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Immunogenicity regulatory guidance and industry recommendations have evolved over the last two decades since unexpected immune reactions were first reported with erythropoietin. Since then, the guidelines and practices for immunogenicity have stemmed from a reaction to a high-risk molecule causing significant clinical impact. Similar thinking is often applied to all biotherapeutic drugs, even when a well-defined risk assessment suggests otherwise. In recent years, the current testing paradigm for immunogenicity has been challenged with more informative approaches being proposed. In a Focus Workshop held by the European Bioanalysis Forum in September 2023, the current immunogenicity testing paradigm was challenged based on the experience and learning of 20+ years of immunogenicity strategies. The workshop recommendations proposed a new paradigm, challenging the value of multiple tiers depending on the immunogenicity risk assessment based on context of use and moving toward treating immunogenicity as a pharmacodynamic biomarker for the drug. Such rethinking ultimately results in the appropriate and efficient focusing of resources on immunogenicity testing strategies that benefit patients most, moving to a new paradigm where implementation of appropriate and truly informative immunogenicity testing strategies, depending on the context-of-use, become the norm .
[Box: see text].
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The rationale of this study stems from the concern of a radiation-induced accident or terrorist-mediated nuclear attack resulting in large populations of people exposed to nonlethal radiation doses or after a course of definitive radiation therapy which could substantially increase the risk for cancer induction after exposure. Currently, there are no safe and effective interventions to reduce this increased cancer risk to humans. We have tested the hypothesis that the mTOR inhibitor, rapamycin, administered in the diet of mice would reduce or delay radiation-induced cancer when given after radiation exposure. A total-body irradiation (TBI) of 3 Gy was administered to female C3H/Hen mice. Immediately after TBI, along with untreated control groups, animals were placed on chow containing different concentrations of encapsulated rapamycin (14, 40, 140 mg/kg chow). Animals remained on the respective control or rapamycin diets and were followed for their entire lifespan (total of 795 mice). The endpoint for the study was tumor formation (not to exceed 1 cm) or until the animal reached a humane endpoint at which time the animal was euthanized and evaluated for the presence of tumors (pathology evaluated on all animals). Kaplan-Meier survival curves revealed that all three concentrations of rapamycin afforded a significant survival advantage by delaying the time at which tumors appeared and reduction of the incidence of certain tumor types such as hepatocellular carcinomas. The survival advantage was dependent on the rapamycin concentration used. Further, there was a survival advantage when delaying the rapamycin chow by 1 month after TBI. Rapamycin is FDA-approved for human use and could be considered for use in individuals exposed to nonlethal TBI from a nuclear accident or attack or after significant therapeutic doses for cancer treatment.
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The hypothesis of this study was that there were changes in biomarkers registered by innovative technologies in cows with subclinical acidosis. The aim of this study was to identify changes in the in-line milk fat-to-protein ratio and cow feeding behaviors such as reticulorumen pH, reticulorumen temperature, cow activity, and water intake with subclinical acidosis. From a total of 98 cows, 59 cows were selected to meet the following criteria (2 or more lactations, with 31 days in milk (DIM)). The selected animals were separated into two groups based on general clinical examination and reticulorumen pH: the subclinical acidosis group (SCA, n = 23) and the healthy group (HC, n = 36). During the diagnosis of subclinical acidosis and following the clinical examination of the healthy group using the BROLIS HerdLine system, the daily averages of milk yield (kg/day), milk fat (%), milk protein (%), and the milk fat-to-protein ratio were recorded. Simultaneously, by using Smaxtec technology, reticulorumen parameters and cow activity, including pH, temperature (°C), rumination time (minutes/day), and water intake (hours/day), were registered. Changes in parameters measured using innovative technologies were able to identify cows with subclinical acidosis. Cows with subclinical acidosis had a lower reticulorumen pH by 18.8% (p < 0.0001), a decreased milk yield by 10.49% (p < 0.001), a lower milk fat-to-protein ratio by 11.88% (p < 0.01), and a decreased rumination time by 6.59% (p < 0.01). However, the activity of these cows was higher by 57.19% (p < 0.001) compared to healthy cows. From a practical point of view, we suggest that veterinarians and farmers track parameters such as reticulorumen pH, milk yield, milk fat-to-protein ratio, rumination time, and activity for the identification of subclinical acidosis.
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INTRODUCTION: Low back pain (LBP) is highly prevalent after lower limb amputation (LLA) and contributes to substantial reductions in quality of life and function. Towards understanding pathophysiological mechanisms underlying LBP after LLA, this article compares lumbar spine pathologies and muscle morphologies between individuals with LBP, with and without LLA. MATERIALS AND METHODS: We queried electronic medical records of Service members with and without LLA who sought care for LBP at military treatment facilities between January 2002 and May 2020. Two groups with cLBP, one with (n = 15) and one without unilateral transtibial LLA (n = 15), were identified and randomly chosen from a larger sample. Groups were matched by age, mass, and sex. Lumbar muscle morphology, Pfirrmann grades, Modic changes, facet arthrosis, Meyerding grades, and lordosis angle were determined from radiographs and magnetic resonance images available in the medical record. Independent t-tests compared variables between cohorts while multiple regression models determined if intramuscular fat influenced Pfirrmann grades. Chi-square determined differences in presence of spondylolysis and facet arthrosis. RESULTS: Lordosis angle was larger with LLA (P = 0.01). Spondylolysis was more prevalent with LLA (P = 0.008; 40%) whereas facet arthrosis was similar between cohorts (P = 0.3). Muscle area was not different between cohorts, yet intramuscular fat was greater with LLA (P ≤ 0.05). Intramuscular fat did not influence Pfirrmann grades (P > 0.15). CONCLUSIONS: Despite similar lumbar muscle size, those with unilateral LLA may be predisposed to progress to symptomatic spondylolisthesis and intramuscular fat. Surgical and/or rehabilitation interventions may mitigate long-term effects of diminished spinal health, decrease LBP-related disability, and improve function for individuals with LLA.
Subject(s)
Communication , Deception , Democracy , Politics , Humans , Reproducibility of Results , Research Personnel , Social ChangeABSTRACT
The spread of misinformation through media and social networks threatens many aspects of society, including public health and the state of democracies. One approach to mitigating the effect of misinformation focuses on individual-level interventions, equipping policymakers and the public with essential tools to curb the spread and influence of falsehoods. Here we introduce a toolbox of individual-level interventions for reducing harm from online misinformation. Comprising an up-to-date account of interventions featured in 81 scientific papers from across the globe, the toolbox provides both a conceptual overview of nine main types of interventions, including their target, scope and examples, and a summary of the empirical evidence supporting the interventions, including the methods and experimental paradigms used to test them. The nine types of interventions covered are accuracy prompts, debunking and rebuttals, friction, inoculation, lateral reading and verification strategies, media-literacy tips, social norms, source-credibility labels, and warning and fact-checking labels.
Subject(s)
Communication , Humans , Social Media , Deception , Social NormsABSTRACT
This study aims to understand the influence of mirth, anger, and hope, as elicited by messages with different humor types, on support for global warming action, and the potential moderating role of individual climate concern. Although mirth did not significantly vary across the different stimuli, the analysis found that climate concern moderated the influence of hope on support for global warming actions. The implications of these findings, especially for respondents who were least supportive of actions to combat global warming, are discussed.
Subject(s)
Climate Change , Global Warming , ClimateABSTRACT
Misinformation can decrease public confidence in vaccines, and reduce vaccination intent and uptake. One strategy for countering these negative impacts comes from inoculation theory. Similar to biological vaccination, inoculation theory posits that exposure to a weakened form of misinformation can develop cognitive immunity, reducing the likelihood of being misled. Online games offer an interactive, technology-driven, and scalable solution using an active form of inoculation that engages and incentivizes players to build resilience against misinformation. We document the development of the critical thinking game Cranky Uncle Vaccine. The game applies research findings from inoculation theory, critical thinking, humor in science communication, and serious games. The game content was iterated through a series of co-design workshops in Kampala (Uganda), Kitale (Kenya), and Kigali (Rwanda). Workshop participants offered feedback on cartoon character design, gameplay experience, and the game's content, helping to make the game more culturally relevant and avoid unintended consequences in East African countries. Our co-design methodology offers an approach for further adaptation of the Cranky Uncle Vaccine game to other regions, as well as a template for developing locally relevant interventions to counter future infodemics.
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Communication , Vaccines , Humans , Kenya , Uganda , RwandaABSTRACT
The 2017 March for Science was an international march organized in response to concerns over the Trump administration's misuse of science that drew unprecedented numbers of supporters as well as attention from the media, celebrities, and political figures. The March's turnout and publicity begs the question: what motivates people to defend science? Using data from a survey of March for Science listserv members in the US, we used a structural equation model to test posited relationships between self- and collective response efficacy, perceived threat, anger, fear, and the intention to engage in advocacy to defend science. We found that each of these constructs were associated with the intention to engage in advocacy, illuminating the motivators that lead to this intention and how individuals may be activated to engage on behalf of science in the future. These insights have both theoretical and practical significance, as advocacy is integral for both supporting and advancing fact-based policy- and decision-making.
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Anger , Fear , Humans , Surveys and Questionnaires , PolicyABSTRACT
Democracy relies on a shared body of knowledge among citizens, for example trust in elections and reliable knowledge to inform policy-relevant debate. We review the evidence for widespread disinformation campaigns that are undermining this shared knowledge. We establish a common pattern by which science and scientists are discredited and how the most recent frontier in those attacks involves researchers in misinformation itself. We list several ways in which psychology can contribute to countermeasures.
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Communication , Democracy , Humans , PoliticsABSTRACT
Identifying cows that are at greater risk for disease prior to calving would be a valuable addition to transition management. Prior to the commercial release of software features in an automated behavioral monitoring system, designed to identify cows in the dry period at greater risk of disease postpartum, a retrospective analysis was carried out in five dairy herds to evaluate whether the software could identify prepartum cows that subsequently received health treatments postpartum and whether prepartum alerts (transition alerts) are associated with a reduction in milk production in the subsequent lactation. Herd management and production records were analyzed for cows receiving treatment in the first 21 d of lactation (days in milk, DIM) for clinical mastitis, reproductive tract disease (metritis, retained fetal membranes), metabolic disease (hypocalcemia, ketosis and displaced abomasum) and for cows exiting the herd by 60 DIM. Data was gathered for 986 cows, 382 (38.7%) of which received a transition alert and 604 (61.3%) that did not. During the first 21 DIM 312 (31.6%) cows went on to receive a disease treatment, of these 51.9% (n = 162/312) were transition alert cows and 48.1% (n = 150/312) non-transition alert cows, while 8.6% (n = 33/382) alert cows exited the herd by 60 DIM compared to 4.8% (n = 29/604) of cows that did not receive an alert. A cow receiving a transition alert (OR = 1.76, 95% confidence interval (CI) = 1.27-2.44) and increasing parity (OR = 2.03, 95% CI = 1.44-2.86) were both associated with increased risk of receiving a disease treatment in the first 21 DIM. The occurrence of a transition alert was negatively associated with both week 4 milk yield (daily average yield in fourth week of lactation) and predicted 305 d yield. Transition alerts correctly predicted 62.5% (95% CI: 59.3-65.5) of treatments with a sensitivity of 42.4% (95% CI: 37.4-45.5) and a specificity of 75.2% (95% CI: 71.5-78.6). Associations were identified between postpartum health and production outcomes and prepartum behavioral measures from an automated activity monitoring system.
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BACKGROUND: Food insecurity (FI) prevalence was consistently >10% over the past 20 years, indicating chronic economic hardship. Recession periods exacerbate already high prevalence of FI, reflecting acute economic hardship. To monitor FI and respond quickly to changes in prevalence, an abbreviated food security scale measuring presence and severity of household FI in adults and children is needed. OBJECTIVE: Our aim was to develop an abbreviated, sensitive, specific, and valid food security scale to identify severity levels of FI in households with children. DESIGN: Cross-sectional and longitudinal survey data were analyzed for years 1998 to 2022. PARTICIPANTS/SETTING: Participants were racially diverse primary caregivers of 69,040 index children younger than 4 years accessing health care in 5 US cities. STATISTICAL ANALYSES PERFORMED: Sensitivity, specificity, positive and negative predictive values, accuracy, and area under the receiver operator curve were used to test combinations of questions for the most effective abbreviated scale to assess levels of severity of adult and child FI compared with the Household Food Security Survey Module. Adjusted logistic regression models assessed convergent validity between the Abbreviated Child and Adult Food Security Scale (ACAFSS) and health measures. McNemar tests examined the ACAFSS performance in times of acute economic hardship. RESULTS: The ACAFSS exhibited 91.2% sensitivity; 99.6% specificity; 98.3% and 97.6% positive and negative predictive values, respectively; 97.7% accuracy; and a 99.6% area under the receiver operator curve, while showing high convergent validity. CONCLUSIONS: The ACAFSS is highly sensitive, specific, and valid for detecting severity levels of FI among racially diverse households with children. The ACAFSS is recommended as a stand-alone scale or a follow-up scale after households with children screen positive for FI risk. The ACAFSS is also recommended for planning interventions and evaluating their effects not only on the binary categories of food security and FI, but also on changes in levels of severity, especially when rapid decision making is crucial.
Subject(s)
Poverty , United States , Humans , Adult , Child , Cross-Sectional Studies , Cities , Logistic ModelsABSTRACT
BACKGROUND: The aim of this study was to investigate the risk factors for and the impact of ultrasound-diagnosed endometritis (UDE) on lactating dairy cows' reproductive performance. METHODS: Data were analysed from 1123 Holstein and Holstein-Friesian cows from two Scottish dairy farms. A reproductive ultrasound examination was conducted on two occasions, at 43 ± 3 and 50 ± 3 days in milk (DIM), to screen for hyperechoic fluid in the uterus. Statistical analyses were performed using multivariable logistic regression modelling and Cox proportional hazards models. RESULTS: The overall incidence of UDE was 8.8% (99/1123). Risk factors for UDE included calving during autumn/winter seasons, increased parity and the presence of two or more diseases in the first 50 ± 3 days postpartum. The presence of UDE was associated with a reduced odds of pregnancy after all artificial inseminations up to 150 DIM. LIMITATIONS: The retrospective design of this study led to some inherent limitations with the quality and quantity of data collected. CONCLUSIONS: The findings of this study indicate which risk factors should be monitored in postpartum dairy cows to limit the impact of UDE on future reproductive performance.
Subject(s)
Cattle Diseases , Endometritis , Pregnancy , Female , Cattle , Animals , Lactation , Endometritis/diagnostic imaging , Endometritis/epidemiology , Endometritis/veterinary , Retrospective Studies , Reproduction , Fertility , Postpartum Period , Milk , Risk Factors , Scotland/epidemiology , Cattle Diseases/diagnostic imaging , Cattle Diseases/epidemiologyABSTRACT
Coagulopathy can occur in trauma, and it can affect septic patients as a host tries to respond to infection. Sometimes, it can lead to disseminated intravascular coagulopathy (DIC) with a high potential for mortality. New research has delineated risk factors that include neutrophil extracellular traps and endothelial glycocalyx shedding. Managing DIC in septic patients focuses on first treating the underlying cause of sepsis. Further, the International Society on Thrombolysis and Haemostasis (ISTH) has DIC diagnostic criteria. "Sepsis-induced coagulopathy" (SIC) is a new category. Therapy of SIC focuses on treating the underlying infection and the ensuing coagulopathy. Most therapeutic approaches to SIC have focused on anticoagulant therapy. This review will discuss SIC and DIC and how they are relevant to prolonged casualty care (PCC).
Subject(s)
Disseminated Intravascular Coagulation , Sepsis , Humans , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/therapy , Sepsis/complications , Sepsis/diagnosis , Sepsis/therapyABSTRACT
INTRODUCTION: Low- and middle-income countries (LMICs) are committed to achieving the Sustainable Development Goal 3.1 to reduce maternal mortality. The Ministry of Health and Family Welfare of India recommends prophylactic uterotonic administration to every woman following delivery to reduce the risk of postpartum hemorrhage (PPH), as PPH is the leading cause of maternal mortality in LMICs, including India. In 2018, the World Health Organization first recognized heat-stable carbetocin for PPH prevention. Governments are now considering its introduction into their public health systems. METHODS: A decision-tree model was developed from the public healthcare system perspective to compare the value of heat-stable carbetocin versus oxytocin and misoprostol among women giving birth in public sector healthcare facilities in India. The model accounted for differences in PPH risk and costs based on mode of delivery and healthcare setting, as well as provider behavior to mitigate quality concerns of oxytocin. Model outcomes for each prophylactic uterotonic included the number of PPH events, DALYs due to PPH, deaths due to PPH, and direct medical care costs. The budget impact was estimated based on projected uterotonic uptake between 2022-2026. RESULTS: Compared to oxytocin, heat-stable carbetocin avoided 5,468 additional PPH events, 5 deaths, and 244 DALYs per 100,000 births. Projected direct medical costs to the public healthcare system were lowered by US $171,700 (â¹12.8 million; exchange rate of â¹74.65 = US$1 from 2 Feb 2022) per 100,000 births. Benefits were even greater when compared to misoprostol (7,032 fewer PPH events, 10 fewer deaths, 470 fewer DALYs, and $230,248 saved per 100,000 births). In the budget impact analysis, India's public health system is projected to save US$11.4 million (â¹849 million) over the next five years if the market share for heat-stable carbetocin grows to 19% of prophylactic uterotonics administered. CONCLUSIONS: Heat-stable carbetocin is expected to reduce the number of PPH events and deaths, avoid more DALYs, and reduce costs to the public healthcare system of India. Greater adoption of heat-stable carbetocin for the prevention of PPH could advance India's efforts to achieve its maternal health goals and increase efficiency of its public health spending.
Subject(s)
Misoprostol , Oxytocics , Postpartum Hemorrhage , Pregnancy , Female , Humans , Oxytocin/therapeutic use , Postpartum Hemorrhage/prevention & control , Misoprostol/therapeutic use , Oxytocics/therapeutic use , Cost-Benefit Analysis , Hot Temperature , India/epidemiologyABSTRACT
The glutamatergic system is the primary excitatory pathway within the CNS and is responsible for cognition, memory, learning, emotion, and mood. Because of its significant importance in widespread nervous system function, it is tightly regulated through multiple mechanisms, such as glutamate recycling, microglial interactions, and inflammatory pathways. Imbalance within the glutamatergic system has been implicated in a wide range of pathological conditions including neurodegenerative conditions, neuromuscular conditions, and mood disorders including depression. Major depressive disorder (MDD) is the most common mood disorder worldwide, has a high prevalence rate, and afflicts approximately 280 million people. While there are numerous treatments for the disease, 30-40% of patients are unresponsive to treatment and deemed treatment resistant; approximately another third experience only partial improvement (World Health Organization, Depression fact sheet [Internet], 2020). Esketamine, the S-enantiomer of ketamine, was approved by the Food and Drug Administration for treatment-resistant depression (TRD) in 2019 and has offered new hope to patients. It is the first treatment targeting the glutamatergic system through a complex mechanism. Numerous studies have implicated imbalance in the glutamatergic system in depression and treatment resistance. Esketamine and ketamine principally work through inhibition of the NMDA receptor, though more recent studies have implicated numerous other mechanisms mediating the antidepressant efficacy of these agents. These mechanisms include increase in brain-derived neurotrophic factor (BDNF), activation of mammalian target of the rapamycin complex (mTORC), and reduction in inflammation. Esketamine and ketamine have been shown to decrease inflammation in numerous ways principally through reducing pro-inflammatory cytokines (e.g., TNF-α, IL-6) (Loix et al., Acta Anaesthesiol Belg 62(1):47-58, 2011; Chen et al., Psychiatry Res 269:207-11, 2018; Kopra et al., J Psychopharmacol 35(8):934-45, 2021). This anti-inflammatory effect has also been shown to be involved in the antidepressive properties of both ketamine and esketamine (Chen et al., Psychiatry Res 269:207-11, 2018; Kopra et al., J Psychopharmacol 35(8):934-45, 2021).
Subject(s)
Depressive Disorder, Major , Ketamine , Humans , Ketamine/therapeutic use , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/chemically induced , Depression/drug therapy , Antidepressive Agents/therapeutic use , Inflammation/drug therapy , Inflammation/chemically inducedABSTRACT
INTRODUCTION: A new dosing schedule for the oncology immunotherapy pembrolizumab, every 6 weeks (Q6W), has been approved by the U.S. FDA, reducing the frequency of visits to infusion centers. We quantified the time spent by oncologists, nurses, patients, and caregivers per melanoma-related immunotherapy infusion visit to evaluate its potential impact. METHODS: Surveys were self-completed by 100 oncologists, 101 oncology nurses, and 100 patients with melanoma across the U.S. to quantify the time spent per infusion visit with pembrolizumab (Q3W or Q6W), nivolumab (Q2W or Q4W), or nivolumab+ipilimumab (nivolumab in combination: Q3W; nivolumab maintenance: Q2W or Q4W). Time measures included traveling, waiting, consultation, infusion, post-treatment observation, and caregiving. Respondents were also surveyed regarding the impact of the COVID-19 pandemic on infusion treatments. RESULTS: Responses deemed valid were provided by 89 oncologists, 93 nurses, and 100 patients. For each new [returning] patient treated with pembrolizumab, nivolumab or nivolumab+ipilimumab, oncologists reported to spend an average of 90 [64], 87 [60] and 101 [69] minutes per infusion visit (p-value for between-group difference = 0.300 [0.627]). For first [subsequent] treatment cycles, nurses reported spending 160 [145] average minutes per visit for nivolumab+ipilimumab, versus roughly 120 [110] for the single agents (p-value for between-group difference = 0.018 [0.022]). Patients reported to spend an average of 263, 382, and 224 minutes per visit at the center for pembrolizumab (N = 47), nivolumab (n = 34), and nivolumab+ipilimumab (n = 15) respectively (p-value for between-group difference = 0.0002). Patients also reported that their unpaid (N = 20) and paid caregivers (N = 41) spent with them an average of 966 and 333 minutes, respectively, from the day before to the day after the infusion visit. CONCLUSION: Less frequent immunotherapy infusion visits may result in substantial time savings for oncologists, nurses, patients, and caregivers.
Subject(s)
COVID-19 , Melanoma , Humans , United States , Nivolumab/therapeutic use , Ipilimumab/therapeutic use , Pandemics , Melanoma/drug therapy , Immunotherapy , Health Personnel , Antineoplastic Combined Chemotherapy ProtocolsABSTRACT
BACKGROUND: The risk of spinal cord ischemia (SCI) with aortic aneurysm repair can cause significant neurological morbidity. Prevention of SCI is critical. We sought to identify risk factors that predispose to SCI that may guide strategies to mitigate the occurrence of SCI during and following these procedures. METHODS: This study includes all adults who underwent atraumatic, unruptured, thoracic, and suprarenal aortic aneurysm repairs (endovascular or open) at our institution over 11 years (2010-2020). Our database included patient demographics, aneurysm anatomic features, and operative characteristics and an extreme gradient boost (XGB) machine method was used to develop a predictive model for SCI. The model was trained on an 80% randomly stratified cohort of the data and tested on the remaining 20% testing cohort. Shapley values were used to determine the most important predictive factors of SCI and decision trees were used to identify risk factor threshold values and highest risk factor combinations. RESULTS: Information was collected for 174 adult patients undergoing thoracic and suprarenal aortic repair from 2010 to 2020. Fifty eight percent of the patients were male. Ninety seven (55.7%) patients had open aortic repair and 87 (44.3%) had endovascular repair. Twenty seven (15%) of all patients had major complications and were considered to have SCI. The XGB model converged over the training cohort with a testing cohort accuracy of 0.841 [Sensitivity = 75%, Specificity = 68%] and area under the curve of receiver operating characteristic of 0.774. The XGB model identified older age (> 65 years), history of neurologic disease, hyperlipidemia, diabetes, coronary artery disease, heart failure, poor renal function, < 6 months since last aortic repair, chronic anticoagulant use, preoperational anemia (Hemoglobin < 9), thrombocytopenia (platelet < 90,000), coagulopathy (prothrombin time > 15s and activated partial thromboplastin time > 40s), hypotension (mean arterial pressure < 70 mm Hg), longer operations (> 100 min), aneurysms longer than 5 cm, and anatomic location of aneurysm caudal to T-11 as risk factors for SCI in all types of aortic repair. Diabetic and heart failure patients undergoing longer operations (> 100 min) with thrombocytopenia or aneurysms longer than 5 cm were at the highest risk. CONCLUSIONS: The XGB model accurately identified risk factors of SCI with aortic aneurysm repair that may guide patient selection, timing of surgery, and strategies to minimize the risk of SCI.
Subject(s)
Aortic Aneurysm, Thoracic , Aortic Aneurysm , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Spinal Cord Ischemia , Thrombocytopenia , Adult , Humans , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/etiology , Aortic Aneurysm, Thoracic/surgery , Blood Vessel Prosthesis Implantation/adverse effects , Retrospective Studies , Endovascular Procedures/adverse effects , Treatment Outcome , Risk Factors , Aortic Aneurysm/diagnostic imaging , Aortic Aneurysm/etiology , Aortic Aneurysm/surgery , Spinal Cord Ischemia/diagnosis , Spinal Cord Ischemia/etiology , Spinal Cord Ischemia/prevention & control , Aorta, Abdominal/surgery , Thrombocytopenia/etiologyABSTRACT
Non-lethal doses of ionizing radiation (IR) delivered to humans because of terrorist events, nuclear accidents or radiotherapy can result in carcinogenesis. Means of protecting against carcinogenesis are lacking. We questioned the role of the gut microbiome in IR-induced carcinogenesis. The gut microbiome was modulated by administering broad spectrum antibiotics (Ab) in the drinking water. Mice were given Ab 3 weeks before and 3 weeks after 3 Gy total body irradiation (TBI) or for 6 weeks one month after TBI. Three weeks of Ab treatment resulted in a 98% reduction in total 16S rRNA counts for 4 out of 6 of the phylum groups detected. However, 3 more weeks of Ab treatment (6 weeks total) saw an expansion in the phylum groups Proteobacteria and Actinobacteria. The Ab treatment altered the bacteria diversity in the gut, and shortened the lifespan when Ab were administered before and after TBI. Mortality studies indicated that the adverse Ab lifespan effects were due to a decrease in the time in which solid tumors started to appear and not to any changes in hematopoietic or benign tumors. In contrast, when Ab were administered one month after TBI, lifespan was unchanged compared to the control TBI group. Use of broad-spectrum antibiotics to simulate the germ-free condition did not afford an advantage on carcinogenesis or lifespan.
Subject(s)
Gastrointestinal Microbiome , Humans , Mice , Animals , RNA, Ribosomal, 16S/genetics , Carcinogenesis , Whole-Body Irradiation/adverse effects , Anti-Bacterial Agents/pharmacologyABSTRACT
INTRODUCTION: After over 20 years of war in the Middle East, orthopedic injuries have been among the most prevalent combat-related injuries, accounting for 14% of all surgical procedures at Role 2/3 (R2/R3) facilities according to the DoD Trauma Registry. To further delineate the role of the deployed orthopedic surgeon on the modern battlefield, a retrospective review was performed highlighting both quantitative and qualitative analysis factors associated with orthopedic surgical care during the war in the Middle East. METHODS: A retrospective review was conducted of orthopedic surgeons in the Middle East from 2001 to 2021. A comprehensive literature search was conducted using the PubMed and Embase databases using a two-reviewer strategy. Articles were compiled and reviewed using Covidence. Inclusion criteria included journal articles focusing on orthopedic injuries sustained during the Global War on Terror (GWoT) in an adult U.S. Military population. In the event of a conflict, a third author would determine the relevance of the article. For the remaining articles, a full-text review was conducted to extract relevant predetermined quantitative data, and the Delphi consensus method was then utilized to highlight relevant qualitative themes. RESULTS: The initial search yielded 1,226 potentially relevant articles. In all, 40 studies ultimately met the eligibility criteria. With the consultation of previously deployed orthopedic surgeons at the Walter Reed National Military Medical Center, a retrospective thematic analysis of the 40 studies revealed five themes encompassing the orthopedic surgeons experience throughout GWoT. These themes include unique mechanisms of orthopedic injury compared to previous war injuries due to novel weaponry, differences in interventions depending on R2 versus R3 locations, differences in injuries from those seen in civilian settings, the maintained emphasis on humanitarian aspect of an orthopedic surgeon's mission, and lastly relation of pre-deployment training to perceived deployed success of the orthopedic surgeons. From this extensive review, we found that explosive mechanisms of injury were greatly increased when compared to previous conflicts and were the etiology for the majority of orthopedic injuries sustained. With the increase of complex explosive injuries in the setting of improved body armor and overall survival, R2/3 facilities showed an increased demand for orthopedic intervention including debridement, amputations, and external fixation. Combat injuries sustained during the GWoT differ in the complications, management, and complexity when compared to civilian trauma. "Humanitarian" cases made up a significant number of operative cases for the deployed orthopedic surgeon. Lastly, heterogeneous training opportunities were available prior to deployment (fellowship, combat extremity surgical courses, and dedicated pre-deployment training), and the most commonly identified useful training was learning additional soft-tissue coverage techniques. CONCLUSION: These major themes indicate an emphasis on pre-deployment training and the strategic positioning of orthopedic surgeons to reflect the changing landscape of musculoskeletal trauma care. Moving forward, these authors recommend analyzing the comfort and perceived capability of orthopedic surgeons in these unique military environments to best prepare for a changing operational format and the possibility of future peer-peer conflicts that will likely lead to a lack of medical evacuation and prolonged field care.