnetic resonance.

PURPOSE: Phase-contrast cardiovascular magnetic resonance (PC-CMR) quantification of intracardiac shunt (measuring the pulmonary to systemic flow ratio, Qp/Qs) is typically determined by measuring flow through planes perpendicular the pulmonary trunk (PA) and ascending aorta (Ao). This method is subject to error from presence of background velocity offsets and requires two scan acquisitions. We evaluated an alternate PC-CMR technique for quantifying Qp/Qs using a single modified plane that encompasses both the PA and Ao. MATERIAL AND METHODS: In 53 patients evaluated for intracardiac shunting, PC-CMR measurement in the individual Ao and PA planes and also in a single-acquisition plane was obtained and Qp/Qs calculated by each method. Bland-Altman analysis was performed to evaluate the agreement between the two methods. RESULTS: The 95% confidence limits of agreement ranged from -0.52 to +0.34 indicating good agreement between the two methods. There was excellent agreement on the clinically relevant threshold value of Qp/Qs ratio of 1.5 (representing criteria for surgical correction of shunt). CONCLUSIONS: Qp/Qs determined from the single-acquisition approach agrees well with that of the individual PA and Ao method and offers potential improved accuracy (due to background velocity offset).

Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability.

Transcription is an episodic process characterized by probabilistic bursts, but how the transcriptional noise from these bursts is modulated by cellular physiology remains unclear. Using simulations and single-molecule RNA counting, we examined how cellular processes influence cell-to-cell variability (noise). The results show that RNA noise is higher in the cytoplasm than the nucleus in ∼85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Measurements show further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation-competent states. This multi-state translation-degradation of mRNA also causes substantial noise amplification in protein levels, ultimately accounting for ∼74% of intrinsic protein variability in cell populations. Overall, the results demonstrate how noise from transcriptional bursts is intrinsically amplified by mRNA processing, leading to a large super-Poissonian variability in protein levels.

Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning.

During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes.

Perioperative Pain Control in the Ambulatory Setting.

Across the USA and various parts of the world, ambulatory surgery centers have transitioned to accepting patients with advanced ASA statuses, leading to a larger volume and higher complexity of surgeries performed, while still urging for same-day patient discharges. Inadequate postoperative pain management and opioid analgesia side effects, such as sedation, respiratory depression, and postoperative nausea and vomiting, are the most common complications and most common reasons for readmission after ambulatory surgery. The trend to limiting these complications and achieve a more rapid patient discharge currently emphasizes a multifactorial, balanced analgesia strategy. This article reviews the multimodal approach by detailing the important aspects of specific regional nerve blocks, nerve blockade with catheter techniques, acetaminophen, non-selective NSAIDs, Cox-2 inhibitors, membrane stabilizers, and corticosteroids. Pain management in the ambulatory surgery patient will thus be optimized with a thorough preoperative evaluation, recognizing intraoperative events, and implementing multiple analgesic modalities.

Is Platelet-Rich Plasma a Future Therapy in Pain Management?

Platelet-rich plasma (PRP) has the potential to regenerate tissues and decrease pain through the effects of bioactive molecules and growth factors present in alpha granules. Several PRP preparation systems are available with varying end products, doses of growth factors, and bioactive molecules. This article presents the biology of PRP, the preparation of PRP, and the effects PRP-related growth factors have on tissue healing and repair. Based on available evidence-based literature, the success of PRP therapy depends on the method of preparation and composition of PRP, the patient's medical condition, anatomic location of the injection, and the type of tissue injected.

Risk of Heart Failure and Death After Prolonged Smoking Cessation: Role of Amount and Duration of Prior Smoking.

BACKGROUND: According to the 2004 Surgeon General's Report on Health Consequences of Smoking, after >15 years of abstinence, the cardiovascular risk of former smokers becomes similar to that of never-smokers. Whether this health benefit of smoking cessation varies by amount and duration of prior smoking remains unclear. METHODS AND RESULTS: Of the 4482 adults ≥65 years without prevalent heart failure (HF) in the Cardiovascular Health Study, 2556 were never-smokers, 629 current smokers, and 1297 former smokers with >15 years of cessation, of whom 312 were heavy smokers (highest quartile; ≥32 pack-years). Age-sex-race-adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for centrally adjudicated incident HF and mortality during 13 years of follow-up were estimated using Cox regression models. Compared with never-smokers, former smokers as a group had similar risk for incident HF (aHR, 0.99; 95% CI, 0.85-1.16) and all-cause mortality (aHR, 1.08; 95% CI, 0.96-1.20), but former heavy smokers had higher risk for both HF (aHR, 1.45; 95% CI, 1.15-1.83) and mortality (aHR, 1.38; 95% CI, 1.17-1.64). However, when compared with current smokers, former heavy smokers had lower risk of death (aHR, 0.64; 95% CI, 0.53-0.77), but not of HF (aHR, 0.97; 95% CI, 0.74-1.28). CONCLUSIONS: After >15 years of smoking cessation, the risk of HF and death for most former smokers becomes similar to that of never-smokers. Although this benefit of smoking cessation is not extended to those with ≥32 pack-years of prior smoking, they have lower risk of death relative to current smokers.

Force transmission during adhesion-independent migration.

When cells move using integrin-based focal adhesions, they pull in the direction of motion with large, ∼100 Pa, stresses that contract the substrate. Integrin-mediated adhesions, however, are not required for in vivo confined migration. During focal adhesion-free migration, the transmission of propelling forces, and their magnitude and orientation, are not understood. Here, we combine theory and experiments to investigate the forces involved in adhesion-free migration. Using a non-adherent blebbing cell line as a model, we show that actin cortex flows drive cell movement through nonspecific substrate friction. Strikingly, the forces propelling the cell forward are several orders of magnitude lower than during focal-adhesion-based motility. Moreover, the force distribution in adhesion-free migration is inverted: it acts to expand, rather than contract, the substrate in the direction of motion. This fundamentally different mode of force transmission may have implications for cell-cell and cell-substrate interactions during migration in vivo.

Myosin II controls cellular branching morphogenesis and migration in three dimensions by minimizing cell-surface curvature.

In many cases, cell function is intimately linked to cell shape control. We used endothelial cell branching morphogenesis as a model to understand the role of myosin II in shape control of invasive cells migrating in 3D collagen gels. We applied principles of differential geometry and mathematical morphology to 3D image sets to parameterize cell branch structure and local cell-surface curvature. We find that Rho/ROCK-stimulated myosin II contractility minimizes cell-scale branching by recognizing and minimizing local cell-surface curvature. Using microfabrication to constrain cell shape identifies a positive feedback mechanism in which low curvature stabilizes myosin II cortical association, where it acts to maintain minimal curvature. The feedback between regulation of myosin II by curvature and control of curvature by myosin II drives cycles of localized cortical myosin II assembly and disassembly. These cycles in turn mediate alternating phases of directionally biased branch initiation and retraction to guide 3D cell migration.

Multifunctional RNA nanoparticles.

Our recent advancements in RNA nanotechnology introduced novel nanoscaffolds (nanorings); however, the potential of their use for biomedical applications was never fully revealed. As presented here, besides functionalization with multiple different short interfering RNAs for combinatorial RNA interference (e.g., against multiple HIV-1 genes), nanorings also allow simultaneous embedment of assorted RNA aptamers, fluorescent dyes, proteins, as well as recently developed RNA-DNA hybrids aimed to conditionally activate multiple split functionalities inside cells.