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Background: Prevention of drug-resistant tuberculosis is a global health priority. However, trials evaluating the effectiveness of treating Mycobacterium tuberculosis infection among contacts of persons with drug-resistant tuberculosis are lacking., Methods: We conducted a double-blind, randomized, controlled trial comparing 6 months of daily levofloxacin (weight-based doses) with placebo to treat M. tuberculosis infection. The trial population comprised household contacts of persons with bacteriologically confirmed rifampicin-resistant or multidrug-resistant (MDR) tuberculosis in Vietnam. Contacts of any age with a positive tuberculin skin test or immunologic impairment were eligible. The primary end point was bacteriologically confirmed tuberculosis within 30 months. Secondary end points included grade 3 or 4 adverse events, death from any cause, and acquired drug resistance., Results: Of 3948 persons screened for eligibility, 61 (1.5%) had coprevalent tuberculosis (defined as active tuberculosis disease diagnosed before randomization) and 2041 underwent randomization. Of these 2041 participants, 1995 (97.7%) completed 30 months of follow-up, had a primary end-point event, or died. Confirmed tuberculosis occurred in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% confidence interval [CI], 0.19 to 1.62); this difference was not significant. There was little difference in grade 3 or 4 adverse events between the two groups (risk difference, 1.0 percentage point; 95% CI, -0.3 to 2.4). Adverse events of any grade were reported in 306 participants (31.9%) taking levofloxacin and 125 (13.0%) taking placebo (risk difference, 18.9 percentage points; 95% CI, 14.2 to 23.6). No acquired fluoroquinolone resistance was observed., Conclusions: Although the incidence of tuberculosis was lower in the levofloxacin group than in the placebo group at 30 months, the difference was not significant. (Funded by the National Health and Medical Research Council of Australia; VQUIN MDR Australia New Zealand Clinical Trials Registry number, ACTRN12616000215426.)., (Copyright © 2024 Massachusetts Medical Society.)

Non-sputum tests are needed to improve tuberculosis (TB) diagnosis and close the diagnostic gap. The World Health Organization's target product profile (TPP) for point-of-care (POC) screening tests requires a minimum sensitivity of 90% and a specificity of 70%. Our objective was to identify host blood protein biomarkers meeting TPP criteria. A systematic review was conducted and reported following PRISMA guidelines. Data extraction and quality assessment with Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) were completed for the included studies. Heterogeneity was assessed. For biomarkers reporting sensitivity and specificity in at least four studies, a random-effects meta-analysis was performed for biomarkers with similar cut-offs. We screened 4,651 citations and included 65 studies that enrolled 16,010 participants and evaluated 156 host proteins. Most (47/65) studies enrolled adult pulmonary TB (PTB), with 15 studies in adult extra-pulmonary TB and 5 in children. Small early-stage discovery studies with case-control design were common (24/65) and had a high risk of bias. For adult PTB, CRP, IP-10, NCAM-1, and SAA met TPP criteria in high-quality studies. There was a high degree of heterogeneity in biomarker cut-offs and study design. CRP at 10 mg/L cut-off was meta-analyzed from 10 studies; pooled sensitivity 86% [95% confidence interval (CI): 80-95] and pooled specificity 67% (95% CI: 54-79). In people living with HIV (six studies), CRP pooled sensitivity was 93% (95% CI: 90-95), and pooled specificity was 59% (95% CI: 40-78). We identified promising biomarkers that performed well in high-quality studies. Data overall are limited and highly heterogenous. Further standardized validation across subgroups in prospective studies is needed before translating into POC assays., Importance: To our knowledge, this is the first comprehensive systematic review of host blood protein biomarkers for tuberculosis (TB), and we identified promising biomarkers for a TB screening test., Competing Interests: The authors declare no conflict of interest.

Oxytocin pathways are hypothesized to play important roles in human-animal interactions and may contribute to some benefits of these interspecific social relationships. We explored the effects of naturalistic interactions between children and dogs on oxytocin release in both species, as well as associations between methylation of the oxytocin receptor gene (OXTRm), social behavior, and oxytocin response in this context. Children (N = 55) participated in a within-subjects design involving a) interaction with their pet dog, b) interaction with an unfamiliar dog, and c) a nonsocial control condition (solitary play). We used immunoassays to measure salivary and urinary oxytocin in both the children and dogs, behavioral coding to characterize dog-child interactions, and bisulfite sequencing to quantify methylation of the oxytocin receptor gene (N = 32 children). Child salivary oxytocin decreased moderately across time in all conditions, but the extent of this effect varied between conditions, with greater oxytocin output during interactions with dogs than the control condition. In the pet dog condition, children's salivary oxytocin response was positively associated with the duration of visual co-orientation between the child and dog. Child urinary oxytocin did not deviate substantially from baseline in any condition. Children with higher levels of OXTRm had greater oxytocin output during interactions with their pet dogs, but lower oxytocin output in the control condition, and engaged in lower levels of affectionate interaction with dogs across conditions. Children's pet dogs exhibited increases in salivary oxytocin, but we observed the opposite pattern in the unfamiliar dog, who exhibited decreases in both urinary and salivary oxytocin on average. Collectively, our results support the hypothesis that oxytocin pathways may shape and respond to social interactions between children and dogs, highlighting an important role for companion animals in child development., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The diagnosis of paediatric tuberculosis remains a challenge due to the non-specificity of symptoms and the paucibacillary nature of tuberculosis in children. However, in the development of new tuberculosis diagnostics, the unique needs of children and adolescents are rarely considered in the design process, with delays in evaluation and approval. No clear guidance is available on when and how to include children and adolescents in tuberculosis diagnostic development and evaluation. To address this gap, we conducted a Delphi consensus process with 42 stakeholders, including one qualitative and two quantitative rounds. Consensus was achieved on 20 statements, with agreement that the needs and perspectives of children, adolescents, and their caregivers should be incorporated throughout diagnostic design and evaluation. Opportunities exist for the early use of well characterised samples and prospective enrolment of children and adolescents in tuberculosis diagnostic evaluation, with consideration of the type of test, expected benefit, and potential risks. Pathogen-based tests might be initially optimised and assessed in adults and adolescents, but parallel evaluation in children is needed for host-based tests. Late-stage evaluation and implementation studies should examine combination testing and integration into clinical algorithms. The statements support collaboration between developers, researchers, regulators, and users to widen and accelerate the diagnostic pipeline for paediatric tuberculosis., Competing Interests: Declaration of interests SL receives royalties from UpToDate on the tuberculosis in Pregnancy topic; and receives funding from Merck for her institution for investigator-initiated SARS-CoV-2 related research. EMB and LO are supported by a fellowship from the European Society for Paediatric Infectious Diseases. ELM is supported by a Canadian Institutes of Health Research Fellowship (472823). MPN is supported by an Australian National Health and Medical Research Council Investigator Award 1174455. HJZ is supported by the South African Medical Research Council. All other authors declare no competing interests. This consensus process was supported by the National Institute of Allergy and Infectious Diseases Feasibility of Novel Diagnostics for TB in Endemic Countries for TB studies (U01AI152087, U01AI152084, and U01AI152075)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Oxytocin and cortisol are hormones that can influence cognition and behavior, but the relationships between endogenous concentrations and individual differences in cognitive and behavioral phenotypes remain poorly understood. Across mammals, oxytocin has important roles in diverse social behaviors, and in dogs, it has been implicated in human-oriented behaviors such as social gaze and point-following. Cortisol, an end-product of the hypothalamic-pituitary-adrenal (HPA) axis, is often studied in relation to temperament and emotional reactivity, but it is also known to modulate executive functions. In this study, we measured basal fecal cortisol (n = 247) and plasma oxytocin (n = 249) in dog puppies from a pedigreed population (Canine Companions ®). We collected cognitive and behavioral data from these subjects (n = 247), including measures of human-oriented social cognition, memory, inhibitory control, perceptual discriminations, and temperament. Oxytocin concentrations were estimated to be very highly heritable (h 2 = 0.90-0.99) and cortisol concentrations were estimated to be moderately-highly heritable (h 2 = 0.43-0.47). Bayesian mixed models controlling for relatedness revealed that oxytocin concentrations were positively associated with spatial working memory and displayed a negative quadratic relationship with behavioral laterality, but no credible associations were seen for social measures. Cortisol concentrations exhibited a negative linear relationship with performance on an inhibitory control task and a negative quadratic relationship with bold behavioral reactions to a novel object. Collectively, our results suggest that individual differences in oxytocin and cortisol concentrations are under strong genetic control in dogs and are associated with phenotypic variation in aspects of temperament, behavioral laterality, and executive function., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The large reservoir of tuberculosis (TB) infections is one of the main reasons for the persistent incidence of TB. Accurate diagnostic tests are crucial to correctly identify and treat people with TB infection, which is vital to eliminate TB globally. The rdESAT-6 and rCFP-10 (Cy-Tb) injection ('Cy-Tb'), a TB-specific antigen skin test and STANDARD F TB-Feron FIA ('Standard F TB') measuring interferon-gamma by fluorescence immunoassay assay are two novel tools for the diagnosis of TB infection which offer advantages compared with current tests in low-resource settings and reduced costs to both health systems and TB-affected people. The proposed study aims to evaluate the diagnostic accuracy of these two new tests for TB infection diagnosis., Methods and Analysis: This cross-sectional study aims to assess the diagnostic accuracy for TB infection of the Cy-Tb skin test and Standard F TB assay (investigational tests) compared with the QuantiFERON-TB Gold Plus (QFT-Plus) assay as the immunological reference standard. Three different cohorts of study participants will be recruited at the Vietnam National Lung Hospital: adults with bacteriologically confirmed pulmonary TB (n=100), household contacts of people with TB (n=200) and people without TB infection (n=50). All consenting participants will undergo simultaneous testing with Cy-Tb, Standard F TB and QFT-Plus. The primary endpoint is the diagnostic accuracy of the Cy-Tb skin test and Standard F TB assay, expressed as sensitivity and specificity against the reference standard., Ethics and Dissemination: Ethical approval was granted by the Vietnam National Lung Hospital Institutional Review Board (65/23/CN-HDDD-BVPTU) and the Swedish Ethical Review Authority (Dnr 2023-04271-01). Study results will be disseminated to the scientific community and policymakers through scientific publications., Trial Registration Number: NCT06221735., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Companion dogs are a valuable model for aging research, including studies of cognitive decline and dementia. With advanced age, some dogs spontaneously develop cognitive impairments and neuropathology resembling features of Alzheimer's disease. These processes have been studied extensively in laboratory beagles, but the cognitive assays used in that context-which rely on time-consuming operant procedures-are not easily scalable to large samples of community-dwelling companion dogs. We developed a battery of five short-form tasks targeting three aspects of cognition that are impaired in Alzheimer's disease: spatial memory, executive functions, and social cognition. In Experiment 1, we tested a cross-sectional sample of dogs (N = 123) and estimated associations between age and task performance. Older dogs scored lower on measures of spatial learning, memory, and response flexibility, and spent less time near, but more time gazing at, the experimenter. We found no differences in associations between age and performance across dogs of different body masses, a proxy for expected lifespan. In Experiment 2, we demonstrated the feasibility of these measures in clinical settings (N = 35). Dogs meeting clinical criteria for moderate or severe cognitive impairment scored lower, on average, than dogs characterized as mildly impaired and healthy agers, although these distributions overlapped. However, few dogs in our study cohort met the criteria for moderate or severe impairment. The measures presented here show promise for deployment in large-scale longitudinal studies of companion dogs, such as the Dog Aging Project., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Importance: Military members and veterans (hereafter, veterans) with posttraumatic stress disorder (PTSD) increasingly seek psychiatric service dogs as a complementary intervention, yet the effectiveness of service dogs is understudied., Objective: To estimate the associations between psychiatric service dog partnership and self-reported and clinician-rated PTSD symptom severity, depression, anxiety, and psychosocial functioning after 3 months of intervention among veterans., Design, Setting, and Participants: This nonrandomized controlled trial used standardized and validated assessment instruments completed by participants and administered by blinded clinicians. Recruitment, eligibility screening, and enrollment were conducted between August 2017 and December 2019. Veterans were recruited using the database of an accredited nonprofit service dog organization with constituents throughout the US. Participants were veterans with a PTSD diagnosis; they were allocated to either the intervention group (n = 81) or control group (n = 75). Outcome assessments were performed at baseline and at the 3-month follow-up. Data analyses were completed in October 2023., Interventions: Participants allocated to the intervention group received a psychiatric service dog for PTSD, whereas those allocated to the control group remained on the waiting list based on the date of application submitted to the service dog organization. Both groups had unrestricted access to usual care., Main Outcomes and Measures: The primary outcomes were PTSD symptom severity, depression, and anxiety after 3 months, and the secondary outcomes were psychosocial functioning, such as quality of life and social health. The self-reported PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was used to measure symptom severity, and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) was used to assess PTSD diagnosis (score range for both instruments: 0-80, with higher scores indicating greater PTSD symptoms)., Results: The 156 participants included in the trial had a mean (SD) age of 37.6 (8.3) years and included 117 males (75%), 17 Black or African American individuals (11%), 30 Hispanic individuals (19%), and 117 White individuals (76%). Compared with the control group, the intervention group had significantly lower PTSD symptom severity based on the PTSD Checklist for DSM-5 mean (SD) score (41.9 [16.9] vs 51.7 [16.1]; difference in means, -11.5 [95% CI, -16.2 to -6.6]; P < .001) and the CAPS-5 mean (SD) score (30.2 [10.2] vs 36.9 [10.2]; difference in means, -7.0 [95% CI, -10.8 to -4.5]; P < .001) at 3 months. The intervention group also had significantly lower depression scores (odds ratio [OR], 0.45 [95% CI, 0.23-0.86]; difference in means, -3.3 [95% CI, -6.8 to -0.6]), anxiety (OR, 0.25 [95% CI, 0.13-0.50]; difference in means, -4.4 [95% CI, -6.9 to -2.1]), and most areas of psychosocial functioning (eg, social isolation: OR, 0.34 [95% CI, 0.18-0.64])., Conclusions and Relevance: This nonrandomized controlled trial found that compared with usual care alone, partnership with a trained psychiatric service dog was associated with lower PTSD symptom severity and higher psychosocial functioning in veterans. Psychiatric service dogs may be an effective complementary intervention for military service-related PTSD., Trial Registration: ClinicalTrials.gov ID: NCT03245814.

Background: This scoping review aimed to characterise definitions used to describe subclinical tuberculosis (TB), estimate the prevalence in different populations and describe the clinical characteristics and treatment outcomes in the scientific literature., Methods: A systematic literature search was conducted using PubMed. We included studies published in English between January 1990 and August 2022 that defined "subclinical" or "asymptomatic" pulmonary TB disease, regardless of age, HIV status and comorbidities. We estimated the weighted pooled proportions of subclinical TB using a random-effects model by World Health Organization reported TB incidence, populations and settings. We also pooled the proportion of subclinical TB according to definitions described in published prevalence surveys., Results: We identified 29 prevalence surveys and 71 other studies. Prevalence survey data (2002-2022) using "absence of cough of any duration" criteria reported higher subclinical TB prevalence than those using the stricter "completely asymptomatic" threshold. Prevalence estimates overlap in studies using other symptoms and cough duration. Subclinical TB in studies was commonly defined as asymptomatic TB disease. Higher prevalence was reported in high TB burden areas, community settings and immunocompetent populations. People with subclinical TB showed less extensive radiographic abnormalities, higher treatment success rates and lower mortality, although studies were few., Conclusion: A substantial proportion of TB is subclinical. However, prevalence estimates were highly heterogeneous between settings. Most published studies incompletely characterised the phenotype of people with subclinical TB. Standardised definitions and diagnostic criteria are needed to characterise this phenotype. Further research is required to enhance case finding, screening, diagnostics and treatment options for subclinical TB., Competing Interests: Conflict of interest: All authors report no potential conflicts of interest., (Copyright ©The authors 2024.)

Competing Interests: We declare no competing interests.

Although research has shown that pets appear to provide certain types of social support to children, little is known about the physiological bases of these effects, especially in naturalistic contexts. In this study, we investigated the effect of free-form interactions between children (ages 8-10 years) and dogs on salivary cortisol concentrations in both species. We further investigated the role of the child-dog relationship by comparing interactions with the child's pet dog to interactions with an unfamiliar dog or a nonsocial control condition, and modeled associations between survey measures of the human-animal bond and children's physiological responses. In both children and dogs, salivary cortisol decreased from pre- to post-interaction; the effect was strongest for children interacting with an unfamiliar dog (compared to their pet dog) and for the pet dogs (compared to the unfamiliar dog). We found minimal evidence for associations between cortisol output and behaviors coded from video, but children scoring higher on survey measures of the human-animal bond exhibited the greatest reductions in cortisol when interacting with dogs. Self-reported loneliness was not related to cortisol or the human-animal bond, but measures of both loneliness and the human-animal bond were higher among children who participated after the onset of the COVID-19 pandemic, relative to those who participated before the pandemic. This study builds on previous work that investigated potential stress-buffering effects of human-animal interaction during explicit stressors and demonstrates important physiological correlates of naturalistic interactions between children and dogs, similar to those that occur in daily life., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Scope: The current tools for tuberculosis (TB) treatment monitoring, smear microscopy and culture, cannot accurately predict poor treatment outcomes. Research into new TB treatment monitoring tools (TMTs) is growing, but data are unreliable. In this article, we aim to provide guidance for studies investigating and evaluating TB TMT for use during routine clinical care. Here, a TB TMT would guide treatment during the course of therapy, rather than testing for a cure at the regimen's end. This article does not cover the use of TB TMTs as surrogate endpoints in the clinical trial context., Methods: Guidelines were initially informed by experiences during a systematic review of TB TMTs. Subsequently, a small content expert group was consulted for feedback on initial recommendations. After revision, feedback from substantive experts across sectors was sought., Questions Addressed by the Guideline and Recommendations: The proposed considerations and recommendations for studies evaluating TB TMTs for use during the treatment in routine clinical care fall into eight domains. We provide specific recommendations regarding study design and recruitment, outcome definitions, reference standards, participant follow-up, clinical setting, study population, treatment regimen reporting, and index tests and data presentation. Overall, TB TMTs should be evaluated in a manner similar to diagnostic tests, but TB TMT accuracy must be assessed at multiple timepoints throughout the treatment course, and TB TMTs should be evaluated in study populations who have already received a diagnosis of TB. Study design and outcome definitions must be aligned with the developmental phase of the TB TMT under evaluation. There is no reference standard for TB treatment response, so different reference standards and comparator tests have been proposed, the selection of which will vary depending on the developmental phase of the TMT under assessment. The use of comparator tests can assist in generating evidence. Clarity is required when reporting of timepoints, TMT read-outs, and analysis results. Implementing these recommendations will lead to higher quality TB TMT studies that will allow data to be meaningfully compared, thereby facilitating the development of novel tools to guide individual TB therapy and improve treatment outcomes., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

A strong signature of selection in the domestic dog genome is found in a five-megabase region of chromosome six in which four structural variants derived from transposons have previously been associated with human-oriented social behavior, such as attentional bias to social stimuli and social interest in strangers. To explore these genetic associations in more phenotypic detail-as well as their role in training success in a specialized assistance dog program-we genotyped 1001 assistance dogs from Canine Companions for Independence®, including both successful graduates and dogs released from the training program for behaviors incompatible with their working role. We collected phenotypes on each dog using puppy-raiser questionnaires, trainer questionnaires, and both cognitive and behavioral tests. Using Bayesian mixed models, we found strong associations (95% credibility intervals excluding zero) between genotypes and certain behavioral measures, including separation-related problems, aggression when challenged or corrected, and reactivity to other dogs. Furthermore, we found moderate differences in the genotypes of dogs who graduated versus those who did not; insertions in GTF2I showed the strongest association with training success (β = 0.23, CI 95% = - 0.04, 0.49), translating to an odds-ratio of 1.25 for one insertion. Our results provide insight into the role of each of these four transposons in canine sociability and may inform breeding and training practices for working dog organizations. Furthermore, the observed importance of the gene GTF2I supports the emerging consensus that variation in GTF2I genotypes and expression have important consequences for social behavior broadly., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Oxytocin is a pleiotropic neuropeptide that plays roles in biological processes ranging from birth, lactation, and social bonding to immune function, cardiovascular repair, and regulation of appetite. Although measurements of endogenous oxytocin concentrations have been performed for more than 50 years, the ability to measure oxytocin accurately poses notable challenges. One potential solution for overcoming these challenges involves measurement of oxytocin's carrier molecule - neurophysin I (NP-1) - as a surrogate biomarker. NP-1 is secreted in equimolar concentrations with oxytocin but has a longer half-life, circulates in higher concentrations, and can be measured using a sandwich immunoassay. We report experiments that 1) analytically validate a commercially available NP-1 sandwich immunoassay for use with human plasma and urine samples, 2) confirm the specificity of this assay, based on detection of NP-1 in plasma from wild-type but not oxytocin knockout mice, 3) demonstrate that NP-1 concentrations are markedly elevated in late pregnancy, consistent with studies showing substantial increases in plasma oxytocin throughout gestation, and 4) establish strong correlation between NP-1 and plasma oxytocin concentrations when oxytocin is measured in extracted (but not non-extracted) plasma. The NP-1 assay used in this study has strong analytical properties, does not require time-intensive extraction protocols, and the assay itself can be completed in < 2 h (compared to 16-24 h for a competitive oxytocin immunoassay). Our findings suggest that much like copeptin has become a useful surrogate biomarker in studies of vasopressin, measurements of NP-1 have similar potential to advance oxytocin research., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Service dogs are an increasingly popular complementary intervention for children with autism spectrum disorder. However, despite increasing demand, there remains a lack of empirical research on their potential benefits. The purpose of this study was to evaluate the effects of service dogs on children with autism and their caregivers., Methods: A total of N = 75 families of children with autism were recruited from a non-profit service dog provider in the US, including n = 39 families previously placed with a service dog and n = 36 families engaging in usual care while on the waitlist. Caregivers completed an online survey containing both self- and proxy-report standardized measures of child, caregiver, and family functioning. Linear regressions modeled the relationship between service dog presence and survey outcomes, controlling for relevant child and caregiver covariates., Results: Results indicated that having a service dog was associated with significantly better child sleep behaviors, including better sleep initiation and duration and less sleep anxiety/co-sleeping with medium effect sizes. However, service dog presence was not significantly related to child withdrawal, negative emotionality, emotional self-control, hyperactivity, irritability, and lethargy with small effect sizes. For caregivers, having a service dog was not significantly related to standardized measures of caregiver strain, sleep disturbance, depression, or the impact of the child's condition on family functioning with small effect sizes. Supplemental matched case-control analyses confirmed these findings., Discussion: In conclusion, service dogs were found to positively impact sleep behaviors among children with autism, but may not uniformly relate to other areas of child and caregiver wellbeing. Prospective longitudinal designs, larger sample sizes able to detect small effects, and studies that measure sleep using objective methods are needed to build on these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rodriguez, Rispoli, Kelleher, MacLean and O’Haire.)

Background: Rapid antigen tests (RATs) were crucial during the COVID-19 pandemic. Information provided by the test manufacturer in product package inserts, also known as instructions for use (IFUs), is often the only data available to clinicians, public health professionals, and individuals on the diagnostic accuracy of these tests. We aimed to assess whether manufacturer IFU accuracy data aligned with evidence from independent research., Methods: We searched company websites for package inserts for RATs that were included in the July 2022 update of the Cochrane meta-analysis of SARS-CoV-2 RATs, which served as a benchmark for research evidence. We fitted bivariate hierarchical models to obtain absolute differences in sensitivity and specificity between IFU and Cochrane Review estimates for each test, as well as overall combined differences., Findings: We found 22 (100%) of 22 IFUs of the RATs included in the Cochrane Review. IFUs for 12 (55%) of 22 RATs reported statistically significantly higher sensitivity estimates than the Cochrane Review, and none reported lower estimates. The mean difference between IFU and Cochrane Review sensitivity estimates across tests was 12·0% (95% CI 7·5-16·6). IFUs in three (14%) of 22 diagnostic tests had significantly higher specificity estimates than the Cochrane Review and two (9%) of 22 had lower estimates. The mean difference between IFU and Cochrane Review specificity estimates across tests was 0·3% (95% CI 0·1-0·5). If 100 people with SARS-CoV-2 infection were tested with each of the tests in this study, on average 12 fewer people would be correctly diagnosed than is suggested by the package inserts., Interpretation: Health professionals and the public should be aware that package inserts for SARS-CoV-2 RATs might provide an overly optimistic picture of the sensitivity of a test. Regulatory bodies should strengthen their requirements for the reporting of diagnostic accuracy data in package inserts and policy makers should demand independent validation data for decision making., Funding: None., Competing Interests: Declaration of interests JB has received consulting fees from the New Diagnostics Working Group of the Stop TB Partnership. SB, JD, and JJD are supported by the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre. This Article presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham National Health Services (NHS) Foundation Trust and the University of Birmingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. CMD has received research grants from the US National Institutes of Health, German Ministry of Education and Research, German Alliance for Global Health Research, United States Agency for International Development, FIND, German Center for Infection Research, UNAIDS, WHO, and Roche. CMD also declares a payment from Roche Diagnostics that she accepted as German law requires a manufacturer to pay for the use of data for regulatory purposes. Data was generated as part of an independent evaluation by CMD and team. CMD is an academic editor of PLoS Medicine and sits on the WHO technical advisory group on tuberculosis diagnostics. MP holds a Canada Research Chair Award from the Canadian Institutes of Health Research and serves as an adviser to the following non-profit agencies in global health: Bill & Melinda Gates Foundation; Foundation for Innovative New Diagnostics, WHO, and Stop TB Partnership. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis., ((c) 2023 The authors; licensee World Health Organization.)

Background: Integrated molecular testing could be an opportunity to detect and provide care for both tuberculosis and COVID-19. Many high tuberculosis burden countries, such as Peru, have existing GeneXpert systems for tuberculosis testing with GeneXpert Xpert MTB/RIF Ultra (Xpert Ultra), and a GeneXpert SARS-CoV-2 assay, GeneXpert Xpert Xpress SARS-CoV-2 (Xpert Xpress), is also available. We aimed to assess the feasibility of integrating tuberculosis and COVID-19 testing using one sputum specimen with Xpert Ultra and Xpert Xpress in Lima, Peru., Methods: In this cross-sectional, diagnostic accuracy study, we recruited adults presenting with clinical symptoms or suggestive history of tuberculosis or COVID-19, or both. Participants were recruited from a total of 35 primary health facilities in Lima, Peru. Participants provided one nasopharyngeal swab and one sputum sample. For COVID-19, we tested nasopharyngeal swabs and sputum using Xpert Xpress; for tuberculosis, we tested sputum using culture and Xpert Ultra. We compared diagnostic accuracy of sputum testing using Xpert Xpress with nasopharyngeal swab testing using Xpert Xpress. Individuals with positive Xpert Xpress nasopharyngeal swab results were considered COVID-19 positive, and a positive culture indicated tuberculosis. To assess testing integration, the proportion of cases identified in sputum by Xpert Xpress was compared with Xpert Xpress on nasopharyngeal swabs, and sputum by Xpert Ultra was compared with culture., Findings: Between Jan 11, 2021, and April 26, 2022, we recruited 600 participants (312 [52%] women and 288 [48%] men). In-study prevalence of tuberculosis was 13% (80 participants, 95% CI 11-16) and of SARS-CoV-2 was 35% (212 participants, 32-39). Among tuberculosis cases, 13 (2·2%, 1·2-3·7) participants were concurrently positive for SARS-CoV-2. Regarding the diagnostic yield of integrated testing, Xpert Ultra detected 96% (89-99) of culture-confirmed tuberculosis cases (n=77), and Xpert Xpress-sputum detected 67% (60-73) of COVID-19 cases (n=134). All five study staff reported that integrated molecular testing was easy and acceptable., Interpretation: The diagnostic yield of Xpert Xpress on sputum was moderate, but integrated testing for tuberculosis and COVID-19 with GeneXpert was feasible. However, systematic testing for both diseases might not be the ideal approach for everyone presenting with presumptive tuberculosis or COVID-19, as concurrent positive cases were rare during the study period. Further research might help to identify when integrated testing is most worthwhile and its optimal implementation., Funding: Canadian Institutes of Health Research and International Development Research Centre., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests MP serves as an advisor to the following non-profit agencies in global health: Bill & Melinda Gates Foundation, Foundation for Innovative New Diagnostics, WHO, and Stop TB Partnership. CU-G reports receiving funding from the Foundation of Innovative New Diagnostics, US National Institutes of Health, Abbott, and National Research Council Canada for grants in tuberculosis or COVID research, or both; receiving payment or honoraria for lectures, presentations, or educational events from Abbott and Molbio; and participating on an advisory board for point-of-care testing in infectious diseases., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity-with several important covariates-as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate =  - 0.10, 95% CI: - 0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate =  - 0.07, 95% CI: - 0.09 to - 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

There were approximately 10 million tuberculosis (TB) cases in 2020, of which 500,000 were drug-resistant. Only one third of drug-resistant TB cases were diagnosed and enrolled on appropriate treatment, an issue partly driven by a lack of rapid, accurate drug-susceptibility testing (DST) tools deployable in peripheral settings. In 2014, World Health Organization (WHO) published target product profiles (TPPs) which detailed minimal and optimal criteria to address high-priority TB diagnostic needs, including DST. Since then, the TB community's needs have evolved; new treatment regimens, changes in TB definitions, further emergence of drug resistance, technological advances, and changing end-users requirements have necessitated an update. The DST TPP's revision was therefore undertaken by WHO with the Stop TB Partnership New Diagnostics Working Group. We describe the process of updating the TPP for next-generation TB DST for use at peripheral centres, highlight key updates, and discuss guidance regarding technical and operational specifications., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: PS is a consultant for Genoscreen., (Copyright: © 2023 MacLean et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Tuberculosis (TB) is a leading cause of death in children, but many cases are never diagnosed. Microbiological diagnosis of pulmonary TB is challenging in young children who cannot spontaneously expectorate sputum. Nasopharyngeal aspirates (NPA) may be more easily collected than gastric aspirate and induced sputum and can be obtained on demand, unlike stool. However, further information on its diagnostic yield is needed., Methods: We systematically reviewed and meta-analyzed the diagnostic yield of one NPA for testing by either culture or nucleic acid amplification testing (NAAT) to detect Mycobacterium tuberculosis from children. We searched three bibliographic databases and two trial registers up to 24th November 2022. Studies that reported the proportion of children diagnosed by NPA compared to a microbiological reference standard (MRS) were eligible. Culture and/or WHO-endorsed NAAT on at least one respiratory specimen served as the MRS. We also estimated the incremental yield of two NPA samples compared to one and summarized operational aspects of NPA collection and processing. Univariate random-effect meta-analyses were performed to calculate pooled diagnostic yield estimates., Results: From 1483 citations, 54 were selected for full-text review, and nine were included. Based on six studies including 256 children with microbiologically confirmed TB, the diagnostic yield of NAAT on one NPA ranged from 31 to 60% (summary estimate 44%, 95% CI 36-51%). From seven studies including 242 children with confirmed TB, the diagnostic yield of culture was 17-88% (summary estimate 58%, 95% CI 42-73%). Testing a second NPA increased the yield by 8-19% for NAAT and 4-35% for culture. NPA collection procedures varied between studies, although most children had NPA successfully obtained (96-100%), with a low rate of indeterminate results (< 5%). Data on NPA acceptability and specifically for children under 5 years were limited., Conclusions: NPA is a suitable and feasible specimen for diagnosing pediatric TB. The high rates of successful collection across different levels of healthcare improve access to microbiological testing, supporting its inclusion in diagnostic algorithms for TB, especially if sampling is repeated. Future research into the acceptability of NPA and how to standardize collection to optimize diagnostic yield is needed., Competing Interests: Competing interests The authors declare no competing interests.

Oxytocin has become a popular analyte in behavioral endocrinology in recent years, due in part to its roles in social behavior, stress physiology, and cognition. Urine samples have the advantage of being non-invasive and minimally disruptive to collect, allowing for oxytocin measurements even in some wild populations. However, methods for urinary oxytocin immunoassay have not been sufficiently optimized and rigorously assessed for their potential limitations. Using samples from oxytocin knockout (KO) and wildtype (WT) mice, we find evidence of considerable interference in unextracted urine samples, with similar distributions of measured oxytocin in both genotypes. Importantly, although this interference can be reduced by a reversed-phase solid-phase extraction (SPE), this common approach is not sufficient for eliminating false-positive signal on three immunoassay kits. To better understand the source of the observed interference, we conducted epitope mapping of the Arbor Assays antibody and assessed its cross-reactivity with known, biologically active fragments of oxytocin. We found considerable cross-reactivity (0.5-52% by-molarity) for three fragments of oxytocin that share the core epitope, with more cross-reactivity for longer fragments. Given the presence of some cross-reactivity for even the tripeptide MIF-1, it is likely that many small protein metabolites might be sufficiently similar to the epitope that at high concentrations they interfere with immunoassays. We present a new mixed-mode cation-exchange SPE method that minimizes interference-with knockout samples measuring below the assay's limit of detection-while effectively retaining oxytocin from the urine of wildtype mice. This method demonstrates good parallelism and spike recovery across multiple species (mice, dogs, sifakas, humans). Our results suggest that immunoassays of urine samples may be particularly susceptible to interference, even when using common extraction protocols, but that this interference can be successfully managed using a novel mixed-mode cation exchange extraction. These findings imply that previous conclusions based on urinary oxytocin measurements-especially those involving unextracted samples-may need to be reassessed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Psychiatric service dogs are an emerging complementary intervention for posttraumatic stress disorder (PTSD). Initial evidence suggests that partnership with a service dog may be related to less PTSD symptom severity. However, it remains unclear how or why this might occur. To address this gap, we conducted a longitudinal investigation of 82 post-9/11 military members or veterans and their PTSD service dogs to (1) evaluate service dog characteristics as potential predictors of efficacy, (2) assess dog and human characteristics as potential predictors of veteran-dog bond, and (3) explore potential mechanisms for mental health outcomes. Aim 1 results demonstrated that most service dog characteristics did not predict veterans' mental health outcomes, but lower service dog excitability was associated with less PTSD symptom severity at follow-up. Aim 2 results showed that closer dog-veteran relationships were associated with less excitable dog temperament. Aim 3 results indicated that worse mental health at follow-up was associated with greater use of the specifically trained PTSD service dog task to initiate a social greeting ("make a friend"), whereas better mental health was related to less use of dominance-based training methods, lower perceived emotional/logistical costs of service dog partnership, and closer veteran-dog relationships. More frequent use of the trained service dog task to signal when someone approaches from behind (cover/watch back) was associated with greater anxiety, but less PTSD symptom severity. Overall, veterans spent an average of 82% of their time with service dogs (assessed via Bluetooth proximity between dog collar and veteran smartphone), and most frequently asked their service dogs to perform the trained task for calming their anxiety (calm/comfort anxiety). The present study provides subjective and objective metrics of the heterogeneity among veteran-service dog dyads while also suggesting which of the assessed metrics might be potential mechanisms involved in the intervention., Competing Interests: Dr. O’Haire is a member of the Merrick Scientific Cabinet. Authors declare no other competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Authors declare no other competing interests.

Background: Evaluating the accuracy of extrapulmonary tuberculosis (TB) tests is challenging due to lack of a gold standard. Latent class analysis (LCA), a statistical modeling approach, can adjust for reference tests' imperfect accuracies to produce less biased test accuracy estimates than those produced by commonly used methods like composite reference standards (CRSs). Our objective is to illustrate how Bayesian LCA can address the problem of an unavailable gold standard and demonstrate how it compares to using CRSs for extrapulmonary TB tests., Methods: We re-analyzed a dataset of presumptive extrapulmonary TB cases in New Delhi, India, for three forms of extrapulmonary TB. Results were available for culture, smear microscopy, Xpert MTB/RIF, and a non-microbiological test, cytopathology/histopathology, or adenosine deaminase (ADA). A diagram was used to define assumed relationships between observed tests and underlying latent variables in the Bayesian LCA with input from an inter-disciplinary team. We compared the results to estimates obtained from a sequence of CRSs defined by increasing numbers of positive reference tests necessary for positive disease status., Results: Data were available from 298, 388, and 230 individuals with presumptive TB lymphadenitis, meningitis, and pleuritis, respectively. Using Bayesian LCA, estimates were obtained for accuracy of all tests and for extrapulmonary TB prevalence. Xpert sensitivity neared that of culture for TB lymphadenitis and meningitis but was lower for TB pleuritis, and specificities of all microbiological tests approached 100%. Non-microbiological tests' sensitivities were high, but specificities were only moderate, preventing disease rule-in. CRSs' only provided estimates of Xpert and these varied widely per CRS definition. Accuracy of the CRSs also varied by definition, and no CRS was 100% accurate., Conclusion: Unlike CRSs, Bayesian LCA takes into account known information about test performance resulting in accuracy estimates that are easier to interpret. LCA should receive greater consideration for evaluating extrapulmonary TB diagnostic tests., (© 2022. The Author(s).)

Integrated testing for TB and COVID-19 may help find those TB patients who are not accessing care in the context of the COVID-19 pandemic. Some molecular platforms with assays for both diseases are already commercially available; however, integrated testing approaches need to be systematically evaluated to ensure their appropriate implementation., Competing Interests: E.L.M., L.V.C., C.U.G., and M.P. declare no competing interests. M.R. is an employee of FIND. FIND is a not-for-profit foundation whose mission is to find diagnostic solutions to overcome diseases of poverty in low- and middle-income countries (LMICs). It works closely with the private and public sectors and receives funding from some of its industry partners. It has organizational firewalls to protect it against any undue influences in its work or the publication of its findings. All industry partnerships are subject to review by an independent scientific advisory committee or another independent review body, based on due diligence, TTPs and public sector requirements. FIND catalyzes product development, leads evaluations, takes positions, and accelerates access to tools identified as serving its mission. It provides indirect support to industry (e.g., access to open specimen banks, a clinical trial platform, technical support, expertise, laboratory capacity strengthening in LMICs) to facilitate the development and use of products in these areas. FIND also supports the evaluation of publicly prioritized TB assays and the implementation of WHO-approved (guidance and performance qualification [PQ]) assays using donor grants. In order to carry out test evaluations, FIND has product evaluation agreements with several private sector companies for TB and other diseases, which strictly defines its independence and neutrality vis-à-vis the companies whose products get evaluated and describes roles and responsibilities., (© 2022 Elsevier Inc.)

The ability to represent approximate quantities appears to be phylogenetically widespread, but the selective pressures and proximate mechanisms favouring this ability remain unknown. We analysed quantity discrimination data from 672 subjects across 33 bird and mammal species, using a novel Bayesian model that combined phylogenetic regression with a model of number psychophysics and random effect components. This allowed us to combine data from 49 studies and calculate the Weber fraction (a measure of quantity representation precision) for each species. We then examined which cognitive, socioecological and biological factors were related to variance in Weber fraction. We found contributions of phylogeny to quantity discrimination performance across taxa. Of the neural, socioecological and general cognitive factors we tested, cortical neuron density and domain-general cognition were the strongest predictors of Weber fraction, controlling for phylogeny. Our study is a new demonstration of evolutionary constraints on cognition, as well as of a relation between species-specific neuron density and a particular cognitive ability. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

The process of dog domestication likely involved at least two functional stages. The initial stage occurred when subpopulations of wolves became synanthropes, benefiting from life nearby or in human environments. The second phase was characterized by the evolution of novel forms of interspecific cooperation and social relationships between humans and dogs. Here, we discuss possible roles of the oxytocin system across these functional stages of domestication. We hypothesize that in early domestication, oxytocin played important roles in attenuating fear and stress associated with human contact. In later domestication, we hypothesize that oxytocin's most critical functions were those associated with affiliative social behavior, social engagement, and cooperation with humans. We outline possible neurobiological changes associated with these processes and present a Siberian fox model of canid domestication in which these predictions can be tested. Lastly, we identify limitations of current studies on the neuroendocrinology of domestication and discuss challenges and opportunities for future research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Oxytocin has garnered much interest due to its role in affective states, social behaviors, and diverse physiological functions. However, approaches for measuring endogenous oxytocin concentrations have generated considerable controversy and debate. Common procedures for measuring oxytocin often produce uncorrelated results, and the detected concentrations frequently vary across two orders of magnitude. These findings have led some researchers to argue that immunoassays of plasma oxytocin may be unreliable and nonspecific, particularly when samples are not first processed using an extraction procedure. Here, we assess the specificity of oxytocin immunoassays using plasma samples from wildtype (WT) and oxytocin knockout (KO) mice. Plasma samples from both genotypes were measured using immunoassay and were measured with or without a solid-phase extraction. Using a commercially available kit from Arbor Assays, we demonstrate that both techniques generate a clear contrast between genotypes, with wildtype samples containing high concentrations of oxytocin (unextracted mean = 468 pg/ml; extracted mean = 381 pg/ml), while knockout samples measured below the lower limit of detection. Analytical validations demonstrated good parallelism and spike recovery for both methods. Furthermore, the same wildtype samples measured with both procedures were highly correlated (r = 0.95), although unextracted samples measured at significantly higher concentrations (p = 2.0 ×10 -7 , Cohen's d = 2.65). To test the generalizability of these results across immunoassay kits, we performed additional assays with kits from Cayman Chemical and Enzo Life Sciences. The Cayman Chemical kit produced results similar to Arbor Assays with a clean signal differentiating WT and KO plasma, both with and without an extraction step. The Enzo kit also differentiated the genotypes, with correlation between extracted and unextracted samples, but was considerably more susceptible to interference without the extraction, as evidenced by false positive signal in KO plasma samples. The extent to which these results generalize to other species remains unknown and challenging to assess., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Love and strong social bonds are known buffers in the experience of adversity. Humans often form strong bonds with non-human animals. The human-animal bond refers to a mutually beneficial and dynamic relationship between humans and non-human animals. Previous research suggests that strong bonds with pets may promote resilience in the experience of adversity, but a strong bond with a pet can also complicate this very experience of adversity, particularly among low-resourced and disadvantaged populations. What is the role of the human-animal bond in adversity, and what is the role of adversity in the bond between a human and a non-human animal? In this article we outline the state of research on the role of various types and sources of adversities in multispecies households (i.e., families, relationships) to consider this overarching question. We focus specifically on intimate partner violence, housing discrimination, LGBTQ+ identity-based discrimination, racism, neighborhood disadvantage, and economic inequality. We then outline an agenda for future research about love, adversity, and multispecies relationships, and discuss implications for public policy and community-based interventions.

Dogs are trained for a variety of working roles including assistance, protection, and detection work. Many canine working roles, in their modern iterations, were developed at the turn of the 20th century and training practices have since largely been passed down from trainer to trainer. In parallel, research in psychology has advanced our understanding of animal behavior, and specifically canine learning and cognition, over the last 20 years; however, this field has had little focus or practical impact on working dog training. The aims of this narrative review are to (1) orient the reader to key advances in animal behavior that we view as having important implications for working dog training, (2) highlight where such information is already implemented, and (3) indicate areas for future collaborative research bridging the gap between research and practice. Through a selective review of research on canine learning and behavior and training of working dogs, we hope to combine advances from scientists and practitioners to lead to better, more targeted, and functional research for working dogs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JS declared a shared affiliation with one of the authors CO to the handling editor at time of review., (Copyright © 2021 Hall, Johnston, Bray, Otto, MacLean and Udell.)

Although we know that dogs evolved from wolves, it remains unclear how domestication affected dog cognition. One hypothesis suggests dog domestication altered social maturation by a process of selecting for an attraction to humans. 1-3 Under this account, dogs became more flexible in using inherited skills to cooperatively communicate with a new social partner that was previously feared and expressed these unusual social skills early in development. 4-6 Here, we comparedog (n = 44) and wolf (n = 37) puppies, 5-18 weeks old, on a battery of temperament and cognition tasks. We find that dog puppies are more attracted to humans, read human gestures more skillfully, and make more eye contact with humans than wolf puppies. The two species are similarly attracted to familiar objects and perform similarly on non-social measures of memory and inhibitory control. These results are consistent with the idea that domestication enhanced the cooperative-communicative abilities of dogs as selection for attraction to humans altered social maturation., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human cognition is believed to be unique in part because of early-emerging social skills for cooperative communication. 1 Comparative studies show that at 2.5 years old, children reason about the physical world similarly to other great apes, yet already possess cognitive skills for cooperative communication far exceeding those in our closest primate relatives. 2 , 3 A growing body of research indicates that domestic dogs exhibit functional similarities to human children in their sensitivity to cooperative-communicative acts. From early in development, dogs flexibly respond to diverse forms of cooperative gestures. 4 , 5 Like human children, dogs are sensitive to ostensive signals marking gestures as communicative, as well as contextual factors needed for inferences about these communicative acts. 6-8 However, key questions about potential biological bases for these abilities remain untested. To investigate their developmental and genetic origins, we tested 375 8-week-old dog puppies on a battery of social-cognitive measures. We hypothesized that if dogs' skills for cooperating with humans are biologically prepared, then they should emerge robustly in early development, not require extensive socialization or learning, and exhibit heritable variation. Puppies were highly skillful at using diverse human gestures, and we found no evidence that their performance required learning. Critically, over 40% of the variation in dogs' point-following abilities and attention to human faces was attributable to genetic factors. Our results suggest that these social skills in dogs emerge early in development and are under strong genetic control., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Canine science is rapidly maturing into an interdisciplinary and highly impactful field with great potential for both basic and translational research. The articles in this Frontiers Research Topic, Our Canine Connection: The History, Benefits and Future of Human-Dog Interactions , arise from two meetings sponsored by the Wallis Annenberg PetSpace Leadership Institute, which convened experts from diverse areas of canine science to assess the state of the field and challenges and opportunities for its future. In this final Perspective paper, we identify a set of overarching themes that will be critical for a productive and sustainable future in canine science. We explore the roles of dog welfare, science communication, and research funding, with an emphasis on developing approaches that benefit people and dogs, alike., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 MacLean, Fine, Herzog, Strauss and Cobb.)

Although non-human primates (NHPs) generally appear to predict how knowledgeable agents use knowledge to guide their behavior, the cognitive mechanisms that enable this remain poorly understood. We assessed the conditions under which NHPs' representations of an agent's awareness break down. Free-ranging rhesus macaques (Macaca mulatta) watched as an agent observed a target object being hidden in one of two boxes. While the agent could no longer see the boxes, the box containing the object flipped open and the object either changed in size/shape (Experiment 1) or color (Experiment 2). Monkeys looked longer when the agent searched for the object incorrectly rather than correctly following the color change (a non-geometric manipulation), but not the size/shape change (a geometric manipulation). Even though the agent maintained knowledge of the object's location in both cases, monkeys no longer expected the agent to search correctly after it had been geometrically (but not non-geometrically) manipulated. Experiment 3 confirmed that monkeys were sensitive to the color manipulation used in Experiment 2, making it unlikely that a failure to perceive the color manipulation accounted for our findings. Our results show that NHPs do not always expect that knowledgeable agents will act on their knowledge to obtain their goals, consistent with heuristic-based accounts of how NHPs represent others' mental states. These findings also suggest that geometric changes that occur outside the agent's perceptual access may disrupt attribution of awareness more so than non-geometric changes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Dogs perform a variety of integral roles in our society, engaging in work ranging from assistance (e.g., service dogs, guide dogs) and therapy to detection (e.g., search-and-rescue dogs, explosive detection dogs) and protection (e.g., military and law enforcement dogs). However, success in these roles, which requires dogs to meet challenging behavioral criteria and to undergo extensive training, is far from guaranteed. Therefore, enhancing the selection process is critical for the effectiveness and efficiency of working dog programs and has the potential to optimize how resources are invested in these programs, increase the number of available working dogs, and improve working dog welfare. In this paper, we review two main approaches for achieving this goal: (1) developing selection tests and criteria that can efficiently and effectively identify ideal candidates from the overall pool of candidate dogs, and (2) developing approaches to enhance performance, both at the individual and population level, via improvements in rearing, training, and breeding. We summarize key findings from the empirical literature regarding best practices for assessing, selecting, and improving working dogs, and conclude with future steps and recommendations for working dog organizations, breeders, trainers, and researchers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bray, Otto, Udell, Hall, Johnston and MacLean.)

While our understanding of adult dog cognition has grown considerably over the past 20 years, relatively little is known about the ontogeny of dog cognition. To assess the development and longitudinal stability of cognitive traits in dogs, we administered a battery of tasks to 160 candidate assistance dogs at 2 timepoints. The tasks were designed to measure diverse aspects of cognition, ranging from executive function (e.g., inhibitory control, reversal learning, memory) to sensory discrimination (e.g., vision, audition, olfaction) to social interaction with humans. Subjects first participated as 8-10-week-old puppies, and then were retested on the same tasks at ~ 21 months of age. With few exceptions, task performance improved with age, with the largest effects observed for measures of executive function and social gaze. Results also indicated that individual differences were both early emerging and enduring; for example, social attention to humans, use of human communicative signals, independent persistence at a problem, odor discrimination, and inhibitory control all exhibited moderate levels of rank-order stability between the two timepoints. Using multiple regression, we found that young adult performance on many cognitive tasks could be predicted from a set of cognitive measures collected in early development. Our findings contribute to knowledge about changes in dog cognition across early development as well as the origins and developmental stability of individual differences.

Given their remarkable phenotypic diversity, dogs present a unique opportunity for investigating the genetic bases of cognitive and behavioral traits. Our previous work demonstrated that genetic relatedness among breeds accounts for a substantial portion of variation in dog cognition. Here, we investigated the genetic architecture of breed differences in cognition, seeking to identify genes that contribute to variation in cognitive phenotypes. To do so, we combined cognitive data from the citizen science project Dognition.com with published breed-average genetic polymorphism data, resulting in a dataset of 1654 individuals with cognitive phenotypes representing 49 breeds. We conducted a breed-average genome-wide association study to identify specific polymorphisms associated with breed differences in inhibitory control, communication, memory, and physical reasoning. We found five single nucleotide polymorphisms (SNPs) that reached genome-wide significance after Bonferroni correction, located in EML1, OR52E2, HS3ST5, a U6 spliceosomal RNA, and a long noncoding RNA. When we combined results across multiple SNPs within the same gene, we identified 188 genes implicated in breed differences in cognition. This gene set included more genes than expected by chance that were (1) differentially expressed in brain tissue and (2) involved in nervous system functions including peripheral nervous system development, Wnt signaling, presynapse assembly, and synaptic vesicle exocytosis. These results advance our understanding of the genetic underpinnings of complex cognitive phenotypes and identify specific genetic variants for further research., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug., (Copyright © 2020 by The Author(s).)

Trait heritability is necessary for evolution by both natural and artificial selection, yet we know little about the heritability of cognitive traits. Domestic dogs are a valuable study system for questions regarding the evolution of phenotypic diversity due to their extraordinary intraspecific variation. While previous studies have investigated morphological and behavioral variation across dog breeds, few studies have systematically assessed breed differences in cognition. We integrated data from Dognition.com-a citizen science project on dog cognition-with breed-averaged genetic data from published sources to estimate the among-breed heritability of cognitive traits using mixed models. The resulting dataset included 11 cognitive measures for 1508 adult dogs across 36 breeds. A factor analysis yielded four factors interpreted as reflecting inhibitory control, communication, memory, and physical reasoning. Narrow-sense among-breed heritability estimates-reflecting the proportion of cognitive variance attributable to additive genetic variation-revealed that scores on the inhibitory control and communication factors were highly heritable (inhibitory control: h 2  = 0.70; communication: h 2  = 0.39), while memory and physical reasoning were less heritable (memory: h 2  = 0.17; physical reasoning: h 2  = 0.21). Although the heritability of inhibitory control is partially explained by body weight, controlling for breed-average weight still yields a high heritability estimate (h 2  = 0.50), while other factors are minimally affected. Our results indicate that cognitive phenotypes in dogs covary with breed relatedness and suggest that cognitive traits have strong potential to undergo selection. The highest heritabilities were observed for inhibitory control and communication, both of which are hypothesized to have been altered by domestication.

To characterize the early ontogeny of dog cognition, we tested 168 domestic dog, Canis familiaris , puppies (97 females, 71 males; mean age = 9.2 weeks) in a novel test battery based on previous tasks developed and employed with adolescent and adult dogs. Our sample consisted of Labrador retrievers, golden retrievers and Labrador × golden retriever crosses from 65 different litters at Canine Companions for Independence, an organization that breeds, trains and places assistance dogs for people with disabilities. Puppies participated in a 3-day cognitive battery that consisted of 14 tasks measuring different cognitive abilities and temperament traits such as executive function (e.g. inhibitory control, reversal learning, working memory), use of social cues, sensory discriminations and reactivity to and recovery from novel situations. At 8-10 weeks of age, and despite minimal experience with humans, puppies reliably used a variety of cooperative-communicative gestures from humans. Puppies accurately remembered the location of hidden food for delays of up to 20 s, and succeeded in a variety of visual, olfactory and auditory discrimination problems. They also showed some skill at executive function tasks requiring inhibitory control and reversal learning, although they scored lower on these tasks than is typical in adulthood. Taken together, our results confirm the early emergence of sensitivity to human communication in dogs and contextualize these skills within a broad array of other cognitive abilities measured at the same stage of ontogeny., Competing Interests: Conflict of Interest We declare no conflicts of interest.

Over two decades of research have produced compelling evidence that non-human primates understand some psychological states in other individuals but are unable to represent others' beliefs. Recently, three studies employing anticipatory looking (AL) paradigms reported that non-human primates do show hints of implicitly understanding the beliefs of others. However, measures of AL have been increasingly scrutinized in the human literature owing to extensive replication problems. We argue that new reports of belief representation in non-human primates using AL should be interpreted cautiously because of methodological and theoretical challenges paralleling trends in the human literature. We explore how future work can address these challenges, and conclude by identifying new evolutionary questions raised by the prospect that non-human primates implicitly represent others' beliefs without an explicit belief representation system that guides fitness-relevant behavior., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Across mammals, increased body size is positively associated with lifespan. However, within species, this relationship is inverted. This is well illustrated in dogs (Canis familiaris), where larger dogs exhibit accelerated life trajectories: growing faster and dying younger than smaller dogs. Similarly, some age-associated traits (e.g., growth rate and physiological pace of aging) exhibit accelerated trajectories in larger breeds. Yet, it is unknown whether cognitive performance also demonstrates an accelerated life course trajectory in larger dogs. Here, we measured cognitive development and aging in a cross-sectional study of over 4000 dogs from 66 breeds using nine memory and decision-making tasks performed by citizen scientists as part of the Dognition project. Specifically, we tested whether cognitive traits follow a compressed (accelerated) trajectory in larger dogs, or the same trajectory for all breeds, which would result in limited cognitive decline in larger breeds. We found that all breeds, regardless of size or lifespan, tended to follow the same quadratic trajectory of cognitive aging-with a period of cognitive development in early life and decline in later life. Taken together, our results suggest that cognitive performance follows similar age-related trajectories across dog breeds, despite remarkable variation in developmental rates and lifespan.

In Horschler et al. (Anim Cognit 22(2):187-198, 2019), we found that two components of executive function (short-term memory and self-control) were strongly associated with estimated absolute brain weight across dog breeds, and argued that dogs present a powerful model for studying evolutionary links between cognition and neuroanatomy due to their extraordinary degree of intraspecific morphological variation. In a commentary on this work, Montgomery (Anim Cognit, 2019) raises concerns about the practice of estimating brain weights from brain-body scaling relationships. Montgomery explores the practical significance of this approach, ultimately concluding that such estimations should be avoided. In this response, we point out some limitations of the analyses presented by Montgomery and consider his conclusions in light of these issues. We then explore the extent to which body weight serves as a valid proxy for brain weight under varying conditions. Through simulations, we show that the consequences of using body weight as a proxy for brain weight depend on parameters including effect size, the correlation between brain and body weight, and the variance in brain and body weight within a sample. Under conditions approximating those in Horschler et al. (Anim Cognit 22(2):187-198, 2019), we find that body weight is a reliable proxy for brain weight, and that statistical results from models using either brain weight or body weight as predictor variables are highly convergent. Nonetheless, we wholeheartedly agree with Montgomery that empirical data on brain weight, structure, and cellular composition will be critical for creating new opportunities to investigate the relationships between neuroanatomy and cognition in dogs.

Variation across dog breeds presents a unique opportunity to investigate the evolution and biological basis of complex behavioural traits. We integrated behavioural data from more than 14 000 dogs from 101 breeds with breed-averaged genotypic data ( n = 5697 dogs) from over 100 000 loci in the dog genome. We found high levels of among-breed heritability for 14 behavioural traits (the proportion of trait variance attributable to genetic similarity among breeds). We next identified 131 single nucleotide polymorphisms associated with breed differences in behaviour, which were found in genes that are highly expressed in the brain and enriched for neurobiological functions and developmental processes, suggesting that they may be functionally associated with behavioural differences. Our results shed light on the heritability and genetic architecture of complex behavioural traits and identify dogs as a powerful model in which to address these questions.

Non-human primates can often predict how another agent will behave based on that agent's knowledge about the world. But how do non-human primates represent others' knowledge states? Researchers have recently proposed that non-human primates form "awareness relations" to attribute objectively true information to other minds, as opposed to human-like representations that track others' ignorance or false belief states. We present the first explicit test of the awareness relations hypothesis by examining when rhesus macaques' understanding of other agents' knowledge falters. In Experiment 1, monkeys watched an agent observe a piece of fruit (the target object) being hidden in one of two boxes. While the agent's view was occluded, either the fruit moved out of its box and directly back into it, or the box containing the fruit opened and immediately closed. We found that monkeys looked significantly longer when the agent reached incorrectly rather than correctly after the box's movement, but not after the fruit's movement. This result suggests that monkeys did not expect the agent to know the fruit's location when it briefly and arbitrarily moved while the agent could not see it, but did expect the agent to know the fruit's location when only the box moved while the agent could not see it. In Experiment 2, we replicated and extended both findings with a larger sample, a different target object, and opposite directions of motion in the test trials. These findings suggest that monkeys reason about others' knowledge of objects by forming awareness relations which are disrupted by arbitrary spatial manipulation of the target object while an agent has no perceptual access to it., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Since its discovery more than a century ago, oxytocin has become one of the most intensively studied molecules in behavioral biology. In the last five years, Psychoneuroendocrinology has published more than 500 articles with oxytocin in the title, with many of these articles including measures of endogenous oxytocin concentrations. Despite longstanding interest, methods of measuring endogenous oxytocin are still in active development. The widely varying oxytocin concentrations detected by different approaches to measurement - and lack of correlation among these techniques - has led to controversy and confusion. We identify features of oxytocin that may help to explain why various approaches may be differentially sensitive to diverse conformational states of the oxytocin molecule. We propose that discrepancies in data generated by different methods of measurement are not necessarily an indicator that some methods are valid whereas others are not. Rather, we propose that current challenges in the measurement of oxytocin may be analogous to the parable of the blind men and the elephant, with different methods of sample preparation and measurement being sensitive to different states in which the oxytocin molecule can exist., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Large-scale phylogenetic studies of animal cognition have revealed robust links between absolute brain volume and species differences in executive function. However, past comparative samples have been composed largely of primates, which are characterized by evolutionarily derived neural scaling rules. Therefore, it is currently unknown whether positive associations between brain volume and executive function reflect a broad-scale evolutionary phenomenon, or alternatively, a unique consequence of primate brain evolution. Domestic dogs provide a powerful opportunity for investigating this question due to their close genetic relatedness, but vast intraspecific variation. Using citizen science data on more than 7000 purebred dogs from 74 breeds, and controlling for genetic relatedness between breeds, we identify strong relationships between estimated absolute brain weight and breed differences in cognition. Specifically, larger-brained breeds performed significantly better on measures of short-term memory and self-control. However, the relationships between estimated brain weight and other cognitive measures varied widely, supporting domain-specific accounts of cognitive evolution. Our results suggest that evolutionary increases in brain size are positively associated with taxonomic differences in executive function, even in the absence of primate-like neuroanatomy. These findings also suggest that variation between dog breeds may present a powerful model for investigating correlated changes in neuroanatomy and cognition among closely related taxa.