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Objective: To assess the knowledge of self-care practices, as well as factors responsible for such knowledge among type 2 diabetes patients in two states of Nigeria. Methods: Descriptive, cross sectional survey research design was employed. The study was conducted on type 2 diabetes out-patients attending Endocrinology Clinic at the University of Uyo Teaching Hospital (UUTH) and University of Calabar Teaching Hospital (UCTH) between June 2012 and February 2013. The Diabetes Self-care Knowledge (DSCK-30) was used in evaluating knowledge of self-care practices. Socio-demographic information and respondents’ opinion on the possible barrier(s) to knowledge of self-care were also obtained. Data were analysed using Microsoft Excel and SPSS version 14.0. Statistical significance for all analyses was defined as a p value less than 0.05. Results: A total of 303 out of 380 questionnaires distributed were completed and returned (response rate =79.7%). The majority of the study sample (79.5%) had 70% or more overall knowledge level about self-care. Self-care knowledge was associated with level of education (p

Inventory control has been a major point of discussion in industrial engineering and operations research for over 100 years. Various advanced numerical methods can be used for solving inventory control problems, which makes it a highly multidisciplinary filed attracting researchers from different academic disciplines. This fact makes it a daunting task to subsume the gargantuan spectrum of literature related to inventory control theory in one treatise. In light of this fact, this paper focuses on the timeline of inventory control models with respect to methodologies behind deriving optimal control parameters. Such methodologies include analytical approaches, optimal control theory, dynamic programming, simulation-based optimization and metamodel-based optimization.

Inventory control problems arise in various industries, and each single real-world inventory is replete with non-standard factors and subtleties. Practical stochastic inventory control problems are often analytically intractable, because of their complexity. In this regard, simulation-optimization is becoming more and more popular tool for solving complicated business-driven problems. Unfortunately, simulation, especially detailed, is both time and memory consuming. In the light of this fact, it may be more reasonable to use an alternative cheaper-to-compute metamodel, which is specifically designed in order to approximate an original simulation. In this research we discus metamodelling of stochastic multiproduct inventory control system with perishable products using a multilayer perceptron with a rectified linear unit as an activation function.

The paper describes an eventual combination of discrete-event simulation and genetic algorithm to define the optimal inventory policy in stochastic multi-product inventory systems. The discrete-event model under consideration corresponds to the just-in-time inventory control system with a flexible reorder point. The system operates under stochastic demand and replenishment lead time. The utilized genetic algorithm is distinguished for a non-binary chromosome encoding, uniform crossover and two mutation operators. The paper contains a detailed description of the optimization technique and the numerical example of six- product inventory model. The proposed approach contributes to the field of industrial engineering by providing a simple, but still efficient way to compute nearly-optimal inventory parameters with regard to risk and reliability policy. Besides, the method may be applied in automated ordering systems.

Background: Antimicrobial stewardship (AMS) aims to improve antibiotic use while reducing resistance and its consequences. There is a paucity of data on the availability of AMS programmes in southern Nigeria. Further, there is no data on Nigerian healthcare professionals' knowledge of the WHO 'Access, Watch and Reserve' (AWaRe) classification of antibiotics. This study sought to assess knowledge of AMS and the AWaRe classification of antibiotics among frontline healthcare professionals in Akwa Ibom State, Nigeria., Methods: This was a cross-sectional survey of 417 healthcare professionals, comprising medical doctors, pharmacists and nurses, across 17 public hospitals in Akwa Ibom State, Nigeria. A paper-based self-completion questionnaire was used to collect data from the participants during working hours between September and November 2023. Statistical analysis was done using SPSS version 25.0, with p < 0.05 indicating statistical significance., Results: Four hundred and seventeen out of the 500 healthcare professionals approached agreed to participate, giving an 83.4% response rate. Most of the participants were female (62.1%) and nurses (46.3%). Approximately 57% of participants were familiar with the term antibiotic/antimicrobial stewardship, however, only 46.5% selected the correct description of AMS. Majority (53.0%) did not know if AMS programme was available in their hospitals. 79% of participants did not know about AWaRe classification of antibiotics. Among the 87 (20.9%) who knew, 28.7% correctly identified antibiotics into the AWaRe groups from a given list. Only profession significantly predicted knowledge of AMS and awareness of the AWaRe classification of antibiotics (p < 0.001). Pharmacists were more likely to define AMS correctly than medical doctors (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.16-3.52, p = 0.012), whereas nurses were less likely to be aware of the WHO AWaRe classification of antibiotics than medical doctors (OR = 0.36, 95% CI = 0.18-0.72, p = 0.004)., Conclusions: There was a notable knowledge deficit in both AMS and the AWaRe classification of antibiotics among participants in this study. This highlights the need for educational interventions targeted at the different cadres of healthcare professionals on the role of AMS programmes in reducing antimicrobial resistance and its consequences., (© 2024. The Author(s).)

Assessing the quality of life (QoL) of breast cancer (BC) patients using a triangulation of tools is crucial for understanding their well-being and tailoring specific interventions to improve their overall experience. The study assessed the QoL of BC patients using a combination of generic and disease-specific validated questionnaires. The study utilized a self-administered questionnaire-based cross-sectional design among BC patients attending the Oncology clinic in a Nigerian teaching hospital. The 23-item EORTC-BR23 questionnaire and the 15-item HRQoL 15D questionnaire were provided to consenting eligible respondents for data collection. Descriptive (e.g., frequency, percentages, mean, median, etc.) and inferential (T-test and one-way ANOVA) statistical analyses were conducted on the cleaned data, with significant p values set at less than 0.05. A total of 60 female BC patients participated in the study. Respondents that were aged 41-50 years and 50-60 years were 20 (33.3%) and 19 (31.7%) respectively. Patients who were diagnosed with BC one year ago before the study were 22 (39.3%) with 51 (85%) reporting no positive family history of BC. Patients who had undergone surgery, radiotherapy, hormonal therapy, and chemotherapy were 52 (86.7%), 27 (45.0%), 14 (24.1%), and 54 (90%) respectively. The patients scored 30.00 ± 4.67% and 72.36 ± 2.93% for future perspective and body image, respectively, in the functional scales of the EORTC-BR23 with a maximum possible score of 100%. On the symptom scale, they scored 47.46 ± 2.52% and 63.40 ± 5.03% for side effects of therapy and being upset about hair loss, respectively. The patients' quality of life utility score in the 15-D tool was 0.79 ± 0.02. With p values less than 0.005, age, time since diagnosis, and cancer stage were influential determinants of patients' QoL. The QoL of the participants based on the HRQoL-15D was determined to be high. For the EORTC-BR23, respondents reported high quality of life for body image and sexual function but low quality of life for both sexual enjoyment and future perspective in terms of the functional scale. The symptom scale of EORTC-BR23 showed high symptoms for only the domain of upset by hair loss resulting in low QoL. Socio-demographic factor that affects the QoL of BC patients were age, number of years since diagnosis and stage of BC., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective . To fabricate and validate a novel focused collimator designed to spare normal tissue in a murine hemithoracic irradiation model using 250 MeV protons delivered at ultra-high dose rates (UHDRs) for preclinical FLASH radiation therapy (FLASH-RT) studies. Approach . A brass collimator was developed to shape 250 MeV UHDR protons from our Varian ProBeam. Six 13 mm apertures, of equivalent size to kV x-ray fields historically used to perform hemithorax irradiations, were precisely machined to match beam divergence, allowing concurrent hemithoracic irradiation of six mice while sparing the contralateral lung and abdominal organs. The collimated field profiles were characterized by film dosimetry, and a radiation survey of neutron activation was performed to ensure the safety of staff positioning animals. Main results . The brass collimator produced 1.2 mm penumbrae radiation fields comparable to kV x-rays used in preclinical studies. The penumbrae in the six apertures are similar, with full-width half-maxima of 13.3 mm and 13.5 mm for the central and peripheral apertures, respectively. The collimator delivered a similar dose at an average rate of 52 Gy s -1 for all apertures. While neutron activation produces a high (0.2 mSv h -1 ) initial ambient equivalent dose rate, a parallel work-flow in which imaging and setup are performed without the collimator ensures safety to staff. Significance . Scanned protons have the greatest potential for future translation of FLASH-RT in clinical treatments due to their ability to treat deep-seated tumors with high conformality. However, the Gaussian distribution of dose in proton spots produces wider lateral penumbrae compared to other modalities. This presents a challenge in small animal pre-clinical studies, where millimeter-scale penumbrae are required to precisely target the intended volume. Offering high-throughput irradiation of mice with sharp penumbrae, our novel collimator-based platform serves as an important benchmark for enabling large-scale, cost-effective radiobiological studies of the FLASH effect in murine models., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: Overweight and obesity are increasing global public health problems. Mazdutide is a new dual agonist drug that can potentially reduce weight and blood glucose levels simultaneously. However, the synthesis of evidence on the efficacy and safety of this drug is scarce. Therefore, this study aimed to synthesize evidence on the efficacy and safety of Mazdutide compared to placebo on weight reduction among adults with and without diabetes., Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Data were retrieved from six electronic databases: PubMed, Web of Science, Scopus, Cochrane Library, ClinicalTrial.gov, and Google Scholar, and manually searched from the included references. The data were synthesized using a random effect model. This analysis was performed in the R programming language using the Meta package., Results: A total of seven RCTs involving 680 participants were included in this study. Mazdutide was more effective in reducing body weight (mean difference [MD]= -6.22%, 95% confidence interval [CI]: -8.02% to -4.41%, I 2 = 90.0%), systolic blood pressure (MD = -7.57 mmHg, 95% CI: -11.17 to -3.98 mmHg, I 2 = 46%), diastolic blood pressure (MD = -2.98 mmHg, 95% CI: -5.74 to -0.22 mmHg, I 2 = 56%), total cholesterol (MD = -16.82%, 95% CI: -24.52 to -9.13%, I 2 = 61%), triglycerides (MD = -43.29%, 95% CI: -61.57 to -25.01%, I 2 = 68%), low-density lipoprotein (MD= -17.07%, 95% CI: -25.54 to -8.60%, I 2 = 53%), and high-density lipoprotein (MD = -7.54%, 95% CI: -11.26 to -3.83%, I 2 = 0%) than placebo. Mazdutide was associated with reduced hemoglobin A1c (HbA1c) and fasting plasma glucose in participants with type 2 diabetes. In the subgroup and meta-regression analyses, weight reduction was more significant in non-diabetics compared to diabetics, and in those who received a longer treatment duration (24 weeks) than in those on shorter durations (12-20 weeks). Participants who received Mazdutide had a higher risk of transient mild or moderate gastrointestinal side effects., Conclusion: Mazdutite appears to be effective in weight reduction among patients with and without diabetes, and it has an advantage over other associated comorbidities. However, it was associated with mild or moderate gastrointestinal side effects., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=403859, identifier CRD42023403859., Competing Interests: PS is employed by the CLM consultant LTD; Nevertheless, the company itself has no relation whatsoever with our Mazdutide project. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nalisa, Cuboia, Dyab, Jackson, Felix, Shoki, Mubiana, Oyedeji-Amusa, Azevedo and Jiang.)

Background: The recent rediscovery of the FLASH effect, a normal tissue sparing phenomenon observed in ultra-high dose rate (UHDR) irradiations, has instigated a surge of research endeavors aiming to close the gap between experimental observation and clinical treatment. However, the dependences of the FLASH effect and its underpinning mechanisms on beam parameters are not well known, and large-scale in vivo studies using murine models of human cancer are needed for these investigations., Purpose: To commission a high-throughput, variable dose rate platform providing uniform electron fields (≥15 cm diameter) at conventional (CONV) and UHDRs for in vivo investigations of the FLASH effect and its dependences on pulsed electron beam parameters., Methods: A murine whole-thoracic lung irradiation (WTLI) platform was constructed using a 1.3 cm thick Cerrobend collimator forming a 15 × 1.6 cm 2 slit. Control of dose and dose rate were realized by adjusting the number of monitor units and couch vertical position, respectively. Achievable doses and dose rates were investigated using Gafchromic EBT-XD film at 1 cm depth in solid water and lung-density phantoms. Percent depth dose (PDD) and dose profiles at CONV and various UHDRs were also measured at depths from 0 to 2 cm. A radiation survey was performed to assess radioactivation of the Cerrobend collimator by the UHDR electron beam in comparison to a precision-machined copper alternative., Results: This platform allows for the simultaneous thoracic irradiation of at least three mice. A linear relationship between dose and number of monitor units at a given UHDR was established to guide the selection of dose, and an inverse-square relationship between dose rate and source distance was established to guide the selection of dose rate between 20 and 120 Gy·s -1 . At depths of 0.5 to 1.5 cm, the depth range relevant to murine lung irradiation, measured PDDs varied within ±1.5%. Similar lateral dose profiles were observed at CONV and UHDRs with the dose penumbrae widening from 0.3 mm at 0 cm depth to 5.1 mm at 2.0 cm. The presence of lung-density plastic slabs had minimal effect on dose distributions as compared to measurements made with only solid water slabs. Instantaneous dose rate measurements of the activated copper collimator were up to two orders of magnitude higher than that of the Cerrobend collimator., Conclusions: A high-throughput, variable dose rate platform has been developed and commissioned for murine WTLI electron FLASH radiotherapy. The wide field of our UHDR-enabled linac allows for the simultaneous WTLI of at least three mice, and for the average dose rate to be modified by changing the source distance, without affecting dose distribution. The platform exhibits uniform, and comparable dose distributions at CONV and UHDRs up to 120 Gy·s -1 , owing to matched and flattened 16 MeV CONV and UHDR electron beams. Considering radioactivation and exposure to staff, Cerrobend collimators are recommended above copper alternatives for electron FLASH research. This platform enables high-throughput animal irradiation, which is preferred for experiments using a large number of animals, which are required to effectively determine UHDR treatment efficacies., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Exposure to high-dose ionizing radiation can lead to life-threatening injuries and mortality. Bone marrow is the most sensitive organ to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) with the potential sequelae of infection, hemorrhage, anemia, and death if untreated. The development of medical countermeasures (MCMs) to protect or mitigate radiation injury is a medical necessity. In our well-established murine model of H-ARS we have demonstrated that the prostaglandin E2 (PGE2) analog 16,16 dimethyl-PGE2 (dmPGE2) has survival efficacy as both a radioprotectant and radiomitigator. The purpose of this study was to investigate the pharmacokinetics (PK) and biodistribution of dmPGE2 when used as a radioprotector in irradiated and non-irradiated inbred C57BL/6J mice, PK in irradiated and non-irradiated Jackson Diversity Outbred (JDO) mice, and the PK profile of dmPGE2 in non-irradiated non-human primates (NHPs). The C57BL/6J and JDO mice each received a single subcutaneous (SC) dose of 35 ug of dmPGE2 and were randomized to either receive radiation 30 min later or remain non-irradiated. Plasma and tissue PK profiles were established. The NHP were dosed with 0.1 mg/kg by SC administration and the PK profile in plasma was established. The concentration time profiles were analyzed by standard non-compartmental analysis and the metrics of AUC0-Inf, AUC60-480 (AUC from 60-480 min), Cmax, and t1/2 were evaluated. AUC60-480 represents the postirradiation time frame and was used to assess radiation effect. Overall, AUC0-Inf, Cmax, and t1/2 were numerically similar between strains (C57BL/6J and JDO) when combined, regardless of exposure status (AUC0-Inf: 112.50 ng·h/ml and 114.48 ng·h/ml, Cmax: 44.53 ng/ml and 63.96 ng/ml; t1/2: 1.8 h and 1.1 h, respectively). PK metrics were numerically lower in irradiated C57BL/6J mice than in non-irradiated mice [irradiation ratio: irradiated values/non-irradiated values = 0.71 for AUC60-480 (i.e., 29% lower), and 0.6 for t1/2]. In JDO mice, the radiation ratio was 0.53 for AUC60-480 (i.e., 47% lower), and 1.7 h for t1/2. The AUC0-Inf, Cmax, and t1/2 of the NHPs were 29.20 ng·h/ml, 7.68 ng/ml, and 3.26 h, respectively. Despite the numerical differences seen between irradiated and non-irradiated groups in PK parameters, the effect of radiation on PK can be considered minimal based on current data. The biodistribution in C57BL/6J mice showed that dmPGE2 per gram of tissue was highest in the lungs, regardless of exposure status. The radiation ratio for the different tissue AUC60-480 in C57BL/6J mice ranged between 0.5-1.1 (50% lower to 10% higher). Spleen, liver and bone marrow showed close to twice lower exposures after irradiation, whereas heart had a 10% higher exposure. Based on the clearance values from mice and NHP, the estimated allometric scaling coefficient was 0.81 (95% CI: 0.75, 0.86). While slightly higher than the current literature estimates of 0.75, this scaling coefficient can be considered a reasonable estimate and can be used to scale dmPGE2 dosing from animals to humans for future trials., (© 2024 by Radiation Research Society.)

Assessing the health-related quality of life (HRQoL) of people with diabetes is important to evaluate treatment effectiveness and identify interventions that would be beneficial to the patients. This descriptive cross-sectional study aimed to assess the HRQoL of people with diabetes visiting 15 community pharmacies in Akwa Ibom State, Nigeria, and to identify its determinants. The English (Nigeria) version of the EQ-5D-5L was administered to 420 eligible patients between August and September 2021. Data were analyzed with SPSS (IBM version 25.0) and presented descriptively; differences in HRQoL scores were examined using inferential statistics. Statistical significance was set at p < 0.05. Most participants (56.8%) were female; 193 (49.6%) were between the ages of 30 and 49. The median (interquartile range, IQR) for the EQ VAS and EQ-5D-5L index scores, respectively, were 80.0 (65.0-85.0) and 0.77 (0.62-0.90). Most participants reported problems with usual activities (52.7%), pain/discomfort (60.2%), and anxiety/depression (57.6%). The EQ VAS score and EQ-5D-5L utility index were significantly (p < 0.05) associated with respondents' age, marital status, work status, and personal monthly income. The HRQoL of participants was relatively high. Nevertheless, implementing strategies aimed at pain management and providing psychological support for people with diabetes in Nigeria may improve their HRQoL., (© 2023. The Author(s).)

Background: Assessment of knowledge and perception of healthcare students regarding antimicrobial resistance (AMR) and antimicrobial stewardship (AMS) would facilitate more effective education of these future prescribers., Objectives: To assess knowledge and perception of AMR and AMS among healthcare students in Nigerian universities., Methods: This was a questionnaire-based, cross-sectional survey of medical, nursing and pharmacy undergraduate students from November 2019 to January 2020, using both paper and electronic modes of self-administration., Results: A total of 335 students participated in the survey. Mean age of respondents was 23±3 years; 114 (34.4%) were in their 5th year of study. Most (78.9%) of the respondents agreed that widespread use of antimicrobials promotes AMR. Only 70 (21.1%) were aware that poor hand hygiene promotes AMR; 45.9% (42.7%, 37.3% and 57.7% for medicine, nursing and pharmacy respectively, p = 0.007) agreed that AMR is promoted by substandard quality of antimicrobials. Majority (94.3%) perceived AMR as a worldwide problem. Over half (60.8%) were not familiar with the term 'antimicrobial stewardship'. Eleven (3.3%) and 122 (36.9%) rated their AMS knowledge as 'very good' and 'poor' respectively., Conclusions: Nigerian healthcare students had suboptimal knowledge of AMR and AMS. Current undergraduate healthcare curriculum should be reviewed to incorporate AMS principles., Competing Interests: No conflict of interest exists., (© 2023 Jackson IL et al.)

Development of medical countermeasures (MCM) to mitigate and/ or treat the pulmonary complications associated with exposure to chemical, radiological, and/ or nuclear weapons is a national, public health preparedness posture priority in the United States (US). Pulmonary exposure to either sulfur mustard vapor or radiation causes oxidative damage, vascular injury, hyperinflammation, and pro-fibrotic signaling cascades that lead to life-threatening and potentially debilitating lung disease. There is no MCM currently approved by the US Food and Drug Administration (FDA) to mitigate and/ or treat lung injury caused by sulfur mustard or radiation exposure. Thus, there remains a major unmet public health need for development of threat-agnostic, host-directed therapeutics that target common pathophysiological mechanisms underlying the progression of acute and/ or late lung injury independent of the etiology of disease. This review describes the clinical manifestations and underlying mechanisms of sulfur mustard and radiation-induced lung injury and regulatory considerations for MCM development under the non-traditional Animal Rule pathway.

Objectives: This study aimed to assess willingness to pay (WTP) for clinical pharmacy services among people with diabetes and to determine the factors affecting WTP for these services., Methods: This was a cross-sectional exit survey of 450 people with diabetes visiting 15 community pharmacies in Uyo metropolis, Akwa Ibom State, Nigeria, between August and September 2021. Self-reported questionnaires were administered to eligible patients just before leaving the community pharmacy. Data were analyzed using SPSS (version 25.0). Statistical significance was set at P < .05., Results: Response rate was 87.3%. Two hundred respondents (50.9%) were willing to pay an average amount of US$2.83 (minimum-maximum, US$0.12-US$24.27) for clinical pharmacy services. The two most often cited reasons for those who were unwilling to pay were their inability to pay and their opposition to paying for any healthcare services. Employment status (P < .001), personal monthly income (P < .001), satisfaction with income (P < .001), household monthly income (P < .001), health insurance coverage (P < .001), insulin use (P < .001), perception of the pharmacist's relevance in healthcare (P = .013) and in diabetes care (P < .001), and satisfaction with the pharmacist's services (P < .001) significantly affected WTP choices. None of the patient characteristics predicted the maximum amounts patients were willing to pay., Conclusions: Many of the people with diabetes assessed were willing to pay for clinical services at a reasonable price. Although most patient variables affected their WTP choices, none of the variables predicted the maximum amount they were willing to pay. For possible remuneration for clinical services, community pharmacists should continue to grow their practices and stay current with patient care., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

More than 50 years after the Apollo missions ended, the National Aeronautical and Space Administration (NASA) and other international space agencies are preparing a return to the moon as a step towards deep space exploration. At doses ranging from a fraction of a Gray (Gy) to a few Gy, crew will be at risk for developing bone marrow failure associated with the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) requiring pharmacological intervention to reduce risk to life and mission completion. Four medical countermeasures (MCM) in the colony stimulating factor class of drugs are now approved for treatment of myelosuppression associated with ARS. When taken in conjunction with antibiotics, fluids, antidiarrheals, antiemetics, antipyretics, and other treatments for symptomatic illness, the likelihood for recovery and mission completion can be greatly improved. The current review describes the performance and health risks of deep space flight, ionizing radiation exposure during crewed missions to the moon and Mars, and U.S. Food and Drug Administration (FDA)-approved medical interventions to treat ARS. With an expansion of human exploration missions beyond low Earth orbit (LEO), including near-term Lunar and future Mars missions, inclusion of MCMs to counteract ARS in the spaceflight kit will be critical for preserving crew health and performance., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Isabel L. Jackson is a consultant for Partner Therapeutics, the manufacturer of Leukine®. All other authors declare they have no known competing financial interests or personal relationships that could have appeared, (Copyright © 2022. Published by Elsevier B.V.)

Introduction: The presence of comorbidities could affect the health-related quality of life (HRQoL) of people living with HIV (PLHIV)., Aim: To assess the HRQoL of PLHIV and Hypertension, as well as its association with blood pressure (BP) control., Methods: This cross-sectional study was conducted in the HIV clinic of the University of Uyo Teaching Hospial in Akwa Ibom State, Nigeria, between August and October 2018. The EQ-5D-5L was administered to 201 eligible outpatients in the waiting area of the clinic before consulting the physician. Patients' socio-demographic and clinical data were obtained from the medical records. Blood pressure was measured using an automatic BP monitor. Data were analyzed with SPSS version 20.0., Results: Majority (58.6%) of the respondents were females; mean age was 49.59 ± 8.97 years; mean systolic and diastolic BP were 152.77 ± 19.38 mmHg and 90.28 ± 11.33 mmHg, respectively. EQ-VAS and EQ-5D index scores were 80.99 ± 15.97 and 0.86 ± 0.05, respectively. There were no significant differences in EQ-VAS score (z = - 0.113,  p = 0.910) or EQ-5D utility (z = - 0.523,  p = 0.601) between participants with controlled and uncontrolled BP. Duration on antihypertensive drugs was associated with EQ-VAS score (χ 2 (2) = 6.558,  p = 0.038), while employment status was associated with EQ-5D utility (z = - 2.661,   p = 0.008)., Conclusions: PLHIV and hypertension accessing care at a Nigerian hospital reported a high HRQoL, irrespective of BP control status. Nevertheless, there is a need to provide psychological support and employment for this population to maximise their HRQoL., (© 2022. Italian Society of Hypertension.)

Objectives: To evaluate the effects of pharmaceutical care (PC) interventions on humanistic outcomes in HIV-positive patients with hypertension., Methods: This prospective, open-label, parallel randomized controlled trial was conducted in the HIV clinic of the University of Uyo Teaching Hospital, Akwa Ibom State, Nigeria, from August 2018 to October 2019. Eligible patients were randomized sequentially and equally into two study arms: the control arm (CA), where participants received the traditional care and the intervention arm (IA), where participants received PC by the research pharmacist. The patient's HIV knowledge questionnaire, the Hypertension Knowledge-Level Scale, the Medical Outcome Study-HIV Health Survey and the Patient Satisfaction with Pharmaceutical Service questionnaire were used to assess participants' HIV-related knowledge, hypertension-related knowledge, health-related quality of life (HRQoL) and satisfaction with PC, respectively. These were self-completed at baseline, 6 months and 12 months. Data were analysed using SPSS (IBM version 25.0)., Key Findings: Out of the 206 participants randomized, 182 completed the 12-month follow-up. After 12 months, there was a significant improvement in HIV-related knowledge (∆ = 11.28%, t(180) = 4.41, P < 0.001) and hypertension-related knowledge (∆ = 5.94%, t(180) = 3.25, P = 0.001) in the IA over and above those observed in the CA. Similarly, PC interventions led to significant improvements in HRQoL (∆ = 6.5%, t(180) = 5.50, P < 0.001) and satisfaction with PC in the IA (∆ = 18.12%, t(180) = 11.85, P < 0.001) at the end of the study., Conclusions: PC significantly improved humanistic outcomes in HIV-positive patients with hypertension after a 12-month intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BIO 300, a suspension of synthetic genistein nanoparticles, is being developed for mitigating the delayed effects of acute radiation exposure (DEARE). The purpose of the current study was to characterize the pharmacokinetic (PK) profile of BIO 300 administered as an oral or parenteral formulation 24 h after sham-irradiation, total-body irradiation (TBI) with 2.5-5.0% bone marrow sparing (TBI/BMx), or in nonirradiated sex-matched C57BL/6J mice and non-human primates (NHP). C57BL/6J mice were randomized to the following arms in two consecutive studies: sham-TBI [400 mg/kg, oral gavage (OG)], TBI/BM2.5 (400 mg/kg, OG), sham-TBI [200 mg/kg, subcutaneous (SC) injection], TBI/BM2.5 (200 mg/kg, SC), sham-TBI (100 mg/kg, SC), or nonirradiated [200 mg/kg, intramuscular (IM) injection]. The PK profile was also established in NHP exposed to TBI/BM5.0 (100 mg/kg, BID, OG). Genistein-aglycone serum concentrations were measured in all groups using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The PK profile demonstrates 11% and 19% reductions in Cmax and AUC0-inf, respectively, among mice administered 400 mg/kg, OG, after TBI/BM2.5 compared to the sham-TBI control arm. Administration of 200 mg/kg SC in mice exposed to TBI/BM2.5 showed a 53% increase in AUC0-inf but a 28% reduction in Cmax compared to the sham-TBI mice. The relative bioavailability of the OG route compared to the SC and IM routes in mice was 9% and 7%, respectively. After the OG route, the dose-normalized AUC0-inf was 13.37 (ng.h/mL)/(mg/kg) in TBI/BM2.5 mice compared to 6.95 (ng.h/mL)/(mg/kg) in TBI/BM5.0 NHPs. Linear regression of apparent clearances and weights of mice and NHPs yielded an allometric coefficient of 1.06. Based on these data, the effect of TBI/BMx on BIO 300 PK is considered minimal. Future studies should use SC and IM routes to maximize drug exposure when administered postirradiation. The allometric coefficient is useful in predicting therapeutic drug dose regimens across species for drug approval under the FDA animal rule., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

Background: There is increasing prevalence of diseases associated with ageing such as hypertension, among people living with HIV (PLWHV). This study sought to assess: (1) knowledge related to HIV infection and hypertension, (2) adherence to prescribed medications and (3) clinical outcomes among HIV-positive persons with hypertension at a Nigerian hospital., Methods: The Patient's HIV Knowledge Questionnaire (PHKQ), Hypertension Knowledge-Level Scale (HK-LS) and Adherence to Refills and Medication Scale (ARMS) were administered to 220 eligible patients through the HIV clinic. Demographic and clinical data were also obtained., Results: Participants were predominantly females (57.3%), with a median (IQR) age of 46 (38-58) years; majority were married (67.8%) and employed (60.8%). Participants reported a higher hypertension-related knowledge compared with HIV-related knowledge (63.6% versus 33.3%, Z = -10.263, P < 0.001), but better adherence to antiretroviral medications compared to antihypertensives (100.0% versus 89.3%, Z = -9.118, P < 0.001). Of the 98 participants with documented viral load, 55 (56.1%) had undetectable (<40 copies/ml) values; however, only four (2.0%) of the entire sample had controlled (<140/90 mmHg) blood pressure., Conclusions: Despite having a higher hypertension-related knowledge, adherence to antihypertensive medications and blood pressure control were poor. There is a need for increased attention to HIV education and comorbidities in PLWHV., (© The Author(s) 2020. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cell line misidentification and contamination are major contributors to the reproducibility crisis in academic research. Authentication of cell lines provides assurances of the data generated; however, commercially available cells are often not subjected to rigorous identification testing. In this study, commercially available cell lines underwent testing to confirm cell identity and purity. The methods reported here outline the best practices for cell line authentication. Briefly, a commercially available primary rabbit aortic endothelial cell line was purchased for the intent of producing target proteins necessary for generating species-specific recombinant antibodies. These rabbit-specific antibodies would then be utilized for the development of in-house enzyme-linked immunosorbent assays (ELISA) to evaluate blood-based biomarkers of vascular injury after total-body irradiation. To authenticate the cell line, cell identity and purity were determined by single tandem repeat (STR) testing, flow cytometry, polymerase chain reaction (PCR), and cytochrome c oxidase subunit 1 (CO1) DNA Barcoding in-house and/or through commercial vendors. Fresh cells obtained from a New Zealand White rabbit (Charles River, Wilmington, DE) were used as a positive control. The results of STR and flow cytometry analyses indicated the cells were not contaminated with human or mouse cells, and that the cells were not of endothelial origin. PCR demonstrated that cells were also not of rabbit origin, which was further confirmed by a third-party vendor. An unopened vial of cells was submitted to another vendor for CO1 DNA Barcoding analysis, which identified the cells as being purely of bovine origin. Results revealed that despite purchase through a commercial vendor, the cell line marketed as primary rabbit aortic endothelial cells were of bovine origin. Purity analysis found cells were misidentified rather than contaminated. Further investigation to determine the cell type was not performed. The most cost-effective and efficient methodology for confirming cell line identity was found to be CO1 DNA Barcoding performed by a commercial vendor., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

Introduction: with the introduction of newer and safer antiretroviral drugs, HIV positive persons are now living longer. Consequently, cardiovascular diseases associated with ageing and chronic low grade inflammation due to the presence of the virus are increasingly found in this population. This study aimed to assess the prevalence and control of hypertension among people living with HIV (PLHIV) receiving care at a Nigerian hospital., Methods: this cross-sectional study was conducted as part of the Patient´s HIV Knowledge Questionnaire (PHKQ) validation study among HIV positive outpatients at the University of Uyo Teaching Hospital, Uyo, Akwa Ibom State, Nigeria. Hypertension was self-reported and confirmed by a documented physician diagnosis in the patient´s case notes and/or self-reported use of antihypertensive medication. For each participant, the average of two close blood pressure (BP) measurements obtained using an automatic upper arm BP monitor was taken as the BP. Hypertension control was defined as SBP <140 mmHg and DBP <90 mmHg. Data were analysed using the Statistical Product and Service Solutions (SPSS) v.21.0. Results were considered significant at p < 0.05., Results: prevalence of hypertension among PLHIV was 24.9%. Age (OR = 1.112, CI = 1.074 - 1.151, p < 0.001), body mass index (OR = 1.087, CI = 1.024 - 1.154, p = 0.004) and duration on antiretroviral therapy (OR = 1.169, CI = 1.090 - 1.254, p < 0.001) significantly predicted hypertension. Only 19 (24.4%) participants had controlled hypertension., Conclusion: hypertension is common among PLHIV seeking care at a Nigerian hospital. However, its control remains suboptimal. Regular screening for hypertension, its appropriate treatment and optimal control are essential in PLHIV., Competing Interests: The authors declare no competing interests., (Copyright: Idongesit Linus Jackson et al.)

Purpose: As part of the special issue on 'Women in Science', this review offers a perspective on past and ongoing work in the field of normal (non-cancer) tissue radiation biology, highlighting the work of many of the leading contributors to this field of research. We discuss some of the hypotheses that have guided investigations, with a focus on some of the critical organs considered dose-limiting with respect to radiation therapy, and speculate on where the field needs to go in the future., Conclusions: The scope of work that makes up normal tissue radiation biology has and continues to play a pivotal role in the radiation sciences, ensuring the most effective application of radiation in imaging and therapy, as well as contributing to radiation protection efforts. However, despite the proven historical value of preclinical findings, recent decades have seen clinical practice move ahead with altered fractionation scheduling based on empirical observations, with little to no (or even negative) supporting scientific data. Given our current appreciation of the complexity of normal tissue radiation responses and their temporal variability, with tissue- and/or organ-specific mechanisms that include intra-, inter- and extracellular messaging, as well as contributions from systemic compartments, such as the immune system, the need to maintain a positive therapeutic ratio has never been more urgent. Importantly, mitigation and treatment strategies, whether for the clinic, emergency use following accidental or deliberate releases, or reducing occupational risk, will likely require multi-targeted approaches that involve both local and systemic intervention. From our personal perspective as five 'Women in Science', we would like to acknowledge and applaud the role that many female scientists have played in this field. We stand on the shoulders of those who have gone before, some of whom are fellow contributors to this special issue.

What Is Known and Objective: Pharmaceutical care (PC) has been shown to improve clinical outcomes in hypertensive patients as well as in people living with HIV (PLWHV). The objective of this study was to evaluate the impact of PC on blood pressure (BP) control, viral load and adherence to medications in hypertensive PLWHV., Methods: This was a prospective, randomized controlled study conducted in the University of Uyo Teaching Hospital, Uyo, Akwa Ibom State, Nigeria. Eligible ambulatory patients were randomized equally to two study arms. The control arm (CA) received the traditional care offered at the HIV clinic; the intervention arm (IA) received the traditional care in addition to PC by the research pharmacist, which included structured education/counselling. BP and self-reported medication adherence were measured at baseline, 6 months and 12 months. Viral load was obtained at baseline and after 12 months. Data were analysed with spss, version 25.0., Results and Discussion: Of the 206 participants initially randomized, 182 (91 in each study arm) completed the 12-month follow-up. No significant differences existed in both arms concerning socio-demographic/clinical characteristics of participants at baseline (p > 0.05). After 12 months, BP control was significantly higher in the IA (53.4% vs. 25.2%; p < 0.001, adjusted odds ratio, aOR = 3.20 (95% CI 1.59-6.44). Systolic BP reduced by 0.9 mmHg from baseline in the CA (p = 0.668) and by 16.67 mmHg from baseline value in the IA (p < 0.001). Diastolic BP increased by 1.9 mmHg in the CA (p = 0.444), but reduced by 7.0 mmHg in the IA (p < 0.001). No significant differences were observed in the change from baseline in the proportion with undetectable plasma viral load (UPVL) in both groups (p > 0.05). PC led to an increase in mean adherence to antiretroviral drugs (Δ = 0.55; p = 0.015), and an increase in mean adherence to antihypertensive drugs (Δ = 2.32; p < 0.001) in the IA., What Is New and Conclusion: To our knowledge, this is the first prospective randomized controlled study evaluating the impacts of PC on clinical outcomes in hypertensive PLWHV with a 12-month follow-up. Our results show that PC significantly improved BP control and adherence to antiretroviral and antihypertensive medications, but had no significant effect on viral load in HIV positive patients with hypertension. Providers of care for PLWHV should leverage the established HIV treatment successes for promoting adherence to treatment for common comorbidities like hypertension in PLWHV in order to improve clinical outcomes., (© 2021 John Wiley & Sons Ltd.)

Purpose: Well-controlled ionizing radiation injury animal models for testing medical countermeasure efficacy require robust radiation physics and dosimetry to ensure accuracy of dose-delivery and reproducibility of the radiation dose-response relationship. The objective of this study was to establish a simple, convenient, robust and accurate technique for validating total body irradiation (TBI) exposure of the New Zealand White rabbit., Methods: We use radiotherapy techniques such as computed tomography simulation and a 3 D-conformal radiation therapy treatment planning system (TPS) on three animals to comprehensively design and preplan a TBI technique for rabbits. We evaluate the requirement for bolus, treatment geometry, bilateral vs anterior-posterior treatment delivery, the agreement between monitor units calculated using the TPS vs a traditional hand calculation to the mid-plane, and resulting individual organ doses., Results: The optimal technique irradiates animals on the left-decubitus position using two isocentric bilateral parallel-opposed 6 MV x-ray beams. Placement of a 5 mm bolus and 8.5 mm beam spoiler was shown to increase the dose to within ≤5 mm of the surface, improving dose homogeneity throughout the body of the rabbit. A simple hand calculation formalism, dependent only on mid-abdominal separation, could be used to calculate the number of monitor units (MUs) required to accurately deliver the prescribed dose to the animal. For the representative animal, the total body volume receiving > 95% of the dose, V 95% > 99%, V 100% > 95%, and V 107% < 20%. The area of the body receiving >107% of the prescribed dose was mainly within the limbs, head, and around the lungs of the animal, where the smaller animal width reduces the x-ray attenuation. Individual organs were contoured by an experienced dosimetrist, and each received doses within 95-107% of the intended dose, with mean values ∼104%. Only the bronchus showed a maximal dose >107% (113%) due to the decreased attenuation of the lungs. To validate the technique, twenty animals were irradiated with four optically-stimulated luminescence dosimeters (OSLDs) placed on the surface of each animal (two on each side in the center of the radiation beam). The average dose over all animals was within <0.1% from intended values, with no animal receiving an average dose more than ±3.1% from prescription., Conclusion: The TBI technique developed in this pilot study was successfully used to establish the dose-response relationship for 45-day lethality across the dose-range to induce the hematopoietic-subsyndrome of the acute radiation syndrome (ARS).

Purpose: The purpose if this study was to develop a rabbit model of total body irradiation (TBI) -induced thrombocytopenia and coagulopathy across the dose-range which induces the hematopoietic subsyndrome of the acute radiation syndrome (H-ARS)., Methods: Twenty male New Zealand White rabbits were assigned to arms to receive 6-MV of TBI at a dose of 6.5, 7.5, 8.5 or 9.5 Gy. Animals were treated with moderate levels of supportive care including buprenorphine for pain management, antibiotics, antipyretics for rectal body temperature >104.8 °F, and fluids for signs of dehydration. Animals were closelyfollowed for up to 45 days after TBI for signs of major morbidity/mortality. Hematology and serum chemistry parameters were routinely monitored. Hemostasis parameters were analyzed prior to TBI, 2 and 6 hours post-TBI, and at the time of euthanasia., Results: Animals developed the characteristic signs and symptoms of H-ARS during the first-week post TBI. Animals became thrombocytopenic with signs of severe acute anemia during the second week post TBI. Moribund animals presented with petechia and ecchymosis of the skin and generalized internal hemorrhage. Multiorgan dysfunction characterized by bone marrow failure, gastric ileus, acute renal toxicity, and liver abnormalities were common. Severe abnormalities in coagulation parameters were observed., Conclusions: The presentation of bone marrow failure and multiorogan injury associated with ARS in the New Zealand White rabbit model is consistent with that described in the canine, swine, non-human primate, and in humans. The hemorrhagic syndrome associated with the ARS in rabbits is characterized by thrombocytopenia and hemostasis dysfunction, which appear to underlie the development of multiorgan dysfunction following TBI to rabbits. Taken together, the rabbit recapitulates the pathogenesis of ARS in humans, and may present an alternative small animal model for medical countermeasure pilot efficacy screening, dose-finding and schedule optimization studies prior to moving into large animal models of TBI-induced ARS.

Purpose: The hemorrhagic syndrome is a major cause of morbidity and mortality associated with the acute radiation syndrome (ARS). We previously characterized the dose-response relationship for total body irradiation (TBI)-induced ARS in the New Zealand White (NZW) rabbit. Thrombocytopenia, hemorrhage, and anemia were strongly associated with morbidity/mortality during the first three weeks post-TBI. The objective of the current study was to further characterize the natural history of thrombocytopenia, hemostatic dysfunction and hemorrhage in the rabbit model at a TBI dose range to induce ARS., Methods: Fifty male NZW rabbits were randomized to receive 7.0 or 7.5 Gy of 6 MV-derived TBI. Sham-irradiated controls ( n =  6) were included as a comparator. Animals were treated with minimal supportive care including pain medication, antibiotics, antipyretics for temperature >104.8 °F, and fluids for signs of dehydration. Animals were culled at pre-determined timepoints post-TBI, or for signs of imminent mortality based on pre-defined euthanasia criteria. Hematology parameters, serum chemistry, viscoelasticity of whole blood, coagulation tests, and coagulation factor activities were measured. A gross exam of vital organs was performed at necropsy., Results: Findings in this study include severe neutropenia during the first week post-TBI followed by thrombocytopenia and severe acute anemia with petechial hemorrhages of the skin and hemorrhage of the vital organs during the second to third weeks post-TBI. Abnormalities in whole blood viscoelastometry were observed concurrent with thrombocytopenia and hemorrhage. Antithrombin activity was significantly elevated in animals after exposure to 7.5 Gy, but not 7.0 Gy TBI., Conclusions: The hemorrhagic syndrome in the rabbit model of TBI recapitulates the pathogenesis described in humans following accidental or deliberate exposures. The rabbit may present an alternative to the rodent model as a small animal species for characterization of the full spectrum of multiorgan injury following TBI and early testing of promising medical countermeasures.

Animal models of total-body irradiation (TBI) are used to elucidate normal tissue damage and evaluate the efficacy of medical countermeasures (MCM). The accuracy of these TBI models depends on the reproducibility of the radiation dose-response relationship for lethality, which in turn is highly dependent on robust radiation physics and dosimetry. However, the precise levels of radiation each organ absorbs can change dramatically when different photon beam qualities are used, due to the interplay between their penetration and the natural variation of animal sizes and geometries. In this study, we evaluate the effect of varying the radiation energy, namely cobalt-60 (Co-60); of similar penetration to a 4-MV polyenergetic beam), 6 MV and 15 MV, in the absorbed dose delivered by TBI to individual organs of eight Göttingen minipigs of varying weights (10.3-24.1 kg) and dimensions (17.5-25 cm width). The main organs, i.e. heart, lungs, esophagus, stomach, bowels, liver, kidneys and bladder, were contoured by an experienced radiation oncologist, and the volumetric radiation dose distribution was calculated using a commercial treatment planning system commissioned and validated for Co-60, 6-MV and 15-MV teletherapy units. The dose is normalized to the intended prescription at midline in the abdomen. For each animal and each energy, the body and organ dose volume histograms (DVHs) were computed. The results show that more penetrating photon energies produce dose distributions that are systematically and consistently more homogeneous and more uniform, both within individual organs and between different organs, across all animals. Thoracic organs (lungs, heart) received higher dose than prescribed while pelvic organs (bowel, bladder) received less dose than prescribed, due to smaller and wider separations, respectively. While these trends were slightly more pronounced in the smallest animals (10.3 kg, 19 cm abdominal width) and largest animals (>20 kg, ∼25 cm abdominal width), they were observed in all animals, including those in the 9-15 kg range typically used in MCM models. Some organs received an average absorbed dose representing <80% of prescribed dose when Co-60 was used, whereas all organs received average doses of >87% and >93% when 6 and 15 MV were used, respectively. Similarly, average dose to the thoracic organs reached as high as 125% of the intended dose with Co-60, compared to 115% for 15 MV. These results indicate that Co-60 consistently produces less uniform dose distributions in the Göttingen minipig compared to 6 and 15 MV. Moreover, heterogeneity of dose distributions for Co-60 is accentuated by anatomical and geometrical variations across various animals, leading to different absorbed dose delivered to organs for different animals. This difference in absorbed radiation organ doses, likely caused by the lower penetration of Co-60 and 6 MV compared to 15 MV, could potentially lead to different biological outcomes. While the link between the dose distribution and variation of biological outcome in the Göttingen minipig has never been explicitly studied, more pronounced dose heterogeneity within and between organs treated with Co-60 teletherapy units represents an additional confounding factor which can be easily mitigated by using a more penetrating energy., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Radiotherapy for brain tumors induces neuronal DNA damage and may lead to neurodegeneration and cognitive deficits. We investigated the mechanisms of radiation-induced neuronal cell death and the role of miR-711 in the regulation of these pathways. We used in vitro and in vivo models of radiation-induced neuronal cell death. We showed that X-ray exposure in primary cortical neurons induced activation of p53-mediated mechanisms including intrinsic apoptotic pathways with sequential upregulation of BH3-only molecules, mitochondrial release of cytochrome c and AIF-1, as well as senescence pathways including upregulation of p21 WAF1/Cip1 . These pathways of irradiation-induced neuronal apoptosis may involve miR-711-dependent downregulation of pro-survival genes Akt and Ang-1. Accordingly, we demonstrated that inhibition of miR-711 attenuated degradation of Akt and Ang-1 mRNAs and reduced intrinsic apoptosis after neuronal irradiation; likewise, administration of Ang-1 was neuroprotective. Importantly, irradiation also downregulated two novel miR-711 targets, DNA-repair genes Rad50 and Rad54l2, which may impair DNA damage responses, amplifying the stimulation of apoptotic and senescence pathways and contributing to neurodegeneration. Inhibition of miR-711 rescued Rad50 and Rad54l2 expression after neuronal irradiation, enhancing DNA repair and reducing p53-dependent apoptotic and senescence pathways. Significantly, we showed that brain irradiation in vivo persistently elevated miR-711, downregulated its targets, including pro-survival and DNA-repair molecules, and is associated with markers of neurodegeneration, not only across the cortex and hippocampus but also specifically in neurons isolated from the irradiated brain. Our data suggest that irradiation-induced miR-711 negatively modulates multiple pro-survival and DNA-repair mechanisms that converge to activate neuronal intrinsic apoptosis and senescence. Using miR-711 inhibitors to block the development of these regulated neurodegenerative pathways, thus increasing neuronal survival, may be an effective neuroprotective strategy.

A large-scale nuclear event has the ability to inflict mass casualties requiring point-of-care and laboratory-based diagnostic and prognostic biomarkers to inform victim triage and appropriate medical intervention. Extensive progress has been made to develop post-exposure point-of-care biodosimetry assays and to identify biomarkers that may be used in early phase testing to predict the course of the disease. Screening for biomarkers has recently extended to identify specific metabolomic and lipidomic responses to radiation using animal models. The objective of this review was to determine which metabolites or lipids most frequently experienced perturbations post-ionizing irradiation (IR) in preclinical studies using animal models of acute radiation sickness (ARS) and delayed effects of acute radiation exposure (DEARE). Upon review of approximately 65 manuscripts published in the peer-reviewed literature, the most frequently referenced metabolites showing clear changes in IR induced injury were found to be citrulline, citric acid, creatine, taurine, carnitine, xanthine, creatinine, hypoxanthine, uric acid, and threonine. Each metabolite was evaluated by specific study parameters to determine whether trends were in agreement across several studies. A select few show agreement across variable animal models, IR doses and timepoints, indicating that they may be ubiquitous and appropriate for use in diagnostic or prognostic biomarker panels., Competing Interests: Elisabeth Vicente and Zeljko Vujaskovic declare no conflict of interest. Isabel L. Jackson is on the scientific advisory board of Humanetics Corporation. Jackson is a consultant for Partner Therapeutics and Myelo Therapeutics GmbH. These companies had no role in the design of the study, analyses or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Radiation-induced central nervous system toxicity is a significant risk factor for patients receiving cancer radiotherapy. Surprisingly, the mechanisms responsible for the DNA damage-triggered neuronal cell death following irradiation have yet to be deciphered. Using primary cortical neuronal cultures in vitro, we demonstrated that X-ray exposure induces the mitochondrial pathway of intrinsic apoptosis and that miR-23a-3p plays a significant role in the regulation of this process. Primary cortical neurons exposed to irradiation show the activation of DNA-damage response pathways, including the sequential phosphorylation of ATM kinase, histone H2AX, and p53. This is followed by the p53-dependent up-regulation of the pro-apoptotic Bcl2 family molecules, including the BH3-only molecules PUMA, Noxa, and Bim, leading to mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c, which activates caspase-dependent apoptosis. miR-23a-3p, a negative regulator of specific pro-apoptotic Bcl-2 family molecules, is rapidly decreased after neuronal irradiation. By increasing the degradation of PUMA and Noxa mRNAs in the RNA-induced silencing complex (RISC), the administration of the miR-23a-3p mimic inhibits the irradiation-induced up-regulation of Noxa and Puma. These changes result in an attenuation of apoptotic processes such as MOMP, the release of cytochrome c and caspases activation, and a reduction in neuronal cell death. The neuroprotective effects of miR-23a-3p administration may not only involve the direct inhibition of pro-apoptotic Bcl-2 molecules downstream of p53 but also include the attenuation of secondary DNA damage upstream of p53. Importantly, we demonstrated that brain irradiation in vivo results in the down-regulation of miR-23a-3p and the elevation of pro-apoptotic Bcl2-family molecules PUMA, Noxa, and Bax, not only broadly in the cortex and hippocampus, except for Bax, which was up-regulated only in the hippocampus but also selectively in isolated neuronal populations from the irradiated brain. Overall, our data suggest that miR-23a-3p down-regulation contributes to irradiation-induced intrinsic pathways of neuronal apoptosis. These regulated pathways of neurodegeneration may be the target of effective neuroprotective strategies using miR-23a-3p mimics to block their development and increase neuronal survival after irradiation., Competing Interests: The authors declare no conflict of interest.

Protein therapeutics, also known as biologics, are currently manufactured at centralized facilities according to rigorous protocols. The manufacturing process takes months and the delivery of the biological products needs a cold chain. This makes it less responsive to rapid changes in demand. Here, we report on technology application for on-demand biologics manufacturing (Bio-MOD) that can produce safe and effective biologics from cell-free systems at the point of care without the current challenges of long-term storage and cold-chain delivery. The objective of the current study is to establish proof-of-concept safety and efficacy of Bio-MOD-manufactured granulocyte colony-stimulating factor (G-CSF) in a mouse model of total body irradiation at a dose estimated to induce 30% lethality within the first 30 days postexposure. To illustrate on-demand Bio-MOD production feasibility, histidine-tagged G-CSF was manufactured daily under good manufacturing practice-like conditions prior to administration over a 16-day period. Bio-MOD-manufactured G-CSF improved 30-day survival when compared with saline alone (p = .073). In addition to accelerating recovery from neutropenia, the platelet and hemoglobin nadirs were significantly higher in G-CSF-treated animals compared with saline-treated animals (p < .05). The results of this study demonstrate the feasibility of consistently manufacturing safe and effective on-demand biologics suitable for real-time release., (© 2020 American Institute of Chemical Engineers.)

Background and Purpose: Patients with life-threatening illnesses, such as cancer, experience emotional distress. This study was to investigate the molecular and cellular mechanisms of relevant psychological stressor on tumor growth and therapeutic resistance., Materials and Methods: Stress was induced in C57BL/6J mice bearing LLC lung tumors by exposure to a conspecific mice receiving inescapable foot shocks. Mice were irradiated at 7 Gy for 3 consecutive days. Behaviors were monitored by open field test (OFT), elevated plus maze (EPM), sucrose preference test (SPT), and learned helplessness (LH) test. Protein expression in tissues and cultured cells were measured by Western blot., Results: This study in animals showed that observing a conspecific mouse receiving foot shocks induced depression like behaviors with increased plasma corticosterone and adrenaline levels which increased tumor growth and radioresistance. Stress increased Wnt1, Drosha, and vimentin expression and decreased E-cadherin expression in tumor tissues. The combination of stress and irradiation enhanced radioresistance along with the increase in vimentin expression. The in vitro study showed that a β 2 -adrenergic receptor (β2-AR) agonist blocked irradiation-induced cell apoptosis and decreased cell viability, while silencing β2-AR expression reduced the protective effects of β2-AR agonist. β2-AR agonist obviously increased Wnt1 and Drosha expression in LLC-1 cells., Conclusion: Psychological stress increased tumor growth and enhanced radioresistance associated with the activation of epithelial-mesenchymal transition by stress hormone-stimulated adrenergic receptors., (Copyright © 2020. Published by Elsevier B.V.)

Background Valid and reliable instruments for measuring knowledge about human immuno-deficiency virus (HIV) among people living with the virus are necessary to identify knowledge gaps and evaluate effectiveness or outcomes of education programmes. However such instruments are scarce, particularly in developing countries. Objective This study aimed to develop and validate a self-administered instrument for measuring HIV-related knowledge among people living with HIV in Nigeria. Setting This study was conducted in the HIV/AIDS clinic of the University of Uyo Teaching Hospital, Akwa Ibom State, Nigeria. Methods The Patient's HIV Knowledge Questionnaire (PHKQ) items, designed with response choices of 'yes', 'no' and 'don't know', were developed based on relevant literature and similar published studies. Face and content validity were established. Evidence of construct validity was established by factor analysis and group differences. Factor analysis was done using principal components and varimax rotation with Kaiser Normalization. Estimates of reliability were evaluated using internal consistency approach (with Cronbach's alpha coefficient) as well as the test-retest method for estimating the stability of the PHKQ scores over time (with Pearson's r). Main outcome measure Validity/reliability of the Patient's HIV Knowledge Questionnaire. Result Response rate in this study was 95.0%. Item analysis of the 20-item instrument resulted in the deletion of 5 items; thus the final instrument consists of 15 items. Cronbach's alpha coefficient for the scale was 0.77, while test-retest reliability was 0.80 (p < 0.001). Factor analysis resulted in 3 components-Transmission and Misconceptions, Causes and Treatment Outcomes, and Diet and Immunity-with Cronbach's alpha of 0.70, 0.56 and 0.46 respectively. The Patient's HIV Knowledge Questionnaire differentiated between newly diagnosed (≤ 1 year) individuals and those with at least 10 years since HIV diagnosis, and also between those with only primary education and those who had had up to tertiary education (p < 0.001). Conclusion The Patient's HIV Knowledge Questionnaire appears to be a valid and reliable tool for assessing HIV-related knowledge among people living with HIV in Nigeria. Further studies are needed to explore the instrument's responsiveness to change, and to evaluate its psychometrics in different settings.

Purpose: A large proportion of preclinical or translational studies using radiation have poor replicability. For a study involving radiation exposure to be replicable, interpretable, and comparable, its experimental methodology must be well reported, particularly in terms of irradiation protocol, including the amount, rate, quality, and geometry of radiation delivery. Here we perform the first large-scale literature review of the current state of reporting of essential experimental physics and dosimetry details in the scientific literature., Methods and Materials: For 1758 peer-reviewed articles from 469 journals, we evaluated the reporting of basic experimental physics and dosimetry details recommended by the authoritative National Institute of Standards and Technology symposium., Results: We demonstrate that although some physics and dosimetry parameters, such as dose, source type, and energy, are well reported, the majority are not. Furthermore, highly cited journals and articles are systematically more likely to be lacking experimental details related to the irradiation protocol., Conclusions: These findings show a crucial deficiency in the reporting of basic experimental details and severely affect the reproducibility and translatability of a large proportion of radiation biology studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To assess whether BIO 300, a synthetic genistein nanosuspension, improves the therapeutic index in prostate cancer treatment by preventing radiation-induced erectile dysfunction (ED) without reducing tumor radiosensitivity., Methods and Materials: Male Sprague-Dawley rats were exposed to 25 Gy of 220-kV prostate-confined x-rays. Animals were randomized to receive sham radiation therapy (RT), RT alone, RT with daily BIO 300 at 2 experimental dosing regimens, or RT with daily genistein. Erectile response was evaluated over time. Penile shaft tissue was harvested for histologic analyses. Murine xenograft studies using prostate cancer cell lines determined the effects of BIO 300 dosing on RT efficacy., Results: Prostate-confined RT significantly decreased apomorphine-induced erectile response (P < .05 vs sham RT). Erection frequency in animals receiving prophylactic treatment with BIO 300 starting 3 days before RT was similar to sham controls after RT. Treatment with synthetic genistein did not mitigate loss in erectile frequency. At week 14, post-RT treatment with BIO 300 resulted in significantly higher quality of erectile function compared with both the RT arm and the RT arm receiving genistein starting 3 days before irradiation (P < .05). In hormone-sensitive and insensitive prostate tumor-bearing mice, BIO 300 administration did not negatively affect radiation-induced tumor growth delay., Conclusions: BIO 300 prevents radiation-induced ED, measured by erection frequency, erectile function, and erection quality, when administered 3 days before RT and continued daily for up to 14 weeks. Data also suggest that BIO 300 administered starting 2 hours after RT mitigates radiation-induced ED. Data provide strong nonclinical evidence to support clinical translation of BIO 300 for mitigation of ED while maintaining treatment response to RT., (Copyright © 2019. Published by Elsevier Inc.)

Transparency, openness, and reproducibility are important characteristics in scientific publishing. Although many researchers embrace these characteristics, data sharing has yet to become common practice. Nevertheless, data sharing is becoming an increasingly important topic among societies, publishers, researchers, patient advocates, and funders, especially as it pertains to data from clinical trials. In response, ASTRO developed a data policy and guide to best practices for authors submitting to its journals. ASTRO's data sharing policy is that authors should indicate, in data availability statements, if the data are being shared and if so, how the data may be accessed., (© 2019 The Author(s).)

Detonation of a radiological or nuclear device in a major urban area will result in heterogenous radiation exposure, given to the significant shielding of the exposed population due to surrounding structures. Development of biodosimetry assays for triage and treatment requires knowledge of the radiation dose-volume effect for the bone marrow (BM). This proof-of-concept study was designed to quantify BM damage in the non-human primate (NHP) after exposure to one of four radiation patterns likely to occur in a radiological/nuclear attack with varying levels of BM sparing. Rhesus macaques (11 males, 12 females; 5.30-8.50 kg) were randomized by weight to one of four arms: 1. bilateral total-body irradiation (TBI); 2. unilateral TBI; 3. bilateral upper half-body irradiation (UHBI); and 4. bilateral lower half-body irradiation (LHBI). The match-point for UHBI vs. LHBI was set at 1 cm above the iliac crest. Animals were exposed to 4 Gy of 6 MV X rays. Peripheral blood samples were drawn 14 days preirradiation and at days 1, 3, 5, 7 and 14 postirradiation. Dosimetric measurements after irradiation indicated that dose to the mid-depth xiphoid was within 6% of the prescribed dose. No high-grade fever, weight loss >10%, dehydration or respiratory distress was observed. Animals in the bilateral- and unilateral TBI arms presented with hematologic changes [e.g., absolute neutrophil count (ANC) <500/ll; platelets <50,000/ll] and clinical signs/symptoms (e.g., petechiae, ecchymosis) characteristic of the acute radiation syndrome. Animals in the bilateral UHBI arm presented with myelosuppression; however, none of the animals developed severe neutropenia or thrombocytopenia (ANC remained >500/µl; platelets >50,000/µl during 14-day follow-up). In contrast, animals in the LHBI arm (1 cm above the ilieac crest to the toes) were protected against BM toxicity with no marked changes in hematological parameters and only minor gross pathology [petechiae (1/5), splenomegaly (1/5) and mild pulmonary hemorrhage (1/5)]. The model performed as expected with respect to the dose-volume effect of total versus partial-BM irradiation, e.g., increased shielding resulted in reduced BM toxicity. Shielding of the major blood-forming organs (e.g., skull, ribs, sternum, thoracic and lumbar spine) spared animals from bone marrow toxicity. These data suggest that the biological consequences of the absorbed dose are dependent on the total volume and pattern of radiation exposure.

Introduction: There has been interest in using human blood products in nonhuman primate models of trauma to supplement human studies and to provide evidence to guide novel trauma resuscitation strategies. The compatibility of human RBCs has not been extensively studied in nonhuman primate species., Methods: Whole blood samples were collected from five healthy, nontransfused, not previously pregnant Chinese-bred rhesus macaques. The whole blood was centrifuged, and the plasma was decanted from each sample. Group O-negative human RBCs were mixed with the plasma from the rhesus macaque monkeys. Compatibility testing was performed by an immediate spin test and polyspecific and monospecific anti-human globulin (AHG) tests in glass tubes., Results: Immediate spin testing revealed three out of five plasma samples (60%) from rhesus macaques caused at least 1+ agglutination with the human RBCs. Polyspecific anti-human globulin (AHG) tests demonstrated that two of five plasma samples (40%) from rhesus macaques caused at least 1+ agglutination with the human RBC, while the monospecific AHG testing revealed that the incompatibility was caused by C3d, not IgG., Conclusion: Human RBCs are not compatible with the plasma of some, but not all, Chinese-bred rhesus macaques., (© 2019 AABB.)

Radiation-induced lung injury is a delayed effect of acute radiation exposure resulting in pulmonary pneumonitis and fibrosis. Molecular mechanisms that lead to radiation-induced lung injury remain incompletely understood. Using a murine model of whole-thorax lung irradiation, C57BL/6J mice were irradiated at 8, 10, 12, and 14 Gy and assayed at day 1, 3, and 6 postexposure and compared to nonirradiated (sham) controls. Tryptic digests of lung tissues were analyzed by liquid chromatography-tandem mass spectrometry on a Waters nanoLC instrument coupled to a Thermo Scientific Q Exactive hybrid quadrupole-orbitrap mass spectrometer. Pathway and gene ontology analysis were performed with Qiagen Ingenuity, Panther GO, and DAVID databases. A number of trends were identified in the proteomic data, including protein changes greater than 10 fold, protein changes that were consistently up regulated or down regulated at all time points and dose levels interrogated, time and dose dependency of protein changes, canonical pathways affected by irradiation, changes in proteins that serve as upstream regulators, and proteins involved in key processes including inflammation, radiation, and retinoic acid signaling. The proteomic profiling conducted here represents an untargeted systems biology approach to identify acute molecular events that could potentially be initiating events for radiation-induced lung injury.

Objective:: Non-ablative or mild hyperthermia (HT) has been shown in preclinical (and clinical) studies as a localized radiosensitizer that enhances the tumoricidal effects of radiation. Most preclinical in vivo HT studies use subcutaneous tumor models which do not adequately represent clinical conditions (e.g. proximity of normal/critical organs) or replicate the tumor microenvironment-both of which are important factors for eventual clinical translation. The purpose of this work is to demonstrate proof-of-concept of locoregional radiosensitization with superficially applied, radiofrequency (RF)-induced HT in an orthotopic mouse model of prostate cancer., Methods:: In a 4-arm study, 40 athymic male nude mice were inoculated in the prostate with luciferase-transfected human prostate cancer cells (PC3). Tumor volumes were allowed to reach 150-250 mm 3 (as measured by ultrasound) following which, mice were randomized into (i) control (no intervention); (ii) HT alone; (iii) RT alone; and (iv) HT + RT. RF-induced HT was administered (Groups ii and iv) using the Oncotherm LAB EHY-100 device to achieve a target temperature of 41 °C in the prostate. RT was administered ~30 min following HT, using an image-guided small animal radiotherapy research platform. In each case, a dual arc plan was used to deliver 12 Gy to the target in a single fraction. One animal from each cohort was euthanized on Day 10 or 11 after treatment for caspase-9 and caspase-3 Western blot analysis., Results:: The inoculation success rate was 89%. Mean tumor size at randomization (~16 days post-inoculation) was ~189 mm 3 . Following the administration of RT and HT, mean tumor doubling times in days were: control = 4.2; HT = 4.5; RT = 30.4; and HT + RT = 33.4. A significant difference (p = 0.036) was noted between normalized nadir volumes for the RT alone (0.76) and the HT + RT (0.40) groups. Increased caspase-3 expression was seen in the combination treatment group compared to the other treatment groups., Conclusion:: These early results demonstrate the successful use of external mild HT as a localized radiosensitizer for deep-seated tumors., Advances in Knowledge:: We successfully demonstrated the feasibility of administering external mild HT in an orthotopic tumor model and demonstrated preclinical proof-of-concept of HT-based localized radiosensitization in prostate cancer radiotherapy.

Background and Purpose: BIO 300 nanosuspension (Humanetics Corporation) is being developed as a medical countermeasure (MCM) for the mitigation of the delayed effects of acute radiation exposure, specifically pneumonitis and fibrosis of the lung. The objective of this study was to determine the best dose and treatment duration of BIO 300 to mitigate lung injury and improve the likelihood for survival in C57L/J mice exposed to whole thorax lung irradiation (WTLI)., Experimental Approach: Age- and sex-matched C57L/J mice received a single dose of 11.0 or 12.5 Gy WTLI. BIO 300 (200 or 400 mg·kg -1 , oral gavage) was administered daily starting 24 h post-exposure for a duration of 2, 4, 6 or, in some cases, 10 weeks. Non-treated controls were included for comparison in both sexes. Animals were observed daily for signs of major morbidity. Respiratory function was assessed biweekly. Lungs were collected, weighed and paraffin embedded for histological evaluation post mortem., Key Results: BIO 300 administered at an oral dose of 400 mg·kg -1 for 4 to 6 weeks starting 24 h post-WTLI reduced morbidity associated with WTLI. The improvement in survival correlated with reduced respiratory frequency and enhanced pause. The irradiated lungs of mice treated with BIO 300 (400 mg·kg -1 ) for 4 to 6 weeks displayed less morphological damage and airway loss due to oedema, congestion and fibrotic scarring than the untreated, irradiated controls., Conclusions and Implications: BIO 300 is a promising MCM candidate to mitigate pneumonitis/fibrosis when administered daily for 4-6 weeks starting 24 h post-exposure., (© 2017 The British Pharmacological Society.)

Purpose: Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival., Methods: High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers., Results: A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified., Conclusions: These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

Purpose/objectives: Radiation-induced erectile-dysfunction (RiED) is one of the most common side effects of radiation therapy (RT) and significantly reduces the quality of life (QoL) of cancer patients. Approximately 50% of prostate cancer patients experience RiED within 3 to 5 years after completion of RT. A series of vascular, muscular, and neurogenic injuries after prostate RT lead to RiED; however, the precise role of RT-induced neurogenic injury in RiED has not been fully established. The cavernous nerves (CN) are postganglionic parasympathetic nerves located beside the prostate gland that assist in penile erection. This study was designed to investigate the role of CN injury, tissue damage, and altered signaling pathways in an RiED rat model., Methods and Materials: Male rats were exposed to a single dose of 25 Gy prostate-confined RT. Erectile function was evaluated by intracavernous pressure (ICP) measurements conducted both 9 and 14 weeks after RT. Neuronal injury was evaluated in the CN using quantitative polymerase chain reaction, conduction studies, transmission electron microscopy, and immunoblotting. Masson trichrome staining was performed to elucidate fibrosis level in penile tissues., Results: There were significant alterations in the ICP (P<.0001) of RT rats versus non-RT rats. TEM analysis showed decreased myelination, increased microvascular damage, and progressive axonal atrophy of the CN fibers after RT. Electrophysiologic analysis showed significant impairment of the CN conduction velocity after RT. RT also significantly increased RhoA/Rho-associated protein kinase 1 (ROCK1) mRNA and protein expression. In addition, penile tissue showed increased apoptosis and fibrosis 14 weeks after RT., Conclusions: RT-induced CN injury may contribute to RiED; this is therefore a rationale for developing novel therapeutic strategies to mitigate CN and tissue damage. Moreover, further investigation of the RhoA/ROCK pathway's role in mitigating RiED is necessary., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Molecular mechanisms underlying development of acute pneumonitis and/or late fibrosis following thoracic irradiation remain poorly understood. Here, we hypothesize that heterogeneity in disease progression and phenotypic expression of radiation-induced lung disease (RILD) across murine strains presents an opportunity to better elucidate mechanisms driving tissue response toward pneumonitis and/or fibrosis. Distinct differences in disease progression were observed in age- and sex-matched CBA/J, C57L/J and C57BL/6J mice over 1 year after graded doses of whole-thorax lung irradiation (WTLI). Separately, comparison of gene expression profiles in lung tissue 24 h post-exposure demonstrated >5000 genes to be differentially expressed ( P <0.01; >twofold change) between strains with early versus late onset of disease. An immediate divergence in early tissue response between radiation-sensitive and -resistant strains was observed. In pneumonitis-prone C57L/J mice, differentially expressed genes were enriched in proinflammatory pathways, whereas in fibrosis-prone C57BL/6J mice, genes were enriched in pathways involved in purine and pyrimidine synthesis, DNA replication and cell division. At 24 h post-WTLI, different patterns of cellular damage were observed at the ultrastructural level among strains but microscopic damage was not yet evident under light microscopy. These data point toward a fundamental difference in patterns of early pulmonary tissue response to WTLI, consistent with the macroscopic expression of injury manifesting weeks to months after exposure. Understanding the mechanisms underlying development of RILD might lead to more rational selection of therapeutic interventions to mitigate healthy tissue damage., (© 2017. Published by The Company of Biologists Ltd.)

Lipids represent biologically ubiquitous and highly dynamic molecules in terms of abundance and structural diversity. Whereas the potential for lipids to inform on disease/injury is promising, their unique characteristics make detection and identification of lipids from biological samples analytically demanding. We report the use of ultraperformance convergence chromatography (UPC 2 ), a variant of supercritical fluid chromatography, coupled to high-resolution, data-independent tandem mass spectrometry for characterization of total lipid extracts from mouse lung tissue. The UPC 2 platform resulted in lipid class separation and when combined with orthogonal column chemistries yielded chromatographic separation of intra-class species based on acyl chain hydrophobicity. Moreover, the combined approach of using UPC 2 with orthogonal column chemistries, accurate mass measurements, time-aligned low- and high-collision energy total ion chromatograms, and positive and negative ion mode product ion spectra correlation allowed for confident lipid identification. Of great interest was the identification of differentially expressed ceramides that were elevated 24 h post whole thorax lung irradiation. The identification of lipids that were elevated 24 h post-irradiation signifies a unique opportunity to investigate early mechanisms of action prior to the onset of clinical symptoms in the whole thorax lung irradiation mouse model., (Copyright © 2016 John Wiley & Sons, Ltd.)

Detonation of a 10-kiloton nuclear bomb in an urban setting would result in >1 million casualties, the majority of which would present with combined injuries. Combined injuries, such as peripheral tissue trauma and radiation exposure, trigger inflammatory events that lead to multiple organ dysfunction (MOD) and death, with gastrointestinal (GI) and pulmonary involvement playing crucial roles. The objective of this study was to develop an animal model of combined injuries, peripheral tissue trauma (TBX animal model) combined with total body irradiation with 5% bone marrow shielding (TBI/BM5) to investigate if peripheral tissue trauma contributes to reduced survival. Male C57BL/6J mice were exposed to TBX10%, irradiation (TBI/BM5), or combined injuries (TBX10% + TBI/BM5). Experiments were conducted to evaluate mortality at day 7 after TBI/BM5. Serial euthanasia was performed at day 1, 3 and 6 or 7 after TBI/BM5 to evaluate the time course of pathophysiologic processes in combined injuries. Functional tests were performed to assess pulmonary function and GI motility. Postmortem samples of lungs and jejunum were collected to assess tissue damage. Results indicated higher lethality and shorter survival in the TBX10% +T BI/BM5 group than in the TBX10% or TBI/BM5 groups (day 1 vs. day 7 and 6, respectively). TBI/BM5 alone had no effects on the lungs but significantly impaired GI function at day 6. As expected, in the animals that received severe trauma (TBX10%), we observed impairment in lung function and delay in GI transit in the first 3 days, effects that decreased at later time points. Trauma combined with radiation (TBX10% + TBI/BM5) significantly augmented impairment of the lung and GI function in comparison to TBX10% and TBI/BM5 groups at 24 h. Histologic evaluation indicated that combined injuries caused greater tissue damage in the intestines in TBX10% + TBI/BM5 group when compared to other groups. We describe here the first combined tissue trauma/radiation injury model that will allow conduction of mechanistic studies to identify new therapeutic targets and serve as a platform for testing novel therapeutic interventions.

Differences in the pathogenesis of radiation-induced lung injury among murine strains offer a unique opportunity to elucidate the molecular mechanisms driving the divergence in tissue response from repair and recovery to organ failure. Here, we utilized two well-characterized murine models of radiation pneumonitis/fibrosis to compare and contrast differential gene expression in lungs 24 hours after exposure to a single dose of whole thorax lung irradiation sufficient to cause minor to major morbidity/mortality. Expression of 805 genes was altered as a general response to radiation; 42 genes were identified whose expression corresponded to the threshold for lethality. Three genes were discovered whose expression was altered within the lethal, but not the sublethal, dose range. Time-course analysis of the protein product of the most promising gene, resistin-like molecule alpha, demonstrated a significant difference in expression between radiosensitive versus radiotolerant strains, suggesting a unique role for this protein in acute lung injury.