Pan American League of Associations for Rheumatology Recommendations for the Treatment of Psoriatic Arthritis.

OBJECTIVE: Psoriatic arthritis (PsA) is chronic disease that compromises multiple domains and might be associated with progressive joint damage, increased mortality, functional limitation, and considerably impaired quality of life. Our objective was to generate evidence-based recommendations on the management of PsA in Pan American League of Associations for Rheumatology (PANLAR) countries. METHODS: We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)-ADOLOPMENT approach to adapt the 2019 recommendations of the European Alliance of Associations for Rheumatology. A working group consisting of rheumatologists from various countries in Latin America identified relevant topics for the treatment of PsA in the region. The methodology team updated the evidence and synthesized the information used to generate the final recommendations. These were then discussed and defined by a panel of 31 rheumatologists from 15 countries. RESULTS: Theses guidelines report 15 recommendations addressing therapeutic targets, use of antiinflammatory agents and corticosteroids, treatment with disease-modifying antirheumatic drugs (conventional synthetic, biologic, and targeted synthetic), therapeutic failure, optimization of biologic therapy, nonpharmacological interventions, assessment tools, and follow-up of patients with PsA. CONCLUSION: Here we present a set of recommendations to guide decision making in the treatment of PsA in Latin America, based on the best evidence available, considering resources, medical expertise, and the patient's values and preferences. The successful implementation of these recommendations should be based on clinical practice conditions, healthcare settings in each country, and a tailored evaluation of patients.

Determinants of financial inclusion in households in Peru.

The issue of financial inclusion considers access to and use of quality financial services by household members and different types of companies around the world, allowing us to reach the opportunities that the globalized world offers us. The objective of this research was to identify the socioeconomic factors that determined the inclusion of households in the financial system in Peru in the period of 2021. A quantitative approach was considered, which was non-experimental with a descriptive and correlational design and in which 81,441 pieces of data were obtained from the National Household Survey (ENAHO) of the National Institute of Statistics and Informatics, applying a logit binomial regression. It was determined that 47.02% of households were included in the financial system; 61.93% of those surveyed had their residence in the urban area; on average, respondents had incomplete secondary education; the age of the respondents on average was from 25 to 44 years; the average economic income of the household was less than $251 per month; 72.18% were represented by men as heads of the household and the rest by women; most of the respondents had a cohabiting marital status; the social conditions showed that 23.82% were in the group of being poor; and the majority of households did not have a property title. The determinants of financial inclusion in Peruvian households for 2021 were the area of residence, educational level, age of the respondent, economic income, gender of the respondent, marital status, social status, and property title.

Inducible deletion of Ezh2 in CD4+ T cells inhibits kidney T cell infiltration and prevents interstitial nephritis in MRL/ lpr lupus-prone mice.

Systemic lupus erythematosus is a remitting relapsing autoimmune disease characterized by autoantibody production and multi-organ involvement. T cell epigenetic dysregulation plays an important role in the pathogenesis of lupus. We have previously demonstrated upregulation of the key epigenetic regulator EZH2 in CD4+ T cells isolated from lupus patients. To further investigate the role of EZH2 in the pathogenesis of lupus, we generated a tamoxifen-inducible CD4+ T cell Ezh2 conditional knockout mouse on the MRL/ lpr lupus-prone background. We demonstrate that Ezh2 deletion abrogates lupus-like disease and prevents T cell differentiation. Single-cell analysis suggests impaired T cell function and activation of programed cell death pathways in EZH2-deficient mice. Ezh2 deletion in CD4+ T cells restricts TCR clonal repertoire and prevents kidney-infiltrating effector CD4+ T cell expansion and tubulointerstitial nephritis, which has been linked to end-stage renal disease in patients with lupus nephritis.

Possible Spreading of SARS-CoV-2 from Humans to Captive Non-Human Primates in the Peruvian Amazon.

Human-to-animal transmission events of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) have been reported in both domestic and wild species worldwide. Despite the high rates of contagion and mortality during the COVID-19 (Coronavirus Diseases 2019) pandemic in Peru, no instances of natural virus infection have been documented in wild animals, particularly in the Amazonian regions where human-wildlife interactions are prevalent. In this study, we conducted a surveillance investigation using viral RNA sequencing of fecal samples collected from 76 captive and semi-captive non-human primates (NHPs) in the Loreto, Ucayali, and Madre de Dios regions between August 2022 and February 2023. We detected a segment of the RNA-dependent RNA polymerase (RdRp) gene of SARS-CoV-2 by metagenomic sequencing in a pooled fecal sample from captive white-fronted capuchins (Cebus unicolor) at a rescue center in Bello Horizonte, Ucayali. Phylogenetic analysis further confirmed that the retrieved partial sequence of the RdRp gene matched the SARS-CoV-2 genome. This study represents the first documented instance of molecular SARS-CoV-2 detection in NHPs in the Peruvian Amazon, underscoring the adverse impact of anthropic activities on the human-NHP interface and emphasizing the importance of ongoing surveillance for early detection and prediction of future emergence of new SARS-CoV-2 variants in animals.

The mental health symptoms of individuals with sensory disabilities and the reasons that lead to COVID-19 vaccine refusal and hesitancy.

The relationship between the reasons for COVID-19 vaccine hesitancy or refusal among people with sensory disabilities and mental health conditions (MHCs) are unclear. Data from the Census Bureau's Household Pulse Survey were analyzed to examine reasons for COVID-19 vaccination refusal among persons with sensory disabilities. Multivariable logistic and polytomous regression were used to examine the relationships among sensory disability status, MHC, and reasons for vaccine refusal and hesitancy. Individuals with sensory disabilities had higher proportion of anxiety and depression than those without a sensory disability. Individuals with a sensory disability and MHCs were less likely to obtain a vaccine and have a general distrust in the COVID-19 vaccine and the government than those without a disability or a MHC. These findings can assist in tailoring messages and developing programs to increase COVID-19 vaccination trust and uptake among individuals with disabilities and MHCs.

Genomic data of global clones of CTX-M-65-producing Escherichia coli ST10 from South American llamas inhabiting the Andean Highlands of Peru.

BACKGROUND: The global spread of extended-spectrum ß-lactamase (ESßL)-producing Escherichia coli has been considered a One Health issue that demands continuous genomic epidemiology surveillance in humans and non-human hosts. OBJECTIVES: To report the occurrence and genomic data of ESßL-producing E. coli strains isolated from South American llamas inhabiting a protected area with public access in the Andean Highlands of Peru. METHODS: Two ESßL-producing E. coli strains (E. coli L1LB and L2BHI) were identified by MALDI-TOF. Genomic DNAs were extracted and sequenced using the Illumina NextSeq platform. De novo assembly was performed by CLC Genomic Workbench and in silico prediction was accomplished by curated bioinformatics tools. SNP-based phylogenomic analysis was performed using publicly available genomes of global E. coli ST10. RESULTS: Escherichia coli L1LB generated a total of 4 000 11 and L2BHI a total of 4 002 54 paired-end reads of ca.164 × and ca. 157 ×, respectively. Both E. coli strains were assigned to serotype O8:H4, fimH41, and ST10. The blaCTX-M-65 ESßL gene, along with other medically important antimicrobial resistance genes, was predicted. Broad virulomes, including the presence of the astA gene, were confirmed. The phylogenomic analysis revealed that E. coli L1LB and L2BHI strains are closely related to isolates from companion animals and human hosts, as well as environmental strains, previously reported in North America, South America, Africa, and Asia. CONCLUSION: Presence of ESßL-producing E. coli ST10 in South American camelids with historical and cultural importance supports successful expansion of international clones of priority pathogens in natural areas with public access.

Características clínicas y laboratoriales de los diez primeros pacientes con diagnóstico de Guillain-Barré en Piura, 2023

El síndrome de Guillain Barré es una enfermedad derivada del compromiso en las neuronas del sistema nervioso periférico por una respuesta descontrolada del sistema inmune que conduce daño axonal y/o desmielinización. El objetivo de este reporte fue describir los 10 primeros casos sospechosos de Síndrome de Guillain Barré en Piura. Se logró identificar la presencia de Campylobacter jejuni en las muestras de heces del 80% de los pacientes reportados. Es muy importante reconocer rápida y oportunamente al paciente con diagnóstico sospechoso de Guillain Barré, y realizar los estudios necesarios en un brote para identificar los agentes desencadenantes del cuadro.

Guillain Barré syndrome is a disease derived from compromise in neurons of the peripheral nervous system by an uncontrolled response from the immune system that leads to axonal damage and/or demyelination. The objective of this report was to describe the first 10 suspected cases of Guillain Barre Syndrome in Piura. It was possible to identify the presence of Campylobacter jejuni in the stool samples of 80% of the reported patients. It is very important to quickly and opportunely recognize the patient with a suspected diagnosis of Guillain Barré, and to carry out the necessary studies in an outbreak to identify the triggering agents of the condition.

The Synthesis of Novel aza-Steroids and α, ß-Unsaturated-Cyanoketone from Diosgenin.

Recent studies have demonstrated the antiproliferative and cytotoxic effects of aza-steroids and steroidal sapogenins on human cancer cell lines. The scientific community has shown a growing interest in these compounds as drug candidates for cancer treatment. In the current work, we report the synthesis of new diosgenin oxime derivatives as potential antiproliferative agents. From (25 R)-5α-spirost-3,5,6-triol (1), a diosgenin derivative, ketones 2, 3, 4, and 9 were obtained and used as precursors of the new oximes. A condensation reaction was carried out between the steroidal ketones (2, 3, 4, and 9) with hydroxylamine hydrochloride in 2,4,6-trimethylpyridine to produce five spirostanic oximes (four of them are not reported before) with a 42-96% yield. Also, a new spirostanic α, ß-unsaturated cyanoketone was synthesized via Beckmann fragmentation using thionyl chloride with a 62% yield. Furthermore, we proposed a reaction mechanism with the aim of explaining such transformation.

Pan American League of Associations for Rheumatology recommendations for the management of axial spondyloarthritis.

Axial spondyloarthritis (axSpA) comprises a spectrum of chronic inflammatory manifestations affecting the axial skeleton and represents a challenge for diagnosis and treatment. Our objective was to generate a set of evidence-based recommendations for the management of axSpA for physicians, health professionals, rheumatologists and policy decision makers in Pan American League of Associations for Rheumatology (PANLAR) countries. Grading of Recommendations, Assessment, Development and Evaluation-ADOLOPMENT methodology was used to adapt existing recommendations after performing an independent systematic search and synthesis of the literature to update the evidence. A working group consisting of rheumatologists, epidemiologists and patient representatives from countries within the Americas prioritized 13 topics relevant to the context of these countries for the management of axSpA. This Evidence-Based Guideline article reports 13 recommendations addressing therapeutic targets, the use of NSAIDs and glucocorticoids, treatment with DMARDs (including conventional synthetic, biologic and targeted synthetic DMARDs), therapeutic failure, optimization of the use of biologic DMARDs, the use of drugs for extra-musculoskeletal manifestations of axSpA, non-pharmacological interventions and the follow-up of patients with axSpA.

Discovery of a Digenean (Cryptogonimidae) Living in a Cleft-Lipped Goby, Sicyopterus cynocephalus (Teleostei: Gobiidae) from Ranongga Island, Solomon Islands: Analysis of Multiple Ribosomal DNA Regions.

This study results from a continued investigation of the occurrence and diversity of parasites of freshwater fish in the Solomon Islands. Thus, we revealed a new host as well as a new site of infection and a new geographical area for the cryptogonimid parasite, Stemmatostoma cribbi (Digenea: Cryptogonimidae). The cryptogonimid species was identified based on general morphology and on molecular data of metacercariae found in the gills of the cleft-lipped goby, Sicyopterus cynocephalus, from Ranongga Island, Western Province of the Solomon Islands. This is the first report of a Stemmatostoma sp. digenean parasitizing fish of the genus Sicyopterus in the Indo-Pacific region and the first report of S. cribbi infection in a fish from the Solomon Islands. Phylogenetic analysis performed by Bayesian inference and maximum likelihood confirmed the presence of the cryptogonimid in a well-supported subclade of Stemmatostoma spp.

Genomic analysis of multidrug-resistant Escherichia coli strains carrying the mcr-1 gene recovered from pigs in Lima-Peru.

Antibiotic resistance is a current problem that significantly impacts overall health. The dissemination of antibiotic resistance genes (ARGs) to urban areas primarily occurs through ARG-carrying bacteria present in the gut microbiota of animals raised in intensive farming settings, such as pig production. Hence, this study aimed to isolate and analyzed 87 Escherichia coli strains from pig fecal samples obtained from intensive farms in Lima Department. The isolates were subjected to Kirby-Bauer-Disk Diffusion Test and PCR for mcr-1 gene identification. Disk-diffusion assay revealed a high level of resistance among these isolates to oxytetracycline, ampicillin, cephalothin, chloramphenicol, ciprofloxacin, and doxycycline. PCR analysis identified the mcr-1 gene in 8% (7/87) E. coli isolates. Further, whole genome sequencing was conducted on 17 isolates, including multidrug resistance (MDR) E. coli and/or mcr-1 gene carriers. This analysis unveiled a diverse array of ARGs. Alongside the mcr-1 gene, the blaCTX-M55 gene was particularly noteworthy as it confers resistance to third generation cephalosporins, including ceftriaxone. MDR E. coli genomes exhibited other ARGs encoding resistance to fosfomycin (fosA3), quinolones (qnrB19, qnrS1, qnrE1), tetracyclines (tetA, tetB, tetD, tetM), sulfonamides (sul1, sul2, sul3), amphenicols (cmlA1, floR), lincosamides (inuE), as well as various aminoglycoside resistance genes. Additionally, Multi Locus Sequence Typing (MLST) revealed a high diversity of E. coli strains, including ST10, a pandemic clone. This information provides evidence of the dissemination of highly significant ARGs in public health. Therefore, it is imperative to implement measures aimed at mitigating and preventing the transmission of MDR bacteria carrying ARGs to urban environments.

Cytotoxic Activity, Topoisomerase I Inhibition and In Silico Studies of New Sesquiterpene-aryl Ester Derivatives of (-) Drimenol.

In this study, we aimed to evaluate two sets of sesquiterpene-aryl derivatives linked by an ester bond, their cytotoxic activities, and their capacity to activate caspases 3/7 and inhibit human topoisomerase I (TOP1). A total of 13 compounds were synthesized from the natural sesquiterpene (-)-drimenol and their cytotoxic activity was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and an immortalized non-tumoral cell line (MCF-10). From the results, it was observed that 6a was the most promising compound due to its cytotoxic effect on three cancer cell lines and its selectivity, 6a was 100-fold more selective than 5-FU in MCF-7 and 20-fold in PC-3. It was observed that 6a also induced apoptosis by caspases 3/7 activity using a Capsase-Glo-3/7 assay kit and inhibited TOP1. A possible binding mode of 6a in a complex with TOP1-DNA was proposed by docking and molecular dynamics studies. In addition, 6a was predicted to have a good pharmacokinetic profile for oral administration. Therefore, through this study, it was demonstrated that the drimane scaffold should be considered in the search of new antitumoral agents.

Study of Cannabis Oils Obtained from Three Varieties of C. sativa and by Two Different Extraction Methods: Phytochemical Characterization and Biological Activities.

Currently, much effort is being placed into obtaining extracts and/or essential oils from Cannabis sativa L. for specific therapeutic purposes or pharmacological compositions. These potential applications depend mainly on the phytochemical composition of the oils, which in turn are determined by the type of C. sativa and the extraction method used to obtain the oils. In this work, we have evaluated the contents of secondary metabolites, delta-9-tetrahydrocannabinol (THC), and cannabidiol (CBD), in addition to the total phenolic, flavonoids, and anthraquinone content in oils obtained using solid-liquid extraction (SLE) and supercritical fluid extraction (SCF). Different varieties of C. sativa were chosen by using the ratio of THC to CBD concentrations. Additionally, antioxidant, antifungal and anticancer activities on different cancer cell lines were evaluated in vitro. The results indicate that oils extracted by SLE, with high contents of CBD, flavonoids, and phenolic compounds, exhibit a high antioxidant capacity and induce a high decrease in the cell viability of the tested breast cancer cell line (MCF-7). The observed biological activities are attributed to the entourage effect, in which CBD, phenols and flavonoids play a key role. Therefore, it is concluded that the right selection of C. sativa variety and the solvent for SLE extraction method could be used to obtain the optimal oil composition to develop a natural anticancer agent.

Outpatient substance abuse treatment completion rates for racial-ethnic minorities during the Great Recession.

There has been minimal research linking the effects on racial-ethnic minorities' health outcomes, particularly research focused on racial-ethnic minorities seeking outpatient substance abuse treatment in the United States. The Great Recession from December 2007 to June 2009 in the United States provides the backdrop against the completion of substance abuse treatments among racial-ethnic minorities that may be associated with the impacts on users' social realities. We utilized data from the 2006-2011 Treatment Episode Datasets-Discharge (TEDS-D) dataset which collects data on outpatient substance abuse treatment institutions throughout the United States. The substance abuse treatment completion rates were higher prior to the Great Recession and lower following the Great Recession. Hispanics were more likely than non-Hispanic whites to complete substance abuse treatment, while other minority groups such as Non-Hispanic Blacks, were less likely to do so. Clients in the Northeast and West regions were more likely to successfully complete substance abuse treatment than those in the South. These findings have implications for impacting outpatient substance abuse treatment completion rates following the Great Recession to reduce racial-ethnic disparities which were impacted by region. Even amid an economic recession, treatment for substance abuse should continue to be a top concern.

Antifungal Activity of 2-Allylphenol Derivatives on the Botrytis cinerea Strain: Assessment of Possible Action Mechanism.

Botrytis cinerea is a phytopathogenic fungus that causes serious damage to the agricultural industry by infecting various important crops. 2-allylphenol has been used in China as a fungicide for more than a decade, and it has been shown that is a respiration inhibitor. A series of derivatives of 2-allylphenol were synthesized and their activity against B. cinerea was evaluated by measuring mycelial growth inhibition. Results indicate that small changes in the chemical structure or the addition of substituent groups in the aromatic ring induce important variations in activity. For example, changing the hydroxyl group by methoxy or acetyl groups produces dramatic increases in mycelial growth inhibition, i.e., the IC50 value of 2-allylphenol decreases from 68 to 2 and 1 µg mL-1. In addition, it was found that the most active derivatives induce the inhibition of Bcaox expression in the early stages of B. cinerea conidia germination. This gene is associated with the activation of the alternative oxidase enzyme (AOX), which allows fungus respiration to continue in the presence of respiratory inhibitors. Thus, it seems that 2-allylphenol derivatives can inhibit the normal and alternative respiratory pathway of B. cinerea. Therefore, we believe that these compounds are a very attractive platform for the development of antifungal agents against B. cinerea.

El impacto de la pandemia del COVID-19 en la educación médica: adaptabilidad y experiencia con enseñanza a distancia de la Sociedad Médica Peruano Americana

La pandemia del COVID-19 tuvo un impacto significativo en el cuidado y la educación médicos en el Perú. En respuesta, la Sociedad Médica Peruano Americana (PAMS), una organización médica benéfica con sede en los EE.UU., adoptó sus misiones médicas y educativas en Perú usando estrategias virtuales. Desarrollamos colaboración con varias facultades de medicina y la Asociación Peruana de Facultades de Medicina (ASPEFAM) y ofrecimos un panel de veinte y cuatro miembros para brindar conferencias y seminarios multidisciplinarios en español. Hicimos 19 seminarios, incluyendo temas relacionados y no relacionados al COVID-19, que en los últimos dos años atrajo a 14 489 participantes de 23 países. Ellas fueron la base de 20 publicaciones en revistas médicas peruanas. Nuestro concurso de investigaciones clínicas y nuestro proyecto piloto de mentoría de investigación fueron recibidos positivamente. La pandemia del COVID-19 tuvo un efecto positivo en la misión educativa de PAMS en Perú.

The COVID-19 pandemic had a significant impact on medical care and medical education in Peru. In response, the Peruvian American Medical Society (PAMS), a charitable medical organization based in the USA, pursued its medical and educational missions in Peru by adopting virtual learning technology. We developed closer collaborative relationships with several medical schools and the Peruvian Association of Medical Schools (ASPEFAM) while offering a faculty panel of twenty-four members to provide lectures and multidisciplinary webinars in Spanish. We conducted 19 webinars including COVID -19 and non-COVID-19 related topics that over the last two years attracted 14,489 participants from 23 countries. They were the foundation for twenty publications in Peruvian medical journals. Our clinical investigations competition was positively received as was our pilot project on research mentorship. The COVID -19 pandemic had a positive effect on the educational mission of PAMS in Peru.

Piperonal chalcone derivative incorporating the pyrazolo[3,4-b]pyridine moiety; crystal structure, spectroscopic characterization and quantum chemical investigations.

A single crystal of a piperonal chalcone derivative was obtained, fully characterized, and crystallized by a slow evaporation technique. The synthesized compound was characterized by UV-Visible, FT-IR, HRMS, 1H NMR, and 13C NMR spectroscopic studies and X-ray crystallography, revealing that the crystal belongs to a triclinic crystal system with a P1̄ space group, Z = 2. In the present work, we focus on molecular modeling studies such as Hirshfeld surface analysis, energy framework calculations, frontier molecular orbital analysis, natural bond orbital analysis, and NLO properties of a π-conjugate system combining the chalcone and the pyrazole[3,4-b]pyridine scaffolds to describe the in-depth structural analysis thereof. Good agreement was found between the calculated results and experimental data. In addition, Hirshfeld surface analysis of the crystal structure showed that the intermolecular stabilization in the crystal packing comes mainly from H⋯H bond interactions. The chalcone crystal exhibits significant NLO properties suggesting that it could be considered a potential candidate for application in nonlinear optical devices.

Cancer and brassinosteroids: Mechanisms of action, SAR and future perspectives.

Brassinosteroids are plant hormones whose main function is to stimulate plant growth. However, they have been studied for their biological applications in humans. Brassinosteroid compounds have displayed an important role in the study of cancer pathology and show potential for developing novel anticancer drugs. In this review we describe the relationship of brassinosteroids with cancer with focus on the last decade, the mechanisms of cytotoxic activity described to date, and a structure-activity relationship based on the available information.

Genomic insights into ESBL-producing Escherichia coli isolated from non-human primates in the Peruvian Amazon.

Introduction: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are on the WHO priority pathogens list because they are associated with high mortality, health-care burden, and antimicrobial resistance (AMR), a serious problem that threatens global public health and should be addressed through the One Health approach. Non-human primates (NHP) have a high risk of acquiring these antibiotic-resistant bacteria due to their close phylogenetic relationship with humans and increased anthropogenic activities in their natural environments. This study aimed to detect and analyze the genomes of ESBL-producing Escherichia coli (ESBL-producing E. coli) in NHP from the Peruvian Amazon. Materials and methods: We collected a total of 119 fecal samples from semi-captive Saguinus labiatus, Saguinus mystax, and Saimiri boliviensis, and captive Ateles chamek, Cebus unicolor, Lagothrix lagothricha, and Sapajus apella in the Loreto and Ucayali regions, respectively. Subsequently, we isolated and identified E. coli strains by microbiological methods, detected ESBL-producing E. coli through antimicrobial susceptibility tests following CLSI guidelines, and analyzed their genomes using previously described genomic methods. Results: We detected that 7.07% (7/99) of E. coli strains: 5.45% (3/55) from Loreto and 9.09% (4/44) from Ucayali, expressed ESBL phenotype. Genomic analysis revealed the presence of high-risk pandemic clones, such as ST10 and ST117, carrying a broad resistome to relevant antibiotics, including three blaCTX-M variants: blaCTX-M-15, blaCTX-M-55, and blaCTX-M-65. Phylogenomic analysis confirmed the clonal relatedness of high-risk lineages circulating at the human-NHP interface. Additionally, two ESBL-producing E. coli strains were identified as EPEC (eae) and ExPEC according to their virulence profiles, and one more presented a hypermucoviscous phenotype. Discussion: We report the detection and genomic analysis of seven ESBL-producing E. coli strains carrying broad resistome and virulence factors in NHP from two regions of the Peruvian Amazon. Some of these strains are closely related to high-risk pandemic lineages previously reported in humans and domestic animals, highlighting the negative impact of anthropogenic activities on Amazonian wildlife. To our knowledge, this is the first documentation of ESBL-producing E. coli in NHP from the Amazon, underscoring the importance of adopting the One Health approach to AMR surveillance and minimizing the potential transmission risk of antibiotic-resistant bacteria at the human-NHP interface.