Entities, Uncertainties, and Behavioral Indicators of Consciousness.

Two problems related to the identification of consciousness are the distribution problem-or how and among which entities consciousness is distributed in the world-and the moral status problem-or which species, entities, and individuals have moral status. The use of inferences from neurobiological and behavioral evidence, and their confounds, for identifying consciousness in nontypically functioning humans, nonhuman animals, and artificial intelligence is considered in light of significant scientific uncertainty and ethical biases, with implications for both problems. Methodological, epistemic, and ethical consensus are needed for responsible consciousness science under epistemic and ethical uncertainty. Consideration of inductive risk is proposed as a potential tool for managing both epistemic and ethical risks in consciousness science.

Estimating the prevalence of potential and actionable drug-gene interactions in Irish primary care: A cross-sectional study.

AIMS: Pharmacogenetics (PGx) is increasingly recognized as a strategy for medicines optimisation and prevention of adverse drug reactions. According to guidelines produced by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG), most medicines with drug-gene interactions (DGIs) are prescribed in primary care. This study aimed to estimate the prevalence of potential and actionable DGIs involving all medicines dispensed in Irish primary care. METHODS: Dispensings of 46 drugs to General Medical Services (GMS) patients in the Health Service Executive Primary Care Reimbursement Service Irish pharmacy claims database from 01 January 2021 to 31 December 2021 were analysed to estimate the national prevalence of total dispensings and incidence of first-time dispensings of drugs with potential DGIs according to the CPIC and/or DPWG guidelines. Phenotype frequency data from the UK Biobank and the CPIC were used to estimate the incidence of actionable DGIs. RESULTS: One in five dispensings (12 443 637 of 62 754 498, 19.8%) were medicines with potential DGIs, 1 878 255 of these dispensed for the first time. On application of phenotype frequencies and linked guideline based therapeutic recommendations, 2 349 055 potential DGIs (18.9%) required action, such as monitoring and guarding against maximum dose, drug or dose change. One in five (369 700, 19.7%) first-time dispensings required action, with 139 169 (7.4%) requiring a change in prescribing. Antidepressants, weak opioids and statins were most commonly identified as having actionable DGIs. CONCLUSIONS: This study estimated a high prevalence of DGIs in primary care in Ireland, identifying the need and opportunity to optimize drug therapy through PGx testing.

The Practical Haplotype Graph, a platform for storing and using pangenomes for imputation.

MOTIVATION: Pangenomes provide novel insights for population and quantitative genetics, genomics and breeding not available from studying a single reference genome. Instead, a species is better represented by a pangenome or collection of genomes. Unfortunately, managing and using pangenomes for genomically diverse species is computationally and practically challenging. We developed a trellis graph representation anchored to the reference genome that represents most pangenomes well and can be used to impute complete genomes from low density sequence or variant data. RESULTS: The Practical Haplotype Graph (PHG) is a pangenome pipeline, database (PostGRES & SQLite), data model (Java, Kotlin or R) and Breeding API (BrAPI) web service. The PHG has already been able to accurately represent diversity in four major crops including maize, one of the most genomically diverse species, with up to 1000-fold data compression. Using simulated data, we show that, at even 0.1× coverage, with appropriate reads and sequence alignment, imputation results in extremely accurate haplotype reconstruction. The PHG is a platform and environment for the understanding and application of genomic diversity. AVAILABILITY AND IMPLEMENTATION: All resources listed here are freely available. The PHG Docker used to generate the simulation results is https://hub.docker.com/ as maizegenetics/phg:0.0.27. PHG source code is at https://bitbucket.org/bucklerlab/practicalhaplotypegraph/src/master/. The code used for the analysis of simulated data is at https://bitbucket.org/bucklerlab/phg-manuscript/src/master/. The PHG database of NAM parent haplotypes is in the CyVerse data store (https://de.cyverse.org/de/) and named/iplant/home/shared/panzea/panGenome/PHG_db_maize/phg_v5Assemblies_20200608.db. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gene expression in the female tree swallow brain is associated with inter- and intra-population variation in glucocorticoid levels.

Studies of the evolutionary causes and consequences of variation in circulating glucocorticoids (GCs) have begun to reveal how they are shaped by selection. Yet the extent to which variation in circulating hormones reflects variation in other important regulators of the hypothalamic-pituitary-adrenal (HPA) axis, and whether these relationships vary among populations inhabiting different environments, remain poorly studied. Here, we compare gene expression in the brain of female tree swallows (Tachycineta bicolor) from populations that breed in environments that differ in their unpredictability. We find evidence of inter-population variation in the expression of glucocorticoid and mineralocorticoid receptors in the hypothalamus, with the highest gene expression in a population from an extreme environment, and lower expression in a population from a more consistent environment as well as in birds breeding at an environmentally variable high-altitude site that are part of a population that inhabits a mixture of high and low altitude habitats. Within some populations, variation in circulating GCs predicted differences in gene expression, particularly in the hypothalamus. However, some patterns were present in all populations, whereas others were not. These results are consistent with the idea that some combination of local adaptation and phenotypic plasticity may modify components of the HPA axis affecting stress resilience. Our results also underscore that a comprehensive understanding of the function and evolution of the stress response cannot be gained from measuring circulating hormones alone, and that future studies that apply a more explicitly evolutionary approach to important regulatory traits are likely to provide significant insights.

Is glycaemic control associated with dietary patterns independent of weight change in people newly diagnosed with type 2 diabetes? Prospective analysis of the Early-ACTivity-In-Diabetes trial.

BACKGROUND: It is unclear whether diet affects glycaemic control in type 2 diabetes (T2D), over and above its effects on bodyweight. We aimed to assess whether changes in dietary patterns altered glycaemic control independently of effects on bodyweight in newly diagnosed T2D. METHODS: We used data from 4-day food diaries, HbA1c and potential confounders in participants of the Early-ACTivity-In-Diabetes trial measured at 0, 6 and 12 months. At baseline, a 'carb/fat balance' dietary pattern and an 'obesogenic' dietary pattern were derived using reduced-rank regression, based on hypothesised nutrient-mediated mechanisms linking dietary intake to glycaemia directly or via obesity. Relationships between 0 and 6 month change in dietary pattern scores and baseline-adjusted HbA1c at 6 months (n = 242; primary outcome) were assessed using multivariable linear regression. Models were repeated for periods 6-12 months and 0-12 months (n = 194 and n = 214 respectively; secondary outcomes). RESULTS: Reductions over 0-6 months were observed in mean bodyweight (- 2.3 (95% CI: - 2.7, - 1.8) kg), body mass index (- 0.8 (- 0.9, - 0.6) kg/m2), energy intake (- 788 (- 953, - 624) kJ/day), and HbA1c (- 1.6 (- 2.6, -0.6) mmol/mol). Weight loss strongly associated with lower HbA1c at 0-6 months (ß = - 0.70 [95% CI - 0.95, - 0.45] mmol/mol/kg lost). Average fat and carbohydrate intakes changed to be more in-line with UK healthy eating guidelines between 0 and 6 months. Dietary patterns shifting carbohydrate intakes higher and fat intakes lower were characterised by greater consumption of fresh fruit, low-fat milk and boiled/baked potatoes and eating less of higher-fat processed meats, butter/animal fats and red meat. Increases in standardised 'carb/fat balance' dietary pattern score associated with improvements in HbA1c at 6 months independent of weight loss (ß = - 1.54 [- 2.96, - 0.13] mmol/mol/SD). No evidence of association with HbA1c was found for this dietary pattern at other time-periods. Decreases in 'obesogenic' dietary pattern score were associated with weight loss (ß = - 0.77 [- 1.31, - 0.23] kg/SD) but not independently with HbA1c during any period. CONCLUSIONS: Promoting weight loss should remain the primary nutritional strategy for improving glycaemic control in early T2D. However, improving dietary patterns to bring carbohydrate and fat intakes closer to UK guidelines may provide small, additional improvements in glycaemic control. TRIAL REGISTRATION: ISRCTN92162869 . Retrospectively registered on 25 July 2005.

Safety and efficacy of a biodegradable implant releasing tenofovir alafenamide for vaginal protection in a macaque model.

OBJECTIVES: To advance the initiative of ending the global epidemic, long-lasting HIV protection is needed through sustained release of antiretroviral drugs for months to years. We investigated in macaques the safety and efficacy of biodegradable polycaprolactone implants releasing tenofovir alafenamide for HIV pre-exposure prophylaxis (PrEP). METHODS: Implants were administered subcutaneously in the arm using a contraceptive trocar. Efficacy against vaginal simian-HIV (SHIV) infection was investigated in six pigtailed macaques that received two tenofovir alafenamide implants (0.35 mg/day), one in each arm, for a total release rate of tenofovir alafenamide at 0.7 mg/day. Macaques were exposed to SHIV twice weekly for 6 weeks. Statistical analyses were used to compare outcome with eight untreated controls. Histological assessments were performed on skin biopsies collected near implantation sites. RESULTS: Median (range) tenofovir diphosphate level in PBMCs was 1519 (1068-1898) fmol/106 cells. All macaques with tenofovir alafenamide implants were protected against vaginal SHIV infection. In contrast, 7/8 controls were infected after a median of 4 SHIV exposures (P = 0.0047). Histological assessment of tissues near tenofovir alafenamide implant sites showed inflammation and necrosis in 5/6 animals, which were not evident by visual inspection. CONCLUSIONS: We demonstrated complete protection against vaginal SHIV infection with two implants releasing a total of 0.7 mg of tenofovir alafenamide per day. We also identified tenofovir diphosphate concentrations in PBMCs associated with complete vaginal protection. Consistent with previous findings, we observed adverse local toxicity and necrosis near the tenofovir alafenamide implant site. Improved tenofovir alafenamide implants that are safe and maintain high efficacy have the potential to provide long-lasting protection against vaginal HIV infection.

Modeling the propagation of a high-average-power train of ultrashort laser pulses.

We investigate the interpulse thermal interaction of a train of ultrashort laser pulses and develop a model to describe the isobaric heating of air by a train of pulses undergoing filamentation. We calculate the heating of air from a single laser pulse and the resulting refractive index perturbation encountered by subsequent pulses, and use this to simulate the propagation of a high-power pulse train. The simulations show deflection of laser filaments by the thermal refractive index consistent with previous experimental measurements.

Individual variation in natural or manipulated corticosterone does not covary with circulating glucose in a wild bird.

Animals respond to sudden challenges with a coordinated set of physiological and behavioral responses that enhance the ability to cope with stressors. While general characteristics of the vertebrate stress response are well described, it is not as clear how individual components covary between or within individuals. A rapid increase in glucocorticoids coordinates the stress response and one of the primary downstream results is an increase in glucose availability via reduced glucose utilization. Here, we asked whether between- and within-individual variation in corticosterone directly predict variation in glucose. We collected 2673 paired glucose and corticosterone measures from 776 tree swallows (Tachycineta bicolor) from four populations spanning the species range. In adults, glucose and corticosterone both increased during a standardized restraint protocol in all four populations. Moreover, in one population experimentally increasing a precursor that stimulates corticosterone release resulted in a further increase in both measures. In contrast, nestlings did not show a robust glucose response to handling or manipulation. Despite this group-level variation, there was very little evidence in any population that between-individual variation in corticosterone predicted between-individual variation in glucose regulation. Glucose was moderately repeatable within individuals, but within-individual variation in glucose and corticosterone were unrelated. Our results highlight the fact that a strong response in one aspect of the coordinated acute stress response (corticosterone) does not necessarily indicate that specific downstream components, such as glucose, will show similarly strong responses. These results have implications for understanding the evolution of integrated stress response systems.

Educational interventions and animal consumption: Results from lab and field studies.

Currently, there are many advocacy interventions aimed at reducing animal consumption. We report results from a lab (N = 267) and a field experiment (N = 208) exploring whether, and to what extent, some of those educational interventions are effective at shifting attitudes and behavior related to animal consumption. In the lab experiment, participants were randomly assigned to read a philosophical ethics paper, watch an animal advocacy video, read an advocacy pamphlet, or watch a control video. In the field experiment, we measured the impact of college classes with animal ethics content versus college classes without animal ethics content. Using a pretest, post-test matched control group design, humane educational interventions generally made people more knowledgeable about animals used as food and reduced justifications and speciesist attitudes supporting animal consumption. None of the interventions in either experiment had a direct, measurable impact on self-reported animal consumption. These results suggest that while some educational interventions can change beliefs and attitudes about animal consumption, those same interventions have small impacts on animal consumption.

Existing Ethical Tensions in Xenotransplantation.

The genetic modification of pigs as a source of transplantable organs is one of several possible solutions to the chronic organ shortage. This paper describes existing ethical tensions in xenotransplantation (XTx) that argue against pursuing it. Recommendations for lifelong infectious disease surveillance and notification of close contacts of recipients are in tension with the rights of human research subjects. Parental/guardian consent for pediatric xenograft recipients is in tension with a child's right to an open future. Individual consent to transplant is in tension with public health threats that include zoonotic diseases. XTx amplifies concerns about justice in organ transplantation and could exacerbate existing inequities. The prevention of infectious disease in source animals is in tension with the best practices of animal care and animal welfare, requiring isolation, ethologically inappropriate housing, and invasive reproductive procedures that would severely impact the well-being of intelligent social creatures like pigs.

Toward an Anti-Maleficent Research Agenda.

Important advances in biomedical and behavioral research ethics have occurred over the past few decades, many of them centered on identifying and eliminating significant harms to human subjects of research. Comprehensive attention has not been paid to the totality of harms experienced by animal subjects, although scientific and moral progress require explicit appraisal of these harms. Science is a public good and the prioritizing within, conduct of, generation of, and application of research must soundly address questions about which research is morally defensible and valuable enough to support through funding, publication, tenure, and promotion. Likewise, educational pathways of re-imagined science are critical.

Experiences of Multidisciplinary Working: Perspectives from the Wessex Ghana Stroke Partnership.

INTRODUCTION: Substantial gaps remain in our understanding of stroke in Africa as well as in stroke care, practice and policy on the continent. The effective organization of preventative, therapeutic and rehabilitative stroke services continue to be challenging in many African countries. METHODOLOGY: In this article we define the nature, function and benefits of effective multidisciplinary team (MDT) working. The experiences and perspectives of members of the MDT were collated by focus group discussions as well as individual and country specific contributions. RESULTS: The experiences and perspectives of multidisciplinary team members from the United Kingdom and Ghana implementing these practices at the first stroke unit in Korle Bu Teaching Hospital, Accra, with a transparent discussion of successes and challenges faced throughout development of the service, is presented. MDT working has improved outcomes for patients and families who use the services, including encouraging better shared treatment planning and compliance. More stroke rehabilitation services are provided than previously, including greater self-management education and better secondary prevention care. CONCLUSION: It is hoped that this article will provide an inspirational model for others working to provide stroke care in low-resource settings in Africa and worldwide.

INTRODUCTION: Des lacunes substantielles subsistent dans notre compréhension de l'accident vasculaire cérébral en Afrique ainsi que dans les pratiques et politiques sur le continent. L'organisation efficace des services de prévention, de traitement et de réadaptation des AVC reste un défi dans de nombreux pays africains. MÉTHODOLOGIE: Dans cet article, nous définissons la nature, la fonction et les avantages d'une équipe multidisciplinaire efficace (PCT).Les expériences et les points de vue des membres de la PCT ont été recueillis par des discussions de groupes de réflexion ainsi que contributions individuelles et spécifiques à chaque pays. RÉSULTATS: Les expériences et les perspectives des membres d'équipes multidisciplinaires du Royaume-Uni et du Ghana, qui ont mis en œuvre ces pratiques dans la première unité d'AVC du de l'hôpital universitaire Korle Bu, à Accra, avec une discussion transparente des succès et des défis rencontrés tout au long du développement du service, sont présentées. Le travail de la PCT a amélioré les résultats pour les patients et les familles qui utilisent les services, notamment en encourageant un meilleur partage du traitement, l'organisation et la complaisance. Davantage de services de réadaptation après un AVC sont fournis plus qu'auparavant, y compris une meilleure éducation à l'autogestion et de meilleurs soins de prévention secondaire. CONCLUSION: Nous espérons que cet article constituera un modèle inspirant pour d'autres personnes travaillant à la prise en charge d'AVC dans des contextes à faibles ressources en Afrique et dans le monde. Mots clés: Unité de expériences, multidisciplinaire, Ghana, partenariat.

The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.

BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.

Development and feasibility of quantitative dynamic cardiac imaging for mice using µSPECT.

BACKGROUND: Despite growing interest in coronary microvascular disease (CMVD), there is a dearth of mechanistic understanding. Mouse models offer opportunities to understand molecular processes in CMVD. We have sought to develop quantitative mouse imaging to assess coronary microvascular function. METHODS: We used 99mTc-sestamibi to measure myocardial blood flow in mice with MILabs U-SPECT+ system. We determined recovery and crosstalk coefficients, the influx rate constant from blood to myocardium (K1), and, using microsphere perfusion, constraints on the extraction fraction curve. We used 99mTc and stannous pyrophosphate for red blood cell imaging to measure intramyocardial blood volume (IMBV) as an alternate measure of microvascular function. RESULTS: The recovery coefficients for myocardial tissue (RT) and left ventricular arterial blood (RA) were 0.81 ± 0.16 and 1.07 ± 0.12, respectively. The assumption RT = 1 - FBV (fraction blood volume) does not hold in mice. Using a complete mixing matrix to fit a one-compartment model, we measured K1 of 0.57 ± 0.08 min-1. Constraints on the extraction fraction curve for 99mTc-sestamibi in mice for best-fit Renkin-Crone parameters were α = 0.99 and ß = 0.39. Additionally, we found that wild-type mice increase their IMBV by 22.9 ± 3.3% under hyperemic conditions. CONCLUSIONS: We have developed a framework for measuring K1 and change in IMBV in mice, demonstrating non-invasive µSPECT-based quantitative imaging of mouse microvascular function.

Age influences the thermal suitability of Plasmodium falciparum transmission in the Asian malaria vector Anopheles stephensi.

Models predicting disease transmission are vital tools for long-term planning of malaria reduction efforts, particularly for mitigating impacts of climate change. We compared temperature-dependent malaria transmission models when mosquito life-history traits were estimated from a truncated portion of the lifespan (a common practice) versus traits measured across the full lifespan. We conducted an experiment on adult female Anopheles stephensi, the Asian urban malaria mosquito, to generate daily per capita values for mortality, egg production and biting rate at six constant temperatures. Both temperature and age significantly affected trait values. Further, we found quantitative and qualitative differences between temperature-trait relationships estimated from truncated data versus observed lifetime values. Incorporating these temperature-trait relationships into an expression governing the thermal suitability of transmission, relative R0(T), resulted in minor differences in the breadth of suitable temperatures for Plasmodium falciparum transmission between the two models constructed from only An. stephensi trait data. However, we found a substantial increase in thermal niche breadth compared with a previously published model consisting of trait data from multiple Anopheles mosquito species. Overall, this work highlights the importance of considering how mosquito trait values vary with mosquito age and mosquito species when generating temperature-based suitability predictions of transmission.

Benchmarking background oriented schlieren against interferometric measurement using open source tools.

Gas flow from an under-expanding jet nozzle is measured using synchronized background oriented schlieren and interferometry diagnostics. The gas density distribution is obtained from a shift vector field of the background oriented schlieren and compared to the interferometric data. The comparison makes use of a simple calibration routine and open source Python recipes.

Community Engagement of African Americans in the Era of COVID-19: Considerations, Challenges, Implications, and Recommendations for Public Health.

African Americans, compared with all other racial/ethnic groups, are more likely to contract coronavirus disease 2019 (COVID-19), be hospitalized for it, and die of the disease. Psychosocial, sociocultural, and environmental vulnerabilities, compounded by preexisting health conditions, exacerbate this health disparity. Interconnected historical, policy, clinical, and community factors explain and underpin community-based participatory research approaches to advance the art and science of community engagement among African Americans in the COVID-19 era. In this commentary, we detail the pandemic response strategies of the Morehouse School of Medicine Prevention Research Center. We discuss the implications of these complex factors and propose recommendations for addressing them that, adopted together, will result in community and data-informed mitigation strategies. These approaches will proactively prepare for the next pandemic and advance community leadership toward health equity.

A Belmont Report for Animals?

Human and animal research both operate within established standards. In the United States, criticism of the human research environment and recorded abuses of human research subjects served as the impetus for the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and the resulting Belmont Report. The Belmont Report established key ethical principles to which human research should adhere: respect for autonomy, obligations to beneficence and justice, and special protections for vulnerable individuals and populations. While current guidelines appropriately aim to protect the individual interests of human participants in research, no similar, comprehensive, and principled effort has addressed the use of (nonhuman) animals in research. Although published policies regarding animal research provide relevant regulatory guidance, the lack of a fundamental effort to explore the ethical issues and principles that should guide decisions about the potential use of animals in research has led to unclear and disparate policies. Here, we explore how the ethical principles outlined in the Belmont Report could be applied consistently to animals. We describe how concepts such as respect for autonomy and obligations to beneficence and justice could be applied to animals, as well as how animals are entitled to special protections as a result of their vulnerability.

A within-sibling pair analysis of lifestyle behaviours and BMI z-score in the multi-centre I.Family study.

BACKGROUND AND AIMS: By investigating differences in lifestyle behaviours and BMI in sibling pairs, family-level confounding is minimized and causal inference is improved, compared to cross-sectional studies of unrelated children. Thus, we aimed to investigate within-sibling pair differences in different lifestyle behaviours and differences in BMI z-scores in children and adolescents. METHODS AND RESULTS: We examined three groups of sibling pairs 1) all same-sex sibling pairs with maximum 4 years age difference (n = 1209 pairs from 1072 families in 8 countries, mean age 10.7 years, standard deviation 2.4 years), 2) sibling pairs discordant for overweight (n = 262) and 3) twin pairs (n = 85). Usual dietary intake was estimated by 24-h recalls and time spent in light (LPA) and moderate-to-vigorous physical activity (MVPA) was measured by accelerometers. Screen time, sleep and dieting for weight loss were assessed by questionnaires. Within all 3 groups of sibling pairs, more time in MVPA was associated with lower BMI z-score. Higher energy intake was associated with higher BMI z-score within twin pairs and within all sibling pairs who were not currently dieting for weight loss. Regarding LPA, screen time or sleep duration, no or inconsistent associations were observed for the three groups of sibling pairs. CONCLUSIONS: MVPA and energy intake were associated with BMI differences within sibling and twin pairs growing up in the same home, thus independent of family-level confounding factors. Future studies should explore whether genetic variants regulating appetite or energy expenditure behaviours account for weight differences in sibling pairs.

Lensing properties of rotational gas flow: erratum.

This erratum includes additional references relevant to rotational gas flow negative lenses that were omitted in Appl. Opt.57, 9392 (2018)APOPAI0003-693510.1364/AO.57.009392.