A Nonrandomized Phase 2 Trial of EG-Mirotin, a Novel, First-in-class, Subcutaneously Delivered Peptide Drug for Non-Proliferative Diabetic Retinopathy

ABSTRACTBackgroundEG-Mirotin, which includes an active ingredient; EGT022, targeting Non-Proliferative Diabetic Retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin is a drug that is used before capillary damage progresses to an irreversible stage. Safety and efficacy of EG-Mirotin were investigated in subjects with Type 1 or 2 diabetes and NPDR with the degree from moderate to severe.MethodsSubjects (n=10, 20 eyes) satisfying the selection criteria through the screening test were administered EG-Mirotin once a day (3 mg in 1.5 ml of sterile saline) for 5 days, 5 times in total, and were evaluated of the Ischemic index changes and safety. End-of-study (EOS) is performed approximately 8 weeks ± 1 (57 days ± 7) from the first dose.ResultsA total of 4 Treatment Emergent Adverse Events (TEAE) were observed in 2 subjects out of 10 (20.00%) who received the investigational drug. Among them, no subjects were reported experiencing a TEAE related to the investigational drug. All injections were well tolerated (3 mg in 1.5 ml of sterile saline) with no dose-limiting adverse events, deaths, serious adverse events. The overall average percent change in ischemic index at each evaluation point compared to baseline was statistically significant (Greenhouse-Geisser F=9.456, p=0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F=10.946, p=0.002 for the time*group interaction).ConclusionsEG-Mirotin was well tolerated and found to reverse the ischemia and leakage of capillaries in the retina caused by diabetes.

Real-Life Cause-Effect Relations Between Urinary IL-6 Levels and Specific and Nonspecific Symptoms in a Patient With Mild SLE Disease Activity

BackgroundLittle is known about the real-time cause-effect relations between IL-6 concentrations and SLE symptoms.MethodsA 52-year-old woman with mild SLE activity collected her entire urine for the determination of IL-6/creatinine and protein/creatinine levels (ELISA, HPLC) for a period of 56 days in 12 h intervals (total: 112 measurements). Additionally, she answered questionnaires (VAS) on oral ulceration, facial rash, joint pain, fatigue and tiredness and measured her temperature orally twice a day. Time-series analyses consisted of ARIMA modeling and cross-correlational analyses (one lag = 12 h, significance level = p < 0.05).ResultsStatistical analyses showed that increased urinary IL-6 concentrations preceded increased urinary protein levels by 36–48 h (lag3: r=+.225; p=.017) and that, in the opposite direction of effect, increased urinary protein preceded urinary IL-6 decreases by 12–24 h (lag1: r=–.322; p<.001). Moreover, urinary IL-6 increases co-occurred with increased oral ulceration (lag0: r=+.186; p=.049); after 48–60 h, however, IL-6 increases showed a strong tendency to precede oral ulceration decreases (lag4: r=–.170; p=.072). Increases in facial rash preceded decreases in urinary IL-6 after 84–96 h (lag7: r=–.215; p=.023). As to fatigue, increases in urinary IL-6 co-occurred with decreased fatigue (lag0: r=–.193; p=.042); after 84–96 h, however, IL-6 increases preceded fatigue increases (+lag7: r=+.189; p=.046). Finally, joint pain, tiredness and body temperature did not significantly correlate with urinary IL-6 concentrations in either direction of effect.ConclusionsThe results of this evaluation point to real-life feedback mechanisms between immune activity and SLE symptoms. Comparison with a previous evaluation of this patient suggests a counterregulatory mechanism between Th1 activity and IL-6. These findings are preliminary and require replication to draw firm conclusions about the real-time relation between IL-6 and SLE disease activity.

The Evaluation Point-of-Care Ultrasound in the Post-Anesthesia Unit–A Multicenter Prospective Observational Study

Introduction: Point-of-care ultrasound (POCUS) is the most rapidly growing imaging modality for acute care. Despite increased use, there is still wide variability and less evidence regarding its clinical utility for the perioperative setting compared to other acute care settings. This study sought to demonstrate the impact of POCUS examinations for acute hypoxia and hypotension occurring in the post-anesthesia care unit (PACU) versus traditional bedside examinations. Methods: This study was designed as a multi-center prospective observational study. Adult patients who experienced a reduced mean arterial blood pressure (MAP < 60mmHG) and/or a reduced oxygen saturation (SpO2 < 88%) in the PACU from 7AM to 4PM were targeted. POCUS was available or not for patient assessment based on PACU team training. All providers who performed POCUS exams received standardized training on cardiac and pulmonary POCUS. All POCUS exam findings were recorded on a standardized form and the number of suspected mechanisms to trigger the acute event were captured before and after the POCUS exam. PACU length of stay (minutes) across groups was the primary outcome. Results: In total, 128 patients were included in the study, with 92 patients receiving a POCUS exam. Comparison of PACU time between the POCUS group (median = 96.5 min) and no-POCUS groups (median = 120.5 min) demonstrated a reduction for the POCUS group, p = 0.019. Hospital length of stay and 30-day hospital readmission did not show a significant difference between groups. Finally, there was a reduction in the number of suspected diagnoses from before to after the POCUS examination for both pulmonary and cardiac exams, p-values < 0.001. Conclusions: Implementation of POCUS for assessment of acute hypotension and hypoxia in the PACU setting is associated with a reduced PACU length of stay and a reduction in suspected number of diagnoses.

A Study on the Soundscape Satisfaction Degree of Urban Landscape Garden Parks

Establishing a public response model of soundscape in parks can provide a basis for the optimization of soundscape design. Three representative urban landscape garden parks were selected in Hangzhou, in which a number of evaluation points were chosen along soundwalk paths. Binaural sounds at each evaluation point were sampled by an artificial head and the landscapes of horizontal view and vertical view were obtained by panoramic photos and satellite images, respectively. An evaluation on soundscape of each point was conducted in laboratory based on virtual reality technology, and the correlations between 17 acoustic indicators, 35 landscape indicators and soundscape satisfaction degree were analyzed. The public response model of soundscape satisfaction degree in parks was established. Final indicators entering the model were the loudness level of sound, the aggregation index of water, the largest patch index of water and the landscape shape index of roads, and their standard regression coefficients were -0.666, - 0.561, 0.523 and -0.310, respectively. The impact weights of acoustics and landscape factors on the satisfaction were 32.3% and 67.7%. When the percentage of vegetation area in park exceeds 15%, its contribution to satisfaction degree will be close to a fixed value (reflected in the constant term of the model). The soundscape satisfaction can be effectively improved by reducing the loudness level of sound in parks, increasing the area of the largest water patch with scattered water patches around it, and reducing the shape complexity of road patches.

Extended single-dose toxicity study of [211At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer

Objective Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. Methods [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. Results No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. Conclusions In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

Are China’s Water Resources for Agriculture Sustainable? Evidence from Hubei Province

We assessed the sustainability of agricultural water resources in Hubei Province, a typical agricultural province in central China, for a decade (2008–2018). Since traditional evaluation models often consider only the distance between the evaluation point and the positive or negative ideal solution, we introduce gray correlation analysis and construct a new sustainability evaluation model. Our research results show that only one city had excellent sustainable development capacity of agricultural water resources, and the evaluation value of eight cities fluctuated by around 0.5 (the median of the evaluation result), while the sustainable development capacity of agricultural water resources in other cities was relatively poor. Our findings not only reflect the differences in the natural conditions of water resources among various cities in Hubei, but also the impact of the cities’ policies to ensure efficient agricultural water use for sustainable development. The indicators and methods in this research are not difficult to obtain in most countries and regions of the world. Therefore, the indicator system we have established by this research could be used to study the sustainability of agricultural water resources in other countries, regions, or cities.

Saudi Specialist Certificate Program for Radiology Technology & Medical Imaging: A Commentary

This post-bachelor program is 4 year-long program for Radiographers which is offered by the Saudi Commission for Health Specialties for Saudi Radiographers. This program has no similar programs in the UK or the US. It cost around 12,000 S.R. per year. The program’s aim is to give an advanced level of training for Radiographers to become specialized in one field. The program has three tracks; ultrasound, axial imaging (CT & MRI), and nuclear medicine. This program is similar to the residency programs for physicians. The trainee will finish R1 to R4 like any other physician’s program. The program has an admission test and the top 10 scores are selected in a matching process that includes the GPA, research, volunteering, etc. The matching system is like the matching system for physicians’ programs. Every year the trainee must pass a specific test to move to the next phase of this program. After graduation, the Radiographer will be subspecialized in one field and the salary will increase. The negative thing about this program that it can’t undergo any credential evaluation process in any country globally. The program is called a fellowship program, but its design like a residency program. The scientific committee claims that there are similar programs in the US like the American Board of science in nuclear medicine and in the UK like the institute of physics and bioengineering in medicine. A bachelor’s degree, master’s degree, or Ph.D. can be processed, but a fellowship program that is 4 years for radiologic technologists is very confusing. The program accepts 12 yearly which is a low number in different centers in the kingdom. The program’s supervisors in some centers do follow the educational formatting and some of the mentors do not follow the requirements since the Saudi Commission for Health Specialties does not pay the supervisors and mentors nothing which makes the Saudi Commission for Health Specialties have no way in control them. In some cases, it can result in the trainee not passing the annual exam or shut down the training center. The training centers are not given support from the Saudi Commission for Health Specialties to help them to improve their teaching methods and practice. This program does not focus on research and publishing papers, but in the program, there are some modules about research. furthermore, after finishing the program the radiologic specialist will become a radiologic subspecialist, not a consultant. No Dr. title is added before the graduate name and no degree title is added behind the name for example (B.Sc., M.Sc., P.hD., RRA, FRCR, etc). even though it’s a clinical doctorate degree but no doctor title is given. Many information is missing and many questions about this program need to be addressed. The program did not have specialties like angiography and interventional radiology. The name of this program is a very long name which should be shorter. The good thing about this program is allowing an equal number of male and female radiographers (top 6 males and top 6 females scores). This program required a clinical experience from 2 to 3 years before the candidate can be accepted which illogical because the trainee will have training for 4 years in this program which will teach the trainee all what they need to know in selected specialty. This program need to be revaluated and redesigned to be more inclusive to different fields and to give a new rule for radiographers. Any organization want to propose a new program must study the credential evaluation point very carefully. The future of the graduates from similar programs can be wasted.

High-Precision Kriging Modeling Method Based on Hybrid Sampling Criteria

Finding new valuable sampling points and making these points better distributed in the design space is the key to determining the approximate effect of Kriging. To this end, a high-precision Kriging modeling method based on hybrid sampling criteria (HKM-HS) is proposed to solve this problem. In the HKM-HS method, two infilling sampling strategies based on MSE (Mean Square Error) are optimized to obtain new candidate points. By maximizing MSE (MMSE) of Kriging model, it can generate the first candidate point that is likely to appear in a sparse area. To avoid the ill-conditioned correlation matrix caused by the too close distance between any two sampling points, the MC (MSE and Correlation function) criterion formed by combining the MSE and the correlation function through multiplication and division is minimized to generate the second candidate point. Furthermore, a new screening method is used to select the final expensive evaluation point from the two candidate points. Finally, the test results of sixteen benchmark functions and a house heating case show that the HKM-HS method can effectively enhance the modeling accuracy and stability of Kriging in contrast with other approximate modeling methods.

Comprehensive assessment of alterations in hand deformities over 11 years in patients with rheumatoid arthritis using cluster analysis and analysis of covariance

Background Although drug therapy for rheumatoid arthritis (RA) has recently improved, treating patients with established disease, whose hands have three major deformities (thumb deformity, finger deformities, and ulnar drift), remains a challenge. The underlying complex pathophysiology makes understanding these deformities difficult, and comprehensive assessment methods require accumulated skill with long learning curves. We aimed to establish a simpler composite method to understand the pathophysiology of and alterations in the hand deformities of patients with RA. Methods We established a rheumatoid hand cohort in 2004 and clinically evaluated 134 hands (67 patients). We repeated the evaluations in 2009 (100 hands of 52 patients) and 2015 (63 hands of 37 patients) after case exclusion. Thumb deformities, finger deformities (swan-neck and boutonnière deformity), and ulnar drift were semi-quantitated and entered as parameters into a two-step cross-sectional cluster analysis for the data in 2004. The parameters in each cluster were plotted at each evaluation point. Two-way analysis of covariance was used to examine whether differences existed between evaluation points and clusters of deformity parameters. Results Five clusters most appropriately described hand deformity: (i) cluster 1, minimal deformity; (ii) cluster 2, type 1 thumb deformity; (iii) cluster 3, thumb deformity and severe boutonnière deformity; (iv) cluster 4, type 2 or 3 thumb deformity and severe ulnar drift; and (v) cluster 5, thumb deformity and severe swan-neck deformity. Clusters 1 and 2 had higher function than cluster 5, and cluster 3 had moderate function. Clusters 1–4 had similar disease duration but showed different paths of deformity progression from disease onset. Clusters 1 and 2 represented conservative deformity parameters and clusters 3, 4, and 5 represented progressive deformity parameters. Over time, thumb deformity evolved into other types of deformities and swan-neck deformity worsened significantly. Conclusions Our comprehensive analysis identified five deformity patterns and a progressive course in the rheumatoid hand. Knowledge of the characteristics of progressive deformity parameters may allow rheumatologists to more easily implement practical interventions and determine functional prognosis.