COVID MED - An Early Pandemic Trial of Losartan for Hospitalized COVID-19 Patients

BackgroundACEi/ARB medications have been hypothesized to have potential benefit in COVID-19. Despite concern for increased ACE-2 expression in some animal models, preclinical and observational-retrospective and uncontrolled trials suggested possible benefit. Two RCTs of the ARB losartan from University of Minnesota showed no benefit yet safety signals for losartan in outpatient and hospitalized COVID-19 patients. COVID MED, started early in the pandemic, also assessed losartan in a RCT in hospitalized patients with COVID-19. MethodsCOVID MED was a double-blinded, placebo-controlled, multicenter, platform randomized clinical trial (RCT). Hospitalized COVID-19 patients were randomized to receive standard care and hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued after RCTs showed no benefit. We report data from the losartan arm compared to combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint, the mean COVID-19 Ordinal Severity Score (COSS) slope of change, was compared with the Students t-test. Slow enrollment prompted early termination. ResultsOf 448 screened patients, 15 (3.5%) were randomized/enrolled, 9 to receive losartan and 6 to receive control (lopinavir/ritonavir [N=2], placebo [N=4]); 1 patient who withdrew prior to study drug was excluded yielding 14 patients for analysis (losartan [N=9] vs. control [N=5] [lopinavir/ritonavir [N=2], placebo [N=3]]). Most baseline parameters were balanced. Treatment with losartan was not associated with a difference in mean COSS slope of change in comparison with combined control (p=0.4) or placebo-only control (p=0.05) (trend favoring placebo). 60-day mortality and overall AE and SAE rates were numerically but not significantly higher with losartan. ConclusionsIn this small blinded RCT in hospitalized COVID-19 patients, losartan did not improve outcome vs. control comparisons and was associated with adverse safety signals.

Association between the emergency department length of stay and severity-standardized survival among severe emergency patients

Objective@#The length of stay in the emergency department (ED) is a major contributor to ED overcrowding, which in turn negatively affects the quality of emergency care. Several efforts have been made to reduce the ED length of stay (ED-LOS), including a mandatory target to limit ED-LOS within certain parameters. However, the association between ED-LOS and treatment results is yet to be clarified. The authors investigated the influence of ED-LOS on patient survival by comparing severity-adjusted survival. @*Methods@#This study was a retrospective analysis of data registered in 2018 in the National Emergency Department Information System (NEDIS). Cases registered by the regional and local emergency centers were included for analysis. The standardized W scores (Ws) based on the Emergency Department Initial Evaluation Score were used to assess treatment outcomes represented by severity-standardized survival, and the correlation between the Ws and the ED-LOS was analyzed. @*Results@#A total of 2,281,526 cases were included for analysis. The overall mortality comprised 52,284 cases (2.3%) and the median ED-LOS was 165 minutes (interquartile range, 96-301). Although a longer ED-LOS was associated with poorer outcomes overall, the association was not apparent when an analysis of cases eligible for ED-LOS evaluation in the national evaluation program was carried out. Moreover, in the analysis of severe cases with a predicted survival probability of less than 0.9, an ED-LOS shorter than 6 hours was associated with significantly poorer severity-adjusted survival. @*Conclusion@#The study revealed that the current ED-LOS criteria used in the national evaluation program were not associated with better survival.

Antiviral effects of miRNAs in extracellular vesicles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mutations in SARS-CoV-2 RNA virus

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 2019 (COVID-19). No treatment is available. Micro-RNAs (miRNAs) in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are potential novel therapeutic agents because of their ability to regulate gene expression by inhibiting mRNA. Thus, they may degrade the RNA genome of SARS-CoV-2. EVs can transfer miRNAs to recipient cells and regulate conditions within them. MSC-EVs harbor major therapeutic miRNAs that play important roles in the biological functions of virus-infected host cells. Here, we examined their potential impact on viral and immune responses. MSC-EVs contained 18 miRNAs predicted to interact directly with the 3 UTR of SARS-CoV-2. These EVs suppressed SARS-CoV-2 replication in Vero E6 cells. In addition, five major miRNAs suppressed virus activity in a luciferase reporter assay by binding the 3 UTR. MSC-EVs showed strong regenerative effects and potent anti-inflammatory activity which may prevent lethal cytokine storms. We confirmed that EVs regulated inflammatory responses by several cell types, including human brain cells that express the viral receptor ACE2, suggesting that the brain may be targeted by SARS-CoV-2. miRNAs in MSC-EVs have several advantages as therapeutic agents against SARS-CoV-2: 1) they bind specifically to the viral 3 UTR, and are thus unlikely to have side effects; 2) because the 3 UTR is highly conserved and rarely mutates, MSC-EV miRNAs could be used against novel variants arising during viral replication; and 3) unique cargoes carried by MSC-EVs can have diverse effects, such as regenerating damaged tissue and regulating immunity.

Experience of essay during the clinical clerkship in emergency medicine and inter-rater reliability on essay

Objective@#An essay test is difficult to carry out because of the effort for hand scoring and the concerns about inter-rater reliability, even though the use of a rubric can increase inter-rater reliability. This study examined the feasibility of an essay test in medical school students and whether the use of a rubric increases inter-rater reliability. @*Methods@#An essay test was given to 51 undergraduate students in the third grade of emergency medicine clinical clerkship. Three raters assessed the essay test independently with a prepared rubric immediately after the test. They then did the same essay test without a rubric three months later. The researchers compared the Pearson’s correlation coefficients between raters. The researchers analyzed the validity comparing the correlation coefficient between the essay test and previous multiple-choice questions (MCQ) and feasibility by acceptance. @*Results@#Fifty-one students took the essay test. The Pearson’s correlation coefficient using rubric between raters 1 and 2, 1 and 3, and 2 and 3 were 0.898 (P<0.001), 0.896 (P<0.001), and 0.856 (P<0.001), respectively. Without a rubric, the correlation coefficients were 0.838 (P<0.001), 0.888 (P<0.001), and 0.824 (P<0.001), respectively. The new essay test showed a positive correlation (0.367) with the previous MCQ, and the evidence for validity and feasibility was acceptable. @*Conclusion@#In this study, the rubric did not increase the inter-rater reliability of the essay test. On the other hand, the inter-rater reliability was higher than 0.8, even without a rubric. In addition, the essay test showed evidence of validity and feasibility.

Sulfuretin Prevents Obesity and Metabolic Diseases in Diet Induced Obese Mice

The global obesity epidemic and associated metabolic diseases require alternative biological targets for new therapeutic strategies. In this study, we show that a phytochemical sulfuretin suppressed adipocyte differentiation of preadipocytes and administration of sulfuretin to high fat diet-fed obese mice prevented obesity and increased insulin sensitivity. These effects were associated with a suppressed expression of inflammatory markers, induced expression of adiponectin, and increased levels of phosphorylated ERK and AKT. To elucidate the molecular mechanism of sulfuretin in adipocytes, we performed microarray analysis and identified activating transcription factor 3 (Atf3) as a sulfuretin-responsive gene. Sulfuretin elevated Atf3 mRNA and protein levels in white adipose tissue and adipocytes. Consistently, deficiency of Atf3 promoted lipid accumulation and the expression of adipocyte markers. Sulfuretin’s but not resveratrol’s anti-adipogenic effects were diminished in Atf3 deficient cells, indicating that Atf3 is an essential factor in the effects of sulfuretin. These results highlight the usefulness of sulfuretin as a new anti-obesity intervention for the prevention of obesity and its associated metabolic diseases.

Electrocardiogram Sampling Frequency Range Acceptable for Heart Rate Variability Analysis / 대한의료정보학회지

OBJECTIVES: Heart rate variability (HRV) has gained recognition as a noninvasive marker of autonomic activity. HRV is considered a promising tool in various clinical scenarios. The optimal electrocardiogram (ECG) sampling frequency required to ensure sufficient precision of R–R intervals for HRV analysis has not yet been determined. Here, we aimed to determine the acceptable ECG sampling frequency range by analyzing ECG signals from patients who visited an emergency department with the chief complaint of acute intoxication or overdose. METHODS: The study included 83 adult patients who visited an emergency department with the chief complaint of acute poisoning. The original 1,000-Hz ECG signals were down-sampled to 500-, 250-, 100-, and 50-Hz sampling frequencies with linear interpolation. R–R interval data were analyzed for time-domain, frequency-domain, and nonlinear HRV parameters. Parameters derived from the data on down-sampled frequencies were compared with those derived from the data on 1,000-Hz signals, and Lin's concordance correlation coefficients were calculated. RESULTS: Down-sampling to 500 or 250 Hz resulted in excellent concordance. Signals down-sampled to 100 Hz produced acceptable results for time-domain analysis and Poincaré plots, but not for frequency-domain analysis. Down-sampling to 50 Hz proved to be unacceptable for both time- and frequency-domain analyses. At 50 Hz, the root-mean-squared successive differences and the power of high frequency tended to have high values and random errors. CONCLUSIONS: A 250-Hz sampling frequency would be acceptable for HRV analysis. When frequency-domain analysis is not required, a 100-Hz sampling frequency would also be acceptable.

A case of acute bilateral thalamic infarction presenting in a sleep-like coma after alcohol ingestion

The artery of Percheron is a rare anatomical variant, in which a common trunk arises from one posterior cerebral artery and then branches to supply each of the thalami and the midbrain separately. Occlusion of this artery triggers a bilateral thalamic infarction. The most commonly reported clinical findings are an altered mental status, vertical gaze palsy, and memory impairment. A 51-year-old man was transferred to the emergency department with a sudden loss of consciousness after drinking alcohol. He appeared to be sleeping deeply. His wife insisted that he had not drunk a quantity of alcohol that would render him unconscious. Magnetic resonance imaging of the brain revealed an acute, bilateral, paramedian thalamic infarction. He was admitted and treated with antiplatelet agents. On the following day, four-vessel cerebral angiography revealed stenosis of the left, distal vertebral artery. Three weeks after admission, he was discharged with persistent hypersomnia, memory impairment, and behavioral changes.

Expression of collagenases (matrix metalloproteinase-1, 8, 13) and tissue inhibitor of metalloproteinase-1 of retrodiscal tissue in temporomandibular joint disorder patients

OBJECTIVES: The aim of this study was to reveal how collagenases (matrix metalloproteinase [MMP]-1, 8, 13) and tissue inhibitor of metalloproteinase 1 (TIMP-1) are expressed in immunohistochemistry of retrodiscal tissue in temporomandibular joint disorder patients. MATERIALS AND METHODS: This study was conducted on 39 patients who underwent discoplasty or discectomy. Immunohistochemical staining was undertaken and expression levels of MMP-1, 8, 13, and TIMP-1 were evaluated. The status of internal derangement of disc, osteoarthritis, and joint effusion were analyzed using magnetic resonance imaging (MRI). Disc status observed during operation was also categorized. RESULTS: The more severe disc derangement was observed on MRI, the more increased expression of MMPs and TIMP-1 appeared. Regarding MMP-13 expression, 86.7% of late-stage disc displacement patients showed grade II or III. Expression level of MMPs or TIMP was not statistically significant associated with joint effusion level. In perforation and/or adhesion groups, all patients showed grade II or III expression of MMP-13. Once perforation occurred, MMP-13 showed increased expression with statistical significance. CONCLUSION: MMP-1 and MMP-13 expression seem to be related to progression of osteoarthritis whereas MMP-8 does not seem to have a specific role with regard to temporomandibular joint disorders. TIMP-1 is considered to be partly related to internal derangement rather than osteoarthritis, but it is not significant.

Incidence of Adult In-Hospital Cardiac Arrest Using National Representative Patient Sample in Korea / 대한의료정보학회지

OBJECTIVES: This study analyzed the incidence and characteristics of in-hospital cardiac arrest (IHCA) in Korea based on a sample group of patients that is representative of the population. METHODS: The incidence of IHCA in adults was extracted from HIRA-NIS-2009, a sample of all patients using medical services in Korea. IHCA patients were analyzed according to gender, age, type of medical institute, and classification under the 6th revision of the Korean Standard Classification of Diseases (KCD-6). In addition, to assess the differences arising from the size of medical institutes, the IHCA incidence was analyzed in relation to the number of inpatient beds. RESULTS: Based on the sample data, the total incidence of IHCA in Korea was found to be 2.46 per 1,000 admissions (95% confidence interval [CI], 2.37–2.55). A higher incidence was found among men at 3.18 (95% CI, 3.03–3.33), compared to women at 1.84 (95% CI, 1.74–1.94). The incidence of IHCA was also higher in hospitals that had more than 600 inpatients beds at 5.40 (95% CI, 5.16–5.66) in comparison to those that had less than 600 inpatients beds at 4.09 (95% CI, 3.76–4.36) (p < 0.001). By primary disease, the incidence was the highest for infectious diseases. CONCLUSIONS: We demonstrated that the IHCA incidence based on gender, age, diagnostic group, and number of beds could be analyzed using the insurance claim data from a national representative sample.

Impact of Postthyroidectomy Scar on the Quality of Life of Thyroid Cancer Patients

BACKGROUND: Surgical scars are crucial cosmetic problem, especially when in exposed areas such as the anterior neck following thyroidectomy. OBJECTIVE: To evaluate the impact of post-thyroidectomy scars on quality of life (QoL) of thyroid cancer patients and identify the relationship between scar characteristics and QoL. METHODS: Patients with post-thyroidectomy scars on the neck were recruited. QoL was measured using the Dermatology Life Quality Index (DLQI). Scar characteristics were graded according to Vancouver scar scale (VSS) score. RESULTS: Ninety-seven patients completed a battery of questions at the time of enrollment. Post-thyroidectomy scars were classified according to morphology as linear flat scars, linear bulging scars, hypertrophic scars or adhesive scars. There were 32 patients (33.0%), 9 patients (9.3%), 41 patients (42.3%) and 15 patients (15.5%), respectively, in each group. The mean total DLQI score was 9.02. Domain 2 (daily activities, 2.87 points), which includes questions about clothing, was the most greatly impacted among patients. The total DLQI scores of patients who have experienced scar-related symptoms were significantly higher than those of patients without symptoms (p<0.05). The VSS scores were 3.09 for linear flat scars, 6.89 for linear bulging scars, 6.29 for hypertrophic scars and 5.60 for adhesive scars. However, the DLQI scores did not significantly differ among scar types or VSS scores. CONCLUSION: Post-thyroidectomy scars on the neck affect the QoL of thyroid cancer patients regardless of scar type. Therefore, clinicians should pay attention to the psychological effects of scars on patients and take care to minimize post-thyroidectomy scar.

Osteoradionecrosis of Jaw in Head and Neck Cancer Patient Treated with Free Iliac Bone and Umbilical Fat Pad Graft / 대한악안면성형재건외과학회지

Osteoradionecrosis is one of the most serious complications of patients receiving radiation therapy. It is characterized by hypovascularity, hypocellularity, and hypoxia-inducing necrosis of bone and soft tissue following delayed healing. In this case, a 72-year-old man was referred to the Department of Oral and Maxillofacial Surgery complaining of trismus following extraction three months before first visit. He had a history of right tonsillectomy, radical neck dissection and radiotherapy performed due to right tonsillar cancer seven years prior. After the diagnosis of osteoradionecrosis on right mandibular body and angle, conservative antibiotic therapy was used first, but an orocutaneous fistula gradually formed, and extensive bony destruction and sequestrum were observed. Sequestrectomy, free particulated iliac bone and umbilical fat pad graft were performed via a submandibular approach under general anesthesia. Preoperative regular exams and delicate wound care led to secondary healing of the wound without vascularized free flap reconstruction.

Elastosis Perforans Serpiginosa

Elastosis perforans serpiginosa is a rare skin disease characterized by transepidermal elimination of abnormal elastic fibers. This condition classically presents as small papules arranged in serpiginous or annular patterns on the neck, face, arms, or other flexural areas. While these lesions may spontaneously resolve, they often persist for longer periods of time. Though numerous treatment modalities have been described in the literature, most are not very effective. A 35-year-old man presented to Gangnam Severance Hospital with a 2-year history of skin eruptions on his neck, which were refractory to topical antifungal or steroid treatment. On examination, the patient showed multiple crusted and erythematous papules arranged in an annular pattern with central clearing. A biopsy specimen revealed acanthosis with notable transepidermal elimination of nuclear debris and eosinophilic degenerated elastic fibers from the dermis via an epidermal channel. Verhoeff-van Gieson staining showed dense clumps of altered elastic fibers in the papillary dermis. Based on these findings, a diagnosis of elastosis perforans serpisinosa was made. Treatment with topical 0.05% tretinoin application for 6 months resulted in no improvement.

Structure and Expression Analyses of SVA Elements in Relation to Functional Genes

SINE-VNTR-Alu (SVA) elements are present in hominoid primates and are divided into 6 subfamilies (SVA-A to SVA-F) and active in the human population. Using a bioinformatic tool, 22 SVA element-associated genes are identified in the human genome. In an analysis of genomic structure, SVA elements are detected in the 5' untranslated region (UTR) of HGSNAT (SVA-B), MRGPRX3 (SVA-D), HYAL1 (SVA-F), TCHH (SVA-F), and ATXN2L (SVA-F) genes, while some elements are observed in the 3'UTR of SPICE1 (SVA-B), TDRKH (SVA-C), GOSR1 (SVA-D), BBS5 (SVA-D), NEK5 (SVA-D), ABHD2 (SVA-F), C1QTNF7 (SVA-F), ORC6L (SVA-F), TMEM69 (SVA-F), and CCDC137 (SVA-F) genes. They could contribute to exon extension or supplying poly A signals. LEPR (SVA-C), ALOX5 (SVA-D), PDS5B (SVA-D), and ABCA10 (SVA-F) genes also showed alternative transcripts by SVA exonization events. Dominant expression of HYAL1_SVA appeared in lung tissues, while HYAL1_noSVA showed ubiquitous expression in various human tissues. Expression of both transcripts (TDRKH_SVA and TDRKH_noSVA) of the TDRKH gene appeared to be ubiquitous. Taken together, these data suggest that SVA elements cause transcript isoforms that contribute to modulation of gene regulation in various human tissues.