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  • 1.

    【2hr】A Review of the Effects of Pain and Analgesia on Immune System Function and Inflammation: Relevance for Preclinical Studies

    包量

    机译 疼痛和镇痛作用对免疫系统功能和炎症的影响的综述：与临床前研究的相关性
    摘要：One of the most significant challenges facing investigators, laboratory animal veterinarians, and IACUCs, is how to balance appropriate analgesic use, animal welfare, and analgesic impact on experimental results. This is particularly true for in vivo studies on immune system function and inflammatory disease. Often times the effects of analgesic drugs on a particular immune function or model are incomplete or don't exist. Further complicating the picture is evidence of the very tight integration and bidirectional functionality between the immune system and branches of the nervous system involved in nociception and pain. These relationships have advanced the concept of understanding pain as a protective neuroimmune function and recognizing pathologic pain as a neuroimmune disease. This review strives to summarize extant literature on the effects of pain and analgesia on immune system function and inflammation in the context of preclinical in vivo studies. The authors hope this work will help to guide selection of analgesics for preclinical studies of inflammatory disease and immune system function.
  • 2.

    【2hr】Influence of Pain and Analgesia on Orthopedic and Wound-healing Models in Rats and Mice

    包量

    机译 疼痛和镇痛作用对大鼠和小鼠骨科和伤口愈合模型的影响
    摘要：The surgical stress response and resulting physiologic changes can lead to postoperative complications and negatively impact animal welfare. Although appropriate pain management is crucial to reduce the pain and stress response to surgery, analgesic choice can significantly affect bone and wound healing. This review aims to summarize data from rat and mouse studies and to provide recommendations for integrating analgesia into orthopedic and wound healing models in these species. Data from other species, such as humans, rabbits and other rodents, is included, where available. From these data, we conclude that for orthopedic surgical models, opioids, local anesthetics and dissociative agents have minimal impact on fracture healing; cyclooxygenase 2 (COX2) selective nonsteroidal antiinflammatory drugs (NSAID) may be used in the short-term; and steroids should be avoided. For wound healing models, short-term systemic or topical opioids have negligible impact on wound healing; NSAID or local anesthetics may be used short-term; and systemic steroids should be avoided. Alternative analgesics such as tramadol, gabapentin, ketamine, and acetaminophen warrant consideration and further evaluation for both orthopedic and wound healing models. In all cases, researchers and veterinarians should work together to determine the appropriate analgesic plan to minimize pain, as well as to minimize unwanted effects on the orthopedic and wound healing models themselves.
  • 3.

    【2hr】The Influence of Pain and Analgesia in Rodent Models of Sepsis

    包量

    机译 疼痛和镇痛作用对脓毒症啮齿动物模型的影响
    摘要：Sepsis is a multifaceted host response to infection that dramatically affects patient outcomes and the cost of health care. Animal models are necessary to replicate the complexity and heterogeneity of clinical sepsis. However, these models entail a high risk of pain and distress due to tissue trauma, inflammation, endotoxin-mediated hyperalgesia, and other mechanisms. Several recent studies and initiatives address the need to improve the welfare of animals through analgesics and standardize the models used in preclinical sepsis research. Ultimately, the goal is to provide high-fidelity, humane animal models that better replicate the clinical course of sepsis, to provide more effective translation and advance therapeutic discovery. The purpose of this review is to discuss the current understanding of the roles of pain and analgesia in rodent models of sepsis. The current definitions of sepsis along with an overview of pain in human sepsis are described. Finally, welfare concerns associated with animal models of sepsis and the most recent considerations for relief of pain and distress are reviewed.
  • 4.

    【2hr】The Study of Pain in Rats and Mice

    包量

    机译 大鼠和小鼠疼痛的研究
    摘要：Pain is a clinical syndrome arising from a variety of etiologies in a heterogeneous population, which makes successfully treating the individual patient difficult. Organizations and governments recognize the need for tailored and specific therapies, which drives pain research. This review summarizes the different types of pain assessments currently being used and the various rodent models that have been developed to recapitulate the human pain condition.
  • 5.

    【2hr】Interacting Influences of Sleep, Pain, and Analgesic Medications on Sleep Studies in Rodents

    包量

    机译 睡眠，止痛和止痛药物对啮齿动物睡眠研究的相互作用影响
    • 作者：Linda A Toth
    • 刊名：Comparative Medicine
    • 2019年第6期
    摘要：This overview provides a brief summary of the complex interactions that link sleep, pain, and analgesic medications. Sleep scientists and clinicians are well aware of these relationships and understand that maintaining healthy pain-free subjects in a stable environment is essential to generating interpretable data and valid conclusions. However, these concepts and the data that support bidirectional interactions between sleep and pain may be less known to those who are not sleep scientists yet need such information to protect and advance both animal wellbeing and research validity (for example, veterinarians, IACUC members). Abundant human evidence supports the disruptive effect of pain and the modulatory effects of analgesic drugs on sleep; however, analgesic drugs can alter both sleep and the electroencephalogram, which is the primary objective measure for identifying sleep and evaluating sleep properties in both humans and animals. Consideration of the modulatory and interactive relationships of sleep, pain, and analgesic medications is essential to designing and conducting valid and reproducible sleep research using animal subjects.
  • 6.

    【2hr】AALAS Position Statement on the Humane Care and Use of Laboratory Animals

    包量

    机译 AALAS关于人道关怀和使用实验动物的立场声明
    • 作者：
    • 刊名：Comparative Medicine
    • 2019年第6期
    摘要：The American Association for Laboratory Animal Science endorses the United States Government “Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training” and requires that all papers published in Comparative Medicine report research conducted in conformance with these principles. Research for papers submitted from outside the United States must be in conformance with the guidelines of that country’s government. The Editor reserves the right to reject papers reporting results of research not adhering to these principles.
  • 7.

    【2hr】Experimental Infection of Mice with Veronaea botryosa as a Model for Human Phaeohyphomycosis

    包量

    机译 葡萄孢菌作为人类致病菌模型的小鼠实验性感染
    摘要：is a ubiquitous, dematiaceous mold capable of causing cutaneous and subcutaneous lesions in humans. In the last decade, has been associated with emergent systemic fungal infections in aquatic animals, including cultured sturgeon ( spp.), captive amphibians, and wild reptiles. Recently, repetitive extragenic palindromic PCR (rep-PCR) fingerprinting has demonstrated intraspecific variability among isolates from different clinically affected hosts and geographic regions. However, little is known regarding the pathogenic potential of the different genetic clades, and no mammalian model currently exists to investigate phaeohyphomycosis. In this study, we inoculated immunocompetent heterozygotic ( ) and immunodeficient homozygotic ( ) Hsd:Athymic Nude- mice subcutaneously or through orogastric gavage with 1 of 3 representative strains that had been recovered from white sturgeon ( ), green sea turtle ( ), and human hosts and typed by using rep-PCR analysis. Daily mortality and morbidity were recorded, and dissemination of the fungus was investigated through culture of splenic samples and histologic analysis of the injection site, regional lymph nodes, salivary gland, spleen, liver, mesenteric lymph node, and gastrointestinal tract. No differences in survival, fungal burden, or dissemination were observed between fungal strains, routes of inoculation, or host immune status. Fungal infection was observed after subcutaneous inoculation only, was localized to the inoculation site, and was identified in both and mice. Fungal strain variability was not associated with virulence in a murine model of infection, and this novel mouse model of phaeohyphomycosis recapitulates the human clinical condition.
  • 8.

    【2hr】Effects of Corynebacterium bovis on Engraftment of Patient-derived Chronic Myelomonocytic Leukemia Cells in NSGS Mice

    包量

    机译 牛棒杆菌对NSGS小鼠源性慢性粒单核细胞白血病细胞移植的影响
    摘要：Modeling chronic myelomonocytic leukemia (CMML) in immunodeficient NSGS mice relies on unique human CMML specimens and consistent murine engraftment. Only anecdotal comments have thus far supported the notion that research data may be altered by , an opportunistic cutaneous pathogen of immunodeficient mice. disseminated by asymptomatic and clinically affected mice with hyperkeratotic dermatitis, resulting in resilient facility contamination and infectious recurrence. Herein we report that, compared with PCR-negative counterparts, PCR-positive NSGS mice developed periocular and facial hyperkeratosis and alopecia and had reduced metrics indicative of ineffective human CMML engraftment, including less thrombocytopenia, less splenomegaly, fewer CMML infiltrates in histopathologic sections of murine organs, and fewer human CD45 cells in samples from murine spleen, bone marrow, and peripheral blood that were analyzed by flow cytometry. All CMML model metrics of engraftment were significantly reduced in the PCR-positive cohort compared with the negative cohort. In addition, a survey of comprehensive cancer center practices revealed that most murine facilities do not routinely test for or broadly decontaminate the facility or its equipment after a outbreak, thus increasing the likelihood of recurrence of invalidated studies. Our findings document that CMML engraftment of NSGS mice is diminished—and the integrity of murine research data jeopardized—by infection of immunodeficient mice. In addition, our results indicate that should be excluded from and not tolerated in murine facilities housing immunodeficient strains.
  • 9.

    【2hr】Safety Evaluation of a 405-nm LED Device for Direct Antimicrobial Treatment of the Murine Brain

    包量

    机译 405 nm LED设备对小鼠脑部直接抗菌治疗的安全性评估
    摘要：Antimicrobial resistance is a growing problem in human medicine that extends to biomedical research. Compared with chemical-based therapies, light-based therapies present an alternative to traditional pharmaceuticals and are less vulnerable to acquired bacterial resistance. Due to immunologic privilege and relative tissue sensitivity to topical antibiotics, the brain poses a unique set of difficulties with regard to antimicrobial therapy. This study focused on 405-nm ‘true violet’ light—which has been shown to kill multiple clinically relevant bacterial species in vitro yet leave mammalian cells unscathed—and its effect on the murine brain. We built a 405-nm LED array, validated its power and efficacy against a clinical bacterial isolate in vitro, and then, at the time of craniotomy, treated mice with various doses of 405-nm light (36, 45, and 54 J/cm ). The selected doses caused no behavioral derangements postoperatively or any observable brain pathology as determined postmortem by histologic evaluation and immunofluorescence staining for caspase 3 and glial fibrillary acidic protein, markers of apoptosis and necrosis. True-violet light devices may present an inexpensive refinement to current practices for maintaining open craniotomy sites or reducing bacterial loads in contaminated surgical sites.
  • 10.

    【2hr】Transmissible Cancers and Immune Downregulation in Tasmanian Devil (Sacrophilus harrisii) and Canine Populations

    包量

    机译 塔斯马尼亚恶魔（Sacrophilus harrisii）和犬类人群中的可传播性癌症和免疫下调
    摘要：Known as devil facial tumor disease (DFTD) and canine transmissible venereal tumor (CTVT), transmissible cancer occurs in both Tasmanian devil and canine populations, respectively. Both malignancies show remarkable ability to be transmitted as allografts into subsequent hosts. How DFTD and CTVT avoid detection by immunocompetent hosts is of particular interest, given that these malignancies are rarely seen in other species in nature. Both of these transmissible cancers can downregulate the host immune system, enabling proliferation. DFTD is characterized by epigenetic modifications to the DNA promoter regions of β microglobulin, transporters associated with antigen processing 1 and 2, MHC I, and MHC II—crucial proteins required in the detection and surveillance of foreign material. Downregulation during DFTD may be achieved by altering the activity of histone deacetylases. DFTD has caused widespread destruction of devil populations, placing the species on the brink of extinction. CTVT demonstrates a proliferative phase, during which the tumor evades immune detection, allowing it to proliferate, and a regressive phase when hosts mount an effective immune response. Alteration of TGFβ signaling in CTVT likely impedes the antigen-processing capabilities of canine hosts in addition to hindering the ability of natural killer cells to detect immune system downregulation. Immunosuppressive cytokines such as CXCL7 may contribute to a favorable microenvironment that supports the proliferation of CTVT. When viewed from an evolutionary paradigm, both DFTD and CTVT may conform to a model of host–parasite coevolution. Furthermore, various genetic features, such as genetically active transposons in CTVT and chromosomal rearrangements in DFTD, play important roles in promoting the survival of these disease agents. Understanding the mode of transmission for these transmissible cancers may shed light on mechanisms for human malignancies and reveal opportunities for treatment in the future.
  • 11.

    【2hr】Evaluation of Hybrid Surgical Access Approaches for Pulmonary Valve Implantation in an Acute Swine Model

    包量

    机译 急性猪模型中肺动脉瓣植入的混合外科手术方法的评价。
    摘要：
  • 12.

    【2hr】Cadaveric Porcine Spines as a Model for the Human Epidural Space

    包量

    机译 尸体猪脊柱作为人类硬膜外腔的模型
    摘要：Most patients who undergo epidural anesthesia are pregnant and thus a protected population, which has limited investigations of the human epidural space. Among the several species studied as models for the human spine, the porcine spine has been used as a model for spine instrumentation. Although the spread of colored dye within the porcine epidural space has been investigated, no model has demonstrated in situ spread by using radiopaque contrast dye. To this end, we here used 10 Yorkshire swine cadavers through an approved tissue sharing agreement. Epidural catheters were placed by using a landmark-based loss-of-resistance technique; placement was confirmed through radiography. The catheters were connected to epidural infusion pumps to ensure consistent dosing, 2-mL boluses of contrast dye were injected into the space, and radiographs were taken and recorded after each bolus. The total spread of the contrast dye was analyzed. We demonstrated consistent and reliable spread of fluid in the epidural space among the animals used, with low variability between animals of different weights. Our results support the use of the epidural space of cadaveric swine as a model for the human epidural space. Furthermore, the technique for epidural administration by using the landmark-based loss-of-resistance demonstrated in this model was validated, thus supporting future investigations of medication delivery into the epidural space.
  • 13.

    【2hr】Carriage of Methicillin-resistant Staphylococcus aureus in a Colony of Rhesus (Macaca mulatta) and Cynomolgus (Macaca fascicularis) Macaques

    包量

    机译 恒河猴（猕猴）和食蟹猕猴（猕猴）猕猴菌落的耐甲氧西林金黄色葡萄球菌的运输。
    摘要：Methicillin-resistant (MRSA) carriage and infection are well documented in the human and veterinary literature; however only limited information is available regarding MRSA carriage and infection in laboratory NHP populations. The objective of this study was to characterize MRSA carriage in a representative research colony of rhesus and cynomolgus macaques through a cross-sectional analysis of 300 animals. MRSA carriage was determined by using nasal culture. Demographic characteristics of carriers and noncarriers were compared to determine factors linked to increased risk of carriage, and MRSA isolates were analyzed to determine antimicrobial susceptibility patterns, staphylococcal chromosome cassette mec (SCCmec) type, and multilocus sequence type (ST). Culture results demonstrated MRSA carriage in 6.3% of the study population. Animals with greater numbers of veterinary or experimental interventions including antibiotic administration, steroid administration, dental procedures, and surgery were more likely to carry MRSA. Susceptibility results indicated that MRSA isolates were resistant to β-lactams, and all isolates were resistant to between 1 and 4 nonβ-lactam antibiotics. In addition, 73.7% of MRSA isolates were identified as ST188-SCCmec IV, an isolate previously observed in an unrelated population of macaques and 15.8% were ST3268-SCCmec V, which has only been described in macaques. A single isolate had a novel sequence type, ST3478, and carried SCCmec V. These results suggest that NHP-adapted strains of MRSA exist and highlight the emergence of antimicrobial resistance in laboratory NHP populations.
  • 14.

    【2hr】Prolonged Anesthetic Recovery after Continuous Infusion of Midazolam in 2 Domestic Cats (Felis catus)

    包量

    机译 连续输注咪达唑仑对2只家猫（Felis catus）的麻醉后恢复时间延长
    摘要：Two healthy research cats involved in a randomized, blinded prospective pharmacodynamics study evaluating midazolam continuous-rate infusion as a means to decrease sevoflurane concentrations experienced unexpectedly prolonged recoveries. Midazolam loading doses, infusion rates, and the targeted plasma midazolam concentrations at steady-state were determined by pharmacokinetic modeling based on the results of a preliminary pharmacokinetic study using a single dose of midazolam. In the pharmacodynamics study, cats remained oversedated after recovery from anesthesia, and plasma concentrations of midazolam and its primary metabolite (1-hydroxymidazolam) remained elevated. The use of flumazenil was unsuccessful in timely treatment of oversedation. Administration of intravenous lipid emulsion was used in one of the cats to facilitate recovery and appeared to be effective in both reducing the depth of midazolam-induced oversedation and significantly reducing the plasma concentration of 1-hydroxymidazolam. The effects after the administration of both treatment modalities on clinical signs and plasma drug concentrations in cats are discussed. The observations suggest that cats may eliminate 1-hydroxymidazolam more slowly than expected; consequently dose adjustments may be required when continuous infusion of midazolam is intended. In addition, intravenous lipid emulsion may facilitate recovery from midazolam oversedation, particularly in cases unresponsive to traditional treatment modalities. However, further investigations are warranted to delineate the efficacy of this modality in the treatment of midazolam oversedation.
  • 15.

    【2hr】AALAS Position Statement on the Humane Care and Use of Laboratory Animals

    包量

    机译 AALAS关于人道关怀和使用实验动物的立场声明
    • 作者：
    • 刊名：Comparative Medicine
    • 2019年第4期
    摘要：The American Association for Laboratory Animal Science endorses the United States Government “Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training” and requires that all papers published in Comparative Medicine report research conducted in conformance with these principles. Research for papers submitted from outside the United States must be in conformance with the guidelines of that country’s government. The Editor reserves the right to reject papers reporting results of research not adhering to these principles.
  • 16.

    【2hr】Effects of Rodent Thermoregulation on Animal Models in the Research Environment

    包量

    机译 研究环境中啮齿动物体温调节对动物模型的影响
    摘要：To best promote animal wellbeing and the efficacy of biomedical models, scientific, husbandry, and veterinary professionals must consider the mechanisms, influences, and outcomes of rodent thermoregulation in contemporary research environments. Over the last 2 decades, numerous studies have shown that laboratory mice and rats prefer temperatures that are several degrees warmer than the environments in which they typically are housed within biomedical facilities. Physiologic changes to rodents that are cage-housed under standard temperatures (20 to 26 °C) are attributed to ‘cold stress’ and include alterations in metabolism, cardiovascular parameters, respiration, and immunologic function. This review article describes common behavioral and physiologic adaptations of laboratory mice and rats to cold stress within modern vivaria, with emphasis on environmental enrichment and effects of anesthesia and procedural support efforts. In addition, potential interventions and outcomes for rodents are presented, relative to the importance of repeating and reproducing experiments involving laboratory rodent research models of human disease.
  • 17.

    【2hr】Identifying and Implementing Endpoints for Geriatric Mice

    包量

    机译 识别和实施老年小鼠的终点
    • 作者：Linda A Toth
    • 刊名：Comparative Medicine
    • 2018年第6期
    摘要：The types of changes in physical appearance and behavior that occur in elderly people similarly develop in elderly animals. Signs and symptoms that might cause concern in younger people or mice may be normal in their elderly but generally healthy counterparts. Although numerous scoring methods have been developed to assess rodent health, these systems were often designed for young adults used in specific types of research, such as cancer or neurologic studies, and therefore may be suboptimal for assessing aging rodents. Approaches known as frailty assessments provide a global evaluation of the health of aged mice, rats, and people, and mouse frailty scores correlate well with the likelihood of death. Complementing frailty assessment, prediction of imminent death in aged mice can often be accomplished by focusing on 2 objective parameters—body weight and temperature. Before they die, many (but not all) mice develop marked reductions in body weight and temperature, thus providing signs that close monitoring, intervention, or preemptive euthanasia may be necessary. Timely preemptive euthanasia allows antemortem collection of data and samples that would be lost if spontaneous death occurred; preemptive euthanasia also limits terminal suffering. These approaches to monitoring declining health and predicting death in elderly research mice can aid in establishing and implementing timely interventions that both benefit the research and reduce antemortem suffering.
  • 18.

    【2hr】Effects of Intraoperative Vagal Nerve Stimulation on the Gastrointestinal Microbiome in a Mouse Model of Amyotrophic Lateral Sclerosis

    包量

    机译 术中迷走神经刺激对肌萎缩性侧索硬化小鼠模型胃肠道微生物组的影响
    摘要：The gastrointestinal microbiota (GM) plays a fundamental role in health and disease and contributes to the bidirectional signaling between the gastrointestinal system and brain. The direct line of communication between these organ systems is through the vagus nerve. Therefore, vagal nerve stimulation (VNS), a commonly used technique for multiple disorders, has potential to modulate the enteric microbiota, enabling investigation and possibly treatment of numerous neurologic disorders in which the microbiota has been linked with disease. Here we investigate the effect of VNS in a mouse model of amyotrophic lateral sclerosis (ALS). B6SJL-Tg(SOD1*G93A)dl1Gur (SOD1dl) and wildtype mice underwent ventral neck surgery to access the vagus nerve. During surgery, the experimental group received 1 h of VNS, whereas the sham group underwent 1 h of sham treatment. The third (control) group did not undergo any surgical manipulation. Fecal samples were collected before surgery and at 8 d after the initial collection. Microbial DNA was sequenced to determine the GM profiles at both time points. GM profiles did not differ between genotypes at either the initial or end point. In addition, VNS did not alter GM populations, according to the parameters chosen in this study, indicating that this short intraoperative treatment is safe and has no lasting effects on the GM. Future studies are warranted to determine whether different stimulation parameters or chronic use of VNS affect GM profiles.
  • 19.

    【2hr】Longitudinal Evaluation of Pulmonary Arterial Hypertension in a Rhesus Macaque (Macaca mulatta) Model of HIV Infection

    包量

    机译 恒河猴（猕猴）HIV感染模型中肺动脉高压的纵向评估。
    摘要：Pulmonary arterial hypertension (PAH) is a life-threatening disease with higher incidence in HIV-infected compared with noninfected patients. SIV-infected NHP develop clinical manifestations of HIV infection, including PAH. To understand the pathogenesis of PAH and determine the relationship between hemodynamic changes and clinical characteristics associated with SIV infection, we performed right heart catheterization and echocardiographic imaging of 21 rhesus macaques before and after SIV infection. Between 6 and 12 mo after infection, 11 of the 21 animals had elevated mean pulmonary arterial pressure (mPAP; greater than 25 mm Hg). RV involvement was evident as increased RV glucose uptake in PAH+ macaques on positron emission tomography–coupled CT compared with uninfected animals. RV and pulmonary vascular collagen deposition were elevated in PAH+ animals. At 12 mo after infection, 6 of the 21 macaques (28.6%) exhibited continued increase in mPAP (progressive PAH), whereas 5 animals (23.8%) had reduced pressure (transient PAH). SIV infection of rhesus macaques led to 3 distinct outcomes with regard to hemodynamic function. Hemodynamic alterations correlated with specific inflammatory profiles and increased RV and pulmonary arterial fibrosis but not with viral load, sex, or CD4+ T-cell levels. This model of a natural cause of PAH provides insight into disease pathways that are important for the development of novel therapeutic targets.
  • 20.

    【2hr】System for Scoring Severity of Acute Radiation Syndrome Response in Rhesus Macaques (Macaca mulatta)

    包量

    机译 猕猴急性辐射综合症反应严重程度评分系统
    摘要：We developed a clinical assessment tool for use in an NHP radiation model to 1) quantify severity responses for subsyndromes of the acute radiation syndrome (ARS; that is, hematopoietic and others) and 2) identify animals that required enhanced monitoring. Our assessment tool was based primarily on the MEdical TREatment ProtocOLs for Radiation Accident Victims (METREPOL) scoring system but was adapted for NHP to include additional indices (for example, behaviors) for use in NHP studies involving limited medical intervention. Male (n = 16) and female (n = 12) rhesus macaques (Macaca mulatta; 5 groups: sham and 1.0, 3.5, 6.5, and 8.5 Gy; n = 6 per group) received sham- or bilateral 60Co γ-irradiation at approximately 0.6 Gy/mn. Clinical signs of ARS and blood analysis were obtained before and serially for clinical assessment during the period of 6 h to 60 d after sham or 60Co irradiation. Minimal supportive care (that is, supplemental nutrition, subcutaneous fluid, loperamide, acetaminophen, and topical antibiotic ointment) was prescribed based on clinical observations. Results from clinical signs and assays for assessment of relevant organ systems in individual animals were stratified into ARS severity scores of normal (0), mild (1), moderate (2), and severe (3 or 4). Individual NHP were scored for maximal subsyndrome ARS severity in multiple organ systems by using the proposed ARS scoring system to obtain an overall ARS response category. One NHP died unexpectedly. The multiple-parameter ARS severity scoring tool aided in the identification of animals in the high-dose (6.5 and 8.5 Gy) groups that required enhanced monitoring.
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