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Objectives: Many interventions in bronchiolitis are low-value or poorly studied. Inpatient bronchiolitis management is multidisciplinary, with varying degrees of registered nurse (RN) and respiratory therapist (RT) autonomy. Understanding the perceived benefit of interventions for frontline health care personnel may facilitate deimplementation efforts. Our objective was to examine perceptions surrounding the benefit of common inpatient bronchiolitis interventions., Methods: We conducted a cross-sectional survey of inpatient pediatric RNs, RTs, and physicians/licensed practitioners (P/LPs) (eg, advanced-practice practitioners) from May to December of 2021 at 9 university-affiliated and 2 community hospitals. A clinical vignette preceded a series of inpatient bronchiolitis management questions., Results: A total of 331 surveys were analyzed with a completion rate of 71.9%: 76.5% for RNs, 57.4% for RTs, and 71.2% for P/LPs. Approximately 54% of RNs and 45% of RTs compared with 2% of P/LPs believe albuterol would be "extremely or somewhat likely" to improve work of breathing (P < .001). Similarly, 52% of RNs, 32% of RTs, and 23% of P/LPs thought initiating or escalating oxygen in the absence of hypoxemia was likely to improve work of breathing (P < .001). Similar differences in perceived benefit were observed for steroids, nebulized hypertonic saline, and deep suctioning, but not superficial nasal suctioning. Hospital type (community versus university-affiliated) did not impact the magnitude of these differences., Conclusions: Variation exists in the perceived benefit of several low-value or poorly studied bronchiolitis interventions among health care personnel, with RNs/RTs generally perceiving higher benefit. Deimplementation, educational, and quality improvement efforts should be designed with an interprofessional framework., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: Disproportionately high acute care utilization among children with medical complexity (CMC) is influenced by patient-level social complexity., Objective: The objective of this study was to determine associations between ZIP code-level opportunity and acute care utilization among CMC., Design, Setting, and Participants: This cross-sectional, multicenter study used the Pediatric Health Information Systems database, identifying encounters between 2016-2019. CMC aged 28 days to <16 years with an initial emergency department (ED) encounter or inpatient/observation admission in 2016 were included in primary analyses., Main Outcome and Measures: We assessed associations between the nationally-normed, multi-dimensional, ZIP code-level Child Opportunity Index 2.0 (COI) (high COI = greater opportunity), and total utilization days (hospital bed-days + ED discharge encounters). Analyses were conducted using negative binomial generalized estimating equations, adjusting for age and distance from hospital and clustered by hospital. Secondary outcomes included intensive care unit (ICU) days and cost of care., Results: A total of 23,197 CMC were included in primary analyses. In unadjusted analyses, utilization days decreased in a stepwise fashion from 47.1 (95% confidence interval: 45.5, 48.7) days in the lowest COI quintile to 38.6 (36.9, 40.4) days in the highest quintile (p < .001). The same trend was present across all outcome measures, though was not significant for ICU days. In adjusted analyses, patients from the lowest COI quintile utilized care at 1.22-times the rate of those from the highest COI quintile (1.17, 1.27)., Conclusions: CMC from low opportunity ZIP codes utilize more acute care. They may benefit from hospital and community-based interventions aimed at equitably improving child health outcomes., (© 2022 Society of Hospital Medicine.)

Objective: Prolonged pre-procedural fasting in children is associated with decreased patient and family satisfaction and increased patient hemodynamic instability. Practice guidelines recommend clear liquid fasting times of 2 h. We aimed to decrease pre-procedural clear liquid fasting time from 10 h 13 min to 5 h for pediatric hospital medicine (PHM) patients., Methods: All children admitted to the PHM service at a quaternary care children's hospital with an NPO (nil per os) order associated with a procedure requiring general anesthesia or sedation from November 2, 2017 to September 19, 2021 were included. The primary outcome measure was the average time from clear liquid fasting end time to anesthesia start time. The process measure was the percent of NPO orders including a documented clear liquid fasting end time. Balancing measures were aspiration events and case delays/cancellations. Statistical process control charts were used to analyze outcomes., Results: Shortly after implementation of a SmartPhrase in the NPO order, there was special cause variation resulting in a centerline shift from a mean of 10 h 13 min to 6 h 37 min and an increase in the process measure from a baseline of 2%-52%. Following implementation of a hospital-wide change to the NPO order format, another centerline shift to 6 h 7 min occurred which has been sustained for 6 months. No aspiration events and four NPO violations occurred during the intervention period., Conclusion: Quality improvement methodology and higher reliability interventions safely decreased the average pre-procedural fasting time in hospitalized children., (© 2022 Society of Hospital Medicine.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Vaginal mucosal surfaces naturally offer some protection against sexually transmitted infections (STIs) including Human Immunodeficiency Virus-1, however topical preventative medications or vaccine designed to boost local immune responses can further enhance this protection. We previously developed a novel mucosal vaccine strategy using viral vectors integrated into mouse dermal epithelium to induce virus-specific humoral and cellular immune responses at the site of exposure. Since vaccine integration occurs at the site of cell replication (basal layer 100-400 micrometers below the surface), temporal epithelial thinning during vaccine application, confirmed with high resolution imaging, is desirable. In this study, strategies for vaginal mucosal thinning were evaluated noninvasively using optical coherence tomography (OCT) to map reproductive tract epithelial thickness (ET) in macaques to optimize basal layer access in preparation for future effective intravaginal mucosal vaccination studies. Twelve adolescent female rhesus macaques (5-7kg) were randomly assigned to interventions to induce vaginal mucosal thinning, including cytobrush mechanical abrasion, the chemical surfactant spermicide nonoxynol-9 (N9), the hormonal contraceptive depomedroxyprogesterone acetate (DMPA), or no intervention. Macaques were evaluated at baseline and after interventions using colposcopy, vaginal biopsies, and OCT imaging, which allowed for real-time in vivo visualization and measurement of ET of the mid-vagina, fornices, and cervix. P value ≤0.05 was considered significant. Colposcopy findings included pink, rugated tissue with variable degrees of white-tipped, thickened epithelium. Baseline ET of the fornices was thinner than the cervix and vagina (p<0.05), and mensing macaques had thinner ET at all sites (p<0.001). ET was decreased 1 month after DMPA (p<0.05) in all sites, immediately after mechanical abrasion (p<0.05) in the fornix and cervix, and after two doses of 4% N9 (1.25ml) applied over 14 hrs in the fornix only (p<0.001). Histological assessment of biopsied samples confirmed OCT findings. In summary, OCT imaging allowed for real time assessment of macaque vaginal ET. While varying degrees of thinning were observed after the interventions, limitations with each were noted. ET decreased naturally during menses, which may provide an ideal opportunity for accessing the targeted vaginal mucosal basal layers to achieve the optimum epithelial thickness for intravaginal mucosal vaccination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vincent, Frost, Motamedi, Dick, Wei, Yang, White and Gauduin.)

Background and Objectives: Patient complexity at US children's hospitals is increasing. Hospitals experience concurrent pressure to reduce length of stay (LOS) and readmissions, yet little is known about how these common measures of resource use and quality have changed over time. Our aim was to examine temporal trends in medical complexity, hospital LOS, and readmissions across a sample of US children's hospitals., Methods: Retrospective cohort study of hospitalized patients from 42 children's hospitals in the Pediatric Health Information System from 2013 to 2017. After excluding deaths, healthy newborns, obstetric care, and low volume service lines, we analyzed trends in medical complexity, LOS, and 14-day all-cause readmissions using generalized linear mixed effects models, adjusting for changes in patient factors and case-mix., Results: Between 2013 and 2017, a total of 3 355 815 discharges were included. Over time, the mean case-mix index and the proportion of hospitalized patients with complex chronic conditions or receiving intensive care increased ( P < .001 for all). In adjusted analyses, mean LOS declined 3% (61.1 hours versus 59.3 hours from 2013 to 2017, P < .001), whereas 14-day readmissions were unchanged (7.0% vs 6.9%; P = .03). Reductions in adjusted LOS were noted in both medical and surgical service lines (3.6% and 2.0% decline, respectively; P < .001)., Conclusions: Across US children's hospitals, adjusted LOS declined whereas readmissions remained stable, suggesting that children's hospitals are providing more efficient care for an increasingly complex patient population., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.

A large number of studies have shown that the baboon is one of the most commonly used non-human primate (NHP) research model for the study of immunometabolic complex traits such as type 2 diabetes (T2D), insulin resistance (IR), adipose tissue dysfunction (ATD), dyslipidemia, obesity (OB) and cardiovascular disease (CVD). This paper reports on innovative technologies and advanced research strategies for energetics and translational medicine with this NHP model. This includes the following: measuring resting energy expenditure (REE) with the mobile indirect calorimeter Breezing®; monitoring daily body temperature using subcutaneously implanted data loggers; quantifying metabolic heat with veterinary infrared thermography (IRT) imaging, and non-viral non-invasive, tissue-specific ultrasound-targeted microbubble destruction (UTMD) gene-based therapy. These methods are of broad utility; for example, they may facilitate the engineering of ectopic overexpression of brown adipose tissue (BAT) mUCP-1 via UTMD-gene therapy into baboon SKM to achieve weight loss, hypophagia and immunometabolic improvement. These methods will be valuable to basic and translational research, and human clinical trials, in the areas of metabolism, cardiovascular health, and immunometabolic and infectious diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: This study determined the long-term effects of prolonged hypotension (PH) on liver, muscle, and kidney dysfunction. The hypothesis was that longer duration of PH after hemorrhage will result in greater organ dysfunction., Methods: Baboons were sedated and hemorrhaged (30% blood volume). Systolic blood pressure greater than 80 mm Hg was maintained for 1 hour (1 hr-PH; n = 5), 2 hours (2 hr-PH; n = 5), or 3 hours (3 hr-PH; n = 5). After PH, hemorrhage volume was replaced. Animals were recovered and monitored for 21 days. Control animals were hemorrhaged and immediately resuscitated (0 hr-PH, n = 3). Data are Mean ± Standard Deviation, and analyzed by 2-way repeated measures ANOVA and Holm-Sidak test., Results: Hemorrhage resulted in mild hypotension. Minimal resuscitation was required during the hypotensive phase, and survival rate was 100%. Significant increases (p < 0.001) in alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, and lactate dehydrogenase occurred on Day 1 after PH, and were significantly greater (p < 0.001) in the 2 hr- and 3 hr-PH groups than the 0 hr-PH group. Maximum alanine aminotransferase levels (U/L) were 140 ± 56 (0 hr-PH), 170 ± 130 (1 hr-PH), 322 ± 241 (2 hr-PH), and 387 ± 167 (3 hr-PH). Maximum aspartate aminotransferase levels (U/L) were 218 ± 44 (0 hr-PH), 354 ± 219 (1 hr-PH), 515 ± 424 (2 hr-PH), and 711 ± 278 (3 hr-PH). Maximum creatine phosphokinase values (U/L) were 7834 ± 3681 (0 hr-PH), 24336 ± 22268 (1 hr-PH), 50494 ± 67653 (2 hr-PH), and 59857 ± 32408 (3 hr-PH). Maximum lactic acid dehydrogenase values (U/L) were 890 ± 396 (0 hr-PH), 2055 ± 1520 (1 hr-PH), 3992 ± 4895 (2 hr-PH), and 4771 ± 1884 (3 hr-PH). Plasma creatinine and blood urea nitrogen were unaffected by PH (p > 0.10)., Conclusion: These results indicate that PH up to 3 hours in duration results in transient liver and muscle dysfunction that was most severe after 2 hr-PH and 3 hr-PH. Prolonged hypotension produced minimal effects on the kidney., Level of Evidence: Basic science research, Level of evidence not required for basic science research.

Objective: Worldwide, most new HIV infections occur through mucosal exposure. Immunoglobulin M (IgM) is the first antibody class generated in response to infectious agents; IgM is present in the systemic circulation and in mucosal fluids as secretory IgM. We sought to investigate for the first time the role of IgM in preventing AIDS virus acquisition in vivo., Design: Recombinant polymeric monoclonal IgM was generated from the neutralizing monoclonal IgG1 antibody 33C6-IgG1, tested in vitro, and given by passive intrarectal immunization to rhesus macaques 30 min before intrarectal challenge with simian-human immunodeficiency virus (SHIV) that carries an HIV-1 envelope gene., Results: In vitro, 33C6-IgM captured virions more efficiently and neutralized the challenge SHIV with a 50% inhibitory molar concentration (IC50) that was 1 log lower than that for 33C6-IgG1. The IgM form also exhibited significantly higher affinity and avidity compared with 33C6-IgG1. After intrarectal administration, 33C6-IgM prevented viremia in four out of six rhesus macaques after high-dose intrarectal SHIV challenge. Five out of six rhesus macaques given 33C6-IgG1 were protected at a five times higher molar concentration compared with the IgM form; all untreated controls became highly viremic. Rhesus macaques passively immunized with 33C6-IgM with breakthrough infection had notably early development of autologous neutralizing antibody responses., Conclusion: Our primate model data provide the first proof-of-concept that mucosal IgM can prevent mucosal HIV transmission and have implications for HIV prevention and vaccine development.

Nonhuman primates (NHPs) are alike humans in size, behavior, physiology, biochemistry, and immunology. Given close similarities to humans, the NHP model offers exceptional opportunities to understand the biological mechanisms and translational applications with direct relevance to human conditions. Here, we evaluate the opportunities and limitations of NHPs as animal models for translational regenerative medicine. NHP models of human disease propose exceptional opportunities to advance stem cell-based therapy by addressing pertinent translational concerns related to this research. Nonetheless, the value of these primates must be carefully assessed, taking into account the expense of specialized equipment and requirement of highly specialized staff. Well-designed initial fundamental studies in small animal models are essential before translating research into NHP models and eventually into human trials. In addition, we suggest that applying a directed and collaborative approach, as seen in the evolution of stroke NHP models, will greatly benefit the translation of stem cell therapy in other NHP disease models., Competing Interests: There are no conflicts of interest.

Background: Non-human primate (NHP) diabetic models using chemical ablation of β-cells with STZ have been achieved by several research groups. Chemotherapeutic STZ could lead to serious adverse events including nephrotoxicity, hepatotoxicity, and mortality., Methods: We implemented a comprehensive therapeutic strategy that included the tether system, permanent indwelling catheter implants, an aggressive hydration protocol, management for pain with IV nubain and anxiety with IV midazolam, moment-by-moment monitoring of glucose levels post-STZ administration, and continuous intravenous insulin therapy., Results: A triphasic response in blood glucose after STZ administration was fully characterized. A dangerous hypoglycemic phase was also detected in all baboons. Other significant findings were hyperglycemia associated with low levels of plasma leptin, insulin and C-peptide concentrations, hyperglucagonemia, and elevated non-esterified fatty acids (NEFA) concentrations., Conclusions: We successfully induced frank diabetes by IV administering a single dose of pharmaceutical-grade STZ safely and without adverse events in conscious tethered baboons., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Both major forms of diabetes mellitus (DM) involve β-cell destruction and dysfunction. New treatment strategies have focused on replenishing the deficiency of β-cell mass common to both major forms of diabetes by islet transplantation or β-cell regeneration. The pancreas, not the liver, is the ideal organ for islet regeneration, because it is the natural milieu for islets. Since islet mass is known to increase during obesity and pregnancy, the concept of stimulating pancreatic islet regeneration in vivo is both rational and physiologic. This paper proposes a novel approach in which non-viral gene therapy is targeted to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in a non-human primate model (NHP), the baboon. Treated baboons received a gene cocktail comprised of cyclinD2, CDK, and GLP1, which in rats results in robust and durable islet regeneration with normalization of blood glucose, insulin, and C-peptide levels. We were able to generate important preliminary data indicating that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV) glucose tolerance test (IVGTT) curves in STZ hyperglycemic-induced conscious tethered baboons. Immunohistochemistry clearly demonstrated evidence of islet regeneration and restoration of β-cell mass.

Background: Stillbirths in non-human primates are a major problem and represent failure of the maternal-fetal-placental unit to maintain normal relationships because of various endogenous, undetermined or environmental factors., Methods: Records of 236 stillborns and their dams in a Macaca fascicularis colony during a 7-year period were reviewed retrospectively., Results: The 7-year stillbirth incidence was 11.99% (236 stillbirths, 1967 live births). Most (61.02%, n = 144) were of undetermined etiology. Fetal causes included trauma (22.46%, n = 53), fetal pneumonia (0.85%, n = 2) and congenital anomalies (0.42%, n = 1). Maternal causes included dystocia (9.75%, n = 23) and uterine rupture (0.42%, n = 1). Forty-nine placentas were available for histologic evaluation; there was placentitis in five, necrosis in five and placental abruption in two. Most stillbirths occurred close to term. First stillbirths usually occurred in 8- to 12-year-old animals during the first six pregnancies., Conclusions: Most stillbirths were of undetermined etiology. Fetal trauma was the most common cause.

The normal ranges of hematological cell profiles and biochemistry are documented in adult non-pregnant, pregnant, juvenile, and neonatal baboons. Despite the extensive use of the baboon as a model for the study of various aspects of pregnancy, there is no data from paired mothers and their fetuses at different stages of gestation. Hematologic and biochemical profile data were obtained from eight non-pregnant female baboons, 37 mothers and 38 fetal baboons at 30 +/- 2, 90 +/- 2, 125 +/- 2, and 175 +/- 2 days of gestation (mean +/- range; dGA; term, 180 dGA). Changes observed in fetal and maternal blood during normal baboon pregnancy were similar to those reported in human pregnancy. The level of alkaline phosphatase was two times higher in fetal blood circulation than that reported in human pregnancy.

Wilms' tumors, or nephroblastomas, are renal embryonal malignancies with a high incidence in humans. Nephroblastomas are uncommon in nonhuman primates. This report describes three cases of spontaneous proliferative renal tumors in young monkeys: two cases of unilateral kidney nephroblastomas in baboons and a nephroblastomatosis in a cynomolgus macaque. Histologically, both baboon tumors were typical of Wilms' tumors found in humans, with proliferative epithelial cells forming tubules and aborted glomeruli, nephrogenic rests and proliferative fibrovascular tissue. The left kidney of the macaque was markedly enlarged and histologically similar to the baboon tumors, although normal kidney architecture was completely effaced by primitive tubules and occasional glomeruli surrounded by edematous stromal tissue. Cytogenetic analysis did not detect any macaque or baboon equivalents to human Wilms' tumor chromosomal abnormalities. By human pathology classification, the diffuse nature of the macaque tumor is more consistent with nephroblastomatosis than nephroblastoma. This differentiation is the first to be reported in a species other than human. The nephroblastomas described here are the first nephroblastomas to be reported in baboons. Our observations indicate that nonhuman primate nephroblastomatosis and nephroblastomas develop in a similar way to Wilms' tumors in humans, although no genetic marker has been associated with nephroblastomas of nonhuman primates thus far.

Pulmonary congenital anomalies in animals are rare. Previously reported malformations include accessory lung formation, pulmonary hypoplasia, pulmonary agenesis, and various forms of hamartoma. Congenital bronchiolo-alveolar airway malformation, a new entity, is described in a 1-day-old male cynomolgus macaque. This neonate experienced breathing difficulties shortly after birth and died while therapy was being administered. Grossly, the right lung was markedly increased in size, firm, and pink. Histopathologically, sections of right lung showed irregular bronchiole-like and alveolus-like structures. There was marked widening of alveolar septae by loosely arranged mesenchymal cells and many centrally located capillaries. Alveoli were lined by cuboidal epithelial cells. There were scattered islands of immature cartilage. A grossly enlarged lung containing bronchiole-like and alveolus-like structures, immature cartilage islands, and many capillaries within alveolar septae on histopathologic examination, is inconsistent with previously described congenital pulmonary anomalies in animals and humans.

Over 23 months, zinc toxicosis was diagnosed in 35 baboons aged 5-12 months in one galvanized metal and concrete cage complex with conditions that led to excessive exposure to environmental zinc. Clinical signs included reduced pigmentation of hair, skin, and mucous membranes (whiteness), alopecia, dehydration, emaciation, cachexia, dermatitis, diarrhea and, in six cases, severe gangrenous dermatitis of extremities. The syndrome was characterized by pancytopenia, elevated zinc and low copper serum concentrations, low vitamin D and bone-specific alkaline phosphatase levels, and atypical myelomonocytic proliferation of bone marrow. This syndrome emphasizes the importance of proper husbandry and cage design and indicates the potential of infant baboons as a model to study the effects of excessive zinc on development. This is the first report describing the epidemiologic and clinical presentation of zinc toxicosis in infant baboons in captivity.

Heavy metals are essential for the normal progression of maternal and fetal tissue growth and metabolism in pregnancy. Considerable data have been collected for concentrations of various elements in pregnant women, but no comprehensive evaluation of element concentrations in any non-human primate model has been performed. Baboons were studied at the second half of pregnancy. Forty essential and toxic element concentrations were analyzed by absorption spectrophotometry in paired maternal and fetal blood samples; hair and nail samples in pregnant baboons; in placenta, amniotic fluid; and fetal femur, lymph nodes, and liver. Concentrations demonstrated an excellent correlation with concentrations reported in late human pregnancy. Twenty-four elements were below detectable limits in various specimens. We conclude that the pregnant baboon offers unique opportunities to study both normal maternal, fetal, and placental physiology as well as the environmental toxicology of these elements. This information and the ability to use the pregnant baboon as a model is important because essential and toxic elements are key components of the diet as well as major products of manufacturing processes within our industrialized society.

We developed a system that allows individual feeding of adult baboons, 8-15 years of age, maintained in an outdoor group social environment. The purpose of the system is to allow careful monitoring and control of individual diet. Baboons were housed in two group cages, 16 females and a single male in one and 12 females and a single male in the other. Baboons exited the group cage once daily and passed along a chute and over a scale into individual cages where they received their individual diets. Food intake was monitored during their 2-hour stay in the individual cages. Baboons rapidly learned to use this system. Food intake and weight were stable within 20 days. Food consumed decreased during the period of sexual receptivity. The maintenance of the group social environment allowed observations on the group's dominance structure and the relationship of dominance to food consumption. Speed of food access in the group cage was related to dominance. Dominance was not related to food consumed in individual cages. The system permits study of many variables related to behavior and food intake while still retaining critical social interactions.

The abdominal pregnancy is a rare, but life threatening complication of ectopic embryo implantation. Only three cases of abdominal pregnancy have been previously described in primates: in a squirrel monkey, owl monkey and in a rhesus macaque. A 14-year-old wild-caught olive baboon (Papio cynocephalus anubis) was diagnosed at the ultrasound examination with advanced gestational age extrauterine pregnancy. At the initial laparotomy and necropsy the diagnosis of abdominal pregnancy was made on Studdiford's criteria. This case indicates the possibility of developing a model for further study of different types of ectopic pregnancy and indicates a cesarean section as a risk factor for abdominal pregnancy.

Despite the widespread use of bacillus Calmette-Guérin vaccination, Mycobacterium tuberculosis infection remains globally the leading cause of death from a single infectious disease. The complicated and often protracted dynamics of infection and disease make clinical trials to test new tuberculosis vaccines extremely complex. Preclinical selection of only the most promising candidates is therefore essential. Because macaque monkeys develop a disease very similar to humans, they have potential to provide important information in addition to small animal models. To assess the relative merits of rhesus and cynomolgus monkeys as screens for tuberculosis vaccines, we compared the efficacy of bacillus Calmette-Guérin vaccination and the course of infection in both species. Unvaccinated rhesus and cynomolgus monkeys both developed progressive disease with high levels of C-reactive protein, M. tuberculosis-specific IgG, and extensive pathology including cavitation and caseous necrosis. Bacillus Calmette-Guérin vaccination protected cynomolgus almost completely toward the development of pathology, reflected in a striking 2-log reduction in viable bacteria in the lungs compared with nonvaccinated animals. Rhesus, on the other hand, were not protected efficiently by the bacillus Calmette-Guérin. The vaccinated animals developed substantial pathology and had negligible reductions of colony-forming units in the lungs. Comparative studies in these closely related species are likely to provide insight into mechanisms involved in protection against tuberculosis.

The radiation-attenuated Schistosoma mansoni vaccine is highly effective in rodents and primates but has never been tested in humans, primarily for safety reasons. To strengthen its status as a paradigm for a human recombinant antigen vaccine, we have undertaken a small-scale vaccination and challenge experiment in chimpanzees (Pan troglodytes). Immunological, clinical, and parasitological parameters were measured in three animals after multiple vaccinations, together with three controls, during the acute and chronic stages of challenge infection up to chemotherapeutic cure. Vaccination induced a strong in vitro proliferative response and early gamma interferon production, but type 2 cytokines were dominant by the time of challenge. The controls showed little response to challenge infection before the acute stage of the disease, initiated by egg deposition. In contrast, the responses of vaccinated animals were muted throughout the challenge period. Vaccination also induced parasite-specific immunoglobulin M (IgM) and IgG, which reached high levels at the time of challenge, while in control animals levels did not rise markedly before egg deposition. The protective effects of vaccination were manifested as an amelioration of acute disease and overall morbidity, revealed by differences in gamma-glutamyl transferase level, leukocytosis, eosinophilia, and hematocrit. Moreover, vaccinated chimpanzees had a 46% lower level of circulating cathodic antigen and a 38% reduction in fecal egg output, compared to controls, during the chronic phase of infection.

In human airways, beta-defensins function in the elimination of various pathogens. They have been identified in a wide range of species. Here we report the identification and expression of chimpanzee beta-defensin-1 (cBD1), which is a homolog of human beta-defensin-1, in chimpanzee airways and skin. The cBD1 cDNA sequence differs by only one synonymous nucleotide substitution compared to the human cDNA sequence. In situ hybridization revealed that in lung tissue beside alveolar macrophages also airway epithelial cells, endothelial cells and type II pneumocytes express cBD1 mRNA. In skin, cBD1 mRNA was expressed in keratinocytes and endothelial cells. Together, these results show similarity in structure and expression pattern and perhaps in function.