Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures.

There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.

Quantitative Brain Amyloid PET.

Since the development of amyloid tracers for PET imaging, there has been interest in quantifying amyloid burden in the brains of patients with Alzheimer disease. Quantitative amyloid PET imaging is poised to become a valuable approach in disease staging, theranostics, monitoring, and as an outcome measure for interventional studies. Yet, there are significant challenges and hurdles to overcome before it can be implemented into widespread clinical practice. On November 17, 2022, the U.S. Food and Drug Administration, Society of Nuclear Medicine and Molecular Imaging, and Medical Imaging and Technology Alliance cosponsored a public workshop comprising experts from academia, industry, and government agencies to discuss the role of quantitative brain amyloid PET imaging in staging, prognosis, and longitudinal assessment of Alzheimer disease. The workshop discussed a range of topics, including available radiopharmaceuticals for amyloid imaging; the methodology, metrics, and analytic validity of quantitative amyloid PET imaging; its use in disease staging, prognosis, and monitoring of progression; and challenges facing the field. This report provides a high-level summary of the presentations and the discussion.

The impact of misclassification errors on the performance of biomarkers based on next-generation sequencing, a simulation study.

The development of next-generation sequencing (NGS) opens opportunities for new applications such as liquid biopsy, in which tumor mutation genotypes can be determined by sequencing circulating tumor DNA after blood draws. However, with highly diluted samples like those obtained with liquid biopsy, NGS invariably introduces a certain level of misclassification, even with improved technology. Recently, there has been a high demand to use mutation genotypes as biomarkers for predicting prognosis and treatment selection. Many methods have also been proposed to build classifiers based on multiple loci with machine learning algorithms as biomarkers. How the higher misclassification rate introduced by liquid biopsy will affect the performance of these biomarkers has not been thoroughly investigated. In this paper, we report the results from a simulation study focused on the clinical utility of biomarkers when misclassification is present due to the current technological limit of NGS in the liquid biopsy setting. The simulation covers a range of performance profiles for current NGS platforms with different machine learning algorithms and uses actual patient genotypes. Our results show that, at the high end of the performance spectrum, the misclassification introduced by NGS had very little effect on the clinical utility of the biomarker. However, in more challenging applications with lower accuracy, misclassification could have a notable effect on clinical utility. The pattern of this effect can be complex, especially for machine learning-based classifiers. Our results show that simulation can be an effective tool for assessing different scenarios of misclassification.

US FDA public meeting: identification of concepts and terminology for multicomponent biomarkers.

The US FDA convened a virtual public workshop with the goals of obtaining feedback on the terminology needed for effective communication of multicomponent biomarkers and discussing the diverse use of biomarkers observed across the FDA and identifying common issues. The workshop included keynote and background presentations addressing the stated goals, followed by a series of case studies highlighting FDA-wide and external experience regarding the use of multicomponent biomarkers, which provided context for panel discussions focused on common themes, challenges and preferred terminology. The final panel discussion integrated the main concepts from the keynote, background presentations and case studies, laying a preliminary foundation to build consensus around the use and terminology of multicomponent biomarkers.

Gastroprotective effects of Machilus zuihoensis Hayata bark against acidic ethanol-induced gastric ulcer in mice.

Background and aim: In traditional medicine, Machilus zuihoensis Hayata bark (MZ) is used in combination with other medicines to treat gastric cancer, gastric ulcer (GU), and liver and cardiovascular diseases. This study aims to evaluate the gastroprotective effects and possible mechanism(s) of MZ powder against acidic ethanol (AE)-induced GU and its toxicity in mice. Experimental procedure: The gastroprotective effect of MZ powder was analyzed by orally administering MZ for 14 consecutive days before AE-inducing GU. Ulcer index (UI) and protection percentage were calculated, hematoxylin and eosin staining and periodic acid-Schiff staining were performed, and gastric mucus weights were measured. The antioxidative, anti-inflammatory, and anti-apoptotic mechanisms, and possible signaling pathway(s) were studied. Results and conclusion: Pretreatment with MZ (100 and 200 mg/kg) significantly decreased 10 µL/g AE-induced mucosal hemorrhage, edema, inflammation, and UI, resulted in protection percentages of 88.9% and 93.4%, respectively. MZ pretreatment reduced AE-induced oxidative stress by decreasing malondialdehyde level and restoring superoxide dismutase activity. MZ pretreatment demonstrated anti-inflammatory effects by reducing both serum and gastric tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß levels. Furthermore, MZ pretreatment exhibited anti-apoptotic effect by decreasing Bcl-2 associated X protein/B-cell lymphoma 2 ratio. The gastroprotective mechanisms of MZ involved inactivations of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and mitogen activated protein kinase (MAPK) signaling pathways. Otherwise, 200 mg/kg MZ didn't induce liver or kidney toxicity. In conclusion, MZ protects AE-induced GU through mucus secreting, antioxidative, anti-inflammatory, and anti-apoptotic mechanisms, and inhibitions of NF-κB and MAPK signaling pathways.

Rapid Prototyping Techniques for the Development of a Take-Home Surgical Anastomosis Simulation Model.

OBJECTIVE: The objective of this paper is to describe the techniques and process of developing and testing a take-home surgical anastomosis simulation model. DESIGN: Through an iterative process, a simulation model was customized and designed to target specific skill development and performance objectives that focused on anastomotic techniques in thoracic surgery and consist of 3D printed and silicone molded components. Various manufacturing techniques such as silicone dip spin coating and injection molding have been described in this paper and explored as part of the research and development process. The final prototype is a low-cost, take-home model with reusable and replaceable components. SETTING: The study took place at a single-center quaternary care university-affiliated hospital. PARTICIPANTS: The participants included in the model testing were 10 senior thoracic surgery trainees who completed an in-person training session held during an annual hands- on thoracic surgery simulation course. Feedback was then collected in the form of an evaluation of the model from participants. RESULTS: All 10 participants had an opportunity to test the model and complete at least 1 pulmonary artery and bronchial anastomosis. The overall experience was rated highly, with minor feedback provided regarding the set- up and fidelity of the materials used for the anastomoses. Overall, the trainees agreed that the model was suitable for teaching advanced anastomotic techniques and expressed an interest in being able to use this model to practice skill development. CONCLUSIONS: Developed simulation model can be easily reduced, with customized components that accurately simulate real-life vascular and bronchial components suitable for training of anastomoses technique amongst senior thoracic surgery trainees.

Gender trends in cardiothoracic surgery authorship.

OBJECTIVE: In recent years, the historically low proportion of women cardiothoracic surgeons and trainees has been a subject of intense focus. Publications remain a key metric of academic success and career advancement. We sought to identify trends in the gender of first and last author publications in cardiothoracic surgery. METHODS: We searched for publications between 2011 and 2020 in 2 US cardiothoracic surgery journals, identifying those with Medical Subject Heading publication types of clinical trials, observational studies, meta-analyses, commentary, reviews, and case reports. A commercially available, validated software (Gender-API) was used to associate gender with author names. Association of American Medical Colleges Physician Specialty Data Reports were used to identify concurrent changes in the proportion of active women in cardiothoracic surgery. RESULTS: We identified 6934 (57.1%) pieces of commentary; 3694 (30.4%) case reports; 1030 (8.5%) reviews, systematic analyses, meta-analyses, or observational studies; and 484 (4%) clinical trials. In total, 15,189 total names were included in analysis. Over the 10-year study period, first authorship by women rose from 8.5% to 16% (0.42% per year, on average), whereas the percentage of active US women cardiothoracic physicians rose from 4.6% to 8% (0.42% per year). Last authorship was generally flat over the decade, going from 8.9% in 2011% to 7.8% in 2020 and on average, increased at just 0.06% per year (P = .79). CONCLUSIONS: Over the past decade, authorship by women has steadily increased, more so at the first author position. Author-volunteered gender identification at the time of manuscript acceptance may be useful to more accurately follow trends in publication.

The conservation and diversity of the exons encoding the glycine and arginine rich domain of the fibrillarin gene in vertebrates, with special focus on reptiles and birds.

The nucleolar rRNA 2'-O-methyltransferase fibrillarin (FBL) contains a highly conserved methyltransferase domain at the C-terminus and a diverse glycine arginine-rich (GAR) domain at the N-terminus in eukaryotes. We found that a nine-exon configuration of fbl and exon 2-3 encoded GAR domain are conserved and specific in vertebrates. All internal exons except exon 2 and 3 are of the same lengths in different vertebrate lineages. The lengths of exon 2 and 3 vary in different vertebrate species but the ones with longer exon 2 usually have shorter exon 3 complementarily, limiting lengths of the GAR domain within a certain range. In tetrapods except for reptiles, exon 2 appears to be longer than exon 3. We specifically analyzed different lineages of reptiles for their GAR sequences and exon lengths. The lengths of exon 2 in reptiles are around 80-130-nt shorter and the lengths of exon 3 in reptiles are around 50-90 nt longer than those in other tetrapods, all in the GAR-coding regions. An FSPR sequence is present at the beginning of the GAR domain encoded by exon 2 in all vertebrates, and a specific FXSP/G element (X can be K, R, Q, N, and H) exist in the middle of GAR with phenylalanine as the 3rd exon 3-encoded amino acid residue starting from jawfish. Snakes, turtles, and songbirds contain shorter exon 2 compared with lizards, indicating continuous deletions in exon 2 and insertions/duplications in exon 3 in these lineages. Specifically, we confirmed the presence the fbl gene in chicken and validated the RNA expression. Our analyses of the GAR-encoding exons of fbl in vertebrates and reptiles should provide the basis for further evolutionary analyses of more GAR domain encoding proteins.

Adaptive fuzzy-based stability control and series impedance correction for the grid-tied inverter.

The regenerative braking in the tram allows the energy to be returned to the power grid through a power inverter. Since the inverter location between the tram and the power grid is not fixed, resulting in a wide variety of impedance networks at grid coupling points, posing a severe threat to the stable operation of the grid-tied inverter (GTI). By independently changing the loop characteristics of the GTI, the adaptive fuzzy PI controller (AFPIC) can adjust according to different impedance network parameters. It is challenging to fulfill the stability margin requirements of GTI under high network impedance since the PI controller has phase lag characteristics. A correction method of series virtual impedance is proposed, which connects the inductive link in a series configuration with the inverter output impedance, correcting the inverter equivalent output impedance from resistance-capacitance to resistance-inductance and improving the system stability margin. Feedforward control is adopted to improve the system's gain in the low-frequency band. Finally, the specific series impedance parameters are obtained by determining the maximum network impedance and setting the minimum phase margin of 45°. The realization of virtual impedance is simulated by conversion to an equivalent control block diagram, and the effectiveness and feasibility of the proposed method are verified by simulation and a 1 kW experimental prototype.

Gender differences in Medicare payments to cardiothoracic surgeons in 2019.

OBJECTIVES: The STS Thoracic Surgery Practice and Access Task Force - 2019 Workforce Report noted gender-based differences in the income of cardiothoracic surgeons in the United States. We analysed the 2019 Medicare payment data for thoracic and cardiac surgeons to investigate the gender-based payment gap among cardiothoracic surgeons. METHODS: The 2019 Medicare Physician and Other Practitioners by Provider and Services data set merged with the Doctors and Clinicians National Downloadable File was utilized to conduct a cross-sectional analysis of gender differences in Medicare payments, numbers of services, unique billing codes, years in practice, Medicare beneficiary age, regional population density (rural-urban commuting area code) and patient panel complexity (hierarchical condition category) for providers. The providers' self-reported gender (women or men) and provider type (thoracic surgery or cardiac surgery) were binarily set according to the Center for Medicare and Medicaid Services standards. Independent analyses were performed with thoracic and cardiac surgeons. We also used the 2013 and 2016 Medicare Physician and Other Practitioners by Provider and Services data sets to analyse the trends in adjusted gender-based payment differences across 2013, 2016 and 2019. RESULTS: After controlling for the covariates, women thoracic surgeons received $25,183.50 [95% confidence interval (CI) $16,307.60, $34,059.40] less than the mean Medicare payment than men thoracic surgeons. Likewise, women cardiac surgeons received $20,960 [95% confidence interval (CI) $1,014.80, $40,902.80] less than the mean adjusted Medicare payment than their men counterparts. CONCLUSIONS: In 2019, women cardiothoracic surgeons received a significantly lower mean Medicare payment than men cardiothoracic surgeons after controlling for the number of services, unique billing codes, the complexity of the patient panel, years in practice and regional population density. The payment gap between women and men exhibited no statistically significant change over 2013, 2016 and 2019. Future studies are warranted to understand the association between gender representation and the pay gap.

Effect of hyperbaric oxygen on symptoms of dementia in patients with delayed encephalopathy after acute carbon monoxide poisoning. / é«˜åŽ‹æ°§å¯¹æ€¥æ€§ä¸€æ°§åŒ–ç¢³ä¸­æ¯’è¿Ÿå‘æ€§è„‘ç— æ‚£è€ ç—´å‘†ç—‡çŠ¶çš„å½±å“ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most severe complication of carbon monoxide poisoning, which seriously endangers patients' quality of life. This study aims to investigate the efficacy of hyperbaric oxygen (HBO2) on improving dementia symptoms in patients with DEACMP. METHODS: A retrospective analysis was performed on DEACMP patients, who visited Xiangya Hospital, Central South University from June 2014 to June 2020. Among them, patients who received conventional drug treatment combined with HBO2 treatment were included in an HBO2 group, while those who only received conventional drug treatment were included in a control group. HBO2 was administered once daily. Patients in the HBO2 group received 6 courses of treatment, with each course consisting of 10 sessions. The Hasegawa Dementia Scale (HDS) was used to diagnose dementia, and the Clinical Dementia Rating (CDR) was used to grade the severity of dementia for DEACMP. The Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-Cog), the Functional Activities Questionnaire (FAQ), the Neuropsychiatric Inventory (NPI), and the Clinician's Interview-Based Impression of Change-Plus Caregiver Input (CIBIC-Plus) were performed to assess cognitive function, ability to perform activities of daily living (ADL), behavioral and psychological symptoms, and overall function. The study further analyzed the results of objective examinations related to patients' dementia symptoms, including magnetic resonance imaging detection of white matter lesions and abnormal electroencephalogram (EEG). The changes of the above indicators before and after treatment, as well as the differences between the 2 groups after treatment were compared. RESULTS: There was no significant difference in the HDS score and CDR grading between the 2 groups before treatment (both P>0.05). After treatment, the score of ADAS-Cog, FAQ, NPI, and CIBIC Plus grading of the 2 groups were significantly improved, and the improvement of the above indicators in the HBO2 group was greater than that in the control group (all P<0.05). The effective rate of the HBO2 group in treating DEACMP was significantly higher than that of the control group (89.47% vs 65.87%, P<0.05). The objective examination results (white matter lesions and abnormal EEG) showed that the recovery of patients in the HBO2 group was better than that in the control group. CONCLUSIONS: Hyperbaric oxygen can significantly relieve the symptoms of dementia in patients with DEACMP.

Bayesian Sample Size Planning Tool for Phase I Dose-Finding Trials.

PURPOSE: Through Bayesian inference, we propose a method called BayeSize as a reference tool for investigators to assess the sample size and its associated scientific property for phase I clinical trials. METHODS: BayeSize applies the concept of effect size in dose finding, assuming that the maximum tolerated dose can be identified on the basis of an interval surrounding its true value because of statistical uncertainty. Leveraging a decision framework that involves composite hypotheses, BayeSize uses two types of priors, the fitting prior (for model fitting) and sampling prior (for data generation), to conduct sample size calculation under the constraints of statistical power and type I error. RESULTS: Simulation results showed that BayeSize can provide reliable sample size estimation under the constraints of type I/II error rates. CONCLUSION: BayeSize could facilitate phase I trial planning by providing appropriate sample size estimation. Look-up tables and R Shiny app are provided for practical applications.

Effects of Cordyceps militaris fermentation products on reproductive development in juvenile male mice.

Cordyceps militaris (CM) is a popular medicinal fungus; however, few studies have focused on its impact on the male reproductive system. We evaluated the effects of CM fermentation products on the reproductive development of juvenile male (JM) mice. Mice were divided into four experimental groups, each fed 5% CM products (weight per weight (w/w) in normal diet): extracellular polysaccharides (EPS), fermentation broth (FB), mycelia (MY), and whole fermentation products (FB plus MY, FBMY) for 28 days, while mice in the control group (CT) were fed a normal diet. Basic body parameters, testicular structure, sperm parameters, and sex hormones concentrations were analyzed. Compared to the CT group, mice in the EPS, MY, and FBMY groups showed a significantly increased mean seminiferous tubule area (p < 0.05), mice in the FB and MY groups had significantly higher sperm concentrations (p < 0.05), and mice in the EPS, FB, and FBMY groups showed significantly increased ratios of motile sperm (p < 0.05). Meanwhile, EPS significantly promoted the ability of JM mice to synthesize testosterone (p < 0.05). Furthermore, all CM products significantly increased the food intake of JM mice (p < 0.05) but did not significantly change their water intake and body weight gain (p > 0.05). In conclusion, CM products, especially EPS, exhibit strong androgen-like activities that can promote male reproductive development.

[The Role and Function of Clinical Research Nurses in Anti-tumor Drug Clinical Trials for Lung Cancer Patients].

Clinical trials of anti-tumor drugs is not only the important way to develop new drugs, but also the most advanced treatment methods for malignant tumors, bringing survival benefits to patients. There are a large number of new anti-tumor drug clinical trials for lung cancer patients, covering a wide variety of anti-tumor drugs, and with rapid progress and high efficiency of clinical transformation. These trials could not be carried out successfully without the joint efforts of the research team, in which the research nurses also played a role that should not be underestimated. Combined with the work content of clinical research nurses, this paper introduced the post management, role function, core competence and career development prospect of clinical research nurses in the process of carrying out clinical trial of lung cancer drugs in detail. In order to provide reference for more medical institutions to carry out related work, and promote the further development of clinical research nurses to standardization and specialization.
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Ca2[Ti(HPO4)2(PO4)]·H2O, Ca[Ti2(H2O)(HPO3)4]·H2O, and Ti(H2PO2)3: Solid-State Oxidation via Proton-Coupled Electron Transfer.

Titanium phosphorus oxides (TiPOs) are promising energy-conversion materials, but most are of tetravalent titanium (TiIV), with the trivalent TiIIIPOs less explored because of instability and obstacles in synthesis. In this study, we used a simple synthetic strategy and prepared three new TiIIIPOs with different phosphorus oxoanions: the phosphate Ca2Ti(HPO4)2(PO4)·H2O (1), the phosphite CaTi2(H2O)(HPO3)4·H2O (2), and the hypophosphite Ti(H2PO2)3 (3). Each possesses different structures in one, two, and three dimensions, yet they are related to one another because of their infinite chains. Compound 1 exhibits proton-coupled electron transfer (PCET) reactivity in a solid state, losing one proton from its own HPO4 in oxidation to yield Ca2Ti(HPO4)(PO4)2·H2O (designated as 1O), while compound 2 also exhibits PCET reactivity in which the octahedral core [TiIII(H2O)]3+ gives off two protons to become a titanyl unit [TiIV═O]2+ under oxidation, yielding CaTi2O(HPO3)4·H2O (2O). Both 1O and 2O retain their original frameworks from before oxidation, but there are some changes in the hydrogen and Ti-O bonds that affect the IR absorption and powder X-ray diffraction patterns. Compound 3 represents the first titanium hypophosphite, and two polymorphs were discovered that show structures related to 1 and 2. This work demonstrates a simple strategy that is effective for preparing titanium(III) compounds in a pure phase; further, new findings in the pathways of solid-state PCET reactions promote a greater understanding of the self-sustaining oxidation behavior for TiIIIPO solid materials.

A Trans-Agency Workshop on the Pathophysiology of Radiation-Induced Lung Injury.

Research and development of medical countermeasures (MCMs) for radiation-induced lung injury relies on the availability of animal models with well-characterized pathophysiology, allowing effective bridging to humans. To develop useful animal models, it is important to understand the clinical condition, advantages and limitations of individual models, and how to properly apply these models to demonstrate MCM efficacy. On March 20, 2019, a meeting sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID) brought together medical, scientific and regulatory communities, including academic and industry subject matter experts, and government stakeholders from the Food and Drug Administration (FDA) and the Biomedical Advanced Research and Development Authority (BARDA), to identify critical research gaps, discuss current clinical practices for various forms of pulmonary damage, and consider available animal models for radiation-induced lung injury.

A targeted simulation-extrapolation method for evaluating biomarkers based on new technologies in precision medicine.

New technologies for novel biomarkers have transformed the field of precision medicine. However, in applications such as liquid biopsy for early tumor detection, the misclassification rates of next generation sequencing and other technologies have become an unavoidable feature of biomarker development. Because initial experiments are usually confined to specific technology choices and application settings, a statistical method that can project the performance metrics of other scenarios with different misclassification rates would be very helpful for planning further biomarker development and future trials. In this article, we describe an approach based on an extended version of simulation extrapolation (SIMEX) to project the performance of biomarkers measured with varying misclassification rates due to different technological or application settings when experimental results are only available from one specific setting. Through simulation studies for logistic regression and proportional hazards models, we show that our proposed method can be used to project the biomarker performance with good precision when switching from one to anther technology or application setting. Similar to the original SIMEX model, the proposed method can be implemented with existing software in a straightforward manner. A data analysis example is also presented using a lung cancer data set and performance metrics for two gene panel based biomarkers. Results demonstrate that it is feasible to infer the potential implications of using a range of technologies or application scenarios for biomarkers with limited human trial data.