Pediatric cholesteatoma associated with congenital aural atresia and stenosis.

OBJECTIVE: Investigate presenting features, associated surgical treatment, and outcomes in patients with cholesteatoma associated with congenital aural atresia (CAA) or stenosis (CAS). METHODS: Colorado Multiple Institution Review Board approval was obtained. A retrospective chart review was performed at a single tertiary care children's hospital of all pediatric patients with congenital aural atresia or stenosis with associated cholesteatoma from January 1, 2003, to October 15, 2018. RESULTS: Of the 278 patients identified with CAA or CAS, twelve (4.3 %) were found to have a canal cholesteatoma. There was a male predominance (8:4). Nine patients (75 %) had conductive loss and three (25 %) had mixed loss. Four patients (33.3 %) exhibited canal cholesteatomas extending into the middle ear or mastoid cavity. All patients underwent surgery, and 25 % of patients required revision canalplasty while 58 % of patients required revision surgery for cholesteatoma recidivism. The average age at the time of surgery was 11.3 ± 3.7 years. CONCLUSION: Fewer than 5 % of pediatric patients with congenital aural atresia or stenosis were diagnosed with an acquired canal cholesteatoma. The need for revision surgery was common, occurring in >50 % of cases. Screening patients with CAA/CAS for cholesteatoma with imaging is recommended to avoid the morbidity of delayed identification.

Exascale applications: skin in the game.

As noted in Wikipedia, skin in the game refers to having 'incurred risk by being involved in achieving a goal', where 'skin is a synecdoche for the person involved, and game is the metaphor for actions on the field of play under discussion'. For exascale applications under development in the US Department of Energy Exascale Computing Project, nothing could be more apt, with the skin being exascale applications and the game being delivering comprehensive science-based computational applications that effectively exploit exascale high-performance computing technologies to provide breakthrough modelling and simulation and data science solutions. These solutions will yield high-confidence insights and answers to the most critical problems and challenges for the USA in scientific discovery, national security, energy assurance, economic competitiveness and advanced healthcare. This article is part of a discussion meeting issue 'Numerical algorithms for high-performance computational science'.

Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression.

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

Improvement in Visual Fields After Treatment of Intracranial Meningioma With Bevacizumab.

High-grade (World Health Organization [WHO] Grade II and III) meningiomas constitute a minority of all meningioma cases but are associated with significant morbidity and mortality, due to more aggressive tumor behavior and a tendency to recur despite standard therapy with resection and radiotherapy. They display a higher degree of vascularity than WHO Grade I meningiomas and produce angiogenic and growth factors, including vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF-A, has been used in the treatment of recurrent or progressive meningiomas resistant to standard therapy. We report a patient with a recurrent left frontotemporal meningioma and associated-vision loss who experienced substantial visual field recovery after 3 cycles of bevacizumab. In addition, we provide a review of the literature regarding the efficacy of bevacizumab in the treatment of recurrent meningiomas.

Variation in genes related to cochlear biology is strongly associated with adult-onset deafness in border collies.

Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years) than typically expected for aging dogs (8-10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09 × 10(-13)). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS-guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.

A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces.

Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, ß = 31.34, P = 1.28 × 10(-8) ) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N = 2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N = 2006, P = 0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N = 157, P = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P < 0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder.

A mega-analysis of genome-wide association studies for major depressive disorder.

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

A fish way out of water: case report of a unique airway foreign body.

BACKGROUND: Since the time of Chevalier Jackson, innumerable unique foreign bodies have been documented and removed. Advances in endoscopic airway management have revolutionized the types of foreign bodies that we are able to remove without open surgery. The literature on fish aspiration has mostly encompassed fish bones and parts, not whole live fish. OBJECTIVE: This study aimed to describe the airway management of a high-risk airway foreign body including the mobilization and coordination of multiple specialty teams and anesthetic management. CASE REPORT: We report a case of a 40-year-old man who aspirated a live bluegill fish while attempting to use it as bait. The spike-like nature of the bluegill dorsal fin in conjunction with mediastinal air prompted a higher level of concern for potential airway compromise and complication with extraction. We detail the preparation and management of this patient from notification to transportation and ultimately operative intervention. Focus is placed on coordination between anesthesia, otolaryngology, and cardiothoracic surgery, and the key management decisions. CONCLUSION: High-risk airway foreign bodies are always a challenge. When dealing with a live, lodged whole fish, one must have creative management ideas. Close coordination and excellent communication must occur between teams involved to optimize and maintain control of the situation for the best patient outcome.

Impedance probe testing prior to pediatric airway reconstruction.

OBJECTIVE: This study aimed to determine if preoperative impedance testing changed management and if testing was associated with surgical outcome in patients undergoing airway reconstruction. METHODS: Retrospective review of patients who had impedance testing prior to airway reconstruction at a tertiary pediatric hospital from January 2010 to September 2011. Charts were reviewed for demographics, medical/surgical history, impedance testing, and surgical outcomes. RESULTS: Fifty-seven patients were included. Forty-seven (82%) were premature. Forty-seven (82%) had a primary diagnosis of subglottic stenosis. Twenty-six (45%) had prior airway surgery. Thirty-six (63%) had gastroesophageal reflux and 21 (36%) had undergone fundoplication. Patients without fundoplication had a median 46 total reflux, 7 proximal, and 14.5 acidic events compared to a median 5 total reflux, 0 proximal, and 0 acidic events in patients with fundoplication. Impedance testing changed management in 22% (8/36) of nonfundoplication patients and 9.5% (2/21) of fundoplication patients. In unadjusted analysis, fewer fundoplication patients had successful surgery compared to those without (33% vs 67%, P = .01). Prematurity, age at surgery, and previous airway surgery were also important predictors of surgical success. CONCLUSION: Fewer patients than anticipated had a change in management. Impedance testing was unlikely to change management in fundoplication patients. Patients with fundoplication were less likely to have a successful outcome, suggesting that factors other than reflux influence airway reconstruction outcomes.

Links between emotion perception and social participation restriction following stroke.

OBJECTIVES: Stroke can cause impairment in emotion perception, but the social consequences of these problems have not been explored to date. In a group of patients with stroke, this study investigated whether difficulties in emotion perception related to social participation and quality-of-life. It also assessed whether these relationships remained significant when controlling for activity limitations. METHOD: Individuals 1 year post-stroke (n = 28) and control participants (n = 40) were assessed on emotion perception across different modalities. Activity limitations, social participation, and multiple domains of quality-of-life were assessed in patients. RESULTS: Participants with stroke were impaired on emotion perception compared to controls. Emotion perception problems in stroke were significantly correlated with social participation and psychological aspects of QoL, but not with activity limitations. CONCLUSIONS: The strong relationships of emotion perception with social participation and psychological aspects of QoL following stroke may have implications for post-stroke outcomes.

Medical Decision-Making and Revascularization in Ischemic Cardiomyopathy.

Ischemic cardiomyopathy (ICM) is the most common underlying etiology of heart failure in the United States and is a significant contributor to deaths due to cardiovascular disease worldwide. The diagnosis and management of ICM has advanced significantly over the past few decades, and the evidence for medical therapy in ICM is both compelling and robust. This contrasts with evidence for coronary revascularization, which is more controversial and favors surgical approaches. This review will examine landmark clinical trial results in detail as well as provide a comprehensive overview of the current epidemiology, diagnostic approaches, and management strategies of ICM.

Applying natural language processing to identify emergency department and observation encounters for worsening heart failure.

AIMS: Worsening heart failure (WHF) events occurring in non-inpatient settings are becoming increasingly recognized, with implications for prognostication. We evaluate the performance of a natural language processing (NLP)-based approach compared with traditional diagnostic coding for non-inpatient clinical encounters and left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We compared characteristics for encounters that did vs. did not meet WHF criteria, stratified by care setting [i.e. emergency department (ED) and observation stay]. Overall, 8407 (22%) encounters met NLP-based criteria for WHF (3909 ED visits and 4498 observation stays). The use of an NLP-derived definition adjudicated 3983 (12%) of non-primary HF diagnoses as meeting consensus definitions for WHF. The most common diagnosis indicated in these encounters was dyspnoea. Results were primarily driven by observation stays, in which 2205 (23%) encounters with a secondary HF diagnosis met the WHF definition by NLP. CONCLUSIONS: The use of standard claims-based adjudication for primary diagnosis in the non-inpatient setting may lead to misclassification of WHF events in the ED and overestimate observation stays. Primary diagnoses alone may underestimate the burden of WHF in non-hospitalized settings.

An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain.

Dlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma-aminobutyric acid (GABA)-expressing neurons of the forebrain, including local-circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single-nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating Dlx5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease.

The association between changes in echocardiography and risk of heart failure hospitalizations and death in adults with chronic kidney disease.

Adults with chronic kidney disease (CKD) are at increased risk for developing heart failure (HF). However, longitudinal cardiac remodeling in CKD has not been well-characterized and its association with HF outcomes remains unknown. We evaluated the association between change in echocardiographic parameters between baseline and year 4 with the subsequent risk of HF hospitalization and death using Cox proportional hazard models in a landmark analysis of a prospective multicenter CKD cohort. Among 2673 participants, mean ± SD age was 61 ± 11 years, with 45% women, and 56% non-white. A total of 472 hospitalizations for HF and 776 deaths occurred during a median (interquartile range) follow-up duration of 8.0 (6.3-9.1) years. Patients hospitalized for HF experienced larger preceding absolute increases in left ventricular (LV) volumes and decreases in LV ejection fraction. Adverse changes in LV ejection fraction, LV cavity volume, LV mass index, and LV geometry were independently associated with an increased risk of HF hospitalization and death. Among adults with CKD, deleterious cardiac remodeling occurs over a relatively short timeframe and adverse remodeling is associated with increased risk of HF-related morbidity and mortality.

Atrial Speckle Tracking Echocardiography for Detecting Atrial Fibrillation in Cryptogenic Stroke: A Meta-Analysis.

Cryptogenic stroke (CS) accounts for approximately 25% of ischemic stroke cases, with atrial fibrillation (AF) accounting for 30% of CS cases. We investigated the utility of left atrial (LA) speckle-tracking echocardiography in identifying patients at high risk of AF after CS and potentially guiding patients who will benefit from long-term rhythm monitoring devices. Cochrane Library, MEDLINE, and EMBASE were searched for relevant studies. We included studies that examined patients with new CS without a history of AF and further examined LA strain parameters (peak and/or reservoir strain). Continuous data were pooled as a mean difference (MD) comparing patients who developed AF vs no AF.  We used the inverse variance method with the DerSimonian-Laird estimator for tau2 and Hartung-Knapp adjustment for random effect analysis. I2 was used to assess heterogeneity. Thirteen observational studies met our criteria and included 3031 patients with new CS. Of those, 420 patients developed AF on follow-up, and 2611 patients did not develop AF. The AF group vs. no AF had significantly reduced LA reservoir strain (LARS) [MD: -8.61; 95% CI: -10.76, -6.47, I2 = 85%, p < 0.01] at presentation. LARS is significantly lower in patients who developed AF after CS. More studies are needed to validate this data.

Developing Clinical Risk Prediction Models for Worsening Heart Failure Events and Death by Left Ventricular Ejection Fraction.

Background There is a need to develop electronic health record-based predictive models for worsening heart failure (WHF) events across clinical settings and across the spectrum of left ventricular ejection fraction (LVEF). Methods and Results We studied adults with heart failure (HF) from 2011 to 2019 within an integrated health care delivery system. WHF encounters were ascertained using natural language processing and structured data. We conducted boosted decision tree ensemble models to predict 1-year hospitalizations, emergency department visits/observation stays, and outpatient encounters for WHF and all-cause death within each LVEF category: HF with reduced ejection fraction (EF) (LVEF <40%), HF with mildly reduced EF (LVEF 40%-49%), and HF with preserved EF (LVEF ≥50%). Model discrimination was evaluated using area under the curve and calibration using mean squared error. We identified 338 426 adults with HF: 61 045 (18.0%) had HF with reduced EF, 49 618 (14.7%) had HF with mildly reduced EF, and 227 763 (67.3%) had HF with preserved EF. The 1-year risks of any WHF event and death were, respectively, 22.3% and 13.0% for HF with reduced EF, 17.0% and 10.1% for HF with mildly reduced EF, and 16.3% and 10.3% for HF with preserved EF. The WHF model displayed an area under the curve of 0.76 and mean squared error of 0.13, whereas the model for death displayed an area under the curve of 0.83 and mean squared error of 0.076. Performance and predictors were similar across WHF encounter types and LVEF categories. Conclusions We developed risk prediction models for 1-year WHF events and death across the LVEF spectrum using structured and unstructured electronic health record data and observed no substantial differences in model performance or predictors except for death, despite differences in underlying HF cause.

Genetic structure of major depression symptoms across clinical and community cohorts.

Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and aetiological subtypes. There are several challenges to integrating symptom data from genetically-informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data. We conducted genome-wide association studies of major depressive symptoms in three clinical cohorts that were enriched for affected participants (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors. The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for missing data patterns in the community cohorts (use of Depression and Anhedonia as gating symptoms). The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analysing genetic association data.

Mental practice with motor imagery in stroke recovery: randomized controlled trial of efficacy.

This randomized controlled trial evaluated the therapeutic benefit of mental practice with motor imagery in stroke patients with persistent upper limb motor weakness. There is evidence to suggest that mental rehearsal of movement can produce effects normally attributed to practising the actual movements. Imagining hand movements could stimulate restitution and redistribution of brain activity, which accompanies recovery of hand function, thus resulting in a reduced motor deficit. Current efficacy evidence for mental practice with motor imagery in stroke is insufficient due to methodological limitations. This randomized controlled sequential cohort study included 121 stroke patients with a residual upper limb weakness within 6 months following stroke (on average <3 months post-stroke). Randomization was performed using an automated statistical minimizing procedure. The primary outcome measure was a blinded rating on the Action Research Arm test. The study analysed the outcome of 39 patients involved in 4 weeks of mental rehearsal of upper limb movements during 45-min supervised sessions three times a week and structured independent sessions twice a week, compared to 31 patients who performed equally intensive non-motor mental rehearsal, and 32 patients receiving normal care without additional training. No differences between the treatment groups were found at baseline or outcome on the Action Research Arm Test (ANCOVA statistical P=0.77, and effect size partial η2=0.005) or any of the secondary outcome measures. Results suggest that mental practice with motor imagery does not enhance motor recovery in patients early post-stroke. In light of the evidence, it remains to be seen whether mental practice with motor imagery is a valid rehabilitation technique in its own right.

Multivariate analysis of anxiety disorders yields further evidence of linkage to chromosomes 4q21 and 7p in panic disorder families.

Replication has been difficult to achieve in linkage studies of psychiatric disease. Linkage studies of panic disorder have indicated regions of interest on chromosomes 1q, 2p, 2q, 3, 7, 9, 11, 12q13, 12q23, and 15. Few regions have been implicated in more than one study. We examine two samples, the Iowa (IA) and the Columba panic disorder families. We use the fuzzy-clustering method presented by Kaabi et al. [Kaabi et al. (2006); Am J Hum Genet 78: 543-553] to summarize liability to panic disorder, agoraphobia, simple phobia, and social phobia. Kaabi et al. applied this method to the Yale panic disorder linkage families and found evidence of linkage to chromosomes 4q21, 4q32, 7p, and 8. When we apply the same method to the IA families, we obtain overlapping evidence of linkage to chromosomes 4q21 and 7p. Additionally, we find evidence of linkage on chromosomes 1, 5, 6, 16, and 22. The Columbia (CO) data does not indicate linkage to any of the Kaabi et al. peaks, instead implicating chromosomes 2 and 22q11 (2 Mb from COMT). There is some evidence of overlapping linkage between the IA and CO datasets on chromosomes 1 and 14. While use of fuzzy clustering has not produced complete concordance across datasets, it has produced more than previously seen in analyses of panic disorder proper. We conclude that chromosomes 4q21 and 7p should be considered strong candidate regions for panic and fear-associated anxiety disorder loci. More generally, this suggests that analyses including multiple aspects of psychopathology may lead to greater consistency across datasets.

Remdesivir-Induced Extreme Sinus Bradycardia in COVID-19.

During the COVID-19 pandemic, there was an urgent need for any medication to help reduce the high death rate experienced during this deadly surge. Remdesivir is an FDA-approved drug for COVID-19 treatment, given its anti-inflammatory properties. Upon extensive literature search, we found two studies and four cases of COVID-19-induced pneumonia treated with remdesivir who were developing bradycardia. In most of these cases, the bradycardia resolved within one-to-two days of holding remdesivir, which correlated with the half-life of remdesivir. Remdesivir was shown to have benefits in COVID-19-induced pneumonia during the COVID-19 surge; however, its use has been controversial. According to the studies, the sinus bradycardia following remdesivir administration does not impact patients' prognosis in terms of ICU admission and in-hospital mortality. There are multiple case reports noted to report several remdesivir-induced cardiac side effects. In our case, prolonged use and high dosages may induce cardiotoxicity, manifesting as severe bradycardia. Several possible mechanisms for cardiac adverse effects with remdesivir need further investigation and research as COVID-19 remains an active global issue. We present a 53-year-old man hospitalized with COVID-19-induced pneumonia who experienced extreme sinus bradycardia that is likely attributable to remdesivir.