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Spinal cord injury remains a major cause of disability in young adults, and beyond acute decompression and rehabilitation, there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population. Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation, a similar role for complement in spinal neuroinflammation is a focus of ongoing research. In this work, we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins, triggers of complement activation, and role of effector functions in the pathology. We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris, and or activation via antibody binding to damage-associated molecular patterns. Several effector functions of complement have been implicated in spinal cord injury, and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury. Following this pathophysiological review, we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects. This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury, to evaluate the phases of involvement of opsonins and anaphylatoxins, and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.
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Chemical pollutants and/or climate change have the potential to break down reproductive barriers between species and facilitate hybridization. Hybrid zones may arise in response to environmental gradients and secondary contact between formerly allopatric populations, or due to the introduction of non-native species. In freshwater ecosystems, field observations indicate that changes in water quality and chemistry, due to pollution and climate change, are correlated with an increased frequency of hybridization. Physical and chemical disturbances of water quality can alter the sensory environment, thereby affecting chemical and visual communication among fish. Moreover, multiple chemical compounds (e.g. pharmaceuticals, metals, pesticides, and industrial contaminants) may impair fish physiology, potentially affecting phenotypic traits relevant for mate selection (e.g. pheromone production, courtship, and coloration). Although warming waters have led to documented range shifts, and chemical pollution is ubiquitous in freshwater ecosystems, few studies have tested hypotheses about how these stressors may facilitate hybridization and what this means for biodiversity and species conservation. Through a systematic literature review across disciplines (i.e. ecotoxicology and evolutionary biology), we evaluate the biological interactions, toxic mechanisms, and roles of physical and chemical environmental stressors (i.e. chemical pollution and climate change) in disrupting mate preferences and inducing interspecific hybridization in freshwater fish. Our study indicates that climate change-driven changes in water quality and chemical pollution may impact visual and chemical communication crucial for mate choice and thus could facilitate hybridization among fishes in freshwater ecosystems. To inform future studies and conservation management, we emphasize the importance of further research to identify the chemical and physical stressors affecting mate choice, understand the mechanisms behind these interactions, determine the concentrations at which they occur, and assess their impact on individuals, populations, species, and biological diversity in the Anthropocene.
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OBJECTIVE: Chronic pain is known to be an important construct in clinical practice and a particular form of chronic pain, high-impact chronic pain (HICP), has gained recent interest and attention by pain clinicians, epidemiologists, and clinical researchers. The purpose of our Topical Review is to describe the historical development of measures of HICP and to explore the psychometric properties of HICP as well as to present alternative measurement methods. METHODS: We identified strengths and weaknesses of the psychometric characteristics of HICP measures. Limitations of existing HICP measures were discussed and summarized and alternatives to current methods were proposed. RESULTS: HICP operational definitions show variability across studies. All definitions cannot be correct, but which ones are incorrect cannot be determined as there is no gold standard. Random measurement error and recall bias are among the other limitations of current HICP measures. Model-based definitions of HICP, the discrete (for epidemiologic applications) and continuous (for clinical applications) latent variable models are discussed as likely superior alternatives to current methods. CONCLUSIONS: Limitations of existing HICP methods are discussed and alternative development approaches to HICP measures are presented. The use of either discrete or continuous latent variable models would improve upon the psychometric characteristics of current HICP evidence. Examples are used to illustrate the benefits of latent variable models over traditional observed variable conceptualizations as the measurement of HICP continues to develop. SIGNIFICANCE STATEMENT: This work takes the position that current methods of measuring high impact chronic pain (HICP) likely contain substantial error. We have endorsed an alternative approach for several psychometrically grounded reasons. We recommend that future work consider the discrete latent variable framework for dichotomous measures of HICP and the continuous latent variable framework for continuous measures of HICP. The paper provides illustrative examples of these methods for a different patient reported measure that is lacking a gold standard, much like HICP measures.
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Aim: This study evaluated associations between CYP3A4*22 and variants in other pharmacogenes (CYP3A5, SULT2A1, ABCB1, ABCG2, ERCC1) and the risk for palbociclib-associated toxicities. Materials & methods: Two hundred cancer patients who received standard-of-care palbociclib were genotyped and associations with toxicity were evaluated retrospectively. Results: No significant associations were found for CYP3A4*22, CYP3A5*3, ABCB1_rs1045642, ABCG2_rs2231142, ERCC1_rs3212986 and ERCC1_rs11615. Homozygous variant carriers of SULT2A1_rs182420 had higher incidence of dose modifications due to palbociclib toxicity (odds ratio [OR]: 4.334, 95% CI: 1.057-17.767, p = 0.042). ABCG2_rs2231137 variant carriers had borderline higher incidence of grade 3-4 neutropenia (OR: 4.14, 95% CI: 0.99-17.37, p = 0.052). Conclusion: Once validated, SULT2A1 and ABCG2 variants may be useful to individualize palbociclib dosing to minimize toxicities and improve treatment outcomes.
[Box: see text].
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Behavioral nudges in Facebook ads reached nearly 15 million people across six diverse countries and, consequently, many thousands took the step of navigating to governments' vaccine signup sites. However, none of the treatment ads caused significantly more vaccine signup intent than placebo uniformly across all countries. Critically, reporting the descriptive norm that 87% of people worldwide had either been vaccinated or planned vaccination-social proof-did not meaningfully increase vaccine signup intent in any country and significantly backfired in Taiwan. This result contradicts prominent prior findings. A charge to "protect lives in your family" significantly outperformed placebo in Taiwan and Turkey but saw null effects elsewhere. A message noting that vaccination significantly reduces hospitalization risk decreased signup intent in Brazil and had no significant effects in any other country. Such heterogeneity was the hallmark of the study: some messages saw significant treatment effects in some countries but failed in others. No nudge outperformed the placebo in Russia, a location of high vaccine skepticism. In all, widely touted behavioral nudges often failed to promote vaccine signup intent and appear to be moderated by cultural context.
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Many local agencies in the United States and other countries are tasked to install air pollution monitoring systems of highly accurate sensors that have high acquisition, operating, and maintenance costs. The need for expanded coverage of air quality measurements across Salt Lake County (SLCO), Utah is being met by mounting air quality and temperature sensors on an expanding fleet of battery electric buses (BEBs). Monitoring air quality from a mobile sensor network provides real-time insights into air pollution patterns at high temporal and spatial resolution. Mobile measurements contribute to assessing residents' exposure to air pollution, facilitating the implementation of cost-effective public health policies and highlighting disparities. The Electric Bus Air Quality Observation Project was launched in SLCO during July 2021 and has collected millions of observations to date. A BEB traveling at typical traffic speeds (~10â¯mâ¯s-1) can provide multiple measurements along city block lengths of up to ~200â¯m. With careful analysis that factors in the time response of the differing sensors, variability from block-to-block may be attributed to fine-scale factors (e.g., pollution and heat sources, tree shading and urban vegetation, etc.). Preliminary findings showcase the value of increased coverage and resolution. During an extreme heat event in July 2023, both the morning and afternoon temperature readings showed differences of over 6.5⯰C (12⯰F), primarily as an east-west gradient with similar gradients in ozone. We conclude that temperature and pollutant concentration readings, at fine spatial and temporal resolutions, will facilitate future health studies and equitable policy and mitigation strategies. Our study demonstrates that our partnerships established with governmental, non-profit, and transit agencies facilitate the successful transfer of research and development to operational real-time mobile air quality monitoring.
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Background: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit. Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events. Results: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%). Conclusions: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.
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In the last 2 decades, there has been an increase in the geographic range and frequency of vector-borne diseases. Management of mosquito populations has become challenging due to increasing rates of resistance to existing insecticidal products and formulations. Several alternative tools have emerged to suppress or replace mosquito populations. One of these tools is the In2Care Mosquito Station (In2Care station). This dual-action station contains the insect growth regulator pyriproxyfen which disrupts the development of immatures and the entomopathogenic fungus Beauveria bassiana (B. bassiana) strain GHA which kills exposed adult mosquitoes. The In2Care stations have previously been shown to effectively control Aedes aegypti in field settings at a density of 6 stations/acre rather than the label-recommended 10 stations/acre. To further test the efficacy of low station density deployment, we deployed In2Care stations in the Pleasant Street Historic District of Gainesville, Florida, at a density of 3 stations/acre over a period of 2 years in the presence or absence of ground larvicidal applications. The deployment of stations resulted in no measurable impact on Ae. aegypti and Culex quinquefasciatus adult or immature abundance suggesting that the low-density deployment of In2Care stations is insufficient to reduce Ae. aegypti and Cu. quinquefasciatus abundance within treatment areas.
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Highly Superior Autobiographical Memory (HSAM) is a rare form of enhanced memory in which individuals demonstrate an extraordinary ability to remember details of their personal lives with high levels of accuracy and vividness. Neuroimaging studies have identified brain regions - specifically, midline areas within the default network - associated with remembering events from one's past. Extending this research on the neural underpinnings of autobiographical memory, the present study utilizes graph theory analyses to compare functional brain connectivity in a cohort of HSAM (n = 12) and control participants (n = 29). We perform seed-based analysis in resting-state fMRI data to assess how specific cortical regions within the autobiographical memory network are differentially connected in HSAM individuals. Additionally, we apply a whole-brain connectivity analysis to identify differences in brain hub-network topology associated with enhanced autobiographical memory. Seed-based results show converging patterns of increased connectivity in HSAM across midline areas. Whole-brain analysis also reveals enhanced connectivity across medial prefrontal and posterior cingulate cortex in HSAM individuals. Together, these results extend prior research, highlighting cortical hubs within the default network associated with enhanced autobiographical memory.
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The heme-based direct oxygen sensor DosP degrades c-di-GMP, a second messenger nearly unique to bacteria. In stationary phase Escherichia coli, DosP is the most abundant c-di-GMP phosphodiesterase. Ligation of O2 to a heme-binding PAS domain (hPAS) of the protein enhances the phosphodiesterase through an allosteric mechanism that has remained elusive. We determined six structures of full-length DosP in its aerobic or anaerobic conformations, with or without c-di-GMP. DosP is an elongated dimer with the regulatory heme and phosphodiesterase separated by nearly 180 Å. In the absence of substrate, regardless of the heme status, DosP presents an equilibrium of two distinct conformations. Binding of substrate induces DosP to adopt a single, ON-state or OFF-state conformation depending on its heme status. Structural and biochemical studies of this multi-domain sensor and its mutants provide insights into signal regulation of second-messenger levels.
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OBJECTIVES: Acinic cell carcinoma (ACC) most frequently arises in the parotid gland. Treatment consists of surgical resection and sometimes adjuvant therapy. ACC is most often a low-grade malignancy with good prognosis. Higher-grade tumors are often treated aggressively with total parotidectomy, neck dissection, and adjuvant therapy; however, the effect of parotid gland resection extent on oncologic outcomes has not been studied. Herein, we examine predictors of oncologic outcomes, including the effect of extent of resection. METHODS: Patients with diagnosis of parotid ACC treated at our institution were included in this retrospective study. Patient factors were examined, and patients were grouped by extent of resection and tumor grade. RESULTS: 58 patients, including 32 low-grade, 7 intermediate-grade, and 14 high-grade were included. Patients with low-grade tumors were more likely to undergo lesser extent of parotidectomy and less likely to undergo neck dissection. Two patients with low grade tumors developed recurrence, one local and one regional. Recurrence rate did not differ with resection extent in low-grade tumors. High tumor grade was found to be associated with disease progression. There was no association with adjuvant treatment and outcomes. Across all tumor grades advanced AJCC stage was found to be associated with disease progression. CONCLUSIONS: In ACC patients with low-grade tumors and lower disease stage who undergo lesser extent of surgical resection oncologic outcomes were favorable. Patients with high-grade tumors carry a high risk of recurrence, despite aggressive treatment. AJCC stage and histopathologic grade may predict outcomes and guide treatment.
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Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings in vivo. Linear modeling of CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes revealed 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo. Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro; autosomal responses to Xi and/or Y dosage were largely cell-type specific (â¼2.6-fold more variation than sex-chromosomal responses). Targets of the sex-chromosomal transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable, yet they modulate autosomal and Xa genes in a cell-type-specific fashion.
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Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport. This disorder is characterized by profound neurodevelopmental delay and motor disability due to a lack of thyroid hormone in the brain, and coexisting endocrinological symptoms, due to chronic thyrotoxicosis, resulting from elevated thyroid hormone outside the central nervous system (CNS). In February 2024, we reviewed the published literature to identify relevant articles reporting on the current unmet needs of patients with MCT8 deficiency. There are several main challenges in the diagnosis and treatment of MCT8 deficiency, with decreased awareness and recognition of MCT8 deficiency among healthcare professionals (HCPs) associated with misdiagnosis and delays in diagnosis. Diagnostic delay may also be attributed to other factors, including the complex symptomology of MCT8 deficiency only becoming apparent several months after birth and pathognomonic serum triiodothyronine (T3) testing not being routinely performed. For patients with MCT8 deficiency, multidisciplinary team care is vital to optimize the support provided to patients and their caregivers. Although there are currently no approved treatments specifically for MCT8 deficiency, earlier identification and diagnosis of this disorder enables earlier access to supportive care and developing treatments focused on improving outcomes and quality of life for both patients and caregivers.
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Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGF from CAFs directly enhances CRC cell growth via the PI3K/AKT pathway. Treatment with a tropomyosin receptor kinase (Trk) inhibitor decreased YAP and AKT activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk inhibitor may represent a potential therapeutic approach for CRC.
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INTRODUCTION: Reserve Officers' Training Corps (ROTC) trainees are college students who complete military courses and participate in physical and tactical training under the direction of military Service Members assigned to ROTC programs to serve as faculty and staff at US colleges. ROTC trainees report musculoskeletal injuries (MSKIs) attributable to ROTC training in line with MSKI incidence in other training environments. However, concealment is prevalent, as 66% of MSKIs in ROTC go unreported. The current study investigated if a brief, online educational video could increase ROTC trainees' reporting intentions. In addition, we investigated if the message's source (i.e., peer or authority figure) affected reporting intentions. MATERIALS AND METHODS: A repeated measures design was used to evaluate the impact of 2 MSKI educational interventions, one delivered by a high-achieving Army ROTC trainee (peer-led) and the other delivered by an Army ROTC battalion commander (authority-led), on MSKI reporting intentions, as compared to each other and a control intervention. Other than their personal introductions, both individuals had the same script addressing 4 areas: (1) MSKI prevalence in ROTC, (2) evidence of improved outcomes with early treatment, (3) encouraging injury reporting, and (4) addressing specific barriers and stigma beliefs previously identified in ROTC. The control condition consisted of a video demonstrating exercise technique with voiceover. A survey was developed to measure stigma regarding MSKI reporting and intentions to seek help for MSKI. ROTC trainees at 23 universities were invited to participate via an anonymous survey link. Participants completed the following using an online survey platform: (1) pre-intervention MSKI intentions scale, (2) randomly assigned intervention video, and (3) repeat MSKI intentions scale post-intervention. A two-way mixed, ANOVA was performed to assess interaction effects and main effects pre- and post-intervention. RESULTS: One-hundred ROTC trainees (39% female; age = 21 ± 2 years, ROTC experience = 2 ± 1 years) completed the study. Participants were primarily from Army ROTC programs (72 Army, 14 Air Force, and 14 Naval). Pre-intervention survey scores (possible score range 8-56 with lower scores indicating greater intention to seek help): authority-led (n = 31) 20.3 ± 9.4, peer-led (n = 32) 21.8 ± 8.7, control (n = 37) 19.1 ± 10.1, total 20.3 ± 9.4. Post-intervention scores: authority-led 20.9 ± 11.2, peer-led 20.2 ± 10.0, control 17.3 ± 7.7, total 19.7 ± 9.3. There was no significant group*time interaction (F2,97 = 0.92, P = .403, η2partial = 0.02). There were no significant main effects for time (F1,97 = 1.461, P = .230, η2partial =0.015) or group (F2,97 = 1.08, P = .342, η2partial = 0.02). CONCLUSIONS: Findings did not support the use of a single educational intervention video to influence MSKI help-seeking intentions of ROTC trainees. Intentions may already be ingrained such that a single intervention could not influence change. Previous research on concussion reporting indicates that concealment cultures may be systematic and indoctrination of concealment can influence one's reporting intentions. Our sample had already participated in ROTC for 2 years. Future research should evaluate if MSKI help-seeking intentions change over the course of ROTC participation, or even over a military career.
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Intenção , Militares , Humanos , Masculino , Feminino , Militares/psicologia , Militares/estatística & dados numéricos , Grupo Associado , Inquéritos e Questionários , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Adulto , Adulto Jovem , Gravação em Vídeo/métodos , Doenças Musculoesqueléticas/psicologia , Doenças Musculoesqueléticas/terapia , Sistema Musculoesquelético/lesões , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/psicologiaRESUMO
Chronic low back disorders are the leading cause of direct and indirect healthcare burden globally. Exercise training improves pain intensity, mental health and physical function. However, the optimal prescription variables are unknown. We aim to compare the efficacy of various exercise dosages for chronic low back disorders to identify the optimal prescription variables. Six databases (Medline, SPORTDiscus, CINAHL, PsycINFO, EMBASE and CENTRAL), trial registries (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) and reference lists of prior systematic reviews will be searched, and we will conduct forward and backward citation tracking. We will include peer-reviewed randomised controlled trials (individual, cluster or cross-over trials) published in English or German language comparing exercise training to other exercise training or non-exercise training interventions (conservative, non-surgical, non-pharmacological, non-invasive treatments, placebo, sham, usual/standard care, no-treatment control, waitlist control) in adults with chronic low back disorders. Outcomes will include pain intensity, disability, mental health, adverse events, adherence rate, dropout rate and work capacity. Version 2 of the Cochrane risk-of-bias tool will be employed. The dose will be categorised as cumulative dose (total and weekly minutes of exercise training) and individual dose prescription variables (intervention duration, session duration, frequency and intensity). Dose-response model-based network meta-analysis will be used to assess the comparative efficacy of different exercise doses to determine a dose-response relationship. The certainty of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation. Information about optimal exercise training dosage will help in enhancing treatment outcomes.
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Humans have the remarkable cognitive capacity to rapidly adapt to changing environments. Central to this capacity is the ability to form high-level, abstract representations that take advantage of regularities in the world to support generalization1. However, little is known about how these representations are encoded in populations of neurons, how they emerge through learning and how they relate to behaviour2,3. Here we characterized the representational geometry of populations of neurons (single units) recorded in the hippocampus, amygdala, medial frontal cortex and ventral temporal cortex of neurosurgical patients performing an inferential reasoning task. We found that only the neural representations formed in the hippocampus simultaneously encode several task variables in an abstract, or disentangled, format. This representational geometry is uniquely observed after patients learn to perform inference, and consists of disentangled directly observable and discovered latent task variables. Learning to perform inference by trial and error or through verbal instructions led to the formation of hippocampal representations with similar geometric properties. The observed relation between representational format and inference behaviour suggests that abstract and disentangled representational geometries are important for complex cognition.
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Biological soil amendments of animal origin (BSAAO) play an important role in agriculture but can introduce pathogens into soils. Pathogen survival in soil is widely studied, but data are needed on the impacts of strain variability and field management practices. This study monitored the population of 12 Escherichia coli strains (generic, O157, and non-O157) in soils while evaluating the interactions of soil type, irrigation regimen, and soil amendment in three independent, greenhouse-based, randomized complete block design trials. Each E. coli strain (4-5log10 CFU/g) was homogenized in bovine manure amended or non-amended sandy-loam or clay-loam soil. E. coli was enumerated in 25 g samples on 0, 0.167 (4 h), 1, 2, 4, 7, 10, 14, 21, 28, 56, 84, 112, 168, 210, 252, and 336 days post-inoculation (dpi). Regression analyses were developed to understand the impact of strain, soil type, irrigation regimen, and soil amendment on inactivation rates. E. coli survived for 112 to 336 dpi depending on the treatment combination. Pathogenic and generic E. coli survived 46 days [95% Confidence interval (CI)=20.85, 64.72; p=0.001] longer in soils irrigated weekly compared to daily and 146 days (CI=114.50, 184.50; p<0.001) longer in amended soils compared to unamended soils. Pathogenic E. coli strains were non-detectable 69 days (CI=39.58, 98.66, p=0.015) earlier than generic E. coli strains. E. coli inactivation rates demonstrated a tri-phasic pattern, with breakpoints at 26 dpi (CI=22.3, 29.2) and 130 dpi (CI=121.0, 138.1). The study findings demonstrate that using bovine manure as BSAAO in soil enhances E. coli survival, regardless of strain, and adequate food safety practices are needed to reduce the risk of crop contamination. The findings of this study contribute data on E. coli concentrations in amended soils to assist stakeholders and regulators in making risk-based decisions on time intervals between the application of BSAAO and the production and harvest of fruits and vegetables.