Nonutility of procalcitonin for diagnosing bacterial pneumonia in patients with severe COVID-19.

Background: Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. Methods: We retrospectively identified 185 patients hospitalized with severe COVID-19 who underwent lower respiratory culture; 85 had evidence of bacterial superinfection. Receiver operating characteristic curve and area under the curve (AUC) analyses were performed to assess the utility of procalcitonin for diagnosing superinfection. Results: This approach demonstrated that procalcitonin measured at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). The AUC not affected by exposure to antibiotics, treatment with immunomodulatory agents, or timing of procalcitonin measurement. Conclusion: Static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

Evidence of Racial Disparities in the Lung Cancer Screening Process: a Systematic Review and Meta-Analysis.

BACKGROUND: Annual lung cancer screening (LCS) with low-dose chest computed tomography for high-risk individuals reduces lung cancer mortality, with greater reduction observed in Black participants in clinical trials. While racial disparities in lung cancer mortality exist, less is known about disparities in LCS participation. We conducted a systematic review to explore LCS participation in Black compared with White patients in the USA. METHODS: A systematic review was conducted through a search of published studies in MEDLINE, PubMed, EMBASE, Web of Science, and Cumulative Index to Nursing and Allied-Health Literature Database, from database inception through October 2020. We included studies that examined rates of LCS participation and compared rates by race. Studies were pooled using random-effects meta-analysis. RESULTS: We screened 18,300 titles/abstracts; 229 studies were selected for full-text review, of which nine studies met inclusion criteria. Studies were categorized into 2 groups: studies that reported the screening rate among an LCS-eligible patient population, and studies that reported the screening rate among a patient population referred for LCS. Median LCS participation rates were 14.4% (range 1.7 to 62.6%) for eligible patient studies and 68.5% (range 62.6 to 88.8%) for referred patient studies. The meta-analyses showed screening rates were lower in the Black compared to White population among the LCS-eligible patient studies ([OR]=0.43, [95% CI: 0.25, 0.74]). However, screening rates were the same between Black and White patients in the referred patient studies (OR=0.94, [95% CI: 0.74, 1.19]). DISCUSSION: Black LCS-eligible patients are being screened at a lower rate than White patients but have similar rates of participation once referred. Differences in referrals by providers may contribute to the racial disparity in LCS participation. More studies are needed to identify barriers to LCS referral and develop interventions to increase provider awareness of the importance of LCS in Black patients. Trial Registry PROSPERO; No.: CRD42020214213; URL: http://www.crd.york.ac.uk/PROSPERO.

Nonutility of procalcitonin for diagnosing bacterial pneumonia in COVID-19.

Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. To do so, we identified 185 patients with severe COVID-19 who underwent lower respiratory culture; 85 had superinfection. Receiver operating characteristic curve analysis showed that procalcitonin at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). We conclude that static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

Racial Differences in Adherence to Lung Cancer Screening Follow-up: A Systematic Review and Meta-analysis.

BACKGROUND: In 2013, the United States Preventive Services Taskforce instituted recommendations for annual lung cancer screening (LCS) with low-dose chest CT imaging for high-risk individuals. LCS reduces lung cancer mortality, with greater reduction observed in Black participants in clinical trials. Although racial disparities in lung cancer mortality have been well documented, less is known about disparities in LCS participation and adherence to follow-up in clinical practice. RESEARCH QUESTION: What is the association between race and adherence to LCS follow-up? STUDY DESIGN AND METHODS: A systematic review was conducted through a search of published studies in MEDLINE, PubMed, EMBASE, Web of Science, and Cumulative Index to Nursing and Allied Health Literature Database from database inception through October 2020. We included studies that examined rates of adherence to LCS follow-up and compared rates by race. Studies were pooled using random-effects meta-analysis. RESULTS: We screened 18,300 titles and abstracts, and 229 studies were selected for full-text review. Nine studies met inclusion criteria; seven were included in the meta-analysis. Median adherent follow-up rate was 37% (range, 16%-82%). Notable differences among the studies included the proportion of the Black population (range, 4%-47%) and the structure of the LCS programs. The meta-analyses showed lower adherence to LCS follow-up in the Black population (OR, 0.67; 95% CI, 0.55-0.80). This disparity persisted across all malignancy risk levels determined by initial screening results. INTERPRETATION: Lower adherence to LCS follow-up in Black compared with White patients occurs despite the higher potential lung cancer mortality benefit. Literature specifically addressing race-related barriers to LCS adherence remains limited. To ensure equity in LCS benefits, greater outreach to eligible Black patients should be implemented through increased physician education and use of screening program coordinators to focus on this patient population. TRIAL REGISTRY: PROSPERO; No.: CRD42020214213; URL: http://www.crd.york.ac.uk/PROSPERO.

Electronic health record risk score provides earlier prognostication of clinical outcomes in patients admitted to the cardiac intensive care unit.

In this observational study, we compared the prognostic ability of an electronic health record (EHR)-derived risk score, the Rothman Index (RI), automatically derived on admission, to the first 24-hour Sequential Organ Failure Assessment (SOFA) score for outcome prediction in the modern cardiac intensive care unit (CICU). We found that while the 24-hour SOFA score provided modestly superior discrimination for both in-hospital and CICU mortality, the RI upon CICU admission had better calibration for both outcomes. Given the ubiquitous nature of EHR utilization in the United States, the RI may become an important tool to rapidly risk stratify CICU patients within the ICU and improve resource allocation.

Transition From an Open to Closed Staffing Model in the Cardiac Intensive Care Unit Improves Clinical Outcomes.

Background Several studies have shown improved outcomes in closed compared with open medical and surgical intensive care units. However, very little is known about the ideal organizational structure in the modern cardiac intensive care unit (CICU). Methods and Results We retrospectively reviewed consecutive unique admissions (n=3996) to our tertiary care CICU from September 2013 to October 2017. The aim of our study was to assess for differences in clinical outcomes between an open compared with a closed CICU. We used multivariable logistic regression adjusting for demographics, comorbidities, and severity of illness. The primary outcome was in-hospital mortality. We identified 2226 patients in the open unit and 1770 in the closed CICU. The unadjusted in-hospital mortality in the open compared with closed unit was 9.6% and 8.9%, respectively (P=0.42). After multivariable adjustment, admission to the closed unit was associated with a lower in-hospital mortality (odds ratio [OR], 0.69; 95% CI: 0.53-0.90, P=0.007) and CICU mortality (OR, 0.70; 95% CI, 0.52-0.94, P=0.02). In subgroup analysis, admissions for cardiac arrest (OR, 0.42; 95% CI, 0.20-0.88, P=0.02) and respiratory insufficiency (OR, 0.43; 95% CI, 0.22-0.82, P=0.01) were also associated with a lower in-hospital mortality in the closed unit. We did not find a difference in CICU length of stay or total hospital charges (P>0.05). Conclusions We found an association between lower in-hospital and CICU mortality after the transition to a closed CICU. These results may help guide the ongoing redesign in other tertiary care CICUs.

Prevalence of Noncardiac Multimorbidity in Patients Admitted to Two Cardiac Intensive Care Units and Their Association with Mortality.

BACKGROUND: Current cardiac intensive care unit (CICU) practice has seen an increase in patient complexity, including an increase in noncardiac organ failure, critical care therapies, and comorbidities. We sought to describe the changing epidemiology of noncardiac multimorbidity in the CICU population. METHODS: We analyzed consecutive unique patient admissions to 2 geographically distant tertiary care CICUs (n = 16,390). We assessed for the prevalence of 0, 1, 2, and ≥3 noncardiac comorbidities (diabetes, chronic lung, liver, and kidney disease, cancer, and stroke/transient ischemic attack) and their associations with hospital and postdischarge 1-year mortality using multivariable logistic regression. RESULTS: The prevalence of 0, 1, 2, and ≥3 noncardiac comorbidities was 37.7%, 31.4%, 19.9%, and 11.0%, respectively. Increasing noncardiac comorbidities were associated with a stepwise increase in mortality, length of stay, noncardiac indications for ICU admission, and increased utilization of critical care therapies. After multivariable adjustment, compared with those without noncardiac comorbidities, there was an increased hospital mortality for patients with 1 (odds ratio [OR] 1.30; 95% confidence interval [CI], 1.10-1.54, P = .002), 2 (OR 1.47; 95% CI, 1.22-1.77, P < .001), and ≥3 (OR 1.79; 95% CI, 1.44-2.22, P < .001) noncardiac comorbidities. Similar trends for each additional noncardiac comorbidity were seen for postdischarge 1-year mortality (P < .001, all). CONCLUSIONS: In 2 large contemporary CICU populations, we found that noncardiac multimorbidity was highly prevalent and a strong predictor of short- and long-term adverse clinical outcomes. Further study is needed to define the best care pathways for CICU patients with acute cardiac illness complicated by noncardiac multimorbidity.

A 62-Year-Old Woman With Lung Cancer, Ulcerating Rash, and Rapidly Progressive Hypoxemia.

CASE PRESENTATION: A 62-year-old nonsmoking woman with no medical history initially presented with a 3-month history of rash. A painful, erythematous exanthem had progressed from her forehead, cheeks, and upper chest to her eyes (heliotrope rash) and hands, primarily involving the extensor surface finger joints with prominent digital ulceration.

Late INa Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

BACKGROUND: Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (INaL) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs. METHODS: We tested the effects of the selective INaL blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca2+ imaging, and computer modeling. RESULTS: GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7/14 hearts in control versus 1/14 hearts at 100 nmol/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca2+-mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol/L, n=7/12 and 100 nmol/L n=8/12 hearts without EADs and PVTs). Confocal Ca2+ imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca2+ transient duration via accelerating Na+/Ca2+ exchanger (INCX)-mediated Ca2+ efflux from cytosol, thereby reducing EADs. Computer modeling revealed that INaL potentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na+ (Nai) that decreases the depolarizing INCX thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K+ channels (IKs), suggesting important roles of INaL in regulating Nai. CONCLUSIONS: Selective INaL blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Nai. Graphic Abstract: A graphic abstract is available for this article.

Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling.

BACKGROUND: Remodeling of cardiac repolarizing currents, such as the downregulation of slowly activating K+ channels (IKs), could underlie ventricular fibrillation (VF) in heart failure (HF). We evaluated the role of Iks remodeling in VF susceptibility using a tachypacing HF model of transgenic rabbits with Long QT Type 1 (LQT1) syndrome. METHODS AND RESULTS: LQT1 and littermate control (LMC) rabbits underwent three weeks of tachypacing to induce cardiac myopathy (TICM). In vivo telemetry demonstrated steepening of the QT/RR slope in LQT1 with TICM (LQT1-TICM; pre: 0.26±0.04, post: 0.52±0.01, P<0.05). In vivo electrophysiology showed that LQT1-TICM had higher incidence of VF than LMC-TICM (6 of 11 vs. 3 of 11, respectively). Optical mapping revealed larger APD dispersion (16±4 vs. 38±6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53±0.12 vs. 1.17±0.13, p<0.05). LQT1-TICM developed spatially discordant alternans (DA), which caused conduction block and higher-frequency VF (15±1 Hz in LQT1-TICM vs. 13±1 Hz in LMC-TICM, p<0.05). Ca2+ DA was highly dynamic and preceded voltage DA in LQT1-TICM. Ryanodine abolished DA in 5 out of 8 LQT1-TICM rabbits, demonstrating the importance of Ca2+ in complex DA formation. Computer simulations suggested that HF remodeling caused Ca2+-driven alternans, which was further potentiated in LQT1-TICM due to the lack of IKs. CONCLUSIONS: Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+. Our results strongly support the contention that the downregulation of IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.

Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1.

BACKGROUND: Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current IKs, which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT). OBJECTIVE: The purpose of this study was to investigate the mechanisms underlying pVT using a transgenic rabbit model of LQT1. METHODS: Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive dye and CMOS cameras. RESULTS: Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the right ventricle (RV; n = 16 of 18 pVTs). After the pVT was initiated, complex focal excitations occurred in both the RV and the left ventricle, which caused oscillations of the QRS complexes on ECG, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of 2 types of excitation that interacted to produce complex pVT: Na(+) current (INa)-mediated fast conduction and L-type Ca(2+) current (ICa)-mediated slow conduction coexist, manifesting as pVT. Addition of 2 µM tetrodotoxin to reduce INa converted pVT into monomorphic VT. Reducing late INa in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results. CONCLUSION: Our study demonstrates that pVT in LQT1 rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, wave conduction in pVT exhibits bi-excitability, that is, fast wavefronts driven by INa and slow wavefronts driven by ICa co-exist during pVT.

MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex.

In heart failure (HF), arrhythmogenic spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and afterdepolarizations in cardiac myocytes have been linked to abnormally high activity of ryanodine receptors (RyR2s) associated with enhanced phosphorylation of the channel. However, the specific molecular mechanisms underlying RyR2 hyperphosphorylation in HF remain poorly understood. The objective of the current study was to test the hypothesis that the enhanced expression of muscle-specific microRNAs (miRNAs) underlies the HF-related alterations in RyR2 phosphorylation in ventricular myocytes by targeting phosphatase activity localized to the RyR2. We studied hearts isolated from canines with chronic HF exhibiting increased left ventricular (LV) dimensions and decreased LV contractility. qRT-PCR revealed that the levels of miR-1 and miR-133, the most abundant muscle-specific miRNAs, were significantly increased in HF myocytes compared with controls (2- and 1.6-fold, respectively). Western blot analyses demonstrated that expression levels of the protein phosphatase 2A (PP2A) catalytic and regulatory subunits, which are putative targets of miR-133 and miR-1, were decreased in HF cells. PP2A catalytic subunit mRNAs were validated as targets of miR-133 by using luciferase reporter assays. Pharmacological inhibition of phosphatase activity increased the frequency of diastolic Ca(2+) waves and afterdepolarizations in control myocytes. The decreased PP2A activity observed in HF was accompanied by enhanced Ca(2+)/calmodulin-dependent protein kinase (CaMKII)-mediated phosphorylation of RyR2 at sites Ser-2814 and Ser-2030 and increased frequency of diastolic Ca(2+) waves and afterdepolarizations in HF myocytes compared with controls. In HF myocytes, CaMKII inhibitory peptide normalized the frequency of pro-arrhythmic spontaneous diastolic Ca(2+) waves. These findings suggest that altered levels of major muscle-specific miRNAs contribute to abnormal RyR2 function in HF by depressing phosphatase activity localized to the channel, which in turn, leads to the excessive phosphorylation of RyR2s, abnormal Ca(2+) cycling, and increased propensity to arrhythmogenesis.