A comparative approach for characterizing the relationship among morphology, range-of-motion and locomotor behaviour in the primate shoulder.

Shoulder shape directly impacts forelimb function by contributing to glenohumeral (GH) range-of-motion (ROM). However, identifying traits that contribute most to ROM and visualizing how they do so remains challenging, ultimately limiting our ability to reconstruct function and behaviour in fossil species. To address these limitations, we developed an in silico proximity-driven model to simulate and visualize three-dimensional (3D) GH rotations in living primate species with diverse locomotor profiles, identify those shapes that are most predictive of ROM using geometric morphometrics, and apply subsequent insights to interpret function and behaviour in the fossil hominin Australopithecus sediba. We found that ROM metrics that incorporated 3D rotations best discriminated locomotor groups, and the magnitude of ROM (mobility) was decoupled from the anatomical location of ROM (e.g. high abduction versus low abduction). Morphological traits that enhanced mobility were decoupled from those that enabled overhead positions, and all non-human apes possessed the latter but not necessarily the former. Model simulation in A. sediba predicted high mobility and a ROM centred at lower abduction levels than in living apes but higher than in modern humans. Together these results identify novel form-to-function relationships in the shoulder and enhance visualization tools to reconstruct past function and behaviour.

The susceptibility of disulfide bonds to modification in keratin fibers undergoing tensile stress.

Cysteine residues perform a dual role in mammalian hairs. The majority help stabilize the overall assembly of keratins and their associated proteins, but a proportion of inter-molecular disulfide bonds are assumed to be associated with hair mechanical flexibility. Hair cortical microstructure is hierarchical, with a complex macro-molecular organization resulting in arrays of intermediate filaments at a scale of micrometres. Intermolecular disulfide bonds occur within filaments and between them and the surrounding matrix. Wool fibers provide a good model for studying various contributions of differently situated disulfide bonds to fiber mechanics. Within this context, it is not known if all intermolecular disulfide bonds contribute equally, and, if not, then do the disproportionally involved cysteine residues occur at common locations on proteins? In this study, fibers from Romney sheep were subjected to stretching or to their breaking point under wet or dry conditions to detect, through labeling, disulfide bonds that were broken more often than randomly. We found that some cysteines were labeled more often than randomly and that these vary with fiber water content (water disrupts protein-protein hydrogen bonds). Many of the identified cysteine residues were located close to the terminal ends of keratins (head or tail domains) and keratin-associated proteins. Some cysteines in the head and tail domains of type II keratin K85 were labeled in all experimental conditions. When inter-protein hydrogen bonds were disrupted under wet conditions, disulfide labeling occurred in the head domains of type II keratins, likely affecting keratin-keratin-associated protein interactions, and tail domains of the type I keratins, likely affecting keratin-keratin interactions. In contrast, in dry fibers (containing more protein-protein hydrogen bonding), disulfide labeling was also observed in the central domains of affected keratins. This central "rod" region is associated with keratin-keratin interactions between anti-parallel heterodimers in the tetramer of the intermediate filament.

UV and visible light exposure to hair leads to widespread changes in the hair lipidome.

OBJECTIVE: Scalp hair is among the most exposed parts of the human body, yet the impact of visible and UV light on hair lipids, an important structural component of hair, is poorly researched. We have used lipidomics, a broad-based approach to measure lipids in samples, which has hitherto not been applied to UV-exposed hair in the published literature, and could allow for a wider understanding of how UV light impacts on specific hair lipids. METHODS: Mixed blonde Caucasian hair switches were divided into two groups of five, with half of the hair switches exposed to UV and visible light mimicking normal daytime exposure and half left unexposed. LC-MS lipidomics was used to profile the lipids in the hair samples. RESULTS: A total of 791 lipids and 32 lipid classes with tentative identifications were detected in the hair samples. Nineteen lipid classes and 397 lipids differed between UV-treated and non-treated hair. The main lipid classes that differed were vitamin A fatty acid esters, sterol esters, several ceramides, mono-, di- and triglycerides, phosphatidylethanolamines (all decreased in UV-exposed hair) and bismonoacylglycerolphosphates, acylcarnitines and acylglycines (all increased in UV-exposed hair). Most detected lipids were decreased in UV-exposed hair, supporting earlier work that has found that UV exposure causes oxidation of lipids which would result in a decrease in most lipid classes. CONCLUSION: Light exposure to hair has a widespread impact on the hair lipidome. This study also adds to the emerging literature on the hair lipidome, broadening the range of lipid classes reported in hair.

OBJECTIF: Le cuir chevelu est l'une des parties les plus exposées de l'organisme. Cependant, l'impact de la lumière visible et des UV sur les lipides capillaires, un composant structurel important des cheveux, reste mal étudié. Nous avons utilisé la lipidomique, une approche large pour mesurer les lipides présents dans les échantillons de cheveux, qui n'a jusqu'ici pas été appliquée aux cheveux exposés aux UV dans la littérature publiée. Cette approche pourrait permettre de mieux comprendre l'impact de la lumière UV sur des lipides spécifiques des cheveux. MÉTHODES: Les mèches de cheveux caucasiens blonds mélangés ont été divisées en deux groupes de cinq, la moitié des mèches de cheveux étant exposées aux UV et à une lumière visible imitant l'exposition diurne normale tandis que l'autre moitié est restée non exposée. Le profil lipidique des échantillons de cheveux a été établi grâce à la lipidomique de la LC-MS. RÉSULTATS: Au total, 791 lipides et 32 classes de lipides avec des identifications provisoires ont été détectés dans les échantillons de cheveux. Entre les cheveux traités par UV et les cheveux non traités, dix-neuf classes de lipides et 397 lipides se sont avérés différents. Les principales classes de lipides qui différaient étaient les esters d'acides gras de la vitamine A, les esters de stérols, plusieurs céramides, les monoglycérides, diglycérides et triglycérides, les phosphatidyléthanolamines (tous diminués dans les cheveux exposés aux UV) et les bismonoacylglycérolphosphates, acylcarnitines et acylglycines (tous augmentés dans les cheveux exposés aux UV). La plupart des lipides détectés dans les cheveux exposés aux UV n'étaient présents qu'à taux réduit, soit un résultat cohérent avec une étude antérieure ayant montré que l'exposition aux UV provoque l'oxydation des lipides, ce qui entraînerait une diminution de la plupart des classes de lipides. CONCLUSION: L'exposition des cheveux à la lumière entraîne un impact généralisé sur leur lipidome. Cette étude vient également compléter la littérature émergente sur le lipidome capillaire, élargissant ainsi la gamme de classes lipidiques rapportées dans les cheveux.

Sustaining a nurse-led community partnership to promote environmental justice.

The Westlawn Partnership for a Healthier Environment (WPHE) is a longstanding group of community stakeholders that was formed over a decade ago to identify, prioritize, and address environmental health (EH) concerns in a low-income, predominantly African American, urban neighborhood, which faces a disproportionate burden of EH risks, particularly asthma. Launched by the University of Wisconsin-Milwaukee College of Nursing, which established a nurse-managed health center within the community 30 years ago, WPHE utilized the Protocol of Assessing Community Excellence in Environment Health methodology to develop, implement, and sustain the partnership. WPHE implemented programs for Healthy Homes, Healthy Day Cares, and bicycling, and made system and infrastructure changes within the community to address the top identified EH concerns: indoor and outdoor air pollution, mold exposure, access to safe and healthy food, and pesticide exposure. WPHE's efforts have resulted in significant local, state, and national policy impacts to promote environmental justice. This brief report shares how the partnership was formed, its priorities, major activities and accomplishments, and insights into sustaining a community-based EH partnership, including recommendations for the key role that public health nurses can play to promote environmental justice.

Mapping the accessibility of the disulfide crosslink network in the wool fiber cortex.

The disulfide bond network within the cortex of mammalian hair has a critical influence on the physical and mechanical characteristics of the fiber. The location, pattern, and accessibility of free and crosslinked cysteines underpin the properties of this network, but have been very difficult to map and understand, because traditional protein extraction techniques require the disruption of these disulfide bonds. Cysteine accessibility in both trichocyte keratins and keratin associated proteins (KAPs) of wool was investigated using staged labeling, where reductants and chaotropic agents were used to expose cysteines in a stepwise fashion according to their accessibility. Cysteines thus exposed were labeled with distinguishable alkylation agents. Proteomic profiling was used to map peptide modifications and thereby explore the role of KAPs in crosslinking keratins. Labeled cysteines from KAPs were detected when wool was extracted with reductant only. Among them were sequences from the end domains of KAPs, indicating that those cysteines were easily accessible in the fiber and could be involved in forming interdisulfide linkages with keratins or with other KAPs. Some of the identified peptides were from the rod domains of Types I and II keratins, with their cysteines positioned on the exposed surface of the α-helix. Peptides were also identified from keratin head and tail domains, demonstrating that they are not buried within the filament structure and, hence, have a possible role in forming disulfide linkages. From this study, a deeper understanding of the accessibility and potential reactivity of cysteine residues in the wool fiber cortex was obtained.

Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis.

Memory consolidation has been suggested to be protein synthesis dependent. Previous data indicate that BDNF-induced dendritic protein synthesis is a key event in memory formation through activation of the mammalian target of rapamycin (mTOR) pathway. BDNF also activates calpain, a calcium-dependent cysteine protease, which has been shown to play a critical role in learning and memory. This study was therefore directed at testing the hypothesis that calpain activity is required for BDNF-stimulated local protein synthesis, and at identifying the underlying molecular mechanism. In rat hippocampal slices, cortical synaptoneurosomes, and cultured neurons, BDNF-induced mTOR pathway activation and protein translation were blocked by calpain inhibition. BDNF treatment rapidly reduced levels of hamartin and tuberin, negative regulators of mTOR, in a calpain-dependent manner. Treatment of brain homogenates with purified calpain-1 and calpain-2 truncated both proteins. BDNF treatment increased phosphorylation of both Akt and ERK, but only the effect on Akt was blocked by calpain inhibition. Levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that inactivates Akt, were decreased following BDNF treatment, and calpain inhibition reversed this effect. Calpain-2, but not calpain-1, treatment of brain homogenates resulted in PTEN degradation. In cultured cortical neurons, knockdown of calpain-2, but not calpain-1, by small interfering RNA completely suppressed the effect of BDNF on mTOR activation. Our results reveal a critical role for calpain-2 in BDNF-induced mTOR signaling and dendritic protein synthesis via PTEN, hamartin, and tuberin degradation. This mechanism therefore provides a link between proteolysis and protein synthesis that might contribute to synaptic plasticity.

Nursing Care Throughout the Chimeric Antigen Receptor T-Cell Therapy Process for Multiple Myeloma.

OBJECTIVES: Approvals of chimeric antigen receptor T-cell (CAR-T) therapies for relapsed/refractory multiple myeloma (RRMM) represent advancements in treatment options for a hard-to-treat population. Nursing care during CAR-T therapy is crucial for patients, their caregivers, and the broader CAR-T therapy care team. This manuscript provides an overview of the CAR-T therapy administration process and describes practical considerations for nursing professionals working with patients who receive CAR-T therapy. DATA SOURCES: Current literature describing CAR-T therapies for RRMM and published guidelines on nursing care during CAR-T therapy administration were identified from a PubMed database search. Literature was synthesized with practical considerations from nurses and nurse practitioners with expertise in the administration of CAR-T therapy for MM. A practical overview of the role of nursing professionals throughout all stages of CAR-T therapy administration for RRMM is provided. CONCLUSION: Planning, administration, and posttreatment monitoring for CAR-T therapy requires collaboration between nursing professionals and other healthcare providers as patients migrate between community oncology providers and specialized treatment centers. Nurses help with assessment of patient eligibility and patient and caregiver education before CAR-T therapy. They act in diverse roles across various settings involved in CAR-T therapy administration. Finally, nurses contribute to long-term identification and management of CAR-T-associated toxicities. IMPLICATIONS FOR NURSING PRACTICE: Nurses are crucial to the CAR-T therapy process and make significant contributions to optimizing patient care and subsequent outcomes.

Rural print media portrayal of secondhand smoke and smoke-free policy.

The purpose of this article is to describe how the print media portrays secondhand smoke and smoke-free policy in rural communities. Baseline print media clips from an ongoing 5-year study of smoke-free policy development in 40 rural communities were analyzed. The authors hypothesized that community population size would be positively associated with media favorability toward smoke-free policy. Conversely, pounds of tobacco produced and adult smoking prevalence would be negatively associated with media favorability. There was a positive correlation between population size and percentage of articles favorable toward smoke-free policy. The authors did not find a correlation between adult smoking or tobacco produced and media favorability toward smoke-free policy, but we did find a positive relationship between tobacco produced and percentage of pro-tobacco articles and a negative relationship between adult smoking prevalence and percentage of articles about health/comfort. Implications for targeting pro-health media in rural communities as well as policy-based initiatives for tobacco control are discussed.

Asthma Smarts Education: Increased Disease Knowledge and Reduced School Nurse Visits.

BACKGROUND: Worldwide, asthma is one of the most prevalent chronic diseases. Lack of asthma knowledge can lead to exacerbations, emergency room visits, absenteeism, and decreased quality of life. Asthma prevalence in Milwaukee Public Schools (MPS) is often 20% or higher, and among children ages 5 to 17, asthma is a leading cause of missed school days. A community collaboration created an asthma education program tailored to MPS needs. OBJECTIVE: The purpose of this study was to evaluate the efficacy of brief, school-based asthma education for students with asthma in grades three to five. METHODS: A prospective cohort study of students with asthma in third to fifth grades was developed to assess asthma knowledge improvements via survey (n = 2,066) before and after implementing three 30-minute Asthma Smarts lessons delivered one week apart. Additionally, MPS data was analyzed to explore impact on asthma-related school nursing visits (n = 110). RESULTS: Improvement upon post-testing was shown for all questions in each implementation year with highly significant results (all P < 0.0001). Students that participated in Asthma Smarts made fewer asthma-related visits to the school nurse with a significant difference in the mean number of visits pre and post program (P < 0.001). CONCLUSIONS: This project demonstrates potential for mutually beneficial partnerships addressing gaps in school-based nursing services, and successful support for students with asthma.

Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies.

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM.

Vicriviroc in combination therapy with an optimized regimen for treatment-experienced subjects: 48-week results of the VICTOR-E1 phase 2 trial.

BACKGROUND: Agents that block the CCR5 coreceptor for human immunodeficiency virus (HIV) have demonstrated potent antiretroviral activity. In early clinical studies, the CCR5 antagonist vicriviroc proved to be a safe and effective component of combination antiretroviral therapy. METHODS: This double-blind, dose-ranging, phase 2 trial randomized subjects to receive 30 mg or 20 mg of vicriviroc or placebo once daily plus re-optimized background therapy containing a protease inhibitor with ritonavir. Subjects were adults infected with CCR5-tropic HIV who were experiencing failure of triple antiretroviral regimens. The primary end point was mean change in baseline log(10) HIV RNA level at 48 weeks, based on an intent-to-treat analysis. RESULTS: One hundred fourteen persons received vicriviroc at 30 mg (n = 39), vicriviroc at 20 mg (n =40), or placebo (n = 35). The mean change in baseline HIV RNA level at week 48 was -1.77 log(10) copies/mL for 30 mg of vicriviroc and -1.75 log(10) copies/mL for 20 mg of vicriviroc, compared with -0.79 log(10) copies/mL for placebo (P =.002 and P=.003, respectively, compared with placebo). Mean CD4 counts increased by 102, 136, and 63 cells/mm(3) for 30 mg vicriviroc, 20 mg vicriviroc, and placebo, respectively (P = .260 and P = .039, respectively, compared with placebo). Rates of adverse events (mostly mild-to-moderate) were 111.4, 112.5, and 147.4 events per 100 subject-years, respectively. CONCLUSIONS: Vicriviroc administered with a protease inhibitor plus ritonavir-containing regimen shows potent antiretroviral and immunologic activity sustained over 48 weeks in treatment-experienced patients. CLINICAL TRIALS REGISTRATION: NCT00243230 .

Multi-parameter evaluation of the effect of processing conditions on meat protein modification.

Evaluating the interconnecting effects of pH, temperature and time on food proteins is of relevance to food processing, and food functionality. Here we describe a matrix-based approach in which meat proteins were exposed to combinations of these parameters, selected to cover coordinates in a realistic processing space, and analyzed using redox proteomics. Regions within the matrix showing high levels of protein modification were evaluated for oxidative and other modifications. Both pH and temperature, independently, had a significant effect on the oxidative modifications mostly detected in myofibrillar proteins such as myosin and troponin and also collagen. Heat induced pyroglutamic acid formation was exclusively observed in the myofibrillar proteins. Potential interdependencies between pH, temperature and exposure time were evaluated using a 3-way analysis of variance (ANOVA) on protein modification levels to better understand how industry relevant process parameters influence protein quality and function.

Three-dimensional scapular morphology is associated with rotator cuff tears and alters the abduction moment arm of the supraspinatus.

BACKGROUND: Numerous studies have reported an association between rotator cuff injury and two-dimensional measures of scapular morphology. However, the mechanical underpinnings explaining how these shape features affect glenohumeral joint function and lead to injury are poorly understood. We hypothesized that three-dimensional features of scapular morphology differentiate asymptomatic shoulders from those with rotator cuff tears, and that these features would alter the mechanical advantage of the supraspinatus. METHODS: Twenty-four individuals with supraspinatus tears and twenty-seven age-matched controls were recruited. A statistical shape analysis identified scapular features distinguishing symptomatic patients from asymptomatic controls. We examined the effect of injury-associated morphology on mechanics by developing a morphable model driven by six degree-of-freedom biplanar videoradiography data. We used the model to simulate abduction for a range of shapes and computed the supraspinatus moment arm. FINDINGS: Rotator cuff injury was associated with a cranial orientation of the glenoid and scapular spine (P = .011, d = 0.75) and/or decreased subacromial space (P = .001, d = 0.94). The shape analysis also identified previously undocumented features associated with superior inclination and subacromial narrowing. In our computational model, warping the scapula from a cranial to a lateral orientation increased the supraspinatus moment arm at 20° of abduction and decreased the moment arm at 160° of abduction. INTERPRETATIONS: Three-dimensional analysis of scapular morphology indicates a stronger relationship between morphology and cuff tears than two-dimensional measures. Insight into how morphological features affect rotator cuff mechanics may improve patient-specific strategies for prevention and treatment of cuff tears.

Analysis of Human Faecal Host Proteins: Responsiveness to 10-Week Dietary Intervention Modifying Dietary Protein Intake in Elderly Males.

Faecal proteomics targeting biomarkers of immunity and inflammation have demonstrated clinical application for the identification of changes in gastrointestinal function. However, there are limited comprehensive analyses of the host faecal proteome and how it may be influenced by dietary factors. To examine this, the Homo sapiens post-diet proteome of older males was analysed at the completion of a 10-week dietary intervention, either meeting the minimum dietary protein recommendations (RDA; n = 9) or twice the recommended dietary allowance (2RDA, n = 10). The host faecal proteome differed markedly between individuals, with only a small subset of proteins present in ≥ 60% of subjects (14 and 44 proteins, RDA and 2RDA, respectively, with only 7 common to both groups). No differences were observed between the diet groups on the profiles of host faecal proteins. Faecal proteins were detected from a wide range of protein classes, with high inter-individual variation and absence of obvious impact in response to diets with markedly different protein intake. This suggests that well-matched whole food diets with two-fold variation in protein intake maintained for 10 weeks have minimal impact on human faecal host proteins.

High mortality among patients with AIDS who received a diagnosis of tuberculosis in the first 3 months of antiretroviral therapy.

We analyzed mortality among 201 patients with AIDS and tuberculosis in Haiti. Patients who received a diagnosis of tuberculosis during the first 3 months after the initiation of antiretroviral therapy were 3.25 times more likely to die than were other patients with AIDS and tuberculosis. Failure to recognize active tuberculosis at initiation of antiretroviral therapy leads to increased mortality.

Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To update the 2002 American Academy of Neurology (AAN) guideline regarding immunization and multiple sclerosis (MS). METHODS: The panel performed a systematic review and classified articles using the AAN system. Recommendations were based on evidence, related evidence, principles of care, and inferences according to the AAN 2011 process manual, as amended. MAJOR RECOMMENDATIONS LEVEL B EXCEPT WHERE INDICATED: Clinicians should discuss the evidence regarding immunizations in MS with their patients and explore patients' opinions, preferences, and questions. Clinicians should recommend that patients with MS follow all local vaccine standards, unless there are specific contraindications and weigh local vaccine-preventable disease risks when counseling patients. Clinicians should recommend that patients with MS receive the influenza vaccination annually. Clinicians should counsel patients with MS about infection risks associated with specific immunosuppressive/immunomodulating (ISIM) medications and treatment-specific vaccination guidance according to prescribing information (PI) and vaccinate patients with MS as needed at least 4-6 weeks before initiating patients' ISIM therapy. Clinicians must screen for infections according to PI before initiating ISIM medications (Level A) and should treat patients testing positive for latent infections. In high-risk populations, clinicians must screen for latent infections before starting ISIM therapy even when not specifically mentioned in PI (Level A) and should consult specialists regarding treating patients who screen positive for latent infection. Clinicians should recommend against using live-attenuated vaccines in people with MS receiving ISIM therapies. Clinicians should delay vaccinating people with MS who are experiencing a relapse.

Treatment effect with paliperidone palmitate compared with oral antipsychotics in patients with recent-onset versus more chronic schizophrenia and a history of criminal justice system involvement.

AIM: Long-acting injectable antipsychotics (APs) are not well studied in recent-onset schizophrenia. This exploratory analysis of a study designed to reflect real-world schizophrenia, as defined by patients, interventions and outcomes, compared relative treatment effect between once-monthly paliperidone palmitate (PP) and daily oral APs in patients with recent-onset or chronic illness METHODS: This randomized, open-label, event monitoring board-blinded study compared treatment response in subjects with schizophrenia and a history of criminal justice system involvement following treatment with PP or oral APs for 15 months (ClinicalTrials.gov identifier, NCT01157351). Event-free probabilities were estimated using Kaplan-Meier method; hazard ratios (HRs) were estimated using Cox proportional hazard models. This subgroup analysis analysed data by disease duration (≤5 (recent-onset) or >5 years (chronic illness) since first psychiatric diagnosis). RESULTS: Seventy-seven subjects met the criteria for recent-onset illness; 365 for chronic illness. HRs (95% CI) for treatment failure for oral APs versus PP were 1.73 (0.87-3.45; P = 0.121) for recent-onset and 1.37 (1.02-1.85; P = 0.039) for chronic illness. Most common adverse events for PP versus oral APs were injection site pain (recent-onset, 26% vs. 0%; chronic, 17% vs. 0%), increased weight (14% vs. 6%; 12% vs. 6%), akathisia (14% vs. 9%; 10% vs. 7%), insomnia (12% vs. 17%; 18% vs. 10%) and anxiety (12% vs. 6%; 10% vs. 8%). CONCLUSIONS: Although neither pre-planned nor adequately powered, the estimated HRs suggest that the relative advantage of PP over oral APs for reducing the risk for treatment failure may be greater in patients with recent-onset schizophrenia than in those with more chronic illness.

Replacement, Refinement, and Reduction in Animal Studies With Biohazardous Agents.

Animal models are critical to the advancement of our knowledge of infectious disease pathogenesis, diagnostics, therapeutics, and prevention strategies. The use of animal models requires thoughtful consideration for their well-being, as infections can significantly impact the general health of an animal and impair their welfare. Application of the 3Rs-replacement, refinement, and reduction-to animal models using biohazardous agents can improve the scientific merit and animal welfare. Replacement of animal models can use in vitro techniques such as cell culture systems, mathematical models, and engineered tissues or invertebrate animal hosts such as amoeba, worms, fruit flies, and cockroaches. Refinements can use a variety of techniques to more closely monitor the course of disease. These include the use of biomarkers, body temperature, behavioral observations, and clinical scoring systems. Reduction is possible using advanced technologies such as in vivo telemetry and imaging, allowing longitudinal assessment of animals during the course of disease. While there is no single method to universally replace, refine, or reduce animal models, the alternatives and techniques discussed are broadly applicable and they should be considered when infectious disease animal models are developed.