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In many organisms, interactions among genes lead to multiple functional states, and changes to interactions can lead to transitions into new states. These transitions can be related to bifurcations (or critical points) in dynamical systems theory. Characterizing these collective transitions is a major challenge for systems biology. Here, we develop a statistical method for identifying bistability near a continuous transition directly from high-dimensional gene expression data. We apply the method to data from honey bees, where a known developmental transition occurs between bees performing tasks in the nest and leaving the nest to forage. Our method, which makes use of the expected shape of the distribution of gene expression levels near a transition, successfully identifies the emergence of bistability and links it to genes that are known to be involved in the behavioral transition. This proof of concept demonstrates that going beyond correlative analysis to infer the shape of gene expression distributions might be used more generally to identify collective transitions from gene expression data.

Diagnostic and therapeutic advances during the past decades have substantially improved health outcomes for patients with acute coronary syndrome. Both age-related physiological changes and accumulated cardiovascular risk factors increase the susceptibility to acute coronary syndrome over a lifetime. Compared with younger patients, outcomes for acute coronary syndrome in the large and growing demographic of older adults are relatively worse. Increased atherosclerotic plaque burden and complexity of anatomic disease, compounded by age-related cardiovascular and noncardiovascular comorbid conditions, contribute to the worse prognosis observed in older individuals. Geriatric syndromes, including frailty, multimorbidity, impaired cognitive and physical function, polypharmacy, and other complexities of care, can undermine the therapeutic efficacy of guidelines-based treatments and the resiliency of older adults to survive and recover, as well. In this American Heart Association scientific statement, we (1) review age-related physiological changes that predispose to acute coronary syndrome and management complexity; (2) describe the influence of commonly encountered geriatric syndromes on cardiovascular disease outcomes; and (3) recommend age-appropriate and guideline-concordant revascularization and acute coronary syndrome management strategies, including transitions of care, the use of cardiac rehabilitation, palliative care services, and holistic approaches. The primacy of individualized risk assessment and patient-centered care decision-making is highlighted throughout.

Understanding the organization and evolution of social complexity is a major task because it requires building an understanding of mechanisms operating at different levels of biological organization from genes to social interactions. I discuss here, a unique forward genetic approach spanning more than 30 years beginning with human-assisted colony-level selection for a single social trait, the amount of pollen honey bees (Apis mellifera L.) store. The goal was to understand a complex social trait from the social phenotype to genes responsible for observed trait variation. The approach combined the results of colony-level selection with detailed studies of individual behavior and physiology resulting in a mapped, integrated phenotypic architecture composed of correlative relationships between traits spanning anatomy, physiology, sensory response systems, and individual behavior that affect individual foraging decisions. Colony-level selection reverse engineered the architecture of an integrated phenotype of individuals resulting in changes in the social trait. Quantitative trait locus (QTL) studies combined with an exceptionally high recombination rate (60 kb/cM), and a phenotypic map, provided a genotype-phenotype map of high complexity demonstrating broad QTL pleiotropy, epistasis, and epistatic pleiotropy suggesting that gene pleiotropy or tight linkage of genes within QTL integrated the phenotype. Gene expression and knockdown of identified positional candidates revealed genes affecting foraging behavior and confirmed one pleiotropic gene, a tyramine receptor, as a target for colony-level selection that was under selection in two different tissues in two different life stages. The approach presented here has resulted in a comprehensive understanding of the structure and evolution of honey bee social organization.

IntroductionOur objective was to evaluate physicians' perspectives on the clinical utility of pharmacogenetic (PGx) testing in kidney, liver, heart, and lung transplantation (KLHL-Tx).MethodsA 36-question web-based survey was developed and administered to medical and surgical directors of US KLHL-Tx centers.ResultsThere were 82 respondents (10% response rate). The majority were men (78%), non-Hispanic whites (70%), medical directors (72%), and kidney transplant physicians (35%). Although 78% of respondents reported having some PGx education, most reported lack of confidence in their PGx knowledge and ability to apply a PGx test. Participants reported mixed views about the clinical utility of PGx testing-most agreed with the efficacy of PGx testing, but not the benefits relative to the risks or standard of care. While 55% reported that testing was available at their institution, only 38% ordered a PGx test in the past year, most commonly thiopurine-S-methyltransferase. Physician-reported barriers to PGx implementation included uncertainty about the clinical value of PGx testing and patient financial burden.ConclusionTogether, our findings suggest prospective PGx research and pilot implementation programs are needed to elucidate the clinical utility and value of PGx in KLHL-Tx. These initiatives should include educational efforts to inform the use of PGx testing.

Professors bemoan the great difficulty students have understanding the complexity of their disciplines or functional specializations. Many non-traditional students have work and family commitments that limit the time needed to reflect professionally and to master these concepts. This disconnect has persisted despite decades of work developing more integrated, interdisciplinary curricula. One potential, partial solution is to simply start sooner and partner with liberal arts courses to introduce business students to complexity and paradox before they arrive at the business school. Grounding these concepts in the Classics embeds them in great stories of passion, betrayal, commitment, and emotion normally absent in business courses. Business textbooks and cases are usually sanitized, simplified, and quantified, stripping them of the chaos normally experienced in reality. These classical tales are captivating and compelling, making the business concepts used to analyze them more memorable and hopefully retained until encountered again in the business curriculum. The classics deal with real and raw emotions, with powerful prose more likely to capture and engage students on a very personal level. This article explores how economics can be used to analyze Jane Austen's "Pride and Prejudice," how multi-stakeholder theory can be used to analyze Sophocles' "Antigone," and how business contract law can be used to analyze William Shakespeare's "The Merchant of Venice." Liberal Arts programs will gain additional relevance, commanding further student respect; business schools will stand a better chance of meeting AACSB gold-standard, interdisciplinary learning outcomes when students are exposed to these concepts before arriving at the business school.

While interest in Bayesian statistics has been growing in statistics education, the treatment of the topic is still inadequate in both textbooks and the classroom. Because so many fields of study lead to careers that involve a decision-making process requiring an understanding of Bayesian methods, it is becoming increasingly clear that Bayesian methods should be included in classes that cover the P value and Hypothesis Testing. We discuss several fallacies associated with the P value and Hypothesis Testing, including why Fisher's P value and Neyman-Pearson's Hypothesis Tests are incompatible with each other and cannot be combined to answer the question "What is the probability of the truth of one's belief based on the evidence?" We go on to explain how the Minimum Bayes Factor can be used as an alternative to frequentist methods, and why the Bayesian approach results in more accurate, credible, and relevant test results when measuring the strength of the evidence. We conclude that educators must realize the importance of teaching the correct interpretation of Fisher's P value and its alternative, the Bayesian approach, to students in an introductory statistics course.

Purpose: Recreational nitrous oxide (N2O) misuse is increasing globally. Chronic misuse can cause neurological impairments that require rehabilitation, though literature characterising rehabilitation is limited. This study aimed to evaluate rehabilitation service provision for impairments resulting from N2O misuse. Methods: A retrospective audit of hospitalised patients referred for rehabilitation for N2O toxicity was conducted between 2015 and 2022 at a single metropolitan hospital. Data were collected via medical record audit and analysed via descriptive and non-parametric statistics. Results: 16 eligible cases were identified, aged 18–43 years (50% female/male), with increasing case frequency. 12 cases received inpatient rehabilitation episodes for multifactorial sensorimotor, cognitive and psychosocial impairments. Cases articulated diverse rehabilitation goals and received intervention from a median of 6 clinical disciplines. All cases required assistance to mobilise or perform self-care activities on admission. Functional Independence Measure (FIM) scores significantly improved with rehabilitation (median FIM 84[75–93] to 117[112–123], p <.001). Despite gains in independence, all cases required referral for ongoing rehabilitation post-discharge. Conclusions: Demand for inpatient rehabilitation for disabling N2O toxicity appears to be increasing. In this series, cases were young, exhibited serious impairments, and had multidisciplinary rehabilitation needs. Inpatient rehabilitation led to significant functional improvements, though ongoing disability was evident post-discharge. IMPLICATIONS FOR REHABILITATION: There appears to be rising demand for multidisciplinary rehabilitation to manage neurological disabilities from recreational Nitrous Oxide (N2O) misuse. Heavy N2O misuse can cause serious impairments and activity limitations across sensorimotor, cognitive and psychosocial domains. Intensive, multidisciplinary rehabilitation can improve functional independence for people with disabling N2O toxicity; specialist rehabilitation services should be involved in optimising care of this population. Ongoing disability and the need for longer-term rehabilitation and support following hospital discharge were evident in severe cases of N2O toxicity. [ABSTRACT FROM AUTHOR]

Aims: To compare a low-dosing protocol to standard practice for methadone-buprenorphine transfers. Methods: We undertook a nonrandomized open-label clinical trial across 8 sites from NSW, Australia. Participants prescribed methadone wishing to transfer to buprenorphine could either choose or be randomized to a low-dose transfer or standard care transfer as per NSW health guidelines. The low-dose protocol started at 0.2 mg BD and increased to 16 mg on day 6, with flexible dosing thereafter. The primary outcome was continuation of buprenorphine 1 week post-transfer. Binary logistic regression was used to access the primary outcome with demographic differences between the groups included as covariates. Results: There were 117 participants who commenced the study, 101 in the low-dose arm and 16 in standard care. Mean methadone dose was 82 mg in the low-dose arm and 46 mg in standard care. The primary outcome was met by 81 participants in the low-dose arm (80%) and 13 participants in standard care (81%). There was no significant between-arm difference in the odds of the primary outcome (OR = 2.22; 95% CI: 0.45–10.91; P = 0.327). Four participants (4%) in the low-dose arm experienced precipitated withdrawal against 1 (6%) in standard care. Higher methadone dose decreased the odds of successful transfer by 20% (OR = 0.8 per 10 mg methadone; 95% CI: 0.7–0.99; P = 0.04). Withdrawal scores between the 2 arms were similar. Conclusions: We were unable to detect a difference between low dosing and standard care for methadone to buprenorphine transfers. Increasing methadone dose was a predictor of success; setting (ambulatory or inpatient) was not. [ABSTRACT FROM AUTHOR]

Highly social insects are characterized by caste dimorphism, with distinct size differences of reproductive organs between fertile queens and the more or less sterile workers. An abundance of nutrition or instruction via diet-specific compounds has been proposed as explanations for the nutrition-driven queen and worker polyphenism. Here, we further explored these models in the honeybee (Apis mellifera) using worker nutrition rearing and a novel mutational screening approach using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) method. The worker nutrition-driven size reduction of reproductive organs was restricted to the female sex, suggesting input from the sex determination pathway. Genetic screens on the sex determination genes in genetic females for size polyphenism revealed that doublesex (dsx) mutants display size-reduced reproductive organs irrespective of the sexual morphology of the organ tissue. In contrast, feminizer (fem) mutants lost the response to worker nutrition-driven size control. The first morphological worker mutants in honeybees demonstrate that the response to nutrition relies on a genetic program that is switched "ON" by the fem gene. Thus, the genetic instruction provided by the fem gene provides an entry point to genetically dissect the underlying processes that implement the size polyphenism.

The effect of larval nutrition on female fertility in honey bees is a focus for both scientific studies and for practical applications in beekeeping. In general, morphological traits are standards for classifying queens and workers and for evaluating their quality. In recent years, in vitro rearing techniques have been improved and used in many studies; they can produce queen-like and worker-like bees. Here, we questioned whether queens and workers reared in vitro are the same as queens and workers reared in a natural hive environment. We reared workers and queens both in vitro and naturally in beehives to test how these different environments affect metabolic physiology and candidate genes in newly emerged queens and workers. We found that sugar (glucose and trehalose) levels differed between queens and workers in both in vitro and in-hive-reared bees. The in vitro-reared bees had significantly higher levels of lipids in the abdomen. Moreover, hive reared queens had almost 20 times higher levels of vitellogenin than in vitro-reared queens, despite similar morphologies. In addition, hive-reared bees had significantly higher levels of expression of mrjp1 In conclusion, in vitro rearing produces queens and workers that differ from those reared in the hive environment at physiological and gene expression levels.This article has an associated First Person interview with the first author of the paper.

Variation in endocrine signaling is proposed to underlie the evolution and regulation of social life histories, but the genetic architecture of endocrine signaling is still poorly understood. An excellent example of a hormonally influenced set of social traits is found in the honey bee (Apis mellifera): a dynamic and mutually suppressive relationship between juvenile hormone (JH) and the yolk precursor protein vitellogenin (Vg) regulates behavioral maturation and foraging of workers. Several other traits cosegregate with these behavioral phenotypes, comprising the pollen hoarding syndrome (PHS) one of the best-described animal behavioral syndromes. Genotype differences in responsiveness of JH to Vg are a potential mechanistic basis for the PHS. Here, we reduced Vg expression via RNA interference in progeny from a backcross between 2 selected lines of honey bees that differ in JH responsiveness to Vg reduction and measured JH response and ovary size, which represents another key aspect of the PHS. Genetic mapping based on restriction site-associated DNA tag sequencing identified suggestive quantitative trait loci (QTL) for ovary size and JH responsiveness. We confirmed genetic effects on both traits near many QTL that had been identified previously for their effect on various PHS traits. Thus, our results support a role for endocrine control of complex traits at a genetic level. Furthermore, this first example of a genetic map of a hormonal response to gene knockdown in a social insect helps to refine the genetic understanding of complex behaviors and the physiology that may underlie behavioral control in general.

Several insect pheromones are multifunctional and have both releaser and primer effects. In honey bees (Apis mellifera), the queen mandibular pheromone (QMP) and e-beta-ocimene (eβ), emitted by young worker larvae, have such dual effects. There is increasing evidence that these multifunctional pheromones profoundly shape honey bee colony dynamics by influencing cooperative brood care, a fundamental aspect of eusocial insect behavior. Both QMP and eβ have been shown to affect worker physiology and behavior, but it has not yet been determined if these two key pheromones have interactive effects on hypopharyngeal gland (HPG) development, actively used in caring of larvae, and ovary activation, a component of worker reproductive physiology. Experimental results demonstrate that both QMP and eβ significantly suppress ovary activation compared to controls but that the larval pheromone is more effective than QMP. The underlying reproductive anatomy (total ovarioles) of workers influenced HPG development and ovary activation, so that worker bees with more ovarioles were less responsive to suppression of ovary activation by QMP. These bees were more likely to develop their HPG and have activated ovaries in the presence of eβ, providing additional links between nursing and reproductive physiology in support of the reproductive ground plan hypothesis.

Introduction: The Sydney Medically Supervised Injecting Centre provides a safe, non‐judgemental space where people can inject pre‐obtained substances under the supervision of trained staff. This article describes an unusual incident occurring at the Medically Supervised Injecting Centre in January 2023. Case Presentation: Two regular male clients attending the Medically Supervised Injecting Centre injected a substance they believed to be cocaine. Both clients experienced adverse reactions; one was transported to hospital, while the other became extremely distressed and agitated. Paraphernalia sent for testing returned a result of tiletamine (a dissociative used in veterinary medicine) and no cocaine, 30 h after the incident. Discussion and Conclusions: Where substances are novel or unknown, adverse events are often unexpected and may be more difficult to prepare for. Substance‐induced acute agitation can be alarming and hazardous for people consuming drugs and those around them and may pose challenges for staff. There is a substantial evidence base for the benefits of on‐site drug analysis and drug checking in reducing harms related to drug use, and in enhancing drug market monitoring. This incident was successfully managed by Medically Supervised Injecting Centre and hospital staff, with no major consequence, however clinical management could have been improved using point of care drug testing. [ABSTRACT FROM AUTHOR]