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BackgroundCurrent rapid tests for syphilis and yaws can detect treponemal and non-treponemal antibodies. We aimed to critically appraise the literature for rapid diagnostic tests (RDTs) which can better distinguish an active infection of syphilis or yaws.MethodsWe conducted a systematic review and meta-analysis, searching five databases between January 2010 and October 2021 (with an update in July 2022). A generalised linear mixed model was used to conduct a bivariate meta-analysis for the pooled sensitivity and specificity. Heterogeneity was assessed using the I2statistic. We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) to assess the risk of bias and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to evaluate the certainty of evidence.ResultsWe included 17 studies for meta-analyses. For syphilis, the pooled sensitivity and specificity of the treponemal component were 0.93 (95% CI: 0.86 to 0.97) and 0.98 (95% CI: 0.96 to 0.99), respectively. For the non-treponemal component, the pooled sensitivity and specificity were 0.90 (95% CI: 0.82 to 0.95) and 0.97 (95% CI: 0.92 to 0.99), respectively. For yaws, the pooled sensitivity and specificity of the treponemal component were 0.86 (95% CI: 0.66 to 0.95) and 0.97 (95% CI: 0.94 to 0.99), respectively. For the non-treponemal component, the pooled sensitivity and specificity were 0.80 (95% CI: 0.55 to 0.93) and 0.96 (95% CI: 0.92 to 0.98), respectively.ConclusionsRDTs that can differentiate between active and previously treated infections could optimise management by providing same-day treatment and reducing unnecessary treatment.PROSPERO registration numberCRD42021279587.

Background Perceived stigma is a complex societal phenomenon that is harboured especially by female sex workers because of the interplay of a myriad of factors. As such, a precise measure of the contribution of different social practices and characteristics is necessary for both understanding and intervening in matters related to perceived stigma. We developed a Perceived Stigma Index that measures the factors that greatly contribute to the stigma among sex workers in Kenya, and thereby inform a framework for future interventions. Methods Social Practice Theory was adopted in the development of the Perceived Stigma Index in which three social domains were extracted from data collected in the WHISPER or SHOUT study conducted among female sex workers (FSW), aged 16–35 years in Mombasa, Kenya. The three domains included: Social demographics, Relationship Control and Sexual and Gender-based Violence, and Society awareness of sexual and reproductive history. The factor assessment entailed Exploratory Factor Analysis (EFA), Confirmatory Factor Analysis (CFA), and the internal consistency of the index was measured using Cronbach’s alpha coefficient. Results We developed a perceived stigma index to measure perceived stigma among 882 FSWs with a median age of 26 years. A Cronbach’s alpha coefficient of 0.86 (95% confidence interval (CI) 0.85–0.88) was obtained as a measure of the internal consistency of our index using the Social Practice Theory. In regression analysis, we identified three major factors that contribute to the perceived stigma and consists of : (i) income and family support (β = 1.69; 95% CI); (ii) society’s awareness of the sex workers’ sexual and reproductive history (β = 3.54; 95% CI); and (iii) different forms of relationship control e.g. physical abuse (β = 1.48; 95%CI that propagate the perceived stigma among the FSWs. Conclusion Social practice theory has solid properties that support and capture the multi-dimensional nature of perceived stigma. The findings support the fact that social practices contribute or provoke this fear of being discriminated against. Thus, in offering interventions to curb perceived stigma, focus should fall on the education of the society on the importance of acceptance and integration of the FSWs as part of the society and the eradication of sexual and gender based violence meted out on them. Trial registration The trial was registered in the Australian New Zealand Clinical Trials Registry, ACTRN12616000852459.

INTRODUCTIONMillions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.RATIONALEAs a result of the short evolutionary distance between humans and nonhuman primates, our proteins share near-perfect amino acid sequence identity. Hence, the effects of a protein-altering mutation found in one species are likely to be concordant in the other species. By systematically cataloging common variants of nonhuman primates, we aimed to annotate these variants as being unlikely to cause human disease as they are tolerated by natural selection in a closely related species. Once collected, the resulting resource may be applied to infer the effects of unobserved variants across the genome using machine learning.RESULTSFollowing the strategy outlined above we obtained whole-genome sequencing data for 809 individuals from 233 primate species and cataloged 4.3 million common missense variants. We confirmed that human missense variants seen in at least one nonhuman primate species were annotated as benign in the ClinVar clinical variant database in 99% of cases. By contrast, common variants from mammals and vertebrates outside the primate lineage were substantially less likely to be benign in the ClinVar database (71 to 87% benign), restricting this strategy to nonhuman primates. Overall, we reclassified more than 4 million human missense variants of previously unknown consequence as likely benign, resulting in a greater than 50-fold increase in the number of annotated missense variants compared to existing clinical databases.To infer the pathogenicity of the remaining missense variants in the human genome, we constructed PrimateAI-3D, a semisupervised 3D-convolutional neural network that operates on voxelized protein structures. We trained PrimateAI-3D to separate common primate variants from matched control variants in 3D space as a semisupervised learning task. We evaluated the trained PrimateAI-3D model alongside 15 other published machine learning methods on their ability to distinguish between benign and pathogenic variants in six different clinical benchmarks and demonstrated that PrimateAI-3D outperformed all other classifiers in each of the tasks.CONCLUSIONOur study addresses one of the key challenges in the variant interpretation field, namely, the lack of sufficient labeled data to effectively train large machine learning models. By generating the most comprehensive primate sequencing dataset to date and pairing this resource with a deep learning architecture that leverages 3D protein structures, we were able to achieve meaningful improvements in variant effect prediction across multiple clinical benchmarks. Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology, and is urgent given severe threats these species are facing. Here, we present high coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human-specific. This study will open a wide range of research avenues for future primate genomic research.One-Sentence SummaryThe whole genome sequences of 233 primate species provide insight into the determinants of genetic diversity, phylogenomics, and human uniqueness.

We collected >300 bacterial isolates from overwintering Dark-eyed Juncos ( Junco hyemalis) to find that ∼40% appear to degrade the structural protein of feathers using extracellular keratinase enzymes. A guild of bacteria (∼18% of total counts) grew significantly better on basal salt medium (BSM) plates containing feather meal than on BSM agar-only plates (∼8% total counts). The genus-level profile of the 107 most active keratinolytic bacterial isolates shows that nearly half are Bacillus species. Keratinolytic Frigoribacterium, Microbacterium, Okibacterium, Pantoea, Sphingomonas, Staphylococcus, and Stenotrophomonas were found, among others. Active isolates were shown to degrade whole feathers, used feather meal as a sole carbon and energy source, and produced zones of clearing indicative of extracellular proteases on milk agar plates. Our novel in vitro keratinase assay uses ninhydrin to quantitate the release of amino acids from exogenously added keratin, with Bacillus licheniformis str. ATCC 14580 serving as a positive control. Keratinolytic isolates were grown in the presence of feather meal to induce keratinase release and this conditioned medium, called the enzyme extract, was clarified by centrifugation and filtration. The enzyme reaction was completed in 30 min and was positively correlated with the amount of extract added, until reaching color saturation. Bacillus pumilus str. F166 was the most active isolate and Bacillus cereus str. F65 was about half as active as the positive control. Bacillus cereus str. F27 performed well too. We also have demonstrated strong keratinolytic activity against raw wool α-keratin. Juncos are long-distance migrant birds that carry bacteria on their feathers, both beneficial and harmful to plants. The abundant keratinolytic bacteria on feathers are capable of structurally damaging the feathers, potentially reducing bird fitness and reproductive success. Keratinases have uses in tanning, silage, and remediation. Keratinases may be useful in the treatment of onychomycoses and actinic keratoses in medical and veterinary settings.

With the increase of cosmetic injectable hyaluronic acid (HA), there have been more cases with serious complications, including skin necrosis, blindness, and cerebral embolism. Patients who have recovered from HA filler-induced total vision loss are extremely rare. We report a case of a 27-year-old female who developed severe ocular pain on the right side and total vision loss following a 1.0 ml HA filler injection in the nasal dorsum. She arrived at our hospital 4 hours later. Her visual acuity was no light perception (NLP), and she exhibited eyelid ptosis, ophthalmoplegia, and frontal and nasal ecchymosis. She was promptly treated with subcutaneous and retrobulbar hyaluronidase injections, as well as intra-arterial 1500 IU hyaluronidase injections into the right ophthalmic artery with DSA assistance. Her vision improved from NLP to counting fingers at 1.0 meters. Unfortunately, 13 hours later, she felt an intense headache, and her vision again decreased to NLP. We immediately performed an injection of 1500 IU hyaluronidase combined with 8 mg alteplase for intra-arterial thrombolysis (IAT) into the right ophthalmic artery. Her vision improved immediately afterward. After 3 months, her visual acuity had significantly recovered from NLP (admission vision status) to 20/50 (Snellen chart with glasses). Similarly, skin, conjunctival, eye movement, and ptosis symptoms completely recovered. This case demonstrates that reversal of complete blindness due to embolism of the ophthalmic and central retinal arteries could be accomplished through multidisciplinary therapies, especially IAT using fibrinolytic agents combined with hyaluronidase followed by an anticoagulant regimen. Level of evidence VThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .

This research paper investigates the novel triple remote phosphor layer for improving the remote phosphor’s angular chroma uniformity (ACU) of down-light lamps by using remote micro-patterned phosphor layers (RMPP). In addition, introducing the triple-layer (TL) RMPP is introduced to offer the potential approach to this objective. This analysis also measures the optical efficiency of the layers and the angle distribution of angular correlated color temperature (ACCT). Drawing a comparison between the traditional dual-layer (DL) RMPP and the proposed TL is furthermore critical to this study. According to the findings, the triple-layer phosphor configuration can achieve greater hue consistency while having a correlating colour temperature (CCT) variance merely measured at 441 K. Results in the single RMPP layer are 1390 K of the remote phosphor (RP) sheet setting and 556 K for the ACCT deviation. The recreation employing finite-difference time-domain (FDTD) as well as the approach of ray-tracing ensures an increase in angular color uniformity (ACU). The structure of DL and TL RMPPs results in a 6.68 % and 4.69 % gain in luminous efficiency, respectively, with the standard RMPP layer at a currently driving of 350 mA. The micro-patterned layer’s scattering characteristic and mixing effect may account for the increased ACU and luminous efficiency.

BackgroundMedical students' health and wellbeing are highly concerned during the COVID-19 pandemic. This study examined the impacts of fear of COVID-19 (FCoV-19S), healthy eating behavior, and health-related behavior changes on anxiety and depression.MethodsWe conducted an online survey at 8 medical universities in Vietnam from 7th April to 31st May 2020. Data of 5,765 medical students were collected regarding demographic characteristics, FCoV-19S, health-related behaviors, healthy eating score (HES), anxiety, and depression. Logistic regression analyses were used to explore associations.ResultsA lower likelihood of anxiety and depression were found in students with a higher HES score (OR = 0.98; 95%CI = 0.96, 0.99; p = 0.042; OR = 0.98; 95%CI = 0.96, 0.99; p = 0.021), and in those unchanged or more physical activities during the pandemic (OR = 0.54; 95%CI = 0.44, 0.66; p < 0.001; OR = 0.44; 95%CI = 0.37, 0.52; p < 0.001) as compared to those with none/less physical activity, respectively. A higher likelihood of anxiety and depression were reported in students with a higher FCoV-19S score (OR = 1.09; 95%CI = 1.07, 1.12; p < 0.001; OR = 1.06; 95%CI = 1.04, 1.08; p < 0.001), and those smoked unchanged/more during the pandemic (OR = 6.67; 95%CI = 4.71, 9.43; p < 0.001; OR = 6.77; 95%CI = 4.89, 9.38; p < 0.001) as compared to those stopped/less smoke, respectively. In addition, male students had a lower likelihood of anxiety (OR = 0.79; 95%CI = 0.65, 0.98; p = 0.029) compared to female ones.ConclusionsDuring the pandemic, FCoV-19S and cigarette smoking had adverse impacts on medical students' psychological health. Conversely, staying physically active and having healthy eating behaviors could potentially prevent medical students from anxiety and depressive symptoms.

The current decline in global biodiversity is most evident in amphibians with 41% percent of all species worldwide classified as threatened with extinction. Hence, a major challenge in amphibian conservation is the high number of threatened species, leading to a common approach of identifying priority species and regions for conservation efforts. As a part of one of 36 globally designated biodiversity hotspots, Vietnam is considered to be of particular importance for conservation action. To improve amphibian conservation in Vietnam, this study provides an updated species list and assesses their threat status by compiling data from a variety of sources. Furthermore, a Zoological Information Management System (ZIMS) analysis was conducted to determine the representation of extant amphibians from Vietnam in zoos worldwide. The batrachofauna of Vietnam is characterized by a high level of species richness and local endemism as well as a high rate of new discoveries, with more than half of the endemic species reported exclusively from their type locality, making them especially vulnerable to extinction. Up to 18% of all amphibians extant in Vietnam and 28% of endemic species are classified as threatened with extinction by the IUCN. In many cases, the IUCN Red List status is either missing or outdated, highlighting the urgent need of action. Around 14% of endemic amphibian species have been recorded exclusively from unprotected areas, suggesting prioritization for further research and conservation measures. The continuing decline in many species remains an unresolved problem. As a guide for future research and conservation measures, a list of the top 57 species was compiled. In addition, according to the ZIMS analysis, only 8% of threatened and 3% of endemic amphibian taxa from Vietnam are currently kept in zoos worldwide, and a richness analysis revealed that the highest density of husbandries is found in Europe and North America. To achieve maximum outcome for the conservation of threatened species, this study recommends a general shift by zoos towards maintaining species in greater need of captive assurance populations and breeding programs to support integrative strategies that combine in situ and ex situ conservation efforts following the IUCN’s One Plan Approach.

We report on the correlated investigation between piezoelectric properties and crystalline structure of PbZr0.52Ti0.48O3 (PZT) films under different oxygen pressures in the process of pulsed laser ...

The research aims to introduce a new decision-making model for designing a manufacturing line (ML) project in Vietnamese manufacturing plants. The new model has been built from the theory of made-in-Vietnam lean decision-making model and authenticated via multitude of practical methods (observation, surveys, in-depth interviews, and case studies). This model pursues the method of optimal thinking to make the most effective decision in designing manufacturing lines. The proposed model has been confirmed by practical application. The model would be used not only for Vietnamese enterprises but also for other enterprises in both developing and developed countries.

The polarization hysteresis loops and the dynamics of domain switching in ferroelectric Pb(Zr0.52Ti0.48)O3 (PZT), antiferroelectric PbZrO3 (PZ) and relaxor-ferroelectric Pb0.9La0.1(Zr0.52Ti0.48)O3 (PLZT) thin films deposited on Pt/Ti/SiO2/Si substrates were investigated under various bipolar electric fields during repetitive switching cycles. Fatigue behavior was observed in PZT thin films and was accelerated at higher bipolar electric fields. Degradation of energy storage performance observed in PZ thin films corresponds to the appearance of a ferroelectric state just under a high bipolar electric field, which could be related to the nonuniform strain buildup in some regions within bulk PZ. Meanwhile, PLZT thin films demonstrated fatigue-free in both polarization and energy storage performance and independent bipolar electric fields, which are probably related to the highly dynamic polar nanodomains. More importantly, PLZT thin films also exhibited excellent recoverable energy-storage density and energy efficiency, extracted from the polarization hysteresis loops, making them promising dielectric capacitors for energy-storage applications.

CD4 testing plays an important role in clinical management and epidemiological surveillance of HIV disease. Rapid, point-of-care (POC) CD4 tests can improve patients’ access to CD4 testing, enabling decentralization of HIV services. We conducted a profile review of the Visitect®CD4 and the Visitect®CD4 Advanced Disease (Omega Diagnostics, UK) – the two lateral flow, equipment-free POC CD4 tests, which can be used to identify people with HIV who have CD4 of less than 350 and 200 cells/μl, respectively. Using published data from independent studies, we discussed the performance and utility of these tests, highlighting the advantages as well as their limitations. The tests are user-friendly, acceptable to health care workers, and feasible to implement in primary health care settings and can provide reliable results for clinical decision-making. Hands-on training with pictorial instructions for use is needed to enhance test’s operator confidence in interpretation of test results. Quality assurance program should be in place to ensure the quality of testing. Development of a next-generation test with a cutoff of 100 cells/μl is recommended to identify patients with advanced immunosuppression for initiation of prophylaxis to reduce HIV-related death. Operational research is also needed to identify cost-effective implementation strategies in real-world settings.

The microstructure, ferroelectric, electric-field breakdown strength, and energy-storage properties of relaxor Pb0.9La0.1(Zr0.52Ti0.48)O3 (PLZT) thin films grown on flexible Ti foils using pulsed laser deposition were systematically investigated. Low temperature deposited PLZT thin films showed very slim polarization hysteresis loops with a high difference between maximum and remanent polarizations and low remanent polarization through modulating the film structure with a small columnar-grain size. An ultrahigh recoverable energy density (Ureco) of 40.9 J/cm3, excellent energy efficiency (η) of 80.2% and large breakdown strength (EBD) of 3000 kV/cm were achieved in a PLZT film deposited at the low temperature of 480 °C. More importantly, this film shows excellent charge-discharge cycling endurance with a small variation of both Ureco and η values (less than 3%) after 1010 cycles and good thermal stability under a wide operating temperature range from room temperature to 200 °C. These results indicate that the relaxor PLZT films deposited on thin Ti foils, even at low temperature, are a promising strategy to enhance energy-storage performance for pulse-power energy-storage systems with broad temperature range applications, especially in applications where the device weight is critical (lightweight) due to the thin and low density of Ti foils.

Relaxor-ferroelectric Pb0.9La0.1(Zr0.52Ti0.48)O3 (PLZT) films with a thickness of 1.2 μm were deposited on LaNiO3-buffered Ca2Nb3O10-nanosheet/Si. It was revealed how structural modification of a PLZT film, fabricated using pulsed laser deposition under various ablation rates, can be used to tune its energy-storage performance and piezoelectric-strain. A highest unipolar piezoelectric-strain of 0.71% with extremely low strain-hysteresis of 1.9% and corresponding normalized-strain of 142 pm/V under an electric field of 500 kV/cm were observed in the film deposited at an ablation rate of 50 Hz, and such film consists of vertical columnar-structure. Whereas, the film deposited at a low ablation rate of 10 Hz with dense-structure had the higher recoverable energy-storage density (50.2 J/cm3) and energy-storage efficiency (82.2%) due to the larger electric-breakdown strength (3150 kV/cm). The strongly improved performance by choosing an appropriate film structure is important for practical applications in pulse-power energy-storage as well as for the development of piezo-driven microelectromechanical-systems.

Osteoporosis is a common bone health disorder in hemodialysis patients that is linked with a higher morbidity and mortality rate. While previous studies have explored the associated factors of osteoporosis, there is a lack of studies investigating the impacts of health literacy (HL) and digital healthy diet literacy (DDL) on osteoporosis. Therefore, we aimed to investigate the associations of HL, DDL, and other factors with osteoporosis among hemodialysis patients. From July 2020 to March 2021, a cross-sectional study was conducted on 675 hemodialysis patients in eight hospitals in Vietnam. The data were collected by using the osteoporosis self-assessment tool for Asians (OSTA) and the 12-item short form of the health literacy questionnaire (HLS-SF12) on digital healthy diet literacy (DDL) and hemodialysis dietary knowledge (HDK). In addition, we also collected information about the socio-demographics, the clinical parameters, the biochemical parameters, and physical activity. Unadjusted and adjusted multinomial logistic regression models were utilized in order to investigate the associations. The proportion of patients at low, medium, and high levels of osteoporosis risk was 39.6%, 40.6%, and 19.8%, respectively. In the adjusted models, women had a higher likelihood of osteoporosis risk than men (odds ratio, OR, 3.46; 95% confidence interval, 95% CI, 1.86, 6.44; p < 0.001; and OR, 6.86; 95% CI, 2.96, 15.88; p < 0.001). The patients with rheumatoid arthritis (OR, 4.37; 95% CI, 1.67, 11.52; p = 0.003) and stomach ulcers (OR, 1.95; 95% CI, 1.01, 3.77; p = 0.048) were more likely to have a higher likelihood of osteoporosis risk than those without. The patients who had a higher waist circumference (WC), HL, and DDL were less likely to have a medium level of osteoporosis risk (OR, 0.95; 95% CI, 0.92, 0.98; p = 0.004; OR, 0.92; 95% CI, 0.88, 0.96; p < 0.001; OR, 0.96; 95% CI, 0.93, 0.99; p = 0.017, respectively) and a high level of osteoporosis risk (OR, 0.93; 95% CI, 0.89, 0.97; p = 0.001; OR, 0.89; 95% CI, 0.84, 0.94; p < 0.001; OR, 0.95; 95% CI, 0.91, 0.99; p = 0.008, respectively) compared with a low level of osteoporosis risk and to those with a lower WC, HL, and DDL. In addition, higher levels of hemoglobin (Hb) (OR, 0.79; 95% CI, 0.66, 0.95; p = 0.014), hematocrit (Hct) (OR, 0.95; 95% CI, 0.92, 0.99; p = 0.041), albumin (OR, 0.91; 95% CI, 0.83, 0.99; p = 0.030), and education (OR, 0.37; 95% CI, 0.16, 0.88; p = 0.025) were associated with a lower likelihood of a high level of osteoporosis risk. In conclusion, osteoporosis risk is highly prevalent in hemodialysis patients. Improved HL, DDL, education, WC, albumin, Hb, and Hct levels should be considered in preventing hemodialysis patients from developing osteoporosis.

To describe the frequency, clinical presentation and understand the pathophysiology of toe shortenings during urate-lowering treatment (ULT) of gout, a feature we called the shrinking toe sign.Sequential foot photographs and radiographs of 1141 consecutive gouty patients followed-up for at least 6 months under ULT were retrospectively scrutinized. Features from patients with toe shortenings were extracted from anonymized files. Tophi adjacent to the shortening sites were semi quantified on foot photographs and toe shortenings were measured on radiographs with the Corel draw software (Corel corporation, Canada). Measurement concordance was assessed by concordance correlation coefficients (CCC) and correlation between tophus scores and toe shortenings was analyzed by using linear model with a patient random effect. 97 patients who did not develop toe shortening during ULT were analyzed as controls.Shrinking toes were observed in 10 patients (0.9%) with tophaceous gout at joints with baseline destructive arthropathy. The first and second toes and metatarsophalangeal joints were predominantly involved. The sign was observed after serum urate had been lowered below the 300 and 360 µmol/l targets, in 8 and 2 patients, respectively. Measured shortenings (CCC: 0.99) correlated (p 10The shrinking toe appears as rare feature of severe tophaceous gout, triggered by dissolution of bone-replacing tophi. Our findings reinforce the need to treat gout early, before destruction of bone scaffold by extensive tophi, as MSU crystal dissolution by ULT may further weaken these areas and induce their collapse.

Background Treatment of HIV with antiretroviral therapy (ART) can save lives and stop the spread of the virus. In 2014, UNAIDS launched the 90–90–90 treatment target. By 2020, it remains unattainable in many low and middle-income countries (LMICs). This review aimed to identify research gaps and needs for interventions to improve viral load monitoring and viral suppression for people living with HIV (PLHIV) in LMICs. Methods Medline and PubMed were searched to identify relevant literature, published in English between Dec 2015 and May 2020, using key search terms of a review published in 2016. The primary outcome was initial viral load (VL) monitoring (the proportion of PLHIV on ART and eligible for VL monitoring who receive a VL test). Secondary outcomes include follow-up VL monitoring (the proportion of PLHIV who receive a follow-up VL after an initial elevated VL test), confirmation of treatment failure (the proportion of PLHIV who had two consecutive elevated VL test results) and switching treatment regimen rates (the proportion of PLHIV switching treatment regimen after confirmation of treatment failure). Results The search identified 1829 non-duplicate records, of which 23 were included in the review. More than 80% (19/23) of included studies were conducted in 11 sub-Saharan African countries (SSA) and most were published in 2019–2020. Marked variations in initial VL monitoring coverage were reported across study settings (11–93%) and study populations (adults (25–93%), children and adolescents (2–94%), and pregnant women (32–67%)). Suboptimal uptake of follow-up VL monitoring and low regimen switching rates after confirmed treatment failure were observed. Conclusions Substantial gaps in VL coverage across study settings and study populations remained evident with limited data availability outside of SSA. Further research is needed to fill the data gaps. Interventions to address the ‘failure cascade’ in PLHIV on ART who fail to achieve viral suppression are required.

With the increase of cosmetic injectable hyaluronic acid (HA), there have been more cases with serious complications, including skin necrosis, blindness, and cerebral embolism. Patients who have recovered from HA filler-induced total vision loss are extremely rare. We report a case of a 27-year-old female who developed severe ocular pain on the right side and total vision loss following a 1.0 ml HA filler injection in the nasal dorsum. She arrived at our hospital 4 hours later. Her visual acuity was no light perception (NLP), and she exhibited eyelid ptosis, ophthalmoplegia, and frontal and nasal ecchymosis. She was promptly treated with subcutaneous and retrobulbar hyaluronidase injections, as well as intra-arterial 1500 IU hyaluronidase injections into the right ophthalmic artery with DSA assistance. Her vision improved from NLP to counting fingers at 1.0 meters. Unfortunately, 13 hours later, she felt an intense headache, and her vision again decreased to NLP. We immediately performed an injection of 1500 IU hyaluronidase combined with 8 mg alteplase for intra-arterial thrombolysis (IAT) into the right ophthalmic artery. Her vision improved immediately afterward. After 3 months, her visual acuity had significantly recovered from NLP (admission vision status) to 20/50 (Snellen chart with glasses). Similarly, skin, conjunctival, eye movement, and ptosis symptoms completely recovered. This case demonstrates that reversal of complete blindness due to embolism of the ophthalmic and central retinal arteries could be accomplished through multidisciplinary therapies, especially IAT using fibrinolytic agents combined with hyaluronidase followed by an anticoagulant regimen.Level of evidence VThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .

The profound effect of COVID-19 pandemic has not eluded Vietnam, a lower-middle-income country that borders China, the country where the outbreak originated. Currently facing a second wave, Vietnam experienced several months of insignificant community-transmission, when the epidemic was effectively under control. This paper provides an account of the policies developed by the national COVID-19 response team during the first wave, from January to July 2020. Three key components were identified, including (i) the timely and decisive responses from the national and local authorities in the early phase of the pandemic, (ii) a society-wide approach, supported by an effective risk communication strategy which managed to gain the public trust, and (iii) an effective preventive medicine and infectious disease control system, residing in early case identification, strict isolation, effective contact tracing and compulsory quarantine of close contacts. While several other important components of the health system, such as financing and human resources remain largely under-explored, the results of this study show that a mixture of measures may lead to an effective epidemic management.

Syphilis, a curable sexually transmitted infection, has re-emerged as a global public health threat with an estimated 5.6 million new cases every year. Pregnant women and men who have sex with men are key target populations for syphilis control and prevention programs. Frequent syphilis testing for timely and accurate diagnosis of active infections for appropriate clinical management is a key strategy to effectively prevent disease transmission. However, there are persistent challenges in the diagnostic landscape and service delivery/testing models that hinder global syphilis control efforts. In this commentary, we summarise the current trends and challenges in diagnosis of active syphilis infection and identify the data gaps and key areas for research and development of novel point-of-care diagnostics which could help to overcome the present technological, individual and structural barriers in access to syphilis testing. We present expert opinion on future research which will be required to accelerate the validation and implementation of new point-of-care diagnostics in real-world settings.

We present a 5D axion-neutrino model that explains the Standard Model fermion mass hierarchy and flavor structure, while simultaneously generating a high-quality axion. The axion and right-handed neutrinos transform under a 5D Peccei-Quinn gauge symmetry, and have highly suppressed profiles on the UV brane where the symmetry is explicitly broken. This setup allows neutrinos to be either Dirac, or Majorana with hierarchically small sterile neutrino masses. The axion decay constant originates from the IR scale, which in the holographically dual 4D description corresponds to the confinement scale of some new strong dynamics with a high-quality global Peccei-Quinn symmetry that produces a composite axion and light, composite sterile neutrinos. The sterile neutrinos could be observed in astrophysical or laboratory experiments, and the model predicts specific axion--neutrino couplings., Comment: 8 pages, 3 figures; v2: published version

Automation is the key for small and medium enterprises (SMEs) to gain profit and win market. Investment required for automation projects are normally high and would cost extra whenever upgrade is needed. Sometimes, present automation system cannot adapt to the change and must be replaced. These matters cause SMEs to consider whether to invest on automation or not. This paper proposes a concept for an automation system which can be integrated into larger systems with reasonable prices. A case study in footwear industry is analyzed and prototype of automated conveying system is fabricated to demonstrate the opportunity of this concept. The result of implementation proven that SMEs can save up to 50% of the cost if applying the proposed concepts.

The paper is to develop a stimulated model of an automatic production line in shoe manufacturing industry by integrating Internet of things (IoT) technology and industrial robots. Firstly, a conceptual design and prototype development of the simulated model is proposed for experimental study. Secondly, a control software in combination with human-machine interface (HMI) for the prototype is developed by using the programmable logic controller(PLC) and a Ardruno micro-controller. Finally, a model integrated system for automatic database management is provided by using the IoT technology.

The LEDs lighting device with phosphor ingredient (pcLEDs) is among the most common lighting methods in recent years and evaluated by chromatic uniformity and lighting capacity. Therefore, we introduce the phosphor particles that can improve the scattering efficiency (SEPs) to apply in pcLEDs at 8500 K correlated color temperature (CCT) with the expectation to produce better pcLEDs by enhancing both quantity and quality of emitted light. Combining various materials such as CaF 2 and SiO 2 with yellow Y 3 Al 5 O 12 :Ce 3+ phosphor composition in the pcLEDs simulation created by the LightTools program is the mechanism of this research. The simulated pcLEDs are tested and the results will be verified with Mie-scattering theory. The observation of the simulation leads to the conclusion about the scattering coefficients of SEPs at 455 nm and 595 nm wavelengths. The calculation showed that CaF 2 is better for color homogeneity yet suffer from luminous flux deficiency as the concentration gets higher. On the other hand, SiO 2 is the scattering enhancement material that can maintain high luminous flux regardless of its concentration.

Color uniformity is one of the essentials for the on-going development of WLED. To achieve a high color uniformity index, increasing the scattering events within the phosphor layers was reported to be the most efficient method and in this article, ZnO is the chosen material to apply in this method. After analyzing the scattering properties through the scattering cross-section 𝐶𝑠𝑐𝑎(𝐷,𝜆), scattering coefficient 𝜇𝑠𝑐𝑎(𝜆) and scattering phase function 𝜌(𝜃,𝜆), the which outcomes comfirm that ZnO can enhance the scattered light in the phosphor layers. Moreover, the findings from the study of ZnO concentration from 2% to 26% suggest that color uniformity also depends on the fluctuation of ZnO concentration, therefore, to control color uniformity the focus should be implied on both size and concentration of ZnO. The experimental results from this research show that the luminous flux of WLED is at the peak if the concentration of ZnO is at 6%, and when the concentration of ZnO is at 18% and has 100 nm particles size, the ΔCCT reaches the lowest level. The final choice should be based on the desired characteristic of WLEDs, however, if the WLED need to excel in both luminous flux and ΔCCT then 6% ZnO concentration with particles size from 100 nm-300 nm is the optimal choice.

Additional co-authors: Fabiano R de MELO, P Fan, Cyril C Grueter, Diana C Guzman-Caro, Eckhard W Heymann, Ilka Herbinger, Minh D Hoang, Robert H Horwich, Tatyana Humle, Rachel A Ikemeh, Inaoyom S Imong, Leandro Jerusalinsky, Steig E Johnson, Peter M Kappeler, Maria Cecilia M Kierulff, Inza Kone, Rebecca Kormos, Khac Q LE, Baoguo Li, Andrew J Marshall, Erik Meijaard, Russel A Mittermeier, Yasuyuki Muroyama, Eleonora Neugebauer, Lisa Orth, Erwin Palacios, Sarah K Papworth, Andrew J Plumptre, Ben M Rawson, Johannes Refisch, Jonah Ratsimbazafy, Christian Roos, Joanna M Setchell, Rebecca K Smith, Tene Sop, Christoph Schwitzer, Kathy Slater, Shirley C Strum, William J Sutherland, Mauricio Talebi, Janette Wallis, Serge Wich, Roman M Wittig, Hjalmar S Kuhl

The impact of polarization effects induced by a ferroelectric layer on the on-state performance of ferroelectric gate AlGaN/GaN HEMTs has been studied by using experiments and extensive TCAD simulations. Stress-free and high quality crystalline (111) lead-zirconate-titanate ($\mathrm{P}\mathrm{b}(\mathrm{Z}\mathrm{r}_{x}\mathrm{T}\mathrm{i}_{1-x})\mathrm{O}_{3}$ or PZT) films on top of GaN have been successfully obtained by adopting a single magnesium-oxide (MgO) monolayer as a buffer layer. By adjusting the zirconium composition (x) of PZT, solely the spontaneous polarization in PZT is varied. In addition a onedimensional electrostatic model has been derived showing the impact of the polarization in the ferroelectric gate on the 2DEG sheet density and threshold voltage ($V_{\mathrm{T}\mathrm{H}}$), which is in good agreement with TCAD simulations. The experimental data show for $x=0.20$ a minimum on-resistance $(R_{\mathrm{O}\mathrm{N}})$ of $\sim 9.7\mathrm{k}\Omega$ and for $x=0.52$ a minimal $V_{\mathrm{T}\mathrm{H}}$ of ~-3.3V. The results are important for providing a guide line to optimize ferroelectric gate AlGaN/GaN HEMTs.

Threats to biodiversity are well documented. However, to effectively conserve species and their habitats, we need to know which conservation interventions do (or do not) work. Evidence-based conservation evaluates interventions within a scientific framework. The Conservation Evidence project has summarized thousands of studies testing conservation interventions and compiled these as synopses for various habitats and taxa. In the present article, we analyzed the interventions assessed in the primate synopsis and compared these with other taxa. We found that despite intensive efforts to study primates and the extensive threats they face, less than 1% of primate studies evaluated conservation effectiveness. The studies often lacked quantitative data, failed to undertake postimplementation monitoring of populations or individuals, or implemented several interventions at once. Furthermore, the studies were biased toward specific taxa, geographic regions, and interventions. We describe barriers for testing primate conservation interventions and propose actions to improve the conservation evidence base to protect this endangered and globally important taxon.

Aberrant activation of Wnt/β-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.

Medical staff caring for COVID-19 patients face mental stress, physical exhaustion, separation from families, stigma, and the pain of losing patients and colleagues. Many of them have acquired SARS-CoV-2 and some have died. In Africa, where the pandemic is escalating, there are major gaps in response capacity, especially in human resources and protective equipment. We examine these challenges and propose interventions to protect healthcare workers on the continent, drawing on articles identified on Medline (Pubmed) in a search on 24 March 2020. Global jostling means that supplies of personal protective equipment are limited in Africa. Even low-cost interventions such as facemasks for patients with a cough and water supplies for handwashing may be challenging, as is ‘physical distancing’ in overcrowded primary health care clinics. Without adequate protection, COVID-19 mortality may be high among healthcare workers and their family in Africa given limited critical care beds and difficulties in transporting ill healthcare workers from rural to urban care centres. Much can be done to protect healthcare workers, however. The continent has learnt invaluable lessons from Ebola and HIV control. HIV counselors and community healthcare workers are key resources, and could promote social distancing and related interventions, dispel myths, support healthcare workers, perform symptom screening and trace contacts. Staff motivation and retention may be enhanced through carefully managed risk ‘allowances’ or compensation. International support with personnel and protective equipment, especially from China, could turn the pandemic’s trajectory in Africa around. Telemedicine holds promise as it rationalises human resources and reduces patient contact and thus infection risks. Importantly, healthcare workers, using their authoritative voice, can promote effective COVID-19 policies and prioritization of their safety. Prioritizing healthcare workers for SARS-CoV-2 testing, hospital beds and targeted research, as well as ensuring that public figures and the population acknowledge the commitment of healthcare workers may help to maintain morale. Clearly there are multiple ways that international support and national commitment could help safeguard healthcare workers in Africa, essential for limiting the pandemic’s potentially devastating heath, socio-economic and security impacts on the continent.

Introduction: Regulation of Th1/Th2 balance in the tumor microenvironment (TME) plays an important role in both tumor progression and response to immunotherapy. The IL-4/IL-13 pathway induces an anti-inflammatory (Th2) response by stimulating M2 skewing of tumor associated macrophage (TAM) and myeloid derived suppressor cells (MDSCs), thereby supporting tumor growth by suppressing Th1 response. Therefore, inhibition of the IL-4/IL-13 pathway has the potential to inhibit tumor growth by shifting the TME towards a pro-inflammatory response. To achieve this, we engineered a long-acting IL-13 super-antagonist (i.e., Fc-MDNA413) to target the IL-13Rα1 component of type II IL-4 receptor (IL-4Rα/IL-13α1) expressed on TAMs and MDSCs to inhibit their differentiation and expansion for immuno-oncological applications. Experimental Procedure: Studies conducted include binding analyses by Biacore/SPR, signaling analyses in IL-4/IL-13 cell reporters, in vitro cell proliferation, in vitro M1/M2 macrophage polarization and in vivo efficacy in syngeneic tumor models. Summary of Data: IL-13Rα1 and IL-4Rα constitute the type II IL-4R that drives a Th2 response upon activation by IL-4 and IL-13. Binding studies showed that in comparison to wild-type Fc-IL13, Fc-MDNA413 has higher affinity for IL-13Rα1 but lower affinity for the decoy IL-13Rα2 receptor, indicating a more favorable receptor selectivity. In a cell-based reporter assay, Fc-MDNA413 inhibits both IL-4 and IL-13 induced p-STAT6 signaling, a pathway that drives towards a Th2 response. The antagonism of Fc-MDNA413 was also observed in an IL-13 dependent TF-1 proliferation assay where dose-dependent inhibition of cell proliferation was demonstrated. In a macrophage polarization assay with human primary myeloid cells, Fc-MDNA413 inhibited both IL-4 and IL-13 induced M2 polarization in a dose-dependent manner, consistent with an inhibitory effect on IL-4/IL-13 signaling. Treatment of tumor bearing mice with Fc-MDNA413 inhibited tumor growth in multiple syngeneic tumor models (e.g., EMT6 breast cancer and KLN205 lung cancer) known to have higher percentage of TAMs and MDSCs in TME, hence demonstrating the therapeutic potential of this long-acting IL-4/IL-13 super-antagonist. Conclusion: Fc-MDNA413 is a long-acting IL-4/IL-13 super-antagonist that inhibits IL-4 and IL-13 induced signaling and M2 skewing of macrophages, resulting in tumor growth inhibition in vivo. Ongoing studies include testing in additional syngeneic tumor models, deciphering in vivo mechanism of action and investigating potential synergy with other therapies. Next generation multifunctional superkines that incorporate IL-4/IL-13 antagonism are under development to target immunologically challenging tumors. Citation Format: Aanchal Sharma, Manjunatha Ankathatti Munegowda, Fahar Merchant, Minh D. To. Characterization of a long-acting IL-13 super-antagonist engineered to target tumor associated macrophages and myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5542.

Introduction: Combination studies with engineered IL-2 variants and immune-checkpoint blockade have demonstrated synergy in both pre-clinical models and the clinic. Co-administration of those 2 agents can potentially face challenges related to overlapping toxicities in obtaining optimal doses for synergistic effects. We propose to potentiate the synergy by enabling cis activation of IL-2 agonism and blockade of PD-1/PDL-2 binding with a single anti-PD1-IL2 to generate Bifunctional SuperKines for ImmunoTherapy (BiSKIT). Both human (h) and mouse (m) versions of anti-PD1 are fused with MDNA109FEAA, an IL-2 superkine with enhanced affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). Experimental Procedure: Studies included binding analyses with Biacore/SPR, signaling analyses in an IL-2 cell reporter assay, cell proliferation assay, in vitro pSTAT5 signaling in human PBMCs, PD1/PDL-1 cell reporter assay and efficacy in syngeneic tumor models. Summary of Data: Anti-hPD1-MDNA109FEAA and surrogate anti-mPD1-MDNA109FEAA were tested in both in vitro and in vivo assays. Both constructs demonstrated selective binding to either hPD1 or mPD1 as expected, and the MDNA109FEAA motif retained its receptor selectivity (enhanced affinity to CD122 and no binding to CD25). In both HEK-Blue IL-2 reporter and CTLL-2 proliferation bioassays, anti-PD1-MDNA109FEAA exhibited similar agonistic effect as MDNA109FEAA-Fc, demonstrating that potency towards the IL-2 axis was not diminished. This was further confirmed with pSTAT5 signaling in primary human PBMCs where anti-PD1-MDNA109FEAA showed enhanced activation of CD8 T-cells and NK cells with reduced activity on Treg when compared to rhIL-2. Both constructs were also effective at inhibiting PD1/PDL-1 pathway in respective human and mouse specific cell-based reporter assays. In a CT26 syngeneic colon tumor model, anti-mPD1-MDNA109FEAA exhibited superior efficacy over monotherapy and combination with anti-mPD1 and MDNA109FEAA-Fc when administered at equal molar dosage and same schedule. Conclusion: We have engineered anti-PD1-MDNA109FEAA to enable cis engagement with IL-2 receptor and PD1 as an approach to activate immune cells while reducing their exhaustion. Anti-mPD1-MDNA109FEAA achieved potent efficacy in a CT26 colon tumor model and is currently being evaluated in additional syngeneic tumor models with varying responsiveness to immune checkpoint blockade. Citation Format: Minh D. To, Manjunatha Ankathatti Munegowda, Rosemina Merchant, Aanchal Sharma. An ‘anti-PD1-IL2 beta-only super-agonist’ displays potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5532.

Millions of people in the United States regularly acquire information from weather forecasts for a wide variety of reasons. The rapid growth in mobile device technology has created a convenient means for people to retrieve this data, and in recent years, mobile weather applications (MWAs) have quickly gained popularity. Research on weather sources, however, has been unable to sufficiently capture the importance of this form of information gathering. As use of these apps continues to grow, it is important to gain insight on the usefulness of MWAs to consumers. To better examine MWA preferences and behaviors relating to acquired weather information, a survey of 308 undergraduate students from three different universities throughout the southeast United States was undertaken. Analyses of the survey showed that smartphone MWAs are the primary weather forecast source among college students. Additionally, MWA users tend to seek short-term forecast information, like the hourly forecast, from their apps. Results also provide insight into daily MWA use by college students as well as perceptions of and preferential choices for specific MWA features and designs. The information gathered from this study will allow other researchers to better evaluate and understand the changing landscape of weather information acquisition and how this relates to the uses, perceptions, and values people garner from forecasts. Organizations that provide weather forecasts have an ever-growing arsenal of resources to disseminate information, making research of this topic extremely valuable for future development of weather communication technology.

Men who have sex with men (MSM) are disproportionally affected by the HIV epidemic. Self-efficacy is an important individual psychosocial factor associated with access to and use of health and HIV-related services. We estimated HIV testing prevalence and examined the relationship between HIV testing self-efficacy and self-reported HIV testing behavior among young MSM (YMSM) in Myanmar. We enrolled 585 MSM aged 18–24 years from six urban areas using respondent-driven sampling (RDS) technique. RDS analyses were performed to provide estimates for the key outcome of interest. More than a third (34.5%) had never been tested for HIV, whereas 27.5% and 38.0% had their most recent HIV test more than three months and within the past three months from the time of interview, respectively. Young MSM who reported high self-efficacy (adjusted relative risk ratio [ARR]=7.35, 95%CI = 2.29–23.5) and moderate self-efficacy (ARR = 8.61, 95%CI = 3.09–24.0) were more likely to report having tested for HIV in the past three months compared to their counterparts who reported low self-efficacy. Findings highlight a positive association between self-efficacy and HIV testing uptake, indicating a potential causal relationship. Further research is needed to examine the direction of this association and inform future public health interventions targeting YMSM in Myanmar.

BackgroundRecombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing.MethodsMDNA11 was evaluated using in vitro and in vivo studies including: binding analyses to measure receptor affinity, IL-2 pathway signaling, PK studies in mice, and efficacy studies in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors. Finally, the safety and pharmacodynamic profile of MDNA11 was assessed in non-human primate (NHP).ResultsBinding studies with MDNA11 demonstrated increased affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). As a result, MDNA11 exhibits reduced/limited Treg stimulation while triggering an enhanced activation of natural killer and naïve CD8 T cells compared with rhIL-2. When administered to animals with pre-established tumors, MDNA11 controlled tumor growth in a monotherapy setting and in combination with anti-PD1 or anti-CTLA4 to induce durable tumor clearance with a once weekly dosing regimen. In a NHP model, MDNA11 was well tolerated while triggering durable and potent immune responses including expansion of lymphocytes without significant effect on Tregs and eosinophils, the latter been linked to an increased risk of vascular leak syndrome.ConclusionMDNA11 is a next generation long-acting IL-2 immunotherapeutic with a highly favorable pharmacodynamic profile that translates to a strong therapeutic efficacy in preclinical tumor models and a strong and durable immune response in NHP.