Erratum: Correction of Text in the Article "Evidence of Long-Distance Droplet Transmission of SARS-CoV-2 by Direct Air Flow in a Restaurant in Korea".

This corrects the article on p. e415 in vol. 35, PMID: 33258335.

Evidence of Long-Distance Droplet Transmission of SARS-CoV-2 by Direct Air Flow in a Restaurant in Korea.

BACKGROUND: The transmission mode of severe acute respiratory syndrome coronavirus 2 is primarily known as droplet transmission. However, a recent argument has emerged about the possibility of airborne transmission. On June 17, there was a coronavirus disease 2019 (COVID-19) outbreak in Korea associated with long distance droplet transmission. METHODS: The epidemiological investigation was implemented based on personal interviews and data collection on closed-circuit television images, and cell phone location data. The epidemic investigation support system developed by the Korea Disease Control and Prevention Agency was used for contact tracing. At the restaurant considered the site of exposure, air flow direction and velocity, distances between cases, and movement of visitors were investigated. RESULTS: A total of 3 cases were identified in this outbreak, and maximum air flow velocity of 1.2 m/s was measured between the infector and infectee in a restaurant equipped with ceiling-type air conditioners. The index case was infected at a 6.5 m away from the infector and 5 minutes exposure without any direct or indirect contact. CONCLUSION: Droplet transmission can occur at a distance greater than 2 m if there is direct air flow from an infected person. Therefore, updated guidelines involving prevention, contact tracing, and quarantine for COVID-19 are required for control of this highly contagious disease.

A Novel PBPK Modeling Approach to Assess Cytochrome P450 Mediated Drug-Drug Interaction Potential of the Cytotoxic Prodrug Evofosfamide.

Evofosfamide is a cytotoxic small-molecule prodrug preferentially activated under hypoxic conditions. The cytotoxicity of evofosfamide impacted the generation of in vitro drug-drug interaction (DDI) data, especially in vitro induction results. Therefore, a novel physiologically based pharmacokinetic (PBPK) approach was used, which involved available in vitro and clinical data of evofosfamide and combined it with induction data from the prototypical cytochrome P450 (CYP)3A inducer rifampicin. The area under the concentration-time curve (AUC) ratios of midazolam were above 0.80, indicating that induction of CYP3A by evofosfamide administered weekly is unlikely to occur in humans. Moreover, static and PBPK modeling showed no clinically relevant inhibition via CYP2B6, CYP2D6, and CYP3A4. In conclusion, PBPK models were used to supplement in vitro information of a cytotoxic compound. This approach may set a precedent for future studies of cytotoxic drugs, potentially reducing the need for clinical DDI studies and providing more confidence in the clinical use of approved cytotoxic compounds for which DDI information is sparse.

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models.

Evofosfamide (TH-302) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide. In hypoxic conditions Br-IPM is released and alkylates DNA. Ifosfamide is a chloro-isophosphoramide prodrug activated by hepatic Cytochrome P450 enzymes. Both compounds are used for the treatment of cancer. Ifosfamide has been approved by the FDA while evofosfamide is currently in the late stage of clinical development. The purpose of this study is to compare efficacy and safety profile of evofosfamide and ifosfamide in preclinical non-small cell lung cancer H460 xenograft models. Immunocompetent CD-1 mice and H460 tumor-bearing immunocompromised nude mice were used to investigate the safety profile. The efficacy of evofosfamide or ifosfamide, alone, and in combination with docetaxel or sunitinib was compared in ectopic and intrapleural othortopic H460 xenograft models in animals exposed to ambient air or different oxygen concentration breathing conditions. At an equal body weight loss level, evofosfamide showed greater or comparable efficacy in both ectopic and orthotopic H460 xenograft models. Evofosfamide, but not ifosfamide, exhibited controlled oxygen concentration breathing condition-dependent antitumor activity. However, at an equal body weight loss level, ifosfamide yielded severe hematologic toxicity when compared to evofosfamide, both in monotherapy and in combination with docetaxel. At an equal hematoxicity level, evofosfamide showed superior antitumor activity. These results indicate that evofosfamide shows superior or comparable efficacy and a favorable safety profile when compared to ifosfamide in preclinical human lung carcinoma models. This finding is consistent with multiple clinical trials of evofosfamide as a single agent, or in combination therapy, which demonstrated both anti-tumor activity and safety profile without severe myelosuppression.

Effects of carnitine on peripheral blood mitochondrial DNA copy number and liver function in non-alcoholic fatty liver disease.

BACKGROUND/AIMS: Functional and anatomical abnormalities of mitochondria play an important role in developing steatohepatitis. Carnitine is essential for enhanced mitochondrial beta oxidation through the transfer of long-chain fatty acids into the mitochondria. We examined the impact of carnitine complex on liver function and peripheral blood mitochondria copy number in NAFLD patients. METHODS: Forty-five NAFLD patients were enrolled. Patients were categorized into the carnitine complex-administered group and control group. Before and 3 months after drug administration, a liver function test and peripheral blood mitochondrial DNA and 8-oxo-dG quantitive analysis were conducted. RESULTS: In carnitine treatment group, ALT, AST, and total bilirubin were reduced after medication. There was no difference in AST, ALT, and total bilirubin between before and after treatment in control group. In carnitine group, peripheral mitochondrial DNA copy number was significantly increased from 158.8+/-69.5 copy to 241.6+/-180.6 copy (p=0.025). While in control group the mitochondrial copy number was slightly reduced from 205.5+/-142.3 to 150.0+/-109.7. 8-oxo-dG level was also tended to decrease in carnitine group (p=0.23) and tended to increase in control group (p=0.07). CONCLUSIONS: In NAFLD, the carnitine improved liver profile and peripheral blood mitochondrial DNA copy number. This results suggest that carnitine activate the mitochondria, thereby contributing to the improvement of NAFLD.

Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs.

A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.

A 5Fr catheter approach reduces patient discomfort during transradial coronary intervention compared with a 6Fr approach: a prospective randomized study.

Smaller guiding catheters can help reduce local complications and patient morbidity during transradial coronary intervention (TRI). This study was designed to compare the patient's morbidity, success rate, and the operator's convenience between 5-French (5Fr) and 6-French (6Fr) TRIs. This is a single-center prospective randomized study. Patients who underwent TRI, in 2003, were prospectively randomized to either 5Fr or 6Fr catheter groups (100 patients in each group). Procedure-related patient morbidity as well as clinical and procedural characteristics was scored and analyzed. Procedural success rate was not significantly different between the groups. The number of unsatisfactory supports (6% in 5Fr group, 3% in 6Fr group; P=0.31) and the incidence of local wound complications were not significantly different between the groups. Local wound pain scores were significantly lower in the 5Fr group compared with the 6Fr group, particularly during sheath insertion and removal, and during procedures. Pain scores were higher in female patients than in male patients during sheath removal (male: 1.3+/-1.3, female: 1.7+/-1.5; P=0.049). Radial artery diameter was well correlated with local pain score during sheath removal (r=0.31, P<0.001), and with the height and weight of the patients (height: r=0.33, P<0.001; weight: r=0.27, P<0.001). In conclusion, using a 5Fr catheter during TRI reduce, local access site pain, particularly in female patients with smaller body size, whereas the success and local complication rates were similar to a 6Fr approach.

Feasibility and safety of the transradial approach for the intracoronary spasm provocation test.

An angiography-based spasm provocation test is an accurate diagnostic test of coronary vasospastic angina, but is associated with high patient morbidity, mainly because of the femoral approach and the need for a temporary pacemaker. The purpose of this study was to investigate the safety and feasibility of a transradial ergonovine spasm provocation test. The test was performed prospectively in 174 consecutive patients who were under suspicion of coronary vasospasm at our institution from April 2002 to June 2003. Seventy-eight out of 174 procedures (45%) were performed in an outpatient department. The procedural success rate was 168/174 (96%). All failures were because of access failures, and no major complications were noted. Minor complications were observed in nine patients (severe bradycardia in three, hypotension in two, both in two, and nonsustained ventricular tachycardia in two). The incidence of complications was higher in patients showing prolonged spasm in the right coronary artery. No major local complication was noted other than rebleeding in the puncture site during hemostasis in one patient. The transradial spasm provocation test performed without using a temporary pacemaker may be feasible and safe, with a high success rate and low complication rate as well as low patient morbidity.

Characteristics and prevalence of intrapulmonary shunt detected by contrast echocardiography with harmonic imaging in liver transplant candidates.

We investigated the prevalence and characteristics of intrapulmonary shunt using contrast echocardiography with harmonic imaging in 130 liver transplant candidates. We found a high prevalence of intrapulmonary shunts and a significant correlation between the degree of intrapulmonary shunt and the Child-Pugh classification score.

Identification of proximal left anterior descending artery stenosis with thallium-201 defect patterns in patients with angina pectoris.

We determined the accuracy of perfusion defect patterns in predicting the presence of proximal left anterior descending (LAD) artery stenosis in patients with angina pectoris. The development population consisted of 80 patients with single-vessel LAD stenosis and reversible LAD territory defects on thallium-201 tomography. The types of defect patterns associated with angiographic proximal LAD stenosis in this population were categorized as "proximal LAD patterns." The accuracy of these patterns for identifying proximal LAD stenosis was evaluated in a separate validation population of 152 patients with angina pectoris. The development population demonstrated LAD territory defects of type I (most of the LAD territory; n = 12); type II (apex, apicoanterior, and most of the septum; n = 26), type III (septum; n = 19); type IV (anteroseptum; n = 6); type V (apex; n = 10); and type VI patterns (anterolateral wall; n = 7). Patients with type I, II, and IV patterns were highly associated with proximal LAD stenosis (38 of 44 segments), whereas those with type III, V, and VI patterns were mostly related to distal LAD disease (29 of 36 segments). In the validation population, proximal LAD patterns had a sensitivity, specificity, and accuracy of 72%, 95%, and 91%, respectively, for identifying patients with proximal LAD stenosis. Test sensitivity was 86% when patients without LAD territory defects were excluded from analysis. Results were virtually identical in the subgroup of 84 patients with stable angina. Thus, recognition of LAD territory thallium defect patterns is useful for identifying patients with angina who are likely to have proximal LAD stenosis.

Myocardial thallium defects in apical hypertrophic cardiomyopathy are associated with a benign prognosis. Thallium defects in apical hypertrophy.

BACKGROUND: We investigated whether myocardial thallium-201 defects in patients with apical hypertrophic cardiomyopathy are associated with an unfavorable clinical outcome, and additionally compared the presence of defects to echocardiography and angiography findings. METHODS: Dipyridamole thallium-201 single photon emission tomography was performed in 26 apical hypertrophic cardiomyopathy patients, aged 41-78 (22 men, 6 women). Patients with or without perfusion defects were compared for echocardiographic measurements of wall thickness, chamber dimensions, and fractional shortening. Twelve patients underwent coronary angiography. The occurrence of cardiac events was evaluated during clinical follow-up for a mean period of 4.3 +/- 1.9 years (range: 1.0-7.0 year). RESULTS: Thirteen patients (50%) showed perfusion defects, which were predominantly reversible (fixed in 1) and mostly apical (9 of 13). Patients with and without defects did not differ in symptoms, EKG findings, echocardiographic morphology or fractional shortening (41 +/- 4 vs. 41 +/- 7%). Coronary angiography was normal in all patients in whom it was performed (nine with and three without defects). During follow-up, there were no deaths or myocardial infarction. Of the defect positive group, one case developed paroxysmal supraventricular tachycardia, and another had a cerebrovascular accident. Of the defect negative group, one case developed sick sinus syndrome, while another had a hospital admission for anginal pain. CONCLUSIONS: While reversible thallium defects in the absence of coronary artery disease occur frequently in patients with apical hypertrophic cardiomyopathy, the prognosis remains benign despite the presence of ischemia and there is no evidence for an association with adverse patient outcome.

Predictors of positive head-up tilt test in patients with suspected neurocardiogenic syncope or presyncope.

Neurocardiogenic syncope is the most common cause of syncope in patients who present in outpatient clinics. Head-up tilt test (HUT) has been widely used to diagnose neurocardiogenic syncope. However, the HUT does not always produce a positive response in patients with suspected neurocardiogenic syncope. The aim of the present study was to assess the clinical history and characteristics of patients with suspected neurocardiogenic syncope or presyncope who undertook HUT, and to identify prognostic factors of a positive HUT response. During the first phase of HUT, patients were tilted to a 70-degree angle for 30 minutes. If the first phase produced a negative response, the second phase was subsequently performed involving intravenous isoproterenol administration. Of 711 patients, 423 (59.5%) patients showed a positive HUT response. In contrast to previous studies, this study showed that the vasodepressive type (76.6%) was the most common pattern of positive response, and that the rate of positive response during the first phase was low (7.1%). By multivariate analysis, the occurrence of junctional rhythm was found to be a predictor of an impending positive response in HUT (P < 0.001). The shorter time interval between the last episode and HUT was also a predictor of positive response (P = 0.0015). Younger age (P = 0.0003) and a history of physical injury during a syncopal episode (P = 0.019) were found to be associated with a positive response in the first phase of HUT.