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Introduction Exertional dyspnoea is the primary diagnostic symptom for chronic cardiopulmonary disease populations. Whilst a number of exercise tests are used, there remains no gold standard clinical measure of exertional dyspnoea. The aim of this review was to comprehensively describe and evaluate all types of fixed-intensity exercise tests used to assess exertional dyspnoea in chronic cardiopulmonary populations and, where possible, report the reliability and responsiveness of the tests. Methods A systematic search of five electronic databases identified papers that examined 1) fixed-intensity exercise tests and measured exertional dyspnoea, 2) chronic cardiopulmonary populations, 3) exertional dyspnoea reported at isotime or upon completion of fixed-duration exercise tests, and 4) published in English. Results Searches identified 8785 papers. 123 papers were included, covering exercise tests using a variety of fixed-intensity protocols. Three modes were identified, as follows: 1) cycling (n=87), 2) walking (n=31) and 3) other (step test (n=8) and arm exercise (n=2)). Most studies (98%) were performed on chronic respiratory disease patients. Nearly all studies (88%) used an incremental exercise test. 34% of studies used a fixed duration for the exercise test, with the remaining 66% using an exhaustion protocol recording exertional dyspnoea at isotime. Exertional dyspnoea was measured using the Borg scale (89%). 7% of studies reported reliability. Most studies (72%) examined the change in exertional dyspnoea in response to different interventions. Conclusion Considerable methodological variety of fixed-intensity exercise tests exists to assess exertional dyspnoea and most test protocols require incremental exercise tests. There does not appear to be a simple, universal test for measuring exertional dyspnoea in the clinical setting.

Natural glues offer great potential as bio-inspired solutions to problems associated with the performance of synthetic adhesives. Spider viscous glues are elastic pressure sensitive adhesives (PSAs) that physically adhere to surfaces on contact across a range of environmental conditions. Extracting useful components from these secretions remains a challenge that can be met by the comparative analyses of functional analogues. Here we used 1H NMR spectroscopy and mass spectrometry to ascertain the organic salt compositions of the PSAs of four different species of Australian spiders belonging to two lineages that independently acquired aqueous gluey secretions: the St Andrew’s cross (Argiope keyserlingi), the redback (Latrodectus hasselti), the false widow (Steatoda grossa), and the daddy long-legs spider (Pholcus phalangiodes). The PSAs from each of these spiders contained similar organic salts, albeit in variable concentrations. The adhesives of the false widow and daddy long-legs spider had mixtures of only a few components, of which betaine predominated, while the PSAs of the other spiders predominantly contained small organic acids such as GABA/GABA-amide, isethionate, and choline salts. Our results suggest that the PSA composition of spiders is likely to be influenced more by environmental factors than evolutionary history and are guided by common principles. Our findings could be valuable for facilitating the design of more sustainable synthetic glues.

Reaction time and decision-making (DMA) in football have usually been evaluated using edited images or videos of game situations. The purpose of this research is to design and validate a test that simultaneously evaluates execution time (ET) and decision-making (DMA) in the subcategories of type of action (TA) and direction of movement (DM). Methodology: A quantitative, cross-sectional, and descriptive study of 30 young players. A total of 32 stimuli were programmed, corresponding to 64 responses, from which the total index (TI) was obtained from the division between DMA and ET. Results: The content validity index (CVI = 0.78) showed a high degree of consensus among experts. In the validation process, the intraclass correlation coefficient (ICC) was used to assess intraclass and interobserver reliability, and a moderate level of agreement was found between subjects for the TA (ICC = 0.593) and ET (ICC = 0.602) and a moderate high level of concordance for DM (ICC = 0.804) and TI (ICC = 0.855). Regarding interobserver reliability, an excellent level of agreement was found for all variables: TA (ICC = 0.998), DM (ICC = 0.998), ET (ICC = 1.000), and TI (ICC = 1.000). For the relationship between intraobserver and interobserver variables, statistical significance was established as p < 0.01. Finally, the intraobserver ETM (5.40%) and interobserver ETM (0.42%) was low compared with the reference value (5.9%). Conclusion: The designed test meets the validity criteria since the variables show sufficient intraclass reliability (test–retest) and reliability among observers.

Many digital rock methodologies use a direct simulation approach, where only resolved pores are accounted for. This approach limits the types of rocks that can be analyzed, excluding some types of carbonates, unconventionals, and complex sandstones from the digital rock analysis. This is due to the challenge for single scale imaging to capture the full range of relevant pore sizes present in multiscale rocks. In this paper, a physical model is presented, within the context of an established direct simulation approach, to predict the production of hydrocarbons including the contribution of sub-resolution pores. The direct simulation component of the model employs a multiphase lattice Boltzmann method to simulate multiphase fluid flow displacement in resolved pores. In the production model, the amount of hydrocarbons present in the sub-resolution pores is identified and a physical description of the production behavior is provided. This allows a relative permeability curve to be predicted for rocks where mobile hydrocarbons are present in pores smaller than the image resolution. This simplified model for the oil movement in the unresolved pore space is based on a physical interpretation of different regions marked by simulation resolution limits in a USBM wettability test curve. The proposed methodology is applied to high-resolution microCT images of a sandstone that contains pores at multiple scales, some resolved and some not resolved. To allow for benchmarking, experimental routine and special core analysis data was also obtained. Good agreement to experimental results is observed, specifically in absolute and relative permeability. The presented multiscale model has the potential to extend the classes of reservoir rocks eligible for digital rock analysis and paves the way for further advancements in the modelling of multiscale rocks, particularly unconventionals and carbonates.

Adhesive snares built from silks are fascinating adaptations that have rarely evolved outside spiders. Glowworms (Arachnocampa spp.) are an iconic part of the fauna of Australia and New Zealand that combine the construction of a sticky snare with a bioluminescent lure. Recently, the structure and biomechanical properties of glowworm silk have been studied in detail, but the chemical composition of its adhesive coating, and how it varies between species of Arachnocampa remained unclear, limiting an understanding of the glue function. Here, we studied the chemical composition of the water-soluble fraction of the adhesive droplets from the snares in cave and epigaeic populations of three species of Arachnocampa from mainland Australia, Tasmania, and New Zealand, using a combination of nuclear magnetic resonance and mass spectrometry. We found that glowworm glues comprise a large variety of small organic compounds, with organic acids, amino acids, amino acid derivates, alcohols, urea, and urea derivates being the major fraction, supplemented by small amounts of sugars, fatty acids, and other organic compounds. While there was a general overlap in the compounds detected in the adhesives of all tested Arachnocampa species and populations, the relative amounts differed considerably. We expect that these differences are a product of diet rather than an adaptive response to different environments, but experiments are needed for clarification. The high amount of polar substances and compounds that are hygroscopic at high humidity explains the adhesive properties of the viscous solution and its stability in damp environments. These results contribute to our understanding of the unique prey capture strategy of glowworms. Further, the comparison with convergent spider webs highlights the use of small polar compounds as plasticizers of macro-molecular bioadhesives as a general principle. This may inspire the biomimetic design of novel pressure sensitive adhesives with high performance under high humidity conditions.

BACKGROUND AND OBJECTIVE:The mechanism of dyspnoea associated with pleural effusion is uncertain. A cohort of patients requiring thoracoscopy for unilateral exudative effusion were investigated for associations between dyspnoea and suggested predictors: impaired ipsilateral diaphragm movement, effusion volume and restricted lung inflation. METHODS:Baseline Dyspnoea Index, respiratory function, and ultrasound assessment of ipsilateral diaphragm movement were assessed prior to thoracoscopy, when effusion volume was measured. Transitional Dyspnoea Index (change from baseline) was assessed 4 and 8 weeks after thoracoscopy. Pearson product moment assessed bivariate correlations and a general linear model examined how well total lung capacity (measuring restricted lung inflation), effusion volume and impaired diaphragm movement predicted Baseline Dyspnoea Index. Un-paired t tests compared the groups with normal and impaired diaphragm movement. RESULTS:19 patients were studied (14 malignant etiology). Total lung capacity was associated with Baseline Dyspnoea Index (r = 0.68, P = 0.003). Effusion volume (r = -0.138, P = 0.60) and diaphragm movement (P = 0.09) were not associated with Baseline Dyspnoea Index. Effusion volume was larger with impaired diaphragm movement compared to normal diaphragm movement (2.16 ±SD 0.95 vs.1.16 ±0.92 L, P = 0.009). Total lung capacity was lower with impaired diaphragm movement compared to normal diaphragm movement (65.4 ±10.3 vs 78.2 ±8.6% predicted, P = 0.011). The optimal general linear model to predict Baseline Dyspnoea Index used total lung capacity alone (adjusted R2 = 0.42, P = 0.003). In nine participants with controlled effusion, baseline effusion volume (r = 0.775, P = 0.014) and total lung capacity (r = -0.690, P = 0.040) were associated with Transitional Dyspnoea Index. CONCLUSIONS:Restricted lung inflation was the principal predictor of increased dyspnoea prior to thoracoscopic drainage of effusion, with no independent additional association with either effusion volume or impaired ipsilateral diaphragm movement. Restricted lung inflation may be an important determinant of the dyspnoea associated with pleural effusion.

Abstract Background Unprecedented efforts are underway to eliminate malaria. Mathematical modelling can help to determine the optimal strategies for malaria elimination in different epidemiological settings. This is necessary as there is limited scope for expensive and time-consuming field studies and failure of planned elimination strategies is likely to discourage ongoing investment by funders. However, there has been very little modelling of malaria elimination and little direct involvement of policymakers in its development. There is thus an urgent need for user-friendly and accessible models purpose-designed in collaboration with policymakers to answer pertinent questions arising from the field. Results An internet site is presented with a simple mathematical modelling platform for population level models of malaria elimination. It is freely accessible to all and designed to be flexible so both the platform and models can be developed through interaction with users. The site is an accessible introduction to modelling for a non-mathematical audience, and lessons learned from the project will help inform future development of mathematical models and improve communication of modelling results. Currently it hosts a simple model of strategies for malaria elimination and this will be developed, and more models added, over time. The iterative process of feedback and development will result in an educational and planning tool for non-modellers to assist with malaria elimination efforts worldwide. Conclusions By collaboration with end users, iterative development of mathematical models of malaria elimination through this internet platform will maximize its potential as an educational and public health policy planning tool. It will also assist with preliminary optimisation of local malaria elimination strategies before commitment of valuable resources.

Abstract Background Heterozygous and homozygous carriers of SCN5A-p.Ser1103Tyr, a common genetic variant with functional effects among African-Americans, have an increased risk of sudden death. We hypothesized that some heterozygous carriers may have unequal expression of wild-type and variant alleles and secondarily that predominance of the variant gene copy could further increase risk for sudden death in this population. Methods We quantified allele-specific expression of SCN5A-p.Ser1103Tyr by real-time reverse-transcription polymerase chain reaction (RT-PCR) in heart tissue from heterozygous African-American infants, who died from sudden infant death syndrome (SIDS) or from other causes, to test for allelic expression imbalance. Results We observed significant allelic expression imbalance in 13 of 26 (50%) African-American infant hearts heterozygous for SCN5A-p.Ser1103Tyr, and a significant (p < 0.0001) bimodal distribution of log2 allelic expression ratios. However, there were no significant differences in the mean log2 allelic expression ratios in hearts of infants dying from SIDS as compared to infants dying from other causes and no significant difference in the proportion of cases with greater expression of the variant allele. Conclusions Our data provide evidence that SCN5A allelic expression imbalance occurs in African-Americans heterozygous for p.Ser1103Tyr, but this phenomenon alone does not appear to be a marker for risk of SIDS.

An adult female rhesus macaque presented during routine annual physical examination for evaluation of a 2.5-cm diameter superficial ulcerated dermal lesion that was subsequently diagnosed as a systemic fungal infection caused by Cryptococcus gattii. Cryptococcus gattii is one of several basidiomycetic yeasts responsible for pulmonary, neurologic, and disseminated infections in humans and animals. This report describes the diagnosis, management, and clinical resolution of a C. gattii infection in an immunocompetent 5-year-old female rhesus macaque., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Transmission of HIV-1 to newborns and infants remains high, with 130,000 new infections in 2022 in resource-limited settings. Half of HIV-infected newborns, if untreated, progress to disease and death within 2 years. While immunologic immaturity likely promotes pathogenesis and poor viral control, little is known about immune damage in newborns and infants. Here we examined pathologic, virologic, and immunologic outcomes in rhesus macaques exposed to pathogenic simian-human immunodeficiency virus (SHIV) at 1-2 weeks, defined as newborns, or at 4 months of age, considered infants. Kinetics of plasma viremia and lymph node seeding DNA were indistinguishable in newborns and infants, but levels of viral DNA in gut and lymphoid tissues 6-10 weeks after infection were significantly higher in newborns versus either infant or adult macaques. Two of 6 newborns with the highest viral seeding required euthanasia at 25 days. We observed age-dependent alterations in leukocyte subsets and gene expression. Compared with infants, newborns had stronger skewing of monocytes and CD8+ T cells toward differentiated subsets and little evidence of type I interferon responses by transcriptomic analyses. Thus, SHIV infection reveals distinct immunological alterations in newborn and infant macaques. These studies lay the groundwork for understanding how immune maturation affects pathogenesis in pediatric HIV-1 infection.

Yellow fever virus (YFV) is endemic in >40 countries and causes viscerotropic disease with up to 20%-60% mortality. Successful live-attenuated yellow fever (YF) vaccines were developed in the mid-1930s, but their use is restricted or formally contraindicated in vulnerable populations including infants, the elderly, and people with compromised immune systems. In these studies, we describe the development of a next-generation hydrogen peroxide-inactivated YF vaccine and determine immune correlates of protection based on log neutralizing index (LNI) and neutralizing titer-50% (NT 50 ) studies. In addition, we compare neutralizing antibody responses and protective efficacy of hydrogen peroxide-inactivated YF vaccine candidates to live-attenuated YFV-17D (YF-VAX) in a rhesus macaque model of viscerotropic YF. Our results indicate that an optimized, inactivated YF vaccine elicits protective antibody responses that prevent viral dissemination and lethal infection in rhesus macaques and may be a suitable alternative for vaccinating vulnerable populations who are not eligible to receive replicating live-attenuated YF vaccines., Competing Interests: Declaration of interests Oregon Health & Science University (OHSU), M.K.S., E.H., and I.J.A. have a financial interest in Najít Technologies, Inc., a company that may have a commercial interest in the results of this research and technology. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU and Najít Technologies, Inc. M.S.D. is a consultant or member of a scientific advisory board for InBios, Ocugen, Vir Biotechnology, Topspin Therapeutics, and Moderna. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Emergent BioSolutions, Moderna, and Vir Biotechnology. I.J.A. and E.A.P. are inventors on US patent no. 10,744,198 entitled “Inorganic polyatomic oxyanions for protecting against antigenic damage during pathogen inactivation for vaccine production” and US patent nos. 11,141,475 and 11,633,470 entitled “Inactivating pathogens and producing highly immunogenic inactivated vaccines using a dual oxidation process.” M.K.S. and E.H. are inventors on US patent nos. 8,124,397 and 8,716,000 entitled “Inactivating pathogens with oxidizing agents for vaccine production.” No writing assistance was utilized in the production of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ethanol consumption is associated with positive, negative, and neutral effects on the skeletal system. Our previous work using a nonhuman primate model of voluntary ethanol consumption showed that chronic ethanol use has an impact on skeletal attributes, most notably on biochemical markers of bone turnover. However, these studies were limited by small sample sizes and resulting lack of statistical power. Here, we applied a machine learning framework to integrate data from 155 monkeys (100 ethanol and 55 controls) to identify the bone features associated with chronic ethanol use. Specifically, we analyzed the influence of ethanol consumption on biomarkers of bone turnover and cancellous and cortical bone architecture in tibia. We hypothesized that chronic ethanol use for 6 months to 2.5 years would result in measurable changes to cancellous features and the biochemical markers compared to control animals. We observed a decrease in bone turnover in monkeys exposed to ethanol; however, we did not find that ethanol consumption resulted in measurable changes in bone architecture., (© 2024. The Author(s).)

Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity., (© 2023. The Author(s).)

Rhesus macaques (Macaca mulatta) are amongst the most common nonhuman primate species used in biomedical research. These animals provide a precious resource for translational studies and opportunities to maximize rhesus data use are encouraged. Here we compile data produced from 10 years of investigator-driven pregnancy studies conducted at the Oregon National Primate Research Center (ONPRC). All pregnancies were generated within the consistent and reproducible protocols of the ONPRC time-mated breeding program. The data included are from control animals who did not experience in utero perturbations or experimental manipulations. A total of 86 pregnant rhesus macaques were delivered by cesarean section over a range of gestational days (G) 50 to G159 (where term is G165 ± 10 days in the rhesus macaque), with subsequent immediate tissue harvesting following standardized protocols. Fetal and placental growth measures, and all major organ weights are reported. All data are presented relative to gestational age for the entire cohort and in addition, data are stratified by fetal sex. The outcome is a large reference resource for use by laboratory animal researchers in future comparative fetal development studies., (© 2023 Wiley Periodicals LLC.)

Pesticides have been used in Canada since 1945 as part of large-scale aerial spray applications to control insect pests on forested lands. Some of the pesticides used historically were efficacious, nonselective, persistent, and have led to serious impacts on the environment. A well known, and extensively documented example is the large-scale aerial spray programs in New Brunswick, Canada. From 1952 to 1993, 97% of the 6.2 million ha of the forested lands of New Brunswick were treated with at least one application of one insecticide, the majority of which were applied to control outbreaks of eastern spruce budworm (Choristoneura fumiferana). The most well known insecticide was dichlorodiphenyltrichloroethane (DDT), applied from 1952 to 1968, which still persists in treated soils and adjacent water bodies, and caused the individual and cumulative ecosystem effects that can still be measured today. The insecticides that replaced DDT were nonpersistent and unlikely to be found today. However, during the years of application some of the insecticides were likely to have impacted local ecosystems to some degree. To aid future studies on the efficacy and environmental impact of these insecticides we created a digital spatial data set of known pesticide application in New Brunswick forestry from 1952 to 1993. The data set includes active ingredient, formulation, application rate, tank mix, aircraft type, and other ancillary information. The current version of the data is available on the New Brunswick Department of Natural Resources and Energy Development, GIS Open Data Page and in the supplemental material. Use of the data set for academic and educational purposes is encouraged, provided that both this data paper and the data source are properly cited; the Government of New Brunswick should be acknowledged as the data source (Open Government License http://www.snb.ca/e/2000/data-E.html)., (© 2023 His Majesty the King in Right of Canada and The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America. Reproduced with the permission of the Minister of Natural Resources.)

This study assists the interpretation of glass and paint evidence by filling an existing gap in the background occurrence that reflects the socioeconomic and demographic circumstances in the United States. The collection was performed in a college US city (Morgantown, West Virginia) to determine the effect of the type of clothing worn at different seasons on the presence of glass and paint. Tape lifts and sole scrapings (1038) were collected from 210 participants and up to six clothing and footwear areas per individual. Glass fragments were analyzed via polarized light microscopy (PLM), refractive index (RI), micro-X-Ray fluorescence (μXRF), and scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS), while paint specimens were examined by light microscopy and infrared spectroscopy (μFTIR). Higher occurrences of glass and paint were found in the winter season. The winter collection yielded 10 glass fragments and 68 paint particles, whereas the summer collection resulted in one glass fragment and 23 paint particles. The percentage of individuals with traces varied between seasons; 7% of individuals in the winter and 0.9% in the summer had glass, whereas 36% of individuals in the winter and 19% in the summer bore paint. Lastly, when considering the overall garment and footwear areas, glass was detected in 1.4% of the winter set, compared to 0.2% in the summer collection; paint was found in 9.2% of the winter collection, whereas only 4.2% was found in the summer set. There were no instances where both glass and paint were detected on the clothing and footwear of the same individual., (© 2023 American Academy of Forensic Sciences.)

Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here., (© 2023. The Author(s).)

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen empirically covered in pulmonary infections. Limited studies evaluate the relationship between the MRSA PCR nasal swab assays and clinically diagnosed ventilator-associated pneumonia (VAP), lung abscess, and empyema. This retrospective, single-center study included 161 patients, which aimed to validate the clinical utility of MRSA PCR nasal swabs in VAP, lung abscess, and empyema through sensitivity, specificity, positive predictive value (PPV), and negative predicative value (NPV) analysis. VAP had a 100% sensitivity, 89% specificity, 67% PPV, and 100% NPV.  Lung abscess had a 0% sensitivity, 90% specificity, 0% PPV, 90% NPV. Empyema had a 80% sensitivity, 84% specificity, 42% PPV, and 97% NPV. The study results demonstrate that the MRSA PCR nasal swab assay has the potential to be a vital tool in de-escalating antimicrobial therapy in VAP, lung abscess, and empyema., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rhesus and cynomolgus macaques are the most frequently used nonhuman primate (NHP) species for biomedical research and toxicology studies of novel therapeutics. In recent years, there has been a shortage of laboratory macaques due to a variety of competing factors. This was most recently exacerbated by the surge in NHP research required to address the severe acute respiratory syndrome (SARS)-coronavirus 2 pandemic. Continued support of these important studies has required the use of more varied cohorts of macaques, including animals with different origins, increased exposure to naturally occurring pathogens, and a wider age range. Diarrhea and diseases of the gastrointestinal tract are the most frequently occurring spontaneous findings in macaques of all origins and ages. The purpose of this review is to alert pathologists and scientists involved in NHP research to these findings and their impact on animal health and study endpoints, which may otherwise confound the interpretation of data generated using macaques.

Neuromuscular electrical stimulation (NMES) allows activation of muscle fibers in the absence of voluntary force generation. NMES could have the potential to promote muscle homeostasis in the context of muscle disease, but the impacts of NMES on diseased muscle are not well understood. We used the zebrafish Duchenne muscular dystrophy ( dmd ) mutant and a longitudinal design to elucidate the consequences of NMES on muscle health. We designed four neuromuscular stimulation paradigms loosely based on weightlifting regimens. Each paradigm differentially affected neuromuscular structure, function, and survival. Only endurance neuromuscular stimulation (eNMES) improved all outcome measures. We found that eNMES improves muscle and neuromuscular junction morphology, swimming, and survival. Heme oxygenase and integrin alpha7 are required for eNMES-mediated improvement. Our data indicate that neuromuscular stimulation can be beneficial, suggesting that the right type of activity may benefit patients with muscle disease., Competing Interests: EK, AI, KB, CS, DV, SA, KS, JM, AA, TS, AL, KT, BK, JK, CH No competing interests declared, (© 2022, Kilroy et al.)

Disulfide analogs of the alcohol sobriety medication disulfiram (Antabuse®) were evaluated for antimicrobial activity. Structure-activity relationship analyses of MIC data obtained for methicillin-resistant Staphylococcus aureus (MRSA) and other pathogenic organisms revealed correlations between the lipophilicity and bulkiness of the substituents. Analogs conferring optimal anti-MRSA activity contained S-octyl disulfides and either N,N-dimethyl- or N-pyrrolidine dithiocarbamate substituents. Additional testing revealed that both disulfiram and its S-octyl derivative are capable of sensitizing S. aureus to the bactericidal effects of fosfomycin. Mechanistic studies established that the compounds decrease intracellular levels of the fosB cofactor bacillithiol through a thiol-disulfide exchange reaction. The increased fosfomycin susceptibility in S. aureus was thereby attributed to a depleted cellular bacillithiol pool available for inactivation by fosB., (© 2022. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

While there is voluminous literature on pain in the context of medicine, pain as an aesthetic, representational, and epistemological issue remains undertheorized. The present article, after reviewing the nature of pain and surveying the emerging interdisciplinary field of graphic medicine, seeks to close-read sections of Georgia Webber's Dumb (2018) to demonstrate how the artist transforms the inexpressibility and invisibility of pain into a visual and sensate language. Webber's Dumb articulates a complex sense of pain, in which pain is conceived at once as a generative and also as a disabling force. Webber not only transforms pain into a knowable sensation but also teases out the relationship of pain with the creation of comics-artisanal labor-itself. This article also draws attention to the potential of the comics medium in visualizing and expressing pain, and it concludes by showing how pain is at once biological, cultural, and social.

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus. These animals demonstrated a paucity of CNS myelination accompanied by reactive astrogliosis, and a lack of PLP1 expression throughout white matter. Genetic analysis revealed that these animals were related to one another and that their parents carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These animals therefore represent the first reported non-human primate model of PMD, providing a novel and valuable opportunity for preclinical studies that aim to promote myelination in pediatric hypomyelinating diseases., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Colonic volvulus is an uncommon, often life-threatening condition, in non-human primates. Twenty-six cases of colonic volvulus in rhesus macaques (Macaca mulatta) were identified in necropsy records spanning 38 years at the Oregon National Primate Research Center (ONPRC). This report represents the largest collection of colonic volvuli in rhesus macaques., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Papillomaviruses (PVs) are a diverse group of host species-specific DNA viruses, etiologically linked with various benign and malignant neoplasms of cutaneous and mucosal epithelia. Here, we describe the detection and characterization of the first two PVs naturally infecting Japanese macaques ( Macaca fuscata ), including the determination of their etiological association(s) with the development of original neoplasms. The molecular and phylogenetic analyses were performed on complete genome sequences of Macaca fuscata PV types 1 (MfuPV1) and 2 (MfuPV2), which were completely sequenced in samples of a malignant oral tumor and benign anogenital neoplasm of Japanese macaques, respectively. Subsequently, two type-specific quantitative real-time PCRs were developed to estimate viral loads of MfuPV1 and MfuPV2 and to evaluate their etiological roles. The in silico molecular analyses revealed that both viral genomes encode characteristic PV proteins with conserved functional domains and have a non-coding genomic region with regulatory sequences to regulate and complete the viral life cycle. However, additional experimental evidence is needed to finally confirm the presence and biological functionality of the molecular features of both novel PVs. While MfuPV1, together with PVs identified in other macaques, is classified into the Alphapapillomavirus ( Alpha -PV) species 12, MfuPV2 is most likely a representative of the novel viral species within the Alpha -PV genus. Their relatively high viral loads suggest that both PVs are etiologically linked with the development of the original neoplasms.

Cryptococcus gattii was diagnosed in two female indoor-housed rhesus macaques. Gross and histopathologic findings included an isolated pulmonary cryptococcoma in a non-SIV-infected macaque and disseminated disease centered on the lungs of an SIV-infected macaque. Fungal yeast were positive with special stains, and the diagnoses were confirmed with a lateral flow assay and PCR., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Biomedical research involving animal models continues to provide important insights into disease pathogenesis and treatment of diseases that impact human health. In particular, nonhuman primates (NHPs) have been used extensively in translational research due to their phylogenetic proximity to humans and similarities to disease pathogenesis and treatment responses as assessed in clinical trials. Microscopic changes in tissues remain a significant endpoint in studies involving these models. Spontaneous, expected (ie, incidental or background) histopathologic changes are commonly encountered and influenced by species, genetic variations, age, and geographical origin of animals, including exposure to infectious or parasitic agents. Often, the background findings confound study-related changes, because numbers of NHPs used in research are limited by animal welfare and other considerations. Moreover, background findings in NHPs can be exacerbated by experimental conditions such as treatment with xenobiotics (eg, infectious morphological changes related to immunosuppressive therapy). This review and summary of research-relevant conditions and pathology in rhesus and cynomolgus macaques, baboons, African green monkeys, common marmosets, tamarins, and squirrel and owl monkeys aims to improve the interpretation and validity of NHP studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Periacetabular osteotomy (PAO) is an established treatment for symptomatic acetabular dysplasia in skeletally mature individuals without arthritis. Pelvic nonunion and associated stress fractures are under-reported. Nonunited stress fractures can cause continued buttock pain and pelvic instability. The aim of this study is to report on our experience managing patients with ongoing pain following nonunion of PAO., Patients and Methods: 8 patients presented to a tertiary referral pelvic service with symptomatic PAO nonunion between 2015-2018. All patients underwent open reduction internal fixation of the superior pubic ramus nonunion, with ipsilateral iliac autograft, at an average of 48.1 (15-82) months following initial osteotomy. Demographic and perioperative data were recorded. Follow-up was on average to 9.9 months, once union was confirmed radiographically., Results: All patients were female and average age was 31.8 (18-41) years. In 7/8 (87.5%) patients a modified Stoppa approach was successfully utilised. 1 patient required an ilioinguinal approach due to the amount of rotational correction. All patients went on to union at the superior pubic ramus and reported improvement in mechanical symptoms. 5/8 (62.5%) patients were noted to develop union of the posterior column or inferior pubic ramus stress fracture indirectly. 2/8 (25%) patients developed progression of intra-articular pain, despite restoration of pelvic stability. 1 patient required intraoperative transfusion due to femoral vein injury. There were no other complications seen in this series., Conclusions: To our knowledge, this is the largest case series of surgically managed PAO nonunion. Pelvic instability resulting from nonunion and stress fracture can be satisfactorily addressed by mobilising, grafting and plating the nonunion at the superior pubic ramus. The modified Stoppa approach is suitable in most cases, allowing excellent exposure whilst minimising the insult to soft tissues. The altered anatomy of the pelvis following PAO should be anticipated to reduce the risk to nearby neurovascular structures.

Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Campylobacter coli and Campylobacter jejuni are responsible for 400 million to 500 million cases of enteric disease each year and represent the most common cause of bacterial gastroenteritis worldwide. Despite its global importance, Campylobacter vaccine development has been hampered by the lack of animal models that recapitulate human disease pathogenesis. Here, we describe a naturally occurring Campylobacter -associated diarrhea model in outdoor-housed rhesus macaques. Using this model, we developed novel next-generation H 2 O 2 -based Campylobacter vaccines that induced strong antibacterial antibodies to multiple Campylobacter proteins including flagellin and provided up to 83% protection against severe C. coli -associated diarrhea. Whole-genome sequencing of circulating Campylobacter strains revealed little to no homology within lipooligosaccharide or capsular polysaccharide loci with the Campylobacter vaccine strains used in these studies, indicating that vaccine-mediated immunity was not restricted to a single homologous serotype. Together, these results demonstrate an important advance in vaccine development and a new approach to reducing Campylobacter -associated enteric disease., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility. Most cases are caused by mutations in keratin 5 ( KRT5 ) and keratin 14 ( KRT14 ). Mutations of these genes result in cytoskeletal disruption of the basal keratinocytes. Gross and histopathologic findings of 2 clinically affected homozygous rhesus macaques with an insertion variant mutation in KRT5 are described and compared with 6 deceased phenotypically normal animals that were heterozygous for the KRT5 insertion variant. Animals that were homozygous for the KRT5 insertion variant were stillborn and had widespread loss of the epidermis. Microscopic examination confirmed severe ulceration and basal cell vacuolation with basilar vesicle formation in the remaining intact epidermis. Immunohistochemistry for cytokeratin 5 demonstrated lack of epidermal immunoreactivity in homozygotes. DNA sequencing identified a 34-base pair insertion variant in exon 5 of the KRT5 gene. To our knowledge, this is the first report of epidermolysis bullosa in rhesus macaques.

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS., Competing Interests: The authors have declared that no competing interests exist.

Vertical transmission accounts for most human immunodeficiency virus (HIV) infection in children, and treatments for newborns are needed to abrogate infection or limit disease progression. We showed previously that short-term broadly neutralizing antibody (bNAb) therapy given 24 h after oral exposure cleared simian-human immunodeficiency virus (SHIV) in a macaque model of perinatal infection. Here, we report that all infants given either a single dose of bNAbs at 30 h, or a 21-day triple-drug ART regimen at 48 h, are aviremic with almost no virus in tissues. In contrast, bNAb treatment beginning at 48 h leads to tight control without adaptive immune responses in half of animals. We conclude that both bNAbs and ART mediate effective post-exposure prophylaxis in infant macaques within 30-48 h of oral SHIV exposure. Our findings suggest that optimizing the treatment regimen may extend the window of opportunity for preventing perinatal HIV infection when treatment is delayed.

The development of therapies for retinal disorders is hampered by a lack of appropriate animal models. Higher nonhuman primates are the only animals with retinal structure similar to humans, including the presence of a macula and fovea. However, few nonhuman primate models of genetic retinal disease are known. We identified a lineage of rhesus macaques with a frameshift mutation in exon 3 of the BBS7 gene c.160delG (p.Ala54fs) that is predicted to produce a non-functional protein. In humans, mutations in this and other BBS genes cause Bardet-Biedl syndrome, a ciliopathy and a syndromic form of retinitis pigmentosa generally occurring in conjunction with kidney dysfunction, polydactyly, obesity, and/or hypogonadism. Three full- or half-sibling monkeys homozygous for the BBS7 c.160delG variant, at ages 3.5, 4 and 6 years old, displayed a combination of severe photoreceptor degeneration and progressive kidney disease. In vivo retinal imaging revealed features of severe macular degeneration, including absence of photoreceptor layers, degeneration of the retinal pigment epithelium, and retinal vasculature atrophy. Electroretinography in the 3.5-year-old case demonstrated loss of scotopic and photopic a-waves and markedly reduced and delayed b-waves. Histological assessments in the 4- and 6-year-old cases confirmed profound loss of photoreceptors and inner retinal neurons across the posterior retina, with dramatic thinning and disorganization of all cell layers, abundant microglia, absent or displaced RPE cells, and significant gliosis in the subretinal space. Retinal structure, including presence of photoreceptors, was preserved only in the far periphery. Ultrasound imaging of the kidneys revealed deranged architecture, and renal histopathology identified distorted contours with depressed, fibrotic foci and firmly adhered renal capsules; renal failure occurred in the 6-year-old case. Magnetic resonance imaging obtained in one case revealed abnormally low total brain volume and unilateral ventricular enlargement. The one male had abnormally small testes at 4 years of age, but polydactyly and obesity were not observed. Thus, monkeys homozygous for the BBS7 c.160delG variant closely mirrored several key features of the human BBS syndrome. This finding represents the first identification of a naturally-occurring nonhuman primate model of BBS, and more broadly the first such model of retinitis pigmentosa and a ciliopathy with an associated genetic mutation. This important new preclinical model will provide the basis for better understanding of disease progression and for the testing of new therapeutic options, including gene and cell-based therapies, not only for BBS but also for multiple forms of photoreceptor degeneration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Although IL-15 has been implicated in the pathogenic hyperimmune activation that drives progressive HIV and SIV infection, as well as in the generation of HIV/SIV target cells, it also supports NK and T cell homeostasis and effector activity, potentially benefiting the host. To understand the role of IL-15 in SIV infection and pathogenesis, we treated two cohorts of SIVmac239-infected rhesus macaques (RM; Macaca mulatta ), one with chronic infection, the other with primary infection, with a rhesusized, IL-15-neutralizing mAb (versus an IgG isotype control) for up to 10 wk ( n = 7-9 RM per group). In both cohorts, anti-IL-15 was highly efficient at blocking IL-15 signaling in vivo, causing 1) profound depletion of NK cells in blood and tissues throughout the treatment period; 2) substantial, albeit transient, depletion of CD8 + effector memory T cells (T EM ) (but not the naive and central memory subsets); and 3) CD4 + and CD8 + T EM hyperproliferation. In primary infection, reduced frequencies of SIV-specific effector T cells in an extralymphoid tissue site were also observed. Despite these effects, the kinetics and extent of SIV replication, CD4 + T cell depletion, and the onset of AIDS were comparable between anti-IL-15- and control-treated groups in both cohorts. However, RM treated with anti-IL-15 during primary infection manifested accelerated reactivation of RM rhadinovirus. Thus, IL-15 support of NK cell and T EM homeostasis does not play a demonstrable, nonredundant role in SIV replication or CD4 + T cell deletion dynamics but may contribute to immune control of oncogenic γ-herpesviruses., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Ehrlichia chaffeensis (Rickettsiales: Anaplasmatacae), an understudied bacterial pathogen emerging in the eastern United States, is increasing throughout the range of its vector, the lone star tick [Amblyomma americanum, L. (Acari: Ixodidae)]. To mitigate human disease risk, we must understand what factors drive E. chaffeensis prevalence. Here, we report patterns of E. chaffeensis prevalence in southeastern Virginia across 4 yr and ask how seasonal weather patterns affect variation in rates of E. chaffeensis occurrence. We collected A. americanum nymphs at 130 plots across southeastern Virginia in 2012, 2013, 2015, and 2016, and used polymerase chain reaction and gel electrophoresis to test for the presence of E. chaffeensis DNA. Prevalence estimates varied among years, ranging from 0.9% to 3.7%, and persistence of E. chaffeensis occurrence varied across space, with some sites never testing positive, and one site testing positive every year. Using generalized linear mixed-effects models, we related E. chaffeensis occurrence to temperature, humidity, vapor-pressure deficit, and precipitation during seasons up to 21 mo prior to sampling. Surprisingly, all support was lent to a positive effect of temperature during the previous fall and winter (i.e., prior to the nymphs' hatching), which we hypothesize to influence reservoir host population dynamics through changes to mortality or natality. Although further work is necessary to truly elucidate the mechanisms at play, our study shows E. chaffeensis distribution to be very dynamic across multiple dimensions, demanding broad concerted monitoring efforts that can consider both space and time.

We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7 -/- ). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7 -/- macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-year disease course. Histological analyses showed an accumulation of cerebral, cerebellar and cardiac storage material as well as degeneration of neurons, white matter fragmentation and reactive gliosis throughout the brain of affected animals. This novel CLN7 -/- macaque model recapitulates key behavioral and neuropathological features of human Batten Disease and provides novel insights into the pathophysiology linked to CLN7 mutations. These animals will be invaluable for evaluating promising therapeutic strategies for this devastating disease., (Published by Elsevier Inc.)

Aims: A paucity of literature exists on prevalence of diabetic retinopathy (DR) in sub-Saharan Africa. We aim to estimate the prevalence of DR and visual impairment in Zambia's Copperbelt province through a cross-sectional study., Methods: All patients with a diagnosis of diabetes mellitus attending a DR screening programme were eligible to participate. Fundus photographs were graded in accordance with the DR grading system used in the UK National Health service (NHS). Visual impairment data were collected from visual acuity measurements recorded using Snellen chart., Results: A total of 2689 patients were screened and of these, 2153 patients had a least one eye of gradable quality for analysis. Fifty-five per cent (1190/2153) of patients were male. Mean age was 56 (SD 11). Fifty-two per cent (1113/2153) showed evidence of diabetic retinopathy (DR). Thirty-six per cent of patients graded (779/2153) had sight threatening DR. Proliferative DR was found in 7% (14/208) of type 1 diabetics compared to 5% (42/921) type 2 diabetics (p = <0.001). Duration of diabetes, random blood glucose, systolic and diastolic BP, and use of insulin and oral hypoglycaemics were strongly associated with DR in univariate analysis. The associations of increased systolic BP, random blood glucose, duration of diabetes and insulin use with DR were maintained in multivariate analysis., Conclusion: We observed a high prevalence of sight threatening DR which is close to the upper range of estimates that currently exist on DR. This study represents further evidence of global health inequality and the scale of the epidemic which sub-Saharan African countries now face.