Preclinical assessment and randomized Phase I study of CT-P63, a broadly neutralizing antibody targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant morbidity and mortality worldwide. Despite a successful vaccination programme, the emergence of mutated variants that can escape current levels of immunity mean infections continue. Herein, we report the development of CT-P63, a broad-spectrum neutralizing monoclonal antibody. In vitro studies demonstrated potent neutralizing activity against the most prevalent variants, including Delta and the BA.1 and BA.2 sub-lineages of Omicron. In a transgenic mouse model, prophylactic CT-P63 significantly reduced wild-type viral titres in the respiratory tract and CT-P63 treatment proved efficacious against infection with Beta, Delta, and Omicron variants of SARS-CoV-2 with no detectable infectious virus in the lungs of treated animals. A randomized, double-blind, parallel-group, placebo-controlled, Phase I, single ascending dose study in healthy volunteers (NCT05017168) confirmed the safety, tolerability, and pharmacokinetics of CT-P63. Twenty-four participants were randomized and received the planned dose of CT-P63 or placebo. The safety and tolerability of CT-P63 were evaluated as primary objectives. Eight participants (33.3%) experienced a treatment-emergent adverse event (TEAE), including one grade ≥3 (blood creatine phosphokinase increased). There were no deaths, treatment-emergent serious adverse events, TEAEs of special interest, or TEAEs leading to study drug discontinuation in the CT-P63 groups. Serum CT-P63 concentrations rapidly peaked before declining in a biphasic manner and systemic exposure was dose proportional. Overall, CT-P63 was clinically safe and showed broad-spectrum neutralizing activity against SARS-CoV-2 variants in vitro and in vivo.

Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries.

Autism spectrum disorder (ASD) substantially contributes to the burden of mental disorders. Improved awareness and changes in diagnostic criteria of ASD may have influenced the diagnostic rates of ASD. However, while data on trends in diagnostic rates in some individual countries have been published, updated estimates of diagnostic rate trends and ASD-related disability at the global level are lacking. Here, we used the Global Burden of Diseases, Injuries, and Risk Factors Study data to address this gap, focusing on changes in prevalence, incidence, and disability-adjusted life years (DALYs) of ASD across the world. From 1990 to 2019, overall age-standardized estimates remained stable globally. Both prevalence and DALYs increased in countries with high socio-demographic index (SDI). However, the age-standardized incidence decreased in some low SDI countries, indicating a need to improve awareness. The male/female ratio decreased between 1990 and 2019, possibly accounted for by increasing clinical attention to ASD in females. Our results suggest that ASD detection in low SDI countries is suboptimal, and that ASD prevention/treatment in countries with high SDI should be improved, considering the increasing prevalence of the disorder. Additionally, growing attention is being paid to ASD diagnosis in females, who might have been left behind by ASD epidemiologic and clinical research previously. ASD burden estimates are underestimated as GBD does not account for mortality in ASD.

A Radiological Assessment of Chronic Subdural Hematomas.

Chronic subdural hematoma (CSDH), which generally occurs in elderly patients, is a frequently diagnosed condition in neurosurgical departments. Computed tomography (CT) and magnetic resonance imaging (MRI) are the most preferred diagnostic modalities for CSDH assessment. With early diagnosis and adequate management, CSDH may show favorable prognosis in majority of the patients; however, recurrence after surgery can occur in a significant number of patients. The recently increasing number of CSDH studies could reveal the prognostic factors affecting CSDH recurrence. Particularly, radiological characteristics regarding the internal architecture of CSDH are considered closely associated with recurrence in surgically treated CSDH patients. In this literature review, we evaluated the various diagnostic modalities of CSDH and its radiological characteristics on CT and MRI. Furthermore, we summarized the prognostic factors of recurrence for the hematoma type based on the radiological findings.

Validation and assessment of the Investigator® 24plex QS kit for forensic casework application: Comparison with the PowerPlex® fusion system and GlobalFiler™ PCR amplification kits.

Casework evidence samples are likely to be placed under diverse and harsh environments as compared to quantified DNA samples including serial-diluted standard DNA samples. Internal validation of a novel STR kit using casework evidence sample, which is conducted according to various conditions such as DNA contamination and degradation, is crucial before being used as a forensic application. Therefore, this study aimed to elucidate the reliability of the Investigator® 24plex QS kit through DNA derived from casework evidence and to assess whether it is applicable to STR analysis together with PowerPlex® Fusion System and GlobalFiler™ PCR Amplification Kit. DNA was extracted from 189 casework evidence samples in a total of 77 cases. The mismatch of the allelic size of this kit through allelic sizing precision test, was suitable according to ENFSI guidelines. All heterozygous balance of the three kits were above 0.6 recommended value of ENFSI guideline. The number of allele drop-in was most frequent in the GlobalFiler™ PCR Amplification Kit. In addition, the number of allele drop-out was most frequent in the Investigator® 24plex QS kit. The cutoff concentration of DNA detected in three kits of one complete STR was approximately 45 pg/µL on average. Despite of several limitations, the Investigator® 24plex QS kit is considered to have the capability to be used for STR analysis of casework evidence samples.

Comparative effectiveness and cost-effectiveness of Chuna manual therapy versus conventional usual care for nonacute low back pain: study protocol for a pilot multicenter, pragmatic randomized controlled trial (pCRN study).

BACKGROUND: While Chuna manual therapy is a Korean manual therapy widely used primarily for low back pain (LBP)-related disorders in Korea, well-designed studies on the comparative effectiveness of Chuna manual therapy are scarce. METHODS/DESIGN: This study is the protocol for a three-armed, multicenter, pragmatic randomized controlled pilot trial. Sixty severe nonacute LBP patients (pain duration of at least 3 weeks, Numeric Rating Scale (NRS) ≥5) will be recruited at four Korean medicine hospitals. Participants will be randomly allocated to the Chuna group (n = 20), usual care group (n = 20), or Chuna plus usual care group (n = 20) for 6 weeks of treatment. Usual care will consist of orally administered conventional medicine, physical therapy, and back pain care education. The trial will be conducted with outcome assessor and statistician blinding. The primary endpoint will be NRS of LBP at week 7 post randomization. Secondary outcomes include NRS of leg pain, the Oswestry Disability Index (ODI), the Patient Global Impression of Change (PGIC), the Credibility and Expectancy Questionnaire, lumbar range of motion (ROM), the EuroQol-5 Dimension (EQ-5D) health survey, the Health Utility Index III (HUI-III), and economic evaluation and safety data. Post-treatment follow-ups will be conducted at 1, 4, and 10 weeks after conclusion of treatment. DISCUSSION: This study will assess the comparative effectiveness of Chuna manual therapy compared to conventional usual care. Costs and effectiveness (utility) data will be analyzed for exploratory cost-effectiveness analysis. If this pilot study does not reach a definite conclusion due to its small sample size, these results will be used as preliminary results to calculate sample size for future large-scale clinical trials and contribute in the assessment of feasibility of a full-scale multicenter trial. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0001850 . Registered on 17 March 2016.

Assessment of risk of complications in cirrhosis using portal thallium scans.

AIM: To investigate the usefulness of a novel thallium scan shunt index for assessing portosystemic shunt-related cirrhotic complications. METHODS: We enrolled 209 chronic hepatitis B-related cirrhosis patients. After rectal thallium instillation, radioactive isotope activity in the heart and liver was measured. The ratio of radiation uptake between the heart and the liver was calculated (the shunt index). This value indicates the degree of portosystemic circulation shunting. Blood tests, serum biochemistry tests, abdominal ultrasonography, gastroscopy and examination of clinical features such as the occurrence of varices, bleeding and hepatic encephalopathy were performed. Multivariate analysis was used to identify independent risk factors for complications. We compared the cumulative incidence rates of complications during the follow-up period. RESULTS: The thallium scan shunt index was significantly higher in the decompensated liver cirrhosis group than in the compensated liver cirrhosis group (0.91 ± 0.39 vs 0.39 ± 0.32, P < 0.001). It was also higher in the varices group, the hepatic encephalopathy group, and the variceal bleeding group than in the control group (P < 0.001). Multivariate analysis showed that the index was an independent risk factor for predicting decompensated liver cirrhosis. When the cut-off value was 0.75, the shunt index had a sensitivity of 82.6%, a specificity of 84%, a positive predictive value of 61.5%, and a negative predictive value of 94.4% in diagnosing decompensated cirrhosis. When the shunt index was greater than 0.75, there was a significant increase in the number of decompensated events. CONCLUSION: The thallium shunt index is a good predictor of cirrhosis-related complications.

Quantification of nimesulide in human plasma by high-performance liquid chromatography with ultraviolet detector (HPLC-UV): application to pharmacokinetic studies in 28 healthy Korean subjects.

Nimesulide is a selective COX-2 inhibitor that is as effective as the classical non-acidic nonsteroidal anti-inflammatory drugs in the relief of various pain and inflammatory conditions, but is better tolerated with lower incidences of adverse effects than other drugs. After oral dose of 100 mg nimesulide to western subjects, a mean maximal concentration (C(max)) of 2.86 ∼ 6.5 µg/mL was reached at 1.22 ∼ 2.75 h and mean t(1/2ß) of 1.8 ∼ 4.74 h. This study developed a robust method for quantification of nimesulide for the pharmacokinetics and suitability of its dosage in Korea and compared its suitability with other racial populations. Nimesulide and internal standard were extracted from acidified samples with methyl tert-butyl ether and analyzed by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The 28 healthy volunteers took 2 tablets of 100 mg nimesulide and blood concentrations were analyzed during the 24 h post dose. Several pharmacokinetic parameters were represented: AUC(0-infinity) = 113.0 mg-h/mL, C(max) = 12.06 mg/mL, time for maximal concentrations (T(max)) = 3.19 h and t(1/2ß) = 4.51 h. These were different from those of western populations as follows: AUC was 14.5% and C(max) was 28% that of of Korean subjects and T(max) and t(1/2ß) were also different. The validated HPLC-UV method was successfully applied for the pharmacokinetic studies of nimesulide in Korean subjects. Because the pharmacokinetics of nimesulide were different from western populations, its dosage regimen needs to be adjusted for Koreans.

Importance of clinical and echocardiographic hemodynamic assessment in chronic pulmonary embolism.

We describe a 42-year-old man presenting to the emergency department with cardiogenic shock. He had a prior history of acute pulmonary embolism (PE), and had been on anticoagulation for 2 years. Although computed tomographic pulmonary angiography performed at the emergency department showed no change in the extent of PE and did not support a role of surgical treatment, pulmonary embolectomy was recommended by attending physician based on clinical and echocardiographic hemodynamic findings like unstable vital sign and markedly enlarged right ventricle with severely depressed systolic function. Surgery confirmed the presence of fresh thrombi. After surgery, hemodynamic status was progressively improved, but the patient died due to pneumonia and pulmonary hemorrhage.

Establishment of a Stable Cell Line Expressing Green Fluorescence Protein-fused Hypoxia Inducible Factor-1α for Assessment of Carcinogenicity of Chemical Toxicants.

Hypoxia inducible factor 1α (HIF-1α) is a potential marker of carcicnogenesis since it is overexpresssed in many human cancers such as brain, breast, and uterus, and its role has implicated in tumor cell growth and metastasis. In this study, we established a stable cell line that express green fluorescence protein (GFP)-fused hypoxia inducible factor 1α (HIF-1α) and evaluated the potential use of this cell line for assessment of carcinogenicity of chemical toxicants. Western blot analysis as well as fluorescence measurements showed that protein-level of GFP-HIF-1α was significantly enhanced in a dose-dependent manner upon treatment of hypoxia mimicking agents such as dexferrioxamine and CoCl2. Well-Known tumor promoters such as mitomycin and methyl methane-sulfonate. significantly induced the fluorescence intensity of GFP-HIF-1α, whereas the known negative controls such as o-anthranilic acid and benzethonium chloride, did not. These results indicate that HIF-1α could be a biological parameter for detection of tumor initiators/promoters and suggest that the GFP-HIF-1α cell line is a useful system for screening of carcinogenic toxicants.